Therapeutic Intervention in Cancer by Isoliquiritigenin from Licorice: A Natural Antioxidant and Redox Regulator.
Antioxidants (Basel, Switzerland)
Oxidative stress could lead to a variety of body dysfunctions, including neurodegeneration and cancer, which are closely associated with intracellular signal transducers such as reactive oxygen species (ROS). It has been suggested that ROS is the upstream regulator of autophagy, and that it provides a negative feedback regulation to remove oxidative damage. Defects in the ROS-autophagic redox homeostasis could lead to the increased production of ROS and the accumulation of damaged organelles that in turn promote metabolic reprogramming and induce tumorigenesis. One significant characteristic of pancreatic cancer is the reprogramming of cellular energy metabolism, which facilitates the rapid growth, invasiveness, and the survival of cancer cells. Thus, the rectification of metabolic dysfunction is essential in therapeutic cancer targeting. Isoliquiritigenin (ISL) is a chalcone obtained from the plant , which is a powdered root licorice that has been consumed for centuries in different regions of the world. ISL is known to be a natural antioxidant that possesses diversified functions, including redox regulation in cells. This review contains discussions on the herbal source, biological properties, and anticancer potential of ISL. This is the first time that the anticancer activities of ISL in pancreatic cancer has been elucidated, with a coverage of the involvement of antioxidation, metabolic redox regulation, and autophagy in pancreatic cancer development. Furthermore, some remarks on related compounds of the isoflavonoid biosynthetic pathway of ISL will also be discussed.
10.3390/antiox11071349
Natural inhibitors of PI3K/AKT signaling in breast cancer: emphasis on newly-discovered molecular mechanisms of action.
Safdari Yaghoub,Khalili Masoumeh,Ebrahimzadeh Mohammad Ali,Yazdani Yaghoub,Farajnia Safar
Pharmacological research
Epidermal growth factor receptor (EGFR) plays a critical role in the initiation and progression of a variety of human cancers, including breast cancer. An important signaling pathway downstream of EGFR is the PI3K/AKt pathway, which regulates cellular processes as diverse as cell growth, survival, proliferation and migration. Deregulated activity of this pathway may lead to uncontrolled cell growth, survival, migration and invasion, contributing to tumor formation. In this review, we evaluate natural compounds that, in vitro (breast cancer cell lines) and/or in vivo (animal model, clinical) studies, suppress breast cancer cells or tumors mainly by suppressing the PI3K/AKT signaling pathway. The effect of these compounds on cell cycle arrest, inhibition of cell migration and invasion, tumor angiogenesis and metastasis in breast cancer are discussed.
10.1016/j.phrs.2014.12.004
Cyclooxygenase-2 plays a suppressive role for induction of apoptosis in isoliquiritigenin-treated mouse colon cancer cells.
Takahashi Tetsuyuki,Baba Masaki,Nishino Hoyoku,Okuyama Toru
Cancer letters
Cellular damage induced by chronic inflammation is a well known cause of colon carcinogenesis. Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostanoids, is known to play an important role in inflammation. Herbal flavonoid isoliquiritigenin (ILTG) has previously been reported to be a strong suppresser of the COX-2 pathway as well as an inducer of apoptosis. Here we report that the susceptibility to apoptosis by ILTG is dependent on the level of COX-2 in mouse colon adenocarcinoma Colon 26, which spontaneously expresses COX-2. This dependency was observed to be enhanced by blockage of the lipoxigenases (LOXs)-mediated metabolic pathway and attenuated by addition of a number of prostaglandins and thromboxanes. Taken together, these findings indicate that ILTG-induced apoptosis is negatively regulated by the COX-2 expression level.
10.1016/j.canlet.2005.02.025
Isoliquiritigenin-induced differentiation in mouse melanoma B16F0 cell line.
Oxidative medicine and cellular longevity
The chemotherapeutical treatment is very limited for malignant melanoma, a highly lethal disease occurs globally. Natural products derived from traditional Chinese medicine licorice are attractive in quest new treatments due to their anti-tumor activities. A new dietary flavonoid isoliquiritigenin (ISL) were thus investigated to indentify its anti-melanoma activities on mouse melanoma B16F0 cells in present study. Using biochemical and free radical biological experiments in vitro, we identified the pro-differentiated profiles of ISL and evaluated the role of reactive oxygen species (ROS) during B16F0 cell differentiation. The data showed a strong dose-response relationship between ISL exposure and the characteristics of B16F0 differentiation in terms of morphology changes and melanogenesis. The accumulated intercellular ROS during exposure are necessary to support ISL-induced differentiation, which was proven by additional redox modulators. It was confirmed further by the relative activities of enzymes and genes modulated melanogenesis in ISL-treatments with or without ROS modulators. The tumorigenicity of ISL-treated cells was limited significantly by using the colony formation assay in vitro and an animal model assay in vivo respectively. Our research demonstrated that isoliquiritigenin is a differentiation-inducing agent, and its mechanisms involve ROS accumulation facilitating melanogenesis.
10.1155/2012/534934
Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling.
Kwon Gyoo Taik,Cho Han Jin,Chung Won-Yoon,Park Kwang-Kyun,Moon Aree,Park Jung Han Yoon
The Journal of nutritional biochemistry
Isoliquiritigenin (ISL, 4,2',4'-trihydroxychalcone), which is found in licorice, shallot and bean sprouts, is a potent antioxidant with anti-inflammatory and anti-carcinogenic effects. The purpose of this study was to investigate the effects of ISL treatment on the migration, invasion and adhesion characteristics of DU145 human prostate cancer cells. DU145 cells were cultured in the presence of 0-20 micromol/L ISL with or without 10 microg/L epidermal growth factor (EGF). ISL inhibited basal and EGF-induced cell migration, invasion and adhesion dose dependently. ISL decreased EGF-induced secretion of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and vascular endothelial growth factor (VEGF), but increased TIMP-2 secretion in a concentration-dependent manner. In addition, ISL decreased the protein levels of integrin-alpha2, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), and mRNA levels of uPA, MMP-9, VEGF, ICAM and integrin-alpha2. Furthermore, basal and EGF-induced activator protein (AP)-1 binding activity and phosphorylation of Jun N-terminal kinase (JNK), c-Jun and Akt were decreased after ISL treatment. However, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase was not altered. The JNK inhibitor SP600125 inhibited basal and EGF-induced secretion of uPA, VEGF, MMP-9 and TIMP-1, as well as AP-1 DNA binding activity and cell migration. These results provide evidence for the role of ISL as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of prostate cancer cells. The inhibition of JNK/AP-1 signaling may be one of the mechanisms by which ISL inhibits cancer cell invasion and migration.
10.1016/j.jnutbio.2008.06.005
Isoliquiritigenin Induces Mitochondrial Dysfunction and Apoptosis by Inhibiting mitoNEET in a Reactive Oxygen Species-Dependent Manner in A375 Human Melanoma Cells.
Chen Xiao-Yu,Ren Huan-Huan,Wang Dan,Chen Ying,Qu Chuan-Jun,Pan Zhao-Hai,Liu Xiao-Na,Hao Wen-Jin,Xu Wen-Juan,Wang Ke-Jun,Li De-Fang,Zheng Qiu-Sheng
Oxidative medicine and cellular longevity
The mitochondrial protein mitoNEET is a type of iron-sulfur protein localized to the outer membrane of mitochondria and is involved in a variety of human pathologies including cystic fibrosis, diabetes, muscle atrophy, and neurodegeneration. In the current study, we found that isoliquiritigenin (ISL), one of the components of the root of , could decrease the expression of mitoNEET in A375 melanoma cells. We also demonstrated that mitoNEET could regulate the content of reactive oxygen species (ROS), by showing that the ISL-mediated increase in the cellular ROS content could be mitigated by the mitoNEET overexpression. We also confirmed the important role of ROS in ISL-treated A375 cells. The increased apoptosis rate and the decreased mitochondrial membrane potential were mitigated by the overexpression of mitoNEET in A375 cells. These findings indicated that ISL could decrease the expression of mitoNEET, which regulated ROS content and subsequently induced mitochondrial dysfunction and apoptosis in A375 cells. Our findings also highlight mitoNEET as a promising mitochondrial target for cancer therapy.
10.1155/2019/9817576
Isoliquiritigenin inhibits TGF-β1-induced fibrogenesis through activating autophagy via PI3K/AKT/mTOR pathway in MRC-5 cells.
He Jinjuan,Peng Hao,Wang Meifang,Liu Ying,Guo Xingrong,Wang Bin,Dai Longjun,Cheng Xueqin,Meng Zhongji,Yuan Leyong,Cai Fenglin,Tang Yijun
Acta biochimica et biophysica Sinica
Isoliquiritigenin (ISL), a natural flavonoid derived from the root of liquorice, has been reported to possess anti-inflammatory and antioxidant activities. Previous studies have found that ISL plays a crucial role in anti-fibrosis of adipose tissue and renal tissue; however, its effect on pulmonary fibrogenesis has not been demonstrated. In this study, we aimed to explore the roles and the underlying mechanisms of ISL in TGF-β1-induced fibrogenesis using human lung fibroblast-derived MRC-5 cells. Cell proliferation and migration were determined by MTT and wound healing assay, respectively. The expression levels of alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 (COLIA1) and fibronectin (FN), microtubule-associated protein light chain 3 (LC3) and related signaling molecules were detected by quantitative real-time PCR, western blot and immunofluorescence assay, correspondingly. EGFP-LC3 transfection was used for autophagy analysis. The results showed that ISL inhibited the TGF-β1-induced proliferation and migration, and down-regulated the expressions of α-SMA, COLIA1 and FN. ISL treatment led to up-regulation of LC3 in TGF-β1-treated MRC-5 cells, accompanied by significant decrease in the phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In addition, the inhibitory effects of ISL on TGF-β1-induced fibrogenic features in MRC-5 cells were enhanced by pretreatment with autophagy activator Rapmycin and PI3K/AKT inhibitor LY294002 and reversed by autophagy inhibitor 3-methyladenine and PI3K/AKT activator IGF-1. Taken together, our results demonstrated that ISL could attenuate the fibrogenesis of TGF-β1-treated MRC-5 cells by activating autophagy via suppressing the PI3K/AKT/mTOR pathway. Therefore, ISL holds a great potential to be developed as a novel therapeutic agent for the treatment of pulmonary fibrosis.
10.1093/abbs/gmaa067
Isoliquiritigenin suppresses human melanoma growth by targeting miR-301b/LRIG1 signaling.
Xiang Shijian,Chen Huoji,Luo Xiaojun,An Baichao,Wu Wenfeng,Cao Siwei,Ruan Shifa,Wang Zhuxian,Weng Lidong,Zhu Hongxia,Liu Qiang
Journal of experimental & clinical cancer research : CR
BACKGROUND:Isoliquiritigenin (ISL), a natural flavonoid isolated from the root of licorice (Glycyrrhiza uralensis), has shown various pharmacological properties including anti-oxidant, anti-inflammatory and anti-cancer activities. MicroRNAs (miRNAs), a class of small non-coding RNAs, have been reported as post-transcriptional regulators with altered expression levels in melanoma. This study aims to investigate the anti-melanoma effect of ISL and its potential mechanism. METHODS:We investigated the effect of ISL on the proliferation and apoptosis of melanoma cell lines with functional assays, such as CCK-8 assay, colony formation assay and flow cytometry. The protein level of apoptosis related genes were measured by western blotting. High-throughput genome sequencing was used for screening differentially expressed miRNAs of melanoma cell lines after the treatment of ISL. We performed functional assays to determine the oncogenic role of miR-301b, the most differentially expressed miRNA, and its target gene leucine rich repeats and immunoglobulin like domains 1 (LRIG1), confirmed by bioinformatic analysis, luciferase reporter assay, western blotting and immunohistochemical assay in melanoma. Immunocompromised mouse models were used to determine the role of miR-301b and its target gene in melanoma tumorigenesis in vivo. The relationship between miR-301b and LRIG1 was further verified in GEO data set and tissue specimens. RESULTS:Functional assays indicated that ISL exerted significant growth inhibition and apoptosis induction on melanoma cells. MiR-301b is the most differentially expressed miRNA after the treatment of ISL and significantly downregulated. The suppressive effect of ISL on cell growth is reversed by ectopic expression of miR-301b. Intratumorally administration of miR-301b angomir enhances the inhibitory effect of ISL on tumor growth in vivo. Bioinformatic analysis showed that miR-301b may target LRIG1, miR-301b suppresses the luciferase activity of reporter constructs containing 3'UTR of LRIG1 as well as the expression level of LRIG1. And the anti-cancer effect of ISL is mitigated when LRIG1 is silenced in vivo and in vitro. Analysis of the melanoma samples obtained from patients shows that LRIG1 is negatively correlated with miR-301b. CONCLUSIONS:ISL may inhibit the proliferation of melanoma cells by suppressing miR-301b and inducing its target LRIG1.
10.1186/s13046-018-0844-x
Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway.
Huang Yun,Liu Chen,Zeng Wu-Cha,Xu Guo-Yan,Wu Jian-Min,Li Zhi-Wen,Huang Xuan-Yu,Lin Rong-Jin,Shi Xi
Bioscience reports
The overall survival rate of patients with hepatocellular carcinoma (HCC) has remained unchanged over the last several decades. Therefore, novel drugs and therapies are required for HCC treatment. Isoliquiritigenin (ISL), a natural flavonoid predominantly isolated from the traditional Chinese medicine Glycyrrhizae Radix (Licorice), has a high anticancer potential and broad application value in various cancers. Here, we aimed to investigate the anticancer role of ISL in the HCC cell line Hep3B. Functional analysis revealed that ISL inhibited the proliferation of Hep3B cells by causing G1/S cell cycle arrest in vitro. Meanwhile, the inhibitory effect of ISL on proliferation was also observed in vivo. Further analysis revealed that ISL could suppress the migration and metastasis of Hep3B cells in vitro and in vivo. Mechanistic analysis revealed that ISL inhibited cyclin D1 and up-regulated the proteins P21, P27 that negatively regulate the cell cycle. Furthermore, ISL induced apoptosis while inhibiting cell cycle transition. In addition, phosphatidylinositol 3'-kinase/protein kinase B (PI3K/AKT) signal pathway was suppressed by ISL treatment, and the epithelial marker E-cadherin was up-regulated when the mesenchymal markers Vimentin and N-cadherin were down-regulated. In brief, our findings suggest that ISL could be a promising agent for preventing HCC tumorigenesis and metastasis.
10.1042/BSR20192727
The dietary flavonoid isoliquiritigenin induced apoptosis and suppressed metastasis in melanoma cells: An in vitro and in vivo study.
Xiang Shijian,Zeng Haiyan,Xia Fan,Ji Qiufeng,Xue Jianwen,Ren Ruxia,Que Fuchang,Zhou Benjie
Life sciences
AIMS:This study aimed to explore the role of Isoliquiritigenin (ISL) in the proliferation and invasion of melanoma cells and investigate the mechanism of action of this compound. MAIN METHODS:The functional roles of ISL in melanoma cells were determined by CCK8 assay, colony formation assay, flow cytometry and wound healing assay. The antitumor activity of ISL was assessed in vivo in a mouse xenograft model using A2058 cells. Quantitative real-time PCR analysis (RT-qPCR) and western blot assays were used to evaluate the gene and protein expression in cell lines or tumor tissue samples. Bioinformatic analysis, luciferase reporter assay, and gene set enrichment analysis (GSEA) were performed to confirm the mechanism of ISL effect on cell growth and metastasis of melanoma. KEY FINDINGS:ISL suppressed proliferation and migration of melanoma cells via downregulation of miR-27a expression. The inhibitory effect of ISL on growth and metastasis of melanoma cells was reversed by ectopic expression of miR-27a. Bioinformatic analysis showed that miR-27a targets POU class 2 homeobox 3 (POU2F3); this result was verified by the luciferase reporter assay and by a decrease in the expression of POU2F3 by miR-27a intervention. GSEA demonstrated that POU2F3 is associated with the c-MYC/p53 signaling pathway and metastasis. POU2F3 knockdown reversed the inhibitory effect of ISL on the growth and metastasis of melanoma. Additionally, POU2F3 was found to be downregulated in melanoma tissue samples and was negatively correlated with miR-27a. SIGNIFICANCE:ISL inhibits proliferation and metastasis of melanoma via the miR-27a/POU2F3/c-MYC/p53 axis; these results may provide a new thought for the treatment of melanoma.
10.1016/j.lfs.2020.118598
Isoliquiritigenin Suppressed Esophageal Squamous Carcinoma Growth by Blocking EGFR Activation and Inducing Cell Cycle Arrest.
Ye Liping,Zhang Junjie,Zhang Yu,Gu Binbin,Zhu Hongyuan,Mao Xinli
BioMed research international
Isoliquiritigenin (ILQ) is a natural product isolated from licorice root which has served as traditional Chinese medicine for a long time. Recently, the antitumor effects of ILQ have been widely studied in various cancers, but the role and related mechanisms of ILQ in esophageal squamous carcinoma cells (ESCC) are still poorly understood. In our studies, ILQ showed profound antitumor activities in ESCC cells. In vitro, ILQ substantially inhibited cell proliferation and anchorage-independent growth in a panel of human ESCC cells. Mechanism studies showed that EGFR signaling pathway played an important role for ILQ to exert its antitumor activity in ESCC. Exposure to isoliquiritigenin substantially decreased EGF-induced EGFR activation and its downstream Akt and ERK1/2 signaling pathway. EGFR knockdown with shRNA in ESCC cell significantly reduced the sensitivity of cancer cells to ILQ. Moreover, it was found that ILQ had a significantly inhibitory effect on AP-1 family, the protein of Jun and Fos subfamilies was substantially downregulated, and the transcriptional activity of AP-1 family was dramatically suppressed by ILQ. By reducing the expression of cyclin D1, ESCC cells were induced G0/G1 arrest, and cell division was substantially blocked. Finally, the antitumor potency of ILQ was validated in xenograft models and the tumor growth was prominently restrained by ILQ. Briefly, our study showed that ILQ, or its analogue, appeared to be a promising new therapeutic agent for ESCC management.
10.1155/2020/9259852
Isoliquiritigenin Ameliorates Ischemia-Induced Myocardial Injury via Modulating the Nrf2/HO-1 Pathway in Mice.
Drug design, development and therapy
Background:Oxidative stress and inflammatory reaction play critical roles in acute myocardial infarction (AMI). Isoliquiritigenin (ISL), a flavonoid monomer extracted from licorice, has been found to have antioxidant and anti-inflammatory effects in cancer studies. Here, we tested the effect and underlying mechanisms of ISL on ischemia-induced myocardial injury in a mouse AMI model. Methods:Adult C57BL/6 mice were pre-treated by intraperitoneal injection of ISL and/or a specific nuclear factor E2-related factor 2 (Nrf2) inhibitor ML385 for 3 days, respectively. Then, the AMI model was established by ligating the anterior descending branch of the left coronary artery. Myocardial oxidative stress status, inflammatory response, cardiac function and infarction size were assessed after 7th day of surgery. Results:Compared with sham group, the reactive oxygen species (ROS) and malondialdehyde (MDA) level in AMI group were significantly increased. However, the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) level were dramatically decreased. ISL treatment significantly reduced the myocardial infarction area, improved cardiac function, inhibited the production of ROS and MDA and reduced the consumption of SOD and GSH-Px. Interestingly, ISL could significantly increase nuclear Nrf2 and cytosolic heme oxygenase 1 (HO-1) level in the infarcted myocardium and reduce the oxidative stress after AMI. Also, ISL treatment dramatically inhibited the activation of myocardial NF-κB pathway and reduced the expression of pro-inflammatory factors in the AMI group. However, the administration of ML385 not only suppressed the Nrf2/HO-1 activation, the anti-oxidant and anti-inflammatory effects induced by ISL, but also attenuated the beneficial role of ISL on reducing infarct size and improving cardiac function in the mouse with AMI. Conclusion:The results suggested that activation of Nrf2/HO-1 pathway has an essential role in ISL-induced cardiac protection by alleviating myocardial oxidative stress and inflammation response in mice with AMI.
10.2147/DDDT.S362754
Inhibitory effect of DNA topoisomerase inhibitor isoliquiritigenin on the growth of glioma cells.
Zhao Shupeng,Chang Haigang,Ma Pengju,Gao Guojun,Jin Cailing,Zhao Xinli,Zhou Wenke,Jin Baozhe
International journal of clinical and experimental pathology
OBJECTIVE:To investigate the effect of isoliquiritigenin on the activity of DNA topoisomerase (TOP I) and its inhibitory effect on the growth of U87 glioma cells. METHODS:This study investigated the inhibitory effect of isoliquiritigenin on the growth of U87 glioma cells and its cytotoxicity by MTT method and determined the effect of isoliquiritigenin on TOP I activity by agarose gel electrophoresis. On this basis, we studied the interaction between isoliquiritigenin and TOP I and DNA. Finally, we further discussed the effect of isoliquiritigenin on the activity of Caspase 3, the apoptosis protein of U87 glioma cells. RESULTS:Isoliquiritigenin could inhibit the growth of U87 glioma cells (half inhibitory concentration IC50: 0.221 mM) and is of low cytotoxicity to normal cells. Agarose gel electrophoresis showed that isoliquiritigenin had significant inhibitory effect on TOP I activity. Molecular simulation results indicated that isoliquiritigenin took priority of binding to the active center of TOP I, and formed hydrogen bonds with the catalytic site Try723. Finally, Caspase 3 activity detection results suggested that isoliquiritigenin could significantly increase the activity of Caspase 3 (P < 0.05). CONCLUSION:Isoliquiritigenin had a reversible inhibitory effect on TOP I activity, reduced the rate of single strand DNA unwinding in tumor cells, and thus played an important role in inducing the apoptosis of U87 glioma cells.
Isoliquiritigenin Induces Autophagy and Inhibits Ovarian Cancer Cell Growth.
Chen Hsin-Yuan,Huang Tsui-Chin,Shieh Tzong-Ming,Wu Chi-Hao,Lin Li-Chun,Hsia Shih-Min
International journal of molecular sciences
Ovarian cancer is one of the commonest gynecologic malignancies, which has a poor prognosis for patients at the advanced stage. Isoliquiritigenin (ISL), an active flavonoid component of the licorice plant, previously demonstrated antioxidant, anti-inflammatory, and tumor suppressive effects. In this study, we investigated the antitumor effect of ISL on human ovarian cancer in vitro using the human ovarian cancer cell lines, OVCAR5 and ES-2, as model systems. Our results show that ISL significantly inhibited the viability of cancer cells in a concentration- and time-dependent manner. Flow cytometry analysis indicated that ISL induced G2/M phase arrest. Furthermore, the expression of cleaved PARP, cleaved caspase-3, Bax/Bcl-2 ratio, LC3B-II, and Beclin-1 levels were increased in western blot analysis. To clarify the role of autophagy and apoptosis in the effect of ISL, we used the autophagy inhibitor-3-methyladenine (3-MA) to attenuate the punctate fluorescence staining pattern of the p62/sequestosome 1 (SQSTM1, red fluorescence) and LC3 (green fluorescence) proteins after ISL treatment, and 3-MA inhibited the cytotoxicity of ISL. These findings provide new information about the link between ISL-induced autophagy and apoptosis and suggest that ISL is a candidate agent for the treatment of human ovarian cancer.
10.3390/ijms18102025
Isoliquiritigenin Attenuates Neuroinflammation in Traumatic Brain Injury in Young Rats.
Liu Jingjing,Xiong Xin,Sui Yutong
Neuroimmunomodulation
OBJECTIVES:Inflammation and apoptosis play a critical role in the pathological progress of traumatic brain injury (TBI). Isoliquiritigenin is a bioactive component extracted from licorice roots, which possesses anti-inflammatory and anti-apoptotic properties. This study aims to investigate the potential effects of isoliquiritigenin on neuroinflammation in a rat model of TBI. METHODS:The SH-SY5Y cells were subjected to cell injury induced by shear stress and the effect of isoliquiritigenin on cell apoptosis was measured. Male rats received a controlled cortical impact to induce TBI and were then treated with isoliquiritigenin (20 mg/kg). Brain edema and contusion volume were measured to assess brain damage. Morris water maze, the beam-balance test, and the beam-walk test were performed to evaluate the cognitive and motor functions. RESULTS:Levels of proinflammatory cytokines and apoptotic regulators were measured. Results showed that isoliquiritigenin reduced shear stress-induced cell apoptosis in vitro. In young rats subjected to TBI, treatment of isoliquiritigenin reduced brain damage and attenuated motor and cognitive impairments. Isoliquiritigenin also reduced the level of proinflammatory cytokines and Bax and increased Bcl-2 and Bcl-xL in TBI rats. CONCLUSIONS:These findings suggest that isoliquiritigenin possesses beneficial effects in TBI by inhibiting inflammation and apoptosis.
10.1159/000495467
Suppression of lung cancer progression by isoliquiritigenin through its metabolite 2, 4, 2', 4'-Tetrahydroxychalcone.
Journal of experimental & clinical cancer research : CR
BACKGROUND:Licorice is an herb extensively used for both culinary and medicinal purposes. Various constituents of licorice have been shown to exhibit anti-tumorigenic effect in diverse cancer types. However, majority of these studies focus on the aspect of their growth-suppressive role. In this study, we systematically analyzed known licorice's constituents on the goal of identifying component(s) that can effectively suppress both cell migration and growth. METHODS:Effect of licorice's constituents on cell growth was evaluated by MTT assay while cell migration was assessed by both wound-healing and Transwell assays. Cytoskeleton reorganization and focal adhesion assembly were visualized by immunofluorescence staining with labeled phalloidin and anti-paxillin antibody. Activity of Src in cells was judged by western blot using phosphor-Src416 antibody while Src kinase activity was measured using Promega Src kinase assay system. Anti-tumorigenic capabilities of isoliquiritigenin (ISL) and 2, 4, 2', 4'-Tetrahydroxychalcone (THC) were investigated using lung cancer xenograft model. RESULTS:Using a panel of lung cancer cell lines, ISL was identified as the only licorice's constituent capable of inhibiting both cell migration and growth. ISL-led inhibition in cell migration resulted from impaired cytoskeleton reorganization and focal adhesion assembly. Assessing the phosphorylation of 141 cytoskeleton dynamics-associated proteins revealed that ISL reduced the abundance of Tyr421-phosphorylation of cortactin, Tyr925- and Tyr861-phosphorylation of FAK, indicating the involvement of Src because these sites are known to be phosphorylated by Src. Enigmatically, ISL inhibited Src in cells while displayed no effect on Src activity in cell-free system. The discrepancy was explained by the observation that THC, one of the major ISL metabolite identified in lung cancer cells abrogated Src activity both in cells and cell-free system. Similar to ISL, THC deterred cell migration and abolished cytoskeleton reorganization/focal adhesion assembly. Furthermore, we showed both ISL and THC suppressed in vitro lung cancer cell invasion and in vivo tumor progression. CONCLUSION:Our study suggests that ISL inhibits lung cancer cell migration and tumorigenesis by interfering with Src through its metabolite THC. As licorice is safely used for culinary purposes, our study suggests that ISL or THC may be safely used as a Src inhibitor.
10.1186/s13046-018-0902-4
Isoliquiritigenin Inhibits Gastric Cancer Stemness, Modulates Tumor Microenvironment, and Suppresses Tumor Growth through Glucose-Regulated Protein 78 Downregulation.
Biomedicines
Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell-like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy.
10.3390/biomedicines10061350
Isoliquiritigenin suppresses the proliferation and induced apoptosis via miR-32/LATS2/Wnt in nasopharyngeal carcinoma.
Wang Ting-Ting,Chen Zhen-Zhang,Xie Peng,Zhang Wen-Jun,Du Ming-Yu,Liu Ya-Tian,Zhu Hua-Yun,Guo Ye-Song
European journal of pharmacology
Nasopharyngeal Carcinoma is limited by the various severe side-effects and surgery is rarely performed. Iosliquiritigenin has a series of biological activities, such as antiviral, anti-free radical and antitumor. However, the role and underlying mechanism of isoliquiritigenin in nasopharyngeal carcinoma have not been understood yet. Herein, the results revealed that isoliquiritigenin could inhibit cell proliferation in nasopharyngeal carcinoma cell lines, including C666-1 and CNE2, in both Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay. In addition, isoliquiritigenin promoted nasopharyngeal carcinoma cell apoptosis, with the up-regulations of Bax, Caspase-3 and Caspase-9 and the down-regulation of Bcl-2. Meanwhile, isoliquiritigenin suppressed nasopharyngeal carcinoma cells migration and invasion with the down-regulation of matrix metalloproteinases (MMP)-2 and MMP-9. Furthermore, the expression of miR-32 was up-regulated in the nasopharyngeal carcinoma tissues, while isoliquiritigenin could significantly down-regulate the expression of miR-32. And over-expression of miR-32 promoted the nasopharyngeal carcinoma cells growth, migration and invasion, and suppressed apoptosis. However, isoliquiritigenin treatment dramatically inhibited the effect of miR-32. Besides, luciferase reporter assay confirmed that large tumor suppressor 2 (LATS2) was a direct target of miR-32. And isoliquiritigenin increased the expression of LATS2, while silencing of LATS2 promoted the nasopharyngeal carcinoma cells growth. Moreover, western blotting discovered that isoliquiritigenin inhibited nasopharyngeal carcinoma cells growth via Wnt signaling pathway. Finally, CNE2 cells transplanted xenografts tumor model in nude mice were performed and it suggested that isoliquiritigenin could inhibit the development of xenografts nude mice, along with the decrease of tumor volume and the expression of miR-32 and LATS2. Overall, isoliquiritigenin was confirmed to be a potent anti-nasopharyngeal carcinoma compound both in vitro and in vivo, and accomplished by regulation of miR-32/LATS2/Wnt.
10.1016/j.ejphar.2019.04.033
Isoliquiritigenin Inhibits Ovarian Cancer Metastasis by Reversing Epithelial-to-Mesenchymal Transition.
Chen Chen,Huang Shuang,Chen Chang-Liang,Su Sing-Bing,Fang Dong-Dong
Molecules (Basel, Switzerland)
The epithelial-to-mesenchymal transition (EMT) plays a prominent role in cancer metastasis. Isoliquiritigenin (ISL), one of the flavonoids in licorice, has been shown to exhibit anticancer activities in many cancer types through various mechanisms. However, it is unknown whether ISL impacts the EMT process. Here, we show that ISL is able to suppress mesenchymal features of ovarian cancer SKOV3 and OVCAR5 cells, evidenced by an apparent morphological change from a mesenchymal to an epithelial phenotype and reduced levels of mesenchymal markers accompanied by the gain of E-cadherin expression. The suppression of EMT is also supported by the observed decrease in cell migration and in vitro invasion upon ISL treatment. Moreover, we show that ISL effectively blocks the intraperitoneal xenograft development of the SKOV3 cell line and prolonged the survival of tumor-bearing mice. These data suggest that ISL inhibits intraperitoneal ovary tumor development through the suppression of EMT, indicating that ISL may be an effective therapeutic agent against ovarian cancer.
10.3390/molecules24203725
Synergistic anticancer effect of docosahexaenoic acid and isoliquiritigenin on human colorectal cancer cells through ROS-mediated regulation of the JNK and cytochrome c release.
Jin Hao,Kim Hak Sung,Yu Seung Taek,Shin Sae Ron,Lee Sung Hee,Seo Geom Seog
Molecular biology reports
A large body of research has demonstrated a synergistic anticancer effect between docosahexaenoic acid (DHA) and standard chemotherapy regimens against colorectal cancer (CRC). In this study, we investigated the chemotherapeutic potential of cotreatment with DHA and isoliquiritigenin (ISL) against CRC HCT-116 cells. Apoptosis was confirmed by Annexin V/PI staining and expression of apoptosis-associated proteins. The synergistic effect of DHA and ISL combination on apoptosis was detected using combination index approaches. Flow cytometry was carried out using fluorescent probes to measure the production of reactive oxygen species (ROS). DHA and ISL in combination synergistically enhanced the decrease in cell viability versus the compounds used alone. Moreover, we demonstrated that the synergistic anti-CRC activity of cotreatment with these two compounds was achieved by inducing the apoptosis caspase-dependently mediated through augmented ROS generation followed by increased Fas ligand mRNA expression and cytochrome c release. Our data also demonstrated that cotreating with DHA and ISL strongly upregulated the phosphorylation of ERK and JNK, which are functionally associated with ROS induced by the two compounds in combination. Interestingly, further study revealed that inhibiting ERK phosphorylation strongly enhanced Fas ligand mRNA expression and the combination of the two compounds induced stronger cytotoxicity, whereas inhibiting JNK phosphorylation significantly reduced the apoptotic signals mediated by cotreatment with these two compounds. Excessive ROS-induced JNK activation and cytochrome c release from mitochondria played a key role in the synergistic anticancer activity of CRC cells by cotreating with DHA and ISL.
10.1007/s11033-021-06159-6
The effects and mechanisms of isoliquiritigenin loaded nanoliposomes regulated AMPK/mTOR mediated glycolysis in colorectal cancer.
Wang Gang,Yu Yang,Wang Yu-Zhu,Yin Pei-Hao,Xu Ke,Zhang Heng
Artificial cells, nanomedicine, and biotechnology
In this study, isoliquiritigenin (ISL) incorporated nanoliposomes were prepared and their effects on colorectal cancer (CRC) cell lines were investigated. Herein, we sought to explore the anti-cancer mechanisms of ISL loaded nanoliposomes (ISL-NLs) on AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathways mediated glycolysis. Also, the key targets such as caveolin 1 (CAV1), glucose transporters and Akt/mTOR that promote glycolysis, and are activated via the induction of α-enolase (ENO1), fructose bisphosphate aldolase A (ALDOA) and monocarboxylate transporter 4 (MCT4) expressions were also investigated. It was shown that ISL-NLs significantly suppressed the proliferation and glucose uptake of CRC cell by potentially regulating the glycolysis and lactate targets as well as pathways that formed the basis of the anti-CRC effects of ISL-NLs. The mechanism underlying this effect was further validated via the regulation of some key targets such as ENO1, ALDOA, lactate dehydrogenase A (LDHA) and MCT4 in glycolysis coupled with cellular myelocytomatosis oncogene (c-myc), hypoxia-inducible factor 1-alpha (HIF-1α) in protein kinase B/mTOR (Akt/mTOR) pathways. Moreover, the AMPK proteins were identified to be up-regulated while the lactic acid production was suppressed by ISL-NLs in the CRC cells, indicating that ISL-NLs had an inhibitory effect on AMPK mediated glycolysis and lactate production. Altogether, these results have provided insights into the mechanism underlying the key role that liposomal ISL played in the multiple inhibition of AMPK and Akt/mTOR mediated glycolysis and lactate generation, which may be regulated as the alternative metabolic pathways of CRC as well as serve as adjuvant therapy for the disease.
10.1080/21691401.2020.1825092
Perspectives on the Role of Isoliquiritigenin in Cancer.
Cancers
Isoliquiritigenin (2',4',4-trihydroxychalcone, ISL), one of the most important bioactive compounds with a chalcone structure, is derived from licorice root. Licorice is commonly known as , including , , and , which are generally available in common foods and Chinese herbal medicines based on a wide variety of biological functions and pharmacological effects, and its derivative (ISL) is utilized as a food additive and adjunct disease treatment. In this review, we summarized the progress over the last 10 years in the targeted pathways and molecular mechanisms of ISL that are involved in the regulation of the onset and progression of different types of cancers.
10.3390/cancers13010115
Mutagenicities of 61 flavonoids and 11 related compounds.
Nagao M,Morita N,Yahagi T,Shimizu M,Kuroyanagi M,Fukuoka M,Yoshihira K,Natori S,Fujino T,Sugimura T
Environmental mutagenesis
The mutagenicities of 61 flavonoids (naturally occurring flavonoid aglycones and flavonal glycosides and synthetic flavonoids) and those of 11 compounds structurally related to flavonoids were tested with Salmonella typhimurium strains TA100 and TA98. Among the 22 flavone derivatives tested, only wogonin was strongly mutagenic, while five derivatives, apigenin triacetate, acacetin, chrysoeriol, pedalitin, and pedalitin tetraacetate, were only weakly mutagenic. Two bisflavonyl derivatives, neither of which has a 3-hydroxyl group, were not mutagenic. Of the 16 flavonol derivatives tested, all except 3-hydroxyflavone and the tetra- and penta-methyl ethers of quercetin were mutagenic. Of the five flavanone derivatives tested, only 7,4-dihydroxyflavanone was mutagenic, showing weak activity. Of the four flavanolol derivatives tested, hydrorobinetin and taxifolin were weakly mutagenic. Of the six isoflavone derivatives tested, tectorigenin was weakly mutagenic. Of the 11 compounds in the miscellaneous group structurally related to flavonoids, only isoliquiritigenin was mutagenic, showing weak activity. For the emergence of strong mutagenicity, the double bond between positions 2 and 3 and the hydroxyl group at position 3 are required, except in wogonin, which does not have a hydroxyl group at position 3 but is strongly mutagenic to TA100. The 3-O-acetyl ester of flavonol, quercetin, was mutagenic with S9 mix, but 3-O-methyl ethers were not. Six flavonol glycosides, three quercetin glycosides and three kaempferol glycosides were mutagenic after preincubation with "hesperidinase," a crude extract of Aspergillus niger. Of 66 flavonoid agylcones and compounds structurally related to flavonoids, quercetin was the strongest mutagen. The carcinogenicity of this compound should be clarified because it is ubiquitously found in vegetables.
10.1002/em.2860030402
Cytotoxic allyl retrochalcone from the roots of Glycyrrhiza inflata.
Yoon Goo,Jung Young Do,Cheon Seung Hoon
Chemical & pharmaceutical bulletin
Two known retrochalcones, licochalcone A (1) and licochalcone C (2), and one new retrochalcone, licochalcone E (4) were isolated by cytotoxicity-guided fractionation from the roots of Glycyrrhiza inflata along with an ordinary chalcone, isoliquiritigenin (3). The structure of the new retrochalcone was elucidated through a spectroscopic analysis.
10.1248/cpb.53.694
Cytoprotective effects of Glycyrrhizae radix extract and its active component liquiritigenin against cadmium-induced toxicity (effects on bad translocation and cytochrome c-mediated PARP cleavage).
Kim Sang Chan,Byun Sung Hui,Yang Chae Ha,Kim Chul Young,Kim Jin Woong,Kim Sang Geon
Toxicology
Glycyrrhizae radix has been popularly used as one of the oldest and most frequently employed botanicals in herbal medicine in Asian countries, and currently occupies an important place in food products. Cadmium (Cd) induces both apoptotic and non-apoptotic cell death, in which alterations in cellular sulfhydryls participate. In the present study, we determined the effects of G. radix extract (GRE) and its representative active components on cell death induced by Cd and explored the mechanistic basis of cytoprotective effects of G. radix. Incubation of H4IIE cells with GRE inhibited cell death induced by 10 microM Cd. Also, GRE effectively blocked Cd (1 microM)-induced cell death potentiated by buthionine sulfoximine (BSO) without restoration of cellular GSH. GRE prevented both apoptotic and non-apoptotic cell injury induced by Cd (10 microM) or Cd (0.3-1 microM) + BSO. Inhibition of Cd-induced cell injury by pretreatment of cells with GRE suggested that the cytoprotective effect result from alterations in the levels of the protein(s) responsible for cell viability. GRE inhibited mitochondrial Bad translocation by Cd or CD+BSO, and caused restoration of mitochondrial Bcl(xL) and cytochrome c levels. Cd-induced poly(ADP-ribose)polymerase cleavage in control cells or in cells deprived of sulfhydryls was prevented by GRE treatment. Among the major components present in GRE, liquiritigenin, but not liquiritin, isoliquiritigenin or glycyrrhizin, exerted cytoprotective effect. These results demonstrated that GRE blocked Cd-induced cell death by inhibiting the apoptotic processes involving translocation of Bad into mitochondria, decreases in mitochondrial Bcl(xL) and cytochrome c, and poly(ADP-ribose)polymerase cleavage.
10.1016/j.tox.2004.01.010
Anti-oxidant constituents of the roots and stolons of licorice (Glycyrrhiza glabra).
Chin Young-Won,Jung Hyun-Ah,Liu Yue,Su Bao-Ning,Castoro John A,Keller William J,Pereira Michael A,Kinghorn A Douglas
Journal of agricultural and food chemistry
As part of a search for new cancer chemopreventive agents, a new chalcone derivative (1), a novel group of neolignan lipid esters (2), and seven known phenolic compounds (formononetin, glabridin, hemileiocarpin, hispaglabridin B, isoliquiritigenin, 4'-O-methylglabridin, and paratocarpin B) (3-9) were isolated from the roots and stolons of licorice (Glycyrrhiza glabra). The structures of compound 1 and the individual components of isolate 2 were elucidated using various spectroscopic and chemical methods. All isolates were tested in an authentic peroxynitrite anti-oxidant assay. Of these compounds, hispaglabridin B (6), isoliquiritigenin (7), and paratocarpin B (9) were found to be the most potent anti-oxidant agents. Furthermore, isoliquiritigenin (7) was demonstrated to prevent the incidence of 1,2-dimethylhydrazine-induced colon and lung tumors in mice when administered at a dose of 300 mg/kg.
10.1021/jf0703553
Flavonoids inhibit cell growth and induce apoptosis in B16 melanoma 4A5 cells.
Iwashita K,Kobori M,Yamaki K,Tsushida T
Bioscience, biotechnology, and biochemistry
We investigated the growth inhibitory activity of several flavonoids, including apigenin, luteolin, kaempherol, quercetin, butein, isoliquiritigenin, naringenin, genistein, and daizein against B16 mouse melanoma 4A5 cells. Isoliquiritigenin and butein, belonging to the chalcone group, markedly suppressed the growth of B16 melanoma cells and induced cell death. The other flavonoids tested showed little growth inhibitory activity and scarcely caused cell death. In cells treated with isoliquiritigenin or butein, condensation of nuclei and fragmentation of nuclear DNA, which are typical phenomena of apoptosis, were observed by Hoechst 33258 staining and by agarose gel electrophoresis of DNA. Flowcytometric analysis showed that isoliquiritigenin and butein increased the proportion of hypodiploid cells in the population of B16 melanoma cells. These results demonstrate that isoliquiritigenin and butein inhibit cell proliferation and induce apoptosis in B16 melanoma cells. Extracellular glucose decreased the proportion of hypodiploid cells that appeared as a result of isoliquiritigenin treatment. p53 was not detected in cells treated with either of these chalcones, however, protein of the Bcl-2 family were detected. The level of expression of Bax in cells treated with either of these chalcones was markedly elevated and the level of Bcl-XL decreased slightly. Isoliquiritigenin did not affect Bcl-2 expression, but butein down-regulated Bcl-2 expression. From these results, it seems that the pathway by which the chalcones induce apoptosis may be independent of p53 and dependent on proteins of the Bcl-2 family. It was supposed that isoliquiritigenin induces apoptosis in B16 cells by a mechanism involving inhibition of glucose transmembrane transport and promotion of Bax expression. On the other hand, it was suggested that butein induces apoptosis via down-regulation of Bcl-2 expression and promotion of Bax expression. This mechanism differs from the isoliquiritigenin induction pathway.
10.1271/bbb.64.1813
Glycyrrhiza uralensis Fisch. and its active components mitigate Semen Strychni-induced neurotoxicity through regulating high mobility group box 1 (HMGB1) translocation.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Semen Strychni has long been used for the treatment of rheumatoid arthritis, facioplegia and myasthenia gravis due to its anti-inflammation and anti-nociceptive properties in China. However, the fatal neurotoxicity of Semen Strychni has limited its wider clinical application. To investigate the acute toxicity induced by Semen Strychni and the detoxification of liquorice, we evaluated inflammation, oxidative stress and the translocation of high mobility group box 1 (HMGB1) in rats. As a result, there were obvious oxidative stress and inflammation in hippocampus after the Semen Strychni extracts (STR) treatment in rats. Liquorice extracts (LE) and its three active monomers - glycyrrhizic acid (GA), liquiritigenin (LIQ), isoliquiritigenin (ISL) showed the potential for mitigating STR-induced neurotoxicity. HMGB1 levels in cytoplasm and serum and the levels of two downstream receptors RAGE and TLR4 were significantly increased after STR treatment. Through using LE and the monomers, the nucleocytoplasmic transport and release of HMGB1 were inhibited. In addition, the binding between HMGB1 and TLR4 was weakened in detoxification groups comparing with the STR group. Taken together, these findings indicated that liquorice and its active components alleviated acute neurotoxicity induced by Semen Strychni partly via HMGB1-related pathway.
10.1016/j.biopha.2022.112884
Modulation of lipopolysaccharide-induced pro-inflammatory mediators by an extract of Glycyrrhiza glabra and its phytoconstituents.
Thiyagarajan P,Chandrasekaran C V,Deepak H B,Agarwal Amit
Inflammopharmacology
OBJECTIVE:To evaluate the inhibitory property of de-glycyrrhizinated extract of Glycyrrhiza glabra root and its phytoconstituents (glabridin, isoliquiritigenin and glycyrrhizin) on LPS-induced production of pro-inflammatory mediators. MATERIALS AND METHODS:Inhibitory effect of G. glabra extract and its phytoconstituents were studied on lipopolysaccharide (LPS)-induced nitric oxide (NO), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) levels in J774A.1 murine macrophages. RESULTS:G. glabra and isoliquiritigenin significantly inhibited LPS stimulated NO, IL-1 beta and IL-6 production. Glabridin showed significant inhibition of NO and IL-1 beta release, but failed to attenuate IL-6 levels at the tested concentrations. In addition, glycyrrhizin did not exhibit inhibitory response towards any of the LPS-induced pro-inflammatory mediators at the tested concentrations. CONCLUSION:From the results we speculate that the inhibitory effect of G. glabra extract on LPS-induced pro-inflammatory mediators is influenced by glabridin and isoliquiritigenin and is not contributed by glycyrrhizin.
10.1007/s10787-011-0080-x
The potent anti-tumor-promoting agent isoliquiritigenin.
Yamamoto S,Aizu E,Jiang H,Nakadate T,Kiyoto I,Wang J C,Kato R
Carcinogenesis
A topical application of a chalcone derivative, 4,2',4'-trihydroxychalcone (isoliquiritigenin) inhibited epidermal ornithine decarboxylase (ODC) induction and ear edema formation, i.e. inflammation, caused by a topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in CD-1 mice. In addition, isoliquiritigenin potently inhibited 7,12-dimethylbenz[alpha]anthracene (DMBA)-initiated and TPA-promoted skin papilloma formation. This inhibitory effect of isoliquiritigenin was not due to any damage inflicted on the initiated cells but due to its anti-tumor-promoting action. Isoliquiritigenin also inhibited epidermal ODC induction and skin tumor promotion caused by 7-bromomethylbenz[alpha]anthracene (BrMBA), a non-TPA type of tumor-promoting agent, in DMBA-initiated mice. Isoliquiritigenin inhibits neither 12-lipoxygenase nor cyclooxygenase in epidermal subcellular fractions. This compound, however, inhibited TPA-stimulated prostaglandin E2 (PGE2) production in intact epidermal cells. ODC induction caused by TPA was inhibited by a topical application of cyclooxygenase inhibitor, indomethacin. Inhibition of ODC induction by indomethacin was counteracted by a topical application of PGE2, while inhibition caused by isoliquiritigenin was not overcome by PGE2. The results suggest that a mechanism other than the inhibition of PGE2 production is involved in the anti-tumor-promoting action of isoliquiritigenin. Isoliquiritigenin failed to inhibit phospholipase A2 activity of platelet sonicates, but inhibited platelet 12-lipoxygenase and 5-lipoxygenase in polymorphonuclear leukocytes. Therefore, it might be possible that isoliquiritigenin exerts its anti-tumor-promoting action through the lipoxygenase inhibition by acting on cells other than the target epidermal cells. Our present results, in combination with our previous data, demonstrate that some chalcone derivatives and flavonoids which show a potent lipoxygenase inhibitory action act on a common step in the skin tumor promotion caused by two different types of tumor-promoting agents, i.e. TPA and BrMBA, and suggest that these compounds show promise as drugs to prevent tumor promotion.
10.1093/carcin/12.2.317
Isoliquiritigenin inhibits proliferation and induces apoptosis of U87 human glioma cells in vitro.
Zhou Guo-Sheng,Song Lai-Jun,Yang Bo
Molecular medicine reports
Isoliquiritigenin (ISL), a member of the flavonoids, has been demonstrated to possess antitumor activity in various cancer cell lines in vitro and in vivo. In this study, we investigated the antitumor effects of ISL on U87 glioma cells in vitro. As determined by MTT assay, ISL inhibited the proliferation of U87 cells in a time-dependent and dose-dependent manner. The results of fluorescence-activated cell sorting (FACS) analysis suggested that ISL induced the apoptosis of the U87 cells and blocked cell cycle progression at the S and G2/M phases. Moreover, it was identified that ISL induced the apoptosis of the U87 cells in a caspase-dependent manner. Although treatment with the pan-caspase inhibitor Z-VAD-FMK efficiently blocked the ISL-induced caspase activation, it did not eliminate the ISL-induced cell death. Further examination using western blot analysis revealed that ISL upregulated p21/WAF1 and p27. These results indicate that cell cycle arrest and the caspase-mediated apoptosis pathway may participate in the antiproliferative activity of ISL in U87 cells by regulating the expression of specific molecules.
10.3892/mmr.2012.1218
Isoliquiritigenin inhibits tumor growth and protects the kidney and liver against chemotherapy-induced toxicity in a mouse xenograft model of colon carcinoma.
Lee Chang Ki,Son Seung Hwa,Park Kwang Kyun,Park Jung Han Yoon,Lim Soon Sung,Chung Won Yoon
Journal of pharmacological sciences
A growing amount of attention has been focused on the investigation of the effects of chemopreventive agents on the inhibition of cancer cell growth and toxicity in combination with chemotherapeutics. The objective of this study was to determine whether isoliquiritigenin (ISL) has the potential to serve as a beneficial supplement during cisplatin chemotherapy. We found that the administration of ISL alone significantly reduced the size of the solid tumors in CT-26 cell-inoculated BALB/c mice, without any detectable induction of nephrotoxicity, hepatotoxicity, and oxidative stress, and ISL reduced the viability and DNA synthesis of CT-26 murine colon cancer cells in a dose-dependent manner. ISL did not affect the therapeutic efficacy of cisplatin. Furthermore, ISL suppressed cisplatin-induced kidney damage characterized by increases in serum creatinine and blood urea nitrogen, as well as cisplatin-induced liver damage characterized by increases in serum alanine aminotransferase and aspartate aminotransferase. The repeated oral administration of ISL prior to cisplatin treatment exerted a preventive effect on cisplatin-mediated increases in serum nitric oxide and tissue lipid peroxidation levels, and it recovered depleted GSH levels in the tissues. Therefore, supplementation with ISL may be an effective approach to counteracting the side effects of cisplatin therapy in cancer patients.
Isoliquiritigenin prevents the progression of psoriasis-like symptoms by inhibiting NF-κB and proinflammatory cytokines.
Wu Yangping,Chen Xiangzheng,Ge Xiaojun,Xia Hongwei,Wang Yuxi,Su Siyuan,Li Wenting,Yang Tinghan,Wei Mingtian,Zhang Hang,Gou Lantu,Li Jiong,Jiang Xian,Yang Jinliang
Journal of molecular medicine (Berlin, Germany)
UNLABELLED:Isoliquiritigenin (ISL) is an important flavonoid component of licorice and has been reported to possess anti-inflammatory and antioxidant properties, but its exact mechanism of action remains poorly understood. Previously, we demonstrated that ISL could suppress IL-6 expression in multiple myeloma. Here, we further characterized the anti-inflammatory effects of ISL in several psoriasis models, including the keratin 14/vascular endothelial growth factor (VEGF) transgenic mouse, the imiquimod (IMQ)-induced psoriasis-like mouse, and the human keratinocytes HaCaT and NHEK in vitro. We found that ISL ameliorated the inflammatory process in psoriasis models but not in their respective controls. Moreover, the anti-inflammatory effects of ISL were attributed to the suppression of nuclear factor-κB (NF-κB) activity, which consequently resulted in the reduction of pro-inflammation cytokines IL-6 and IL-8 expression. In conclusion, ISL exhibited anti-inflammatory effects in psoriasis models, by downregulating IL-6 and IL-8 via suppression of NF-κB activity, suggesting that ISL might serve as a potential candidate for treatment of psoriasis and other autoimmune inflammatory diseases. KEY MESSAGE:ISL could ameliorate the inflammatory process of psoriasis. ISL could suppress NF-κB and subsequent production of a series of pro-inflammatory cytokines. Dual-inhibitory activity against IL-6 and IL-8 of ISL is implemented via inhibiting NF-κB. ISL exerts no inhibitory effects on normal human keratinocytes or wild-type Balb/c mice, implying its low toxicity and safety.
10.1007/s00109-015-1338-3
Isoliquiritigenin induces apoptosis and autophagy and inhibits endometrial cancer growth in mice.
Wu Chi-Hao,Chen Hsin-Yuan,Wang Chia-Woei,Shieh Tzong-Ming,Huang Tsui-Chin,Lin Li-Chun,Wang Kai-Lee,Hsia Shih-Min
Oncotarget
Endometrial cancer is the most common cancer in women, typically with onset after menopause. Isoliquiritigenin (ISL), a licorice flavonoid, was previously shown to have anti-oxidant, anti-inflammatory, and tumor suppression effects. In this study, we investigated the anti-tumor effect of ISL on human endometrial cancer both in vitro and in vivo. We used telomerase-immortalized human endometrial stromal cells (T-HESCs) and human endometrial cancer cell lines (Ishikawa, HEC-1A, and RL95-2 cells) as targets. The effects of ISL on cell proliferation, cell cycle regulation, and apoptosis or autophagy-related protein expression were examined. In addition, we conducted in vivo experiments to confirm the inhibitory effects of ISL on cancer cells. ISL significantly inhibited the viability of cancer cells in a dose- and time-dependent manner but with little toxicity on normal cells. In addition, flow cytometry analysis indicated that ISL induced sub-G1 or G2/M phase arrest. ISL treatment activated the extracellular signal regulated kinase signaling pathway to enhance the protein expression of caspase-7/LC3BII associated with apoptosis/autophagy. Furthermore, ISL suppressed xenograft tumor growth in vivo. Taken together, these findings suggest that ISL may induce apoptosis, autophagy, and cell growth inhibition, indicating its potential as a therapeutic agent for human endometrial cancer.
10.18632/oncotarget.12369
Isoliquiritigenin in licorice functions as a hepatic protectant by induction of antioxidant genes through extracellular signal-regulated kinase-mediated NF-E2-related factor-2 signaling pathway.
Park Sang Mi,Lee Jong Rok,Ku Sae Kwang,Cho Il Je,Byun Sung Hui,Kim Sang Chan,Park Sook Jahr,Kim Young Woo
European journal of nutrition
PURPOSE:Liver is the major site of biotransformation for exogenous toxins, in having a defense system against oxidative stress as well as cytochrome P450 system. Isoliquiritigenin (isoLQ) is an active component present in Glycyrrhizae radix and has been shown to have various biological activities. This study investigated the effect of isoLQ as a liver protectant against oxidative stress, both in vivo and in vitro, and also its molecular mechanisms. METHODS:We used tert-butylhydroperoxide-induced hepatocyte damage model and cadmium (Cd)-stimulated liver toxicity animal model, which are assessed by immunoblot and flow cytometry as well as plasma and histopathological parameters. RESULTS:In HepG2 cells, pretreatment of 10 and 30 µM isoLQ significantly inhibited the induction of apoptosis and mitochondrial damage, and production of reactive oxygen species. Moreover, isoLQ induced the activation of nuclear factor erythroid 2-related factor-2 (Nrf2), as indicated by an increase in its nuclear translocation and antioxidant response element-luciferase activity. IsoLQ also induced the expression of Nrf2 target phase II enzymes, such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit and NAD(P)H:quinone oxidoreductase 1. IsoLQ also induced phosphorylation of extracellular stimuli-regulated kinase (ERK), and its activation of Nrf2 was mediated with ERK-dependent phosphorylation of Nrf2, as determined by its chemical inhibitor. In rats, oral treatment of 5 and 20 mg/kg isoLQ prevented Cd-induced acute hepatic damage, as assessed by plasma parameters and semiquantative histology, such as the modified HAI grading scores and the degenerative regions in hepatic parenchyma. CONCLUSION:These findings are considered as scientific evidence that isoLQ in licorice has the function of being a hepatic protectant against oxidative damages through ERK-mediated Nrf2 activation.
10.1007/s00394-015-1051-6
Isoliquiritigenin prevents Doxorubicin-induced hepatic damage in rats by upregulating and activating SIRT1.
Al-Qahtani Wahidah H,Alshammari Ghedeir M,Ajarem Jamaan S,Al-Zahrani Amani Y,Alzuwaydi Aishah,Eid Refaat,Yahya Mohammed Abdo
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
This study evaluated if the hepatic protective effect of Isoliquiritigenin (ISL) against doxorubicin (DOX)-treated rats involves upregulating sirtuin-1 (SIRT1) signaling. Adult male was divides into 5 groups (n = 6 rats/each) as control (vehicle), ISL (25 mg/kg), DOX (15 mg/kg), DOX + ISL, and DOX + ISL + EX-527 (a SIRT1 inhibitor, 5 mg/kg). ISL and EX-527 were administered 10 days before and after the single treatment of DOX. Also, cultured AML-12 hepatocytes (5 ×10) were treated with 10 µM of ISL for 24 h with or without DOX-treatments (10 µM) and in the presence or absence of EX-527 (5 µM). ISL prevented hepatocyte damage and decreased serum levels of hepatic transaminases, hepatic levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and hepatic mRNA levels of Bax and caspases-3,8, and 9. In the liver of the control and DOX-treated rats, ISL reduced levels of malondialdehyde (MDA) but increased hepatic levels of glutathione (GSH), superoxide dismutase (SOD), and catalase, as well as mRNA levels of Bcl2. In vitro, ISL stimulated cell survival and lowered levels of ROS but increased GSH levels. In vivo and in vitro, in the livers of control and DOX-treated animals, ISL significantly increased the nuclear activity and mRNA levels of SIRT1, enhanced the nuclear levels of Nrf2, and reduced nuclear levels of NF-κB p65. In conclusion, ISL alleviates DOX-induced hepatocyte toxicity by stimulating the Nrf2/antioxidants axis and concomitant suppression of NF-κB, mainly by upregulating/activating SIRT1.
10.1016/j.biopha.2021.112594
Targeting oral cancer stemness and chemoresistance by isoliquiritigenin-mediated GRP78 regulation.
Hu Fang-Wei,Yu Cheng-Chia,Hsieh Pei-Ling,Liao Yi-Wen,Lu Ming-Yi,Chu Pei-Ming
Oncotarget
Cancer stem cells (CSCs) are cells that drive tumorigenesis, contributing to metastasis and cancer recurrence as well as resistance to chemotherapy of oral squamous cell carcinomas (OSCC). Therefore, approaches to target CSCs become the subject of intense research for cancer therapy. In this study, we demonstrated that isoliquiritigenin, a chalcone-type flavonoid isolated from licorice root, exhibited more toxicity in oral cancer stem cells (OSCC-CSCs) compared to normal cells. Treatment of isoliquiritigenin not only inhibited the self-renewal ability but also reduced the expression of CSC markers, including the ALDH1 and CD44. In addition, the capacities of OSCC-CSCs to invade, metastasize and grow into a colony were suppressed by isoliquiritigenin. Most importantly, we showed that isoliquiritigenin potentiated chemotherapy along with downregulated expression of an ABC transporter that is associated with drug resistance, ABCG2. Moreover, a combination of isoliquiritigenin and Cisplatin significantly repressed the invasion and colony formation abilities of OSCC-CSCs. Our results suggested that administration of isoliquiritigenin reduced the protein expression of mRNA and membrane GRP78, a critical mediator of tumor biology. Overexpression of GRP78 reversed the inhibitory effect of isoliquiritigenin on OSCC-CSCs. Furthermore, isoliquiritigenin retarded the tumor growth in nude mice bearing OSCC xenografts. Taken together, these findings showed that isoliquiritigenin is an effective natural compound that can serve as an adjunct to chemotherapy for OSCC.
10.18632/oncotarget.21338
Anti-proliferative and cytotoxic activities of the flavonoid isoliquiritigenin in the human neuroblastoma cell line SH-SY5Y.
Escobar Stephane J de M,Fong Genevieve M,Winnischofer Sheila M B,Simone Martin,Munoz Lenka,Dennis Joanne M,Rocha Maria Eliane M,Witting Paul K
Chemico-biological interactions
Neuroblastoma is a common childhood cancer with high mortality. We evaluated the capacity of the flavonoid, isoliquiritigenin (4,2',4'-trihydroxychalcone; ISL) to inhibit cellular proliferation and migration in the human neuroblastoma cell line SH-SY5Y. Incubation of cultured SH-SY5Y cells with 20-100 μM ISL decreased cell confluency (15-70%) after 24 h incubation, while 10-100 μM ISL (24 h) depleted intracellular ATP stores (15-90% vs vehicle-treated control) after 24 h incubation. ISL-mediated cell toxicity did not involve intracellular caspase 3/7 activation, externalization of phosphatidylserine on the cell membrane or stimulation of TNF and IL-1β release, all indicating that the flavonoid did not induce apoptosis. Pre-treatment of cells with necrostatin-1, a necroptosis inhibitor, significantly restored ATP levels (ATP levels increased 12-42%) in ISL-treated neuroblastoma cells indicative of enhanced viability. By contrast, RIP1 phosphorylation status remained unchanged in cells treated with ISL although the intracellular ratio of phosphorylated/total parental RIP1 increased after ISL treatment on SH-SY5Y cells indicating that ISL decreased levels of native RIP1. In addition, ISL treatment inhibited SH-SY5Y cell migration/proliferation in a scratch assay and arrested cell cycle transition by significantly decreasing the number of cells in G0/G1 phase and increasing populations by ~10% in S (primarily) and G2/M (lesser extent) phases. The intracellular ratio of phosphorylated/total ERK 1/2 and p38 remained unchanged after ISL treatment (up to 40 μM); ERK activation was only determined at ISL dose well above the experimental IC value as judged by ELISA analyses and this did not correlate with ISL cytotoxicity at lower dose <40 μM; Western blot assay confirmed the detection of phosphorylated (p-)ERK1/2 and (p-)p38 in ISL treated cells. Together the results suggest that ISL exerts anti-proliferative and cytotoxic activity on SHSY5Y cells through the loss of ATP, induction of cell cycle arrest, and cell death largely via a necroptotic mechanism in the absence of apoptotic activity.
10.1016/j.cbi.2018.11.022
Preparation and and evaluation of an isoliquiritigenin-loaded ophthalmic nanoemulsion for the treatment of corneal neovascularization.
Drug delivery
Isoliquiritigenin (ISL), as a natural flavonoid, has been proven to have therapeutic potential for corneal neovascularization (CNV) treatment; however, its therapeutic use is restricted due to its poor aqueous solubility and limited bioavailability. To overcome these limitations, a novel ISL-loaded nanoemulsion (ISL-NE) was designed for inhibiting CNV in this study. ISL-NE formulation was composed of propylene glycol dicaprylate (PGD), Cremophor® EL (EL35), polyethylene glycol 400 (PEG 400) and adding water with sodium hyaluronate, its particle size was 34.56 ± 0.80 nm with a low polydispersity index of less than 0.05, which suggested a narrow size distribution. The results demonstrated that ISL-NE released higher and permeated more drug than ISL suspension (ISL-Susp) in drug release and corneal permeation study. ISL-NE showed no cytotoxicity in human corneal epithelial cells toxicity study, which was consistent with the result of ocular irritation study in rabbit eyes. ISL-NE had bioavailability 5.76-fold, 7.80-fold and 2.13-fold higher than ISL-Sups in tears, cornea and aqueous humor after a single dose of ISL-NE, respectively. Furthermore, the efficacy of ISL-NE treatment (0.2% ISL) was comparable to that of dexamethasone treatment (0.025%) in the inhibition of CNV in mice model. Enzyme-linked immunosorbent assay (ELISA) showed that the expressions of corneal vascular endothelial growth factor (VEGF-A) and matrix metalloproteinase (MMP-2) were decreased. In conclusion, the ISL-NE demonstrated excellent physicochemical properties, good tolerance, and enhanced ocular bioavailability. It could be a promising, safe, and effective treatment for CNV.
10.1080/10717544.2022.2096714
Isoliquiritigenin inhibits the growth of prostate cancer.
Kanazawa Motohiro,Satomi Yoshiko,Mizutani Yoichi,Ukimura Osamu,Kawauchi Akihiro,Sakai Toshiyuki,Baba Masaki,Okuyama Toru,Nishino Hoyoku,Miki Tsuneharu
European urology
OBJECTIVE:Isoliquiritigenin, one of the components in the root of Glycyrrhiza glabra L., is a member of the flavonoids, which are known to have an anti-tumor activity in vitro and in vivo. In this study, we investigated the anti-tumor effect of isoliquiritigenin on prostate cancer in vitro. METHODS:DU145 and LNCaP prostate cancer cell lines were used as targets. We examined the effects of isoliquiritigenin on cell proliferation, cell cycle regulation and cell cycle-regulating gene expression. Further, we investigated the effects of isoliquiritigenin on the GADD153 mRNA and protein expression, and promoter activity. RESULTS:Isoliquiritigenin significantly inhibited the proliferation of prostate cancer cell lines in a dose-dependent and time-dependent manner. Fluorescence-activated cell sorting (FACS) analysis indicated that isoliquiritigenin induced S and G2/M phase arrest. Isoliquiritigenin enhanced the expression of GADD153 mRNA and protein associated with cell cycle arrest. Further, isoliquiritigenin stimulated transcriptional activity of GADD153 promoter dose-dependently. CONCLUSION:These findings suggest that isoliquiritigenin is a candidate agent for the treatment of prostate cancer and GADD153 may play an important role in isoliquiritigenin-induced cell cycle arrest and cell growth inhibition.
Real-time detection of the early event of cytotoxicity of herbal ingredients on single leukemia cells studied in a microfluidic biochip.
Li XiuJun,Xue Xiaoyan,Li Paul C H
Integrative biology : quantitative biosciences from nano to macro
A microfluidic approach has been developed for the real-time detection of drug effects, based on the quantitative measurement of calibrated cytosolic calcium ([Ca(2+)](i)) on single cancer cells. This microfluidic method is rapid by detecting the early event of cytotoxicity of drug candidates on cancer cells, without waiting for a couple of days needed for cell seeding and drug treatment by conventional assays. The miniaturized biochip consists of a V-shaped structure for the single-cell selection and retention. Various test reagents such as the chemotherapy drug (daunorubicin), an ionophore (ionomycin), and herbal ingredients from licorice (isoliquiritigenin or IQ) were investigated for their abilities to stimulate sustained cellular [Ca(2+)](i) elevations. The microfluidic results obtained in hours have been confirmed by conventional cytotoxicity assays which take days to complete. Moreover, any color or chemical interference problems found in the conventional assays of herbal compounds could be resolved. Using the microfluidic approach, IQ (50 microM) has been found to cause a sustained [Ca(2+)](i) elevation and cytotoxic effects on leukemia cells. The microfluidic single-cell analysis not only reduces reagent cost, and demands less cells, but also reveals some phenomena due to cellular heterogeneity that cannot be observed in bulk analysis.
10.1039/b812987h
Glycyrrhiza inflata-derived chalcones, Licochalcone A, Licochalcone B and Licochalcone D, inhibit phosphorylation of NF-kappaB p65 in LPS signaling pathway.
Furusawa Jun-ichi,Funakoshi-Tago Megumi,Mashino Tadahiko,Tago Kenji,Inoue Hideo,Sonoda Yoshiko,Kasahara Tadashi
International immunopharmacology
Licorice root has been used as a traditional medicine for the treatment of gastric ulcer, bronchial asthma and inflammation. Licochalcone A is a major component of Xinjiang licorice, Glycyrrhiza inflata. Previously we showed that Licochalcone A significantly inhibited LPS-induced NF-kappaB transcriptional activation by abrogating the phosphorylation of NF-kappaB p65 at serine 276. Glycyrrhiza inflata contains not only Licochalcone A but also Licochalcone B, Licochalcone C, Licochalcone D, Echinatin and Isoliquiritigenin, harboring the common structure of chalcones. No chalcones had any effect on LPS-induced IkappaB degradation, nuclear translocation and DNA binding activity of NF-kappaB p65; however, we observed that Licochalcone B and Licochalcone D significantly inhibited LPS-induced phosphorylation at serine 276 and transcriptional activation of NF-kappaB, the same as Licochalcone A. Interestingly, we also found that Licochalcone A, Licochalcone B and Licochalcone D effectively inhibited LPS-induced activation of PKA, which is required for the phosphorylation of NF-kappaB p65 at serine 276. Consequently, Licochalcone B and Licochalcone D significantly reduced the LPS-induced production of NO, TNFalpha and MCP-1. On the other hand, Licochalcone C, Echinatin and Isoliquitigenin failed to inhibit LPS-induced NF-kappaB activation. These findings suggest that the anti-inflammatory effect of Glycyrrhiza inflata is ascribable to the potent inhibition of NF-kappaB by Licochalcone A, Licochalcone B and Licochalcone D.
10.1016/j.intimp.2009.01.031
Simultaneous quantification of fifteen compounds in rat plasma by LC-MS/MS and its application to a pharmacokinetic study of Chaihu-Guizhi decoction.
Li Zhuangzhuang,Wen Ran,Du Yiqing,Zhao Shaozhe,Zhao Pan,Jiang Haiqiang,Rong Rong,Lv Qingtao
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
A simple, sensitive and selective high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed and validated for simultaneous determination and pharmacokinetic study of 15 active compounds (Saikosaponin A, Baicalin, Wogonin, Glycyrrhizic acid, Glycyrrhetinic acid, Albiflorin, Paeoniflorin, Liquiritin, Isoliquiritin, Liquiritigenin, Isoliquiritigenin, Cinnamic acid, Gallic acid, Wogonoside and Oroxylin A) in rat plasma. After a feasible protein precipitation using methanol for sample preparation, chromatographic separation was carried out with a Halo® C column (2.1 × 100 mm, 2.7 μm) at 35 °C, water containing 0.1% formic acid and acetonitrile were used as the mobile phase with a flow rate of 0.3 mL/min. Multiple reaction monitoring (MRM) with positive and negative ion switching mode was performed for the quantification of the standards and internal standard in plasma. All the calibration curves showed good linear regression within the linear range (r > 0.9923). In particular, the results of the method validation including specificity, linearity, accuracy, precision, extraction recovery, matrix effect, and stability of compounds in bio-samples were all within the current acceptance criteria. The established method was successfully applied to the pharmacokinetic study of 15 compounds in rats after oral administration of CGD and laid the foundation for studying the active components and mechanism of CGD in vivo.
10.1016/j.jchromb.2018.12.006
A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones.
Gupta Vivek Kumar,Gaur Rashmi,Sharma Atin,Akther Jawed,Saini Mahak,Bhakuni Rajendra Singh,Pathania Ranjana
Bioorganic chemistry
Staphylococcus aureus is the leading cause of bacteraemia and the dwindling supply of effective antibacterials has exacerbated the problem of managing infections caused by this bacterium. Isoliquiritigenin (ISL) is a plant flavonoid that displays therapeutic potential against S. aureus. The present study identified a novel mannich base derivatives of ISL, IMRG4, active against Vancomycin intermediate S. aureus (VISA). IMRG4 damages the bacterial membranes causing membrane depolarization and permeabilization, as determined by loss of salt tolerance, flow cytometric analysis, propidium idodie and fluorescent microscopy. It reduces the intracellular invasion of HEK-293 cells by S. aureus and decreases the staphylococcal load in different organs of infected mice models. In addition to anti-staphylococcal activity, IMRG4 inhibits the multidrug efflux pump, NorA, which was determined by molecular docking and EtBr efflux assays. In combination, IMRG4 significantly reduces the MIC of norfloxacin for clinical strains of S. aureus including VISA. Development of resistance against IMRG4 alone and in combination with norfloxacin was low and IMRG4 prolongs the post-antibiotic effect of norfloxacin. These virtues combined with the low toxicity of IMRG4, assessed by MTT assay and haemolysis, makes it an ideal candidate to enter drug development pipeline against S. aureus.
10.1016/j.bioorg.2018.10.024
Comparative pharmacokinetics of nine major bioactive components in normal and ulcerative colitis rats after oral administration of Lizhong decoction extracts by UPLC-TQ-MS/MS.
Shen Yumeng,Cui Xiang,Jiang Shu,Qian Da-Wei,Duan Jin-Ao
Biomedical chromatography : BMC
Lizhong decoction (LZD), a classic formula, has been used to treat ulcerative colitis (UC) for thousands of years in clinical practice. However, the pharmacokinetic characteristics of its major bioactive components in rats under different physiological and pathological states are not clear. Thus, in this study, a rapid and sensitive analytical method, ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS) method, was developed and applied to simultaneously determine glycyrrhizic acid, liquiritin, isoliquiritin, glycyrrhizin, isoliquiritigenin, 6-gingerol, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Re in normal and UC rats after oral administration of LZD extract. A Waters BEH C UPLC column was used for chromatographic separation, while acetonitrile and 0.1% formic acid were selected as mobile phase. The linearity of nine analytes was >0.9920. Inter- and intra-day accuracy was ≤ 11.4% and precision was from 1.1 to 12.7%. Additionally, stable and suitable extraction recoveries were also obtained. The established method was validated and found to be specific, accurate and precise for nine analytes. Furthermore, it was successfully applied to the pharmacokinetic investigation of nine major components after oral administration of LZD extracts to normal and model rats, respectively. The results showed that the pharmacokinetic parameters (C , T , AUC , AUC ) in the plasma of UC rats were significantly different from those of normal rats, which could provide a reference for the clinical application of LZD.
10.1002/bmc.4521
Natural products in licorice for the therapy of liver diseases: Progress and future opportunities.
Li Xiaojiaoyang,Sun Rong,Liu Runping
Pharmacological research
Liver diseases related complications represent a significant source of morbidity and mortality worldwide, creating a substantial economic burden. Oxidative stress, excessive inflammation, and dysregulated energy metabolism significantly contributed to liver diseases. Therefore, discovery of novel therapeutic drugs for the treatment of liver diseases are urgently required. Licorice is one of the most commonly used herbal drugs in Traditional Chinese Medicine for the treatment of liver diseases and drug-induced liver injury (DILI). Various bioactive components have been isolated and identified from the licorice, including glycyrrhizin, glycyrrhetinic acid, liquiritigenin, Isoliquiritigenin, licochalcone A, and glycycoumarin. Emerging evidence suggested that these natural products relieved liver diseases and prevented DILI through multi-targeting therapeutic mechanisms, including anti-steatosis, anti-oxidative stress, anti-inflammation, immunoregulation, anti-fibrosis, anti-cancer, and drug-drug interactions. In the current review, we summarized the recent progress in the research of hepatoprotective and toxic effects of different licorice-derived bioactive ingredients and also highlighted the potency of these compounds as promising therapeutic options for the treatment of liver diseases and DILI. We also outlined the networks of underlying molecular signaling pathways. Further pharmacology and toxicology research will contribute to the development of natural products in licorice and their derivatives as medicines with alluring prospect in the clinical application.
10.1016/j.phrs.2019.04.025
Validation of an LC-MS/MS method for simultaneous detection of diverse components of Qinxing Qingre Zhike Granule in rat plasma and its application to pharmacokinetic study after oral administration to rats.
Wang Zilingyun,An Rui,Du Guangli,Liang Kun,Li Guowen
Biomedical chromatography : BMC
A sensitive and validated method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established to test the plasma concentrations of active ingredients in Qinxing Qingre Zhike Granule, namely geniposide, liquiritin, isoliquiritin, baicalin, wogonoside, baicalein, liquiritigenin, isoliquiritigenin and glycyrrhetinic acid. The analysis was performed on an Ultimate XB-C column at the flow rate of 0.4 mL min in a single run of 18 min. The mobile phase was composed of 0.05% formic acid in water and acetonitrile with gradient elution. Positive and negative scanning and selected multiple reaction monitoring modes were applied for quantization. The proposed method showed good linearity in the given ranges from 0.6800-340.0 to 3.920-1960 ng mL with r > 0.9917 for all the analytes. The precision (RSD) was no more than 12%, and the accuracy (RE) was less than ±11% for intra- and inter-day. The extract recovery and matrix effect were acceptable for the requirements of biological sample analysis. Moreover, the developed method was effectively applied to the pharmacokinetic investigation of Qinxing Qingre Zhike Granule after oral administration in rats.
10.1002/bmc.4524
2'-Hydroxychalcone Induced Cytotoxicity Oxidative Stress in the Lipid-Loaded Hepg2 Cells.
Qian Yun,Yang Yang,Wang Kai,Zhou Wenjun,Dang Yanqi,Zhu Mingzhe,Li Fenghua,Ji Guang
Frontiers in pharmacology
Licorice is a common herb used in traditional Chinese medicine, and has been widely used clinically. Physiologically, although it is relatively safe, licorice-induced hepatotoxicity in the presence of other diseases needs to be evaluated. The present study was conducted to investigate the toxicological effects of the bioactive components of licorice in HepG2 cells cultured with or without free fatty acid (FFA). The compounds, isoliquiritigenin, licorice chalcone A, bavachalcone, and 2'-hydroxy chalcone (2'-HC) inhibited cell proliferation at certain concentrations in lipid loaded cells with limited effects on the normal cells. The representative compound 2'-HC (at a concentration of ≥ 20µM) increased the oxygen consumption rate, ATP production, mitochondrial membrane potential, generation of total and mitochondrial reactive oxygen species (ROS) production, and expression of inflammatory cytokines (TNF-α, IL-6, and IL-8) and Caspase-9 protein; and reduced the expression of SOD1. In addition, we found exaggerated lipid accumulation in HepG2 cells treated with FFA. Our results suggest that 2'-HC at a concentration of ≥ 20µM might cause damage to the hepatocytes. The toxicity may be related to excess ROS production and inadequate SOD1 expression, leading to apoptosis, inflammation, and cellular dysfunctions.
10.3389/fphar.2019.01390
Licorice flavonoids inhibit eotaxin-1 secretion by human fetal lung fibroblasts in vitro.
Jayaprakasam Bolleddula,Doddaga Srinivasulu,Wang Rong,Holmes Daniel,Goldfarb Joseph,Li Xiu-Min
Journal of agricultural and food chemistry
Glycyrrhiza uralensis (Gan-Cao), commonly called "licorice", is one of the most commonly used herbs in traditional Chinese medicine (TCM). In the United States, licorice products are most often consumed as flavoring and sweetening agents in food products. The licorice triterpenoid glycyrrhizin has several biological activities, including anti-inflammatory activity. Other potential anti-inflammatory constituents in G. uralensis have not been fully investigated. Airway eosinophilic inflammation is a major feature of allergic asthma. Eotaxin-1 (eotaxin) is involved in the recruitment of eosinophils to sites of antigen-induced inflammation in asthmatic airways. Because human lung fibroblasts are the major source of eotaxin, inhibition of eosinophil recruitment by suppression of fibroblast eotaxin production is a potentially valuable approach for the pharmacological intervention in asthma. A systematic bioassay-guided purification of G. uralensis yielded five flavonoids: liquiritin, liquiritigenin, isoliquiritigenin, 7,4'-dihydroxyflavone, and isoononin. The structures of the compounds were established by (1)H and (13)C nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) studies. The potential ability of these isolated pure compounds and glycyrrhizin to inhibit secretion of eotaxin-1 by human fetal lung fibroblasts (HFL-1) was tested. Liquiritigenin, isoliquiritigenin, and 7,4'-dihydroxyflavone were more effective than liquiritin, isoononin, and glycyrrhizin in suppressing eotaxin secretion. A concentration-response study showed the IC(50) concentrations of liquiritigenin, isoliquiritigenin, and 7,4'-dihydroxyflavone were 4.2, 0.92, and 0.21 microg/mL, respectively, demonstrating that Glycyrrhiza flavonoids inhibit eotaxin-1 secretion in vitro.
10.1021/jf802601j
Two flavonoids extracts from Glycyrrhizae radix inhibit in vitro hepatitis C virus replication.
Sekine-Osajima Yuko,Sakamoto Naoya,Nakagawa Mina,Itsui Yasuhiro,Tasaka Megumi,Nishimura-Sakurai Yuki,Chen Cheng-Hsin,Suda Goki,Mishima Kako,Onuki Yuko,Yamamoto Machi,Maekawa Shinya,Enomoto Nobuyuki,Kanai Takanori,Tsuchiya Kiichiro,Watanabe Mamoru
Hepatology research : the official journal of the Japan Society of Hepatology
AIM:Traditional herbal medicines have been used for several thousand years in China and other Asian countries. In this study we screened herbal drugs and their purified compounds, using the Feo replicon system, to determine their effects on in vitro HCV replication. METHODS:We screened herbal drugs and their purified extracts for the activities to suppress hepatitis C virus (HCV) replication using an HCV replicon system that expressed chimeric firefly luciferase reporter and neomycin phosphotransferase (Feo) genes. We tested extracts and 13 purified compounds from the following herbs: Glycyrrhizae radix; Rehmanniae radix; Paeoniae radix; Artemisiae capillari spica; and Rhei rhizoma. RESULTS:The HCV replication was significantly and dose-dependently suppressed by two purified compounds, isoliquiritigenin and glycycoumarin, which were from Glycyrrhizae radix. Dose-effect analyses showed that 50% effective concentrations were 6.2 +/- 1.0 microg/mL and 15.5 +/- 0.8 microg/mL for isoliquiritigenin and glycycoumarin, respectively. The MTS assay did not show any effect on cell growth and viability at these effective concentrations, indicating that the effects of the two compounds were specific to HCV replication. These two compounds did not affect the HCV IRES-dependent translation nor did they show synergistic action with interferon-alpha. CONCLUSION:Two purified herbal extracts, isoliquiritigenin and glycycoumarin, specifically suppressed in vitro HCV replication. Further elucidation of their mechanisms of action and evaluation of in vivo effects and safety might constitute a new anti-HCV therapeutics.
10.1111/j.1872-034X.2008.00398.x
Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell.
Auyeung Kathy Ka-Wai,Ko Joshua Ka-Shun
Investigational new drugs
Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses antitumorigenic property. We attempted to compare the anticarcinogenic mechanism of formononetin with that of the known proapoptotic flavonoid isoliquiritigenin (ISL) in human cancer cells. We first evaluated the effects of formononetin and ISL on HCT 116 colon cancer cell viability. Immunofluorescence staining was then performed to observe the morphological changes of cancer cells undergoing apoptosis, which had been substantiated using Annexin V-FITC/propidium iodide staining. Western immunoblotting and flow cytometry were also employed to study parameters associated with apoptosis and cell proliferation. Our data show that formononetin and ISL both inhibited the growth of colon cancer cells and promoted apoptosis. These processes were accompanied by caspase activation and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-x(L). Besides, the novel proapoptotic protein NSAID-activated gene (NAG-1) and its upstream regulator were overexpressed in drug-treated cells. Nevertheless, only ISL was found to induce a G2 arrest. These findings exemplify that both formononetin and ISL could cause growth inhibition and facilitate apoptosis in colon cancer cells, while only ISL is capable of inducing phase-specific cell cycle arrest. This suggests that the anticarcinogenic activities of different herbal flavonoids may involve both common and differential mechanisms of action, which could be developed as potential anticancer drugs.
10.1007/s10637-008-9207-3
Neuroprotective and anti-inflammatory effects of flavonoids isolated from Rhus verniciflua in neuronal HT22 and microglial BV2 cell lines.
Cho Namki,Choi Ji Hoon,Yang Heejung,Jeong Eun Ju,Lee Ki Yong,Kim Young Choong,Sung Sang Hyun
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
The neuroprotective and anti-inflammatory activities of the methanolic extract of Rhus verniciflua Stokes (Anacardiaceae) were investigated with mouse hippocampal and microglial cells. Bioactivity-guided isolation yielded 10 flavonoids including fustin (1), fisetin (2), sulfuretin (3), butein (4), butin (5), eriodictyol (6), morin hydrate (7), quercetin (8), kaempferol (9) and isoliquiritigenin (10). Among the isolated flavonoids, compounds 2-5 significantly protected the murine hippocampal HT22 cells against glutamate-induced neurotoxicity and attenuated reactive oxygen species (ROS) generations. In addition, these flavonoids significantly maintained antioxidative defense systems preserving the activities of superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GSH-Px) and the content of glutathione (GSH) decreased by glutamate insult. These compounds also showed significant inhibitory effects on LPS-induced nitric oxide (NO) production in BV2 cells. Especially, compound 4 dose-dependently suppressed the expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These results suggest that these flavonoids possess therapeutic potentials as a multipotent agent against neurodegenerative diseases related to oxidative stress and pathological inflammatory responses.
10.1016/j.fct.2012.03.052
Analytical strategy to reveal the in vivo process of multi-component herbal medicine: a pharmacokinetic study of licorice using liquid chromatography coupled with triple quadrupole mass spectrometry.
Qiao Xue,Ye Min,Xiang Cheng,Wang Qing,Liu Chun-Fang,Miao Wen-Juan,Guo De-An
Journal of chromatography. A
Although various techniques have been employed to analyze drug metabolites, the metabolism of multi-component herbal medicine has seldom been fully addressed. In contrast to chemical drugs, a number of compounds in herbal medicine could get into circulation and then be metabolized. Moreover, these compounds may have metabolic interactions which make their pharmacokinetics (PK) even more complicated. The present work aims to elucidate the multi-component pharmacokinetics of a herbal medicine, and to demonstrate how PK behaviors were altered by co-existing constituents. Licorice (Glycyrrhiza uralensis Fisch.), a most commonly used herbal medicine, was chosen as a model. A strategy was proposed to compare the PK profiles of licorice extract with those of nine single compounds. These compounds were major bioactive constituents of licorice, and represented various structural types (flavanone, chalcone, isoflavone, saponin, and coumarin). We established a segmented selected reaction monitoring LC/MS/MS method to simultaneously monitor 63 licorice metabolites in rat plasma, and obtained the PK profiles of 55 metabolites. The results indicated that interactions among licorice compounds altered their PK behaviors in 4 aspects: improvement in bioavailability for aglycones (133- and 109-fold increase for liquiritigenin and isoliquiritigenin, respectively), prolongation in system circulation for glycosides (0.3h delay in T(max) for liquiritin apioside and isoliquiritin apioside), decrease of potential toxicity for saponins such as glycyrrhizic acid, and shift in plasma distribution for phase II metabolites. This is the first attempt to systematically reveal the in vivo process of licorice. Moreover, the study indicates noticeable interactions to alter pharmacokinetics among licorice compounds, which may be characteristic for herbal medicines.
10.1016/j.chroma.2012.08.041
Natural chalcones as dual inhibitors of HDACs and NF-κB.
Orlikova B,Schnekenburger M,Zloh M,Golais F,Diederich M,Tasdemir D
Oncology reports
Histone deacetylase enzymes (HDACs) are emerging as a promising biological target for cancer and inflammation. Using a fluorescence assay, we tested the in vitro HDAC inhibitory activity of twenty-one natural chalcones, a widespread group of natural products with well-known anti-inflammatory and antitumor effects. Since HDACs regulate the expression of the transcription factor NF-κB, we also evaluated the inhibitory potential of the compounds on NF-κB activation. Only four chalcones, isoliquiritigenin (no. 10), butein (no. 12), homobutein (no. 15) and the glycoside marein (no. 21) showed HDAC inhibitory activity with IC50 values of 60-190 µM, whereas a number of compounds inhibited TNFα-induced NF-κB activation with IC50 values in the range of 8-41 µM. Interestingly, three chalcones (nos. 10, 12 and 15) inhibited both TNFα-induced NF-κB activity and total HDAC activity of classes I, II and IV. Molecular modeling and docking studies were performed to shed light into dual activity and to draw structure-activity relationships among chalcones (nos. 1-21). To the best of our knowledge this is the first study that provides evidence for HDACs as potential drug targets for natural chalcones. The dual inhibitory potential of the selected chalcones on NF-κB and HDACs was investigated for the first time. This study demonstrates that chalcones can serve as lead compounds in the development of dual inhibitors against both targets in the treatment of inflammation and cancer.
10.3892/or.2012.1870
Polyphenols inhibit indoleamine 3,5-dioxygenase-1 enzymatic activity--a role of immunomodulation in chemoprevention.
Chen Sophie S,Corteling Randolph,Stevanato Lara,Sinden John
Discovery medicine
Metastasis is one of the cancer hallmarks described by Hanahan and Weinberg. Emerging evidence shows that it requires interplays between cancer cells and micro-environmental biofactors. Indoleamine 3,5-dioxygenase-1 (IDO-1) produced by cancer, local lymph nodes, and satellite cells have been demonstrated as one of the biofactors. Aberrant IDO-1 activity has partially contributed to immunosuppressive environment by repressing T lymphocyte and natural killer cell activities, and activating regulatory T cells (Treg, CD4+CD25+). Clinical investigations further show a negative correlation between the enzyme activity and prognosis in patients with various cancer types. The findings suggest a possible role of IDO-1 inhibitor in restoring host anti-tumor immunity and attenuating cancer metastasis. Data from preclinical and phase I/II clinical studies with IDO-1 inhibitors support this hypothesis. Polyphenols as antioxidants are shown to exhibit anticancer activities. However, the underlying mechanism has not been entirely characterized. We recently found that certain flavone molecules profoundly inhibit the enzymatic activity of IDO-1 but not mRNA expression in human neuronal stem cells (hNSC) confirmed by cell-based assay and qRT-PCR. To further the investigation, we studied additional anti-cancer phytochemicals including chalcone, flavonol, isoflavone, and diterpene. Here we summarize the results and show that the inhibitory sensitivity depends on the molecular structure in the following order: apigenin > wogonin > chrysin > biacalein ~ genistein > quercetin. Curcumin and isoliquiritigenin (a chalcone) exhibited toxicity to hNSCs. Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines. The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active. These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy.
[Synthesis and monoamine oxidase B inhibitory activities of isoquiritigenin derivatives].
Kong Zhuo,Sun De-Meng,Chen Ai-Qian,Hu Yun
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Isoquiritigenin,one of the active constituents in the Chinese herb liquorice,is found to have moderate inhibitory activity against rat monoamine oxidase B(MAO-B,IC5047. 2 μmol·L-1). However,the structure-activity relationship(SAR) remains unclear until now. In an attempt to reveal the SAR of inhibition by isoquiritigenin,and to identify more potent and selective inhibitors of MAOB,a series of 13 derivatives based on the scaffold of isoquiritigenin were prepared,and their purities and structures were confirmed by UPLC,1 H-NMR,13 C-NMR and HRMS. These compounds were then evaluated for their ability to inhibit the enzymatic activity of human MAO-B. The SAR of inhibition was summarized and a potent compound C8 with high inhibitory activity(IC501. 4 μmol·L-1) and selectivity(>57 folds over MAO-A) was identified. Enzyme kinetics studies suggested that C8 acted as a competitive inhibitor. In addition,C8 showed little cytotoxicity to glial cells in vitro,which could be a promising lead compound for further study.
10.19540/j.cnki.cjcmm.20190807.201
Diversity of -Glycosyltransferases Contributes to the Biosynthesis of Flavonoid and Triterpenoid Glycosides in .
Chen Kuan,Hu Zhi-Min,Song Wei,Wang Zi-Long,He Jun-Bin,Shi Xiao-Meng,Cui Qing-Hua,Qiao Xue,Ye Min
ACS synthetic biology
Licorice () is a popular medicinal plant containing more than 70 flavonoid and triterpenoid glycosides. Thus far, only a few reports are available on the glycosylation enzymes involved in their biosynthesis. In this work, we mined the transcriptome data of and discovered 43 candidate genes for -glycosyltransferase (-GT). Among them, 17 genes could be expressed in , and functions of the enzymes were analyzed by catalyzing eight native substrates. As a result, we characterized 11 -GTs, including isoflavone 7--GTs, flavonol 3--GTs, and promiscuous -GTs catalyzing flavones, chalcones, and triterpenoids. They could efficiently synthesize key licorice compounds such as liquiritin, isoliquiritin, ononin, and 3--β-d-glucuronosyl glycyrrhetinic acid. The diversity of -GTs contributes to the biosynthesis of various glycosides in licorice. These enzymes could also be used as biocatalytic tools to synthesize other bioactive -glycosides.
10.1021/acssynbio.9b00171
Pharmacokinetic comparisons of two different combinations of Shaoyao-Gancao Decoction in rats: competing mechanisms between paeoniflorin and glycyrrhetinic acid.
Xu Chang-Hua,Wang Ping,Wang Yang,Yang Yan,Li Dong-Hua,Li Hui-Fen,Sun Su-Qin,Wu Xian-Zhong
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Shaoyao-Gancao Decoction (SGD), a well-known traditional Chinese medicine prescription, is a combination of Radix Paeoniae Alba (Paeonia lactiflora Pall, root) and Glycyrrhizae uralensis (Glycyrrhiza uralensis Fisch., root and rhizome, honeyed) for spasmolysis and emergency pain relief. Paeoniflorin (PF) and glycyrrhetinic acid (GA) are two typical active components of SGD for pain relief. AIM OF THE STUDY:To study comparative pharmacokinetics of ten bioactive compounds in SGDs with two different combinations of RP and GU, and therefore to investigate the herb-herb interaction mechanisms of Shaoyao-Gancao Decoction for better spasmolysis and emergency pain relief in rats. MATERIALS AND METHODS:Herbal IR macro-fingerprinting was implemented to provide the full chemical fingerprints of RP, GU and SGD decoctions and to investigate the variation rule of the full chemical profile of SGDs with various combinations of RP and GU. A specifically developed HPLC-MS/MS assay coupled with protein precipitation method was employed to determine the plasma concentrations of the ten analytes. Male Wistar rats were orally administered with SGD1 (RP:GU, 1:1 (w/w)) and SGD2 ((RP:GU, 4:1 (w/w)) equivalent to 9.5 g/kg body weight of GU. RESULTS:Full chemical fingerprints of RP, GU and SGDs with various combinations of RP and GU were provided in the form of IR macro-fingerprints. Except for liquiritin, there were statistically significant differences (p<0.05 or p<0.01) of these analytes between SGD1 and SGD2 in in vivo pharmacokinetic study. Compared with the results when oral administrated with SGD1, six glycosides (PF, albiflorin, oxypaeoniflorin, isoliquiritin, ononin, and glycyrrhizin) exhibited higher systematic exposure levels (AUC0-t) and slower elimination rates (CL) whereas two glycones (GA and isoliquiritigenin) were the reverse when administrated with SGD2. CONCLUSIONS:Increasing the amount of RP attenuated the inhibitory effect of GA via competing being consumed by intestinal bacteria (or β-glucosidase) to reduce the conversion amount of glycyrrhizin to GA and subsequently to afford significantly higher bioavailability and longer efficacy of PF, glycyrrhizin, albiflorin, oxypaeoniflorin, isoliquiritin, and ononin, leading to better spasmolysis and emergency pain relief.
10.1016/j.jep.2013.06.049
Pharmacokinetic comparisons of different combinations of Shaoyao-Gancao-Decoction in rats: simultaneous determination of ten active constituents by HPLC-MS/MS.
Wang Yang,Xu Changhua,Wang Ping,Lin Xiaoyan,Yang Yan,Li Donghua,Li Huifen,Wu Xianzhong,Liu Hongbin
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
A specific HPLC-MS/MS method was developed and validated for simultaneous determination of ten constituents including albiflorin, oxypaeoniflorin, paeoniflorin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, ononin, glycyrrhizin and glycyrrhetinic acid in rat plasma using genistein as an internal standard (IS). The rat plasma samples were prepared by a one-step direct protein precipitation procedure with methanol. HPLC separation was achieved on a Zorbax XDB-C18 column (2.1mm×50mm i.d., 3.5μm) with gradient elution (A: 0.1% aqueous formic acid; B: methanol with 0.1% formic acid) at a flow rate of 0.5mL/min in a run time of 7min. All analytes and IS were detected by multiple reaction monitoring scanning with electrospray ionization in the negative ion mode. Calibration curves showed good linearity (r>0.998) over a wide concentration range for all analytes. The intra- and inter-day precisions were all within 15% and the accuracies were in the range of -6.2% to 10.1%. The validated method was successfully applied to determination and comparative pharmacokinetics investigation of the ten constituents in rat plasma after oral administration of different combinations (Radix Paeoniae Alba:Glycyrrhiza uralensis=1:1 or 4:1) of Shaoyao-Gancao-Decoction (SGD) extracts. Pharmacokinetic parameters were evaluated by a compartment model. There were perceptible differences in pharmacokinetic parameters (Cmax, AUC0-t, CL) of the analytes except for liquiritin between the two groups of SGD.
10.1016/j.jchromb.2013.06.021
Employing bifunctional enzymes for enhanced extraction of bioactives from plants: flavonoids as an example.
Xu Ming-Shu,Chen Shuo,Wang Wen-Quan,Liu Si-Qin
Journal of agricultural and food chemistry
A cost-effective and environmentally friendly approach was developed to improve the extraction of active ingredients from plants, in which a bifunctional enzyme was employed for not only facilitating cell wall degradation but also increasing the bioactivity of target compounds in the extract. In the aqueous extraction of flavonoids from Glycyrrhizae radix, Trichoderma viride cellulase, a commercial cell-wall-degrading enzyme, was found to efficiently deglycosylate liquiritin and isoliquiritin, which are of high content but low bioactivity, into their aglycones that have much higher physiological activities for dietary and medicinal uses. Under optimized conditions, the extraction yield of liquiritigenin and isoliquiritigenin aglycones reached 4.23 and 0.39 mg/g of dry weight (dw) with 6.51- and 3.55-fold increases, respectively. The same approach was expanded to the extraction of flavonoids from Scutellariae radix using Penicillium decumbens naringinase, where enhanced production of more bioactive bacalein and wogonin was achieved via enzymatic deglycosylation of bacalin and wogonoside.
10.1021/jf402125y
Evaluation of cytotoxiciy and tumor-specificity of licorice flavonoids based on chemical structure.
Ohno Hirokazu,Araho Daisuke,Uesawa Yoshihiro,Kagaya Hajime,Ishihara Mariko,Sakagami Hiroshi,Yamamoto Masaji
Anticancer research
BACKGROUND:The mechanism of cytotoxicity induction by flavonoids has been studied by many investigators, but their tumor specificity is not clear. To address this point, 10 licorice flavonoids were subjected to quantitative structure-activity relationship (QASR) analysis with cytotoxicity assay with four human oral carcinoma and three normal cell lines. MATERIALS AND METHODS:Cytotoxicity was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method. Physico-chemical, structural, and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method. RESULTS:Licurazid and isoliquiritigenin had the highest cytotoxicity against tumor cells, and liquiritin, isoliquiritin and licurazid had the highest tumor specificity, suggesting an antitumor potential for licurazid. Chalcones had slightly higher cytotoxicity and tumor specificity than flavanones. The number of sugar units in the molecule was somewhat negatively-correlated with cytotoxicity, but not with tumor specificity. Parameters that reflect the three-dimensional structure, molecular volume and number of phenolic OH groups were significantly correlated with cytotoxicity, but not with tumor specificity. On the other hand, solvation energy was significantly correlated with tumor specificity, but not with cytotoxicity. CONCLUSION:These physicochemical descriptors may be useful to estimate cytotoxicity or tumor specificity of structurally-related compounds to these licorice flavonoids.
Effects of ILTG on DAPK1 promoter methylation in colon and leukemia cancer cell lines.
Zorko Bryan A,Pérez Lynette Bueno,De Blanco Esperanza J Carcache
Anticancer research
AIMS:The aim of this study was to describe quantitatively the potential demethylating effects of the plant-derived compound isoliquritigenin (ILTG) on the death-associated protein kinase-1 (DAPK1) promoter region of colon cancer and leukemia cell lines. METHODS:Methylation-specific real-time polymerase chain reaction-melting curve analysis (MSP-MCA) was the primary method used. A simple cytotoxicity assay and an ethidium bromide displacement assay were used to evaluate the chemopreventive indices and account for any problems in fluorometric assessment caused by intercalating potential of the compound of interest. RESULTS:ILTG was able to affect the melting curve significantly when using MSP-MCA. ILTG exhibited a demethylating activity on HT-29 colon cancer and HL-60 leukemia cells. CONCLUSION:ILTG found in licorice (Glycyrrhiza glabra) may have the potential for being a cancer chemopreventive agent. From the specific assays performed in this experiment, ILTG appears to possess potential for development as a demethylating agent for either colon cancer or leukemia cancer prevention.
Potential detoxification effect of active ingredients in liquorice by upregulating efflux transporter.
He Yufei,Ci Xiaoyan,Xie Ying,Yi Xiulin,Zeng Yong,Li Yazhuo,Liu Changxiao
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:As one of most widely used herbal medicine, liquorice exhibits diverse pharmacological activities, for instance, analgesic, antitussive, antiarrhythmic, anti-inflammatory, and immune regulation. Additionally, detoxification effects were observed in combination of liquorice with other herbal drugs. The mechanism of detoxification of liquorice has been extensively investigated through material basis and interference with CYPs though, investigations of its effect on transporters were very limited, according to the literature. PURPOSE:The objective of this study was attempt to investigate the effect of active ingredients existing in liquorice on the efflux transporters as to clarify the potential mechanism of detoxification of liquorice. METHODS:Multiple analytical approaches have been explored, including flow cytometry, fluorescent detection, RT-PCR, Western blot to measure the function, activity as well as mRNA/protein expression of efflux transporters on LS-180 cell model after treatments with active compounds of liquorice. Additionally, Caco-2 cell model was utilized to further investigate the potential impact of those ingredients on efflux transporter. RESULTS:The resulting data indicated that those active ingredients, including flavonoids (liquiritin, liquiritigenin, isoliquiritin, isoliquiritigenin and licochalcone A) and pentacyclic triterpene saponin (glycyrrhetinic acid) were able to upregulate the expression of efflux transporters, for example P-gp, BCRP and MRP2. The gene expressions were approximately over 2.5 folds by comparison with that of control, and up to 13 folds and 16 folds for BCRP by isoliquiritin and isoliquiritigenin, and further confirmed by Western blot. The functional assay also supported up-regulation of efflux transporter by those ingredients. Flow cytometry study showed that the level of rhodamine123 as probe substrate in LS-180 cells decreased to approximately 50% after treatment with active ingredients of liquorice, compared with that of control. The fluorescent assay confirmed that change of rhodamine 123 was correlated with the concentrations of active ingredients given. The efflux transport of rhodamine 123 was enhanced in Caco-2 cell models as well. CONCLUSION:The study clarified potential detoxification mechanism of liquorice by up-regulating efflux transporter as to reduce absorption of xenobiotics across small intestinal membrane, which provided a new insight into pharmacological function of liquorice.
10.1016/j.phymed.2018.10.033
Structure-based identification of novel CK2 inhibitors with a linear 2-propenone scaffold as anti-cancer agents.
Qi Xiaoqian,Zhang Na,Zhao Lijiao,Hu Liming,Cortopassi Wilian A,Jacobson Matthew P,Li Xitao,Zhong Rugang
Biochemical and biophysical research communications
Protein kinase CK2 has emerged as an attractive cancer therapeutic target. Previous studies have highlighted the challenge of optimizing CK2 ATP-competitive inhibitors that have low druggability due to their polycyclic ring scaffolds. Therefore the development of novel inhibitors with non-polycyclic scaffolds emerges as a promising strategy for drug discovery targeting CK2. In this current study, based on the similar predicted binding poses of the linear 2-propenone scaffold of isoliquiritigenin with that of the polycyclic inhibitor CX-4945, a series of 2-propenone derivatives containing an amine-substituted five-membered heterocycle and a benzoic acid were designed, synthesized and evaluated for their in vitro CK2 inhibition and anti-cancer activity. Compound 8b was found to be the most potent CK2 inhibitor (IC = 0.6 μM) with the anti-proliferative activity on HepG2 cancer cells (IC = 14 μM), compared to the activity of isoliquiritigenin (IC = 17 μM and 51 μM, respectively). Molecular docking was performed to understand the binding modes of the newly designed 2-propenone derivatives with CK2. Compound 8b formed the most favorable network of hydrogen bonds with both the hinge region and positive area. Our results indicate that CK2 derivatives with a linear 2-propenone scaffold are promising candidates for anti-cancer drug discovery.
10.1016/j.bbrc.2019.03.016
Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents.
Yang Min Hye,Kim Jinwoong,Khan Ikhlas A,Walker Larry A,Khan Shabana I
Life sciences
Natural products are rich sources of gene modulators that may be useful in prevention and treatment of cancer. Recently, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a target of action against diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural agents have been reported to play a pivotal role in regulation of NAG-1 through multiple transcriptional mechanisms. The aim of this paper is to review the NAG-1 modulators derived from natural products including plants, marine organisms, and microorganisms. Plant extracts belonging to the families of Fabaceae (Astragalus membranaceus), Ranunculaceae (Coptis chinensis), Menispermaceae (Coscinium fenestratum), Umbelliferae (Pleurospermum kamtschaticum), Lamiaceae (Marubium vulgare), and Rosaceae (Prunus serotina) increased the protein expression of NAG-1 in human colon cancer or hepatocarcinoma cells. Phytochemicals in the class of flavonoids (apigenin, quercetin, isoliquiritigenin, and 2'-hydroxyflavanone), isoflavonoids (formononetin and genistein), catechins (epigallocatechin gallate and epicatechin gallate), stilbenoids (resveratrol and pinosylvin), phenolics (6-gingerol), phloroglucinols (rottlerin and aspidin PB), terpenoids (18 α-glycyrrhetinic acid, platycodin D, pseudolaric acid B, and xanthorrhizol), alkaloids (berberine, capsaicin, and indole-3-carbinol), lignans (isochaihulactone), anthraquinones (damnacanthal), and allyl sulfides (diallyl disulfide) elicited NAG-1 overexpression in various cancer cells. Pectenotoxin-2 from marine organisms and prodigiosin and anisomycin from microorganisms were also reported as NAG-1 modulators. Several transcription factors including EGR-1, p53, ATF-3, Sp1 and PPARγ were involved in natural products-induced NAG-1 transcriptional signaling pathway.
10.1016/j.lfs.2014.01.075
Effect of genotype and environment on five bioactive components of cultivated licorice (Glycyrrhiza uralensis F) populations in northern China.
Biological & pharmaceutical bulletin
Methods to improve the bioactive component content of cultivated licorice have become the bottleneck of industrial licorice extraction for pharmaceutical use. To evaluate the effects of genotype, environment and their interaction on major bioactive components, we analyzed the five bioactive components: liquiritin (LQ), liquiritigenin (LQG), glycyrrhizin (GL), isoliquiritin (ILQ) and isoliquiritigenin (ILQG) of four diverse licorice varieties grown in four distinct environments in northern China during 2010-11. Analysis of variance showed that environmental and genotypic effects were significant (P<0.01) for all five bioactive components. Additionally, their interaction was significant (P<0.05) for GL in the 2-year study period. LQ and ILQ were mainly affected by genetic factors and have great potential for genetic improvement, whereas LQG and ILQG were mainly affected by environmental factors. GL was similarly affected by environmental and genetic factors. Biplot of the principal component analysis showed that for quality breeding, G2 (WNT-1) and G3 (JX-1) are two relatively preferable genotypes, and E2 (Chifeng) location is suitable for accumulation of the bioactive components of these two genotypes. Stepwise regression analysis showed that sunshine and rainfall are the dominant environmental factors for licorice bioactive component accumulation; increased duration of sunshine is advantageous to GL accumulation whereas declining rainfall is conducive to LQG and ILQG accumulation. These results provide a theoretical basis for initiating licorice breeding programs with increased bioactive components and improved quality.
Antiobesity and lipid lowering effects of Glycyrrhiza chalcones: experimental and computational studies.
Birari Rahul B,Gupta Shikhar,Mohan C Gopi,Bhutani Kamlesh K
Phytomedicine : international journal of phytotherapy and phytopharmacology
Twelve flavonoids (1-12), isolated from Glycyrrhiza glabra roots were evaluated for their pancreatic lipase (PL) inhibitory activity in vitro. The structures of the isolated compounds were elucidated by spectroscopic methods. Amongst all the compounds 7, 8, 10 and 11 showed strong inhibition against PL with IC(50) values of 7.3 μM, 35.5 μM, 14.9 μM and 37.6 μM, respectively. Molecular docking studies on the most active compound 7 revealed that it binds with the key amino acid residues of the PL active site. In silico absorption, distribution, metabolism and excretion (ADME) parameters were also computed on the active compounds to determine their preliminary pharmacokinetic properties. Further, investigations were carried out to determine the antiobesity and lipid lowering effects of 7 and 10 in high fat diet (HFD) fed male SD rats. In the rats supplemented with compound 7 the body weight increase was only 23.2±3.6 g as compared to 64.2±0.5 g in the HFD control group while in the rats treated with compound 10 showed 23.2±3.6 g weight gain only. Compound 7 decreased the levels of plasma total cholesterol (TC) to 84.6±1.4 mg/dl and plasma total triglycerides (TG) to 128.8±6.0 mg/dl. Compound 10 also lowered the plasma TC and TG levels considerably. The results indicate the potential of the chalcone scaffold as a source of PL inhibitors for preventing obesity.
10.1016/j.phymed.2011.01.002
Chalcones as Promising Lead Compounds on Cancer Therapy.
Current medicinal chemistry
Chalcones constitute a group of phenolic compounds that command an increasing interest on cancer research. Natural chalcones are widespread through the plant kingdom. The most abundant and investigated chalcones are isoliquiritigenin, flavokawain and xanthohumol, which are present in the Fabaceae, Piperaceae, Cannabaceae, and Moraceae families. These chalcones have been shown to be promising lead antitumor-chemopreventive drugs by three different activities: antioxidants, cytotoxic and apoptosis inducers. In the recent years, SAR (structure-activity relationship) has contributed towards the improvement of anticancer properties of chalcones by substituting aryl rings and introducing heterocyclic moieties. This review summarizes the anticancer activities shown by natural chalcones and the SAR and describes how different chemical moiety modifications could lead them to be therapeutically useful in the treatment of cancer.
10.2174/0929867322666150729114829
Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols.
Gupta Subash C,Tyagi Amit K,Deshmukh-Taskar Priya,Hinojosa Myriam,Prasad Sahdeo,Aggarwal Bharat B
Archives of biochemistry and biophysics
Human tumor necrosis factor (TNF), first isolated by our group as an anticancer agent, has been now shown to be a primary mediator of inflammation. Till today 19 different members of the TNF superfamily which interact with 29 different receptors, have been identified. Most members of this family exhibit pro-inflammatory activities, in part through the activation of the transcription factor, nuclear factor-kappaB (NF-κB). Thus TNF and the related pro-inflammatory cytokines have been shown to play a key role in most chronic diseases such as cancer, rheumatoid arthritis, cardiovascular diseases, psoriasis, neurologic diseases, Crohn's disease, and metabolic diseases. Therefore, agents that can modulate the TNF-mediated inflammatory pathways may have potential against these pro-inflammatory diseases. Although blockers of TNF-α, such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved for human use, these blockers exhibit numerous side effects. In this review, we describe various plant-derived polyphenols that can suppress TNF-α activated inflammatory pathways both in vitro and in vivo. These polyphenols include curcumin, resveratrol, genistein, epigallocatechin gallate, flavopiridol, silymarin, emodin, morin isoliquiritigenin, naringenin, ellagic acid, apigenin, kaempferol, catechins, myricetin, xanthohumol, fisetin, vitexin, escin, mangostin and others. Thus these polyphenols are likely to have potential against various pro-inflammatory diseases.
10.1016/j.abb.2014.06.006
Preliminary identification of the absorbed bioactive components and metabolites in rat plasma after oral administration of Shaoyao-Gancao decoction by ultra-performance liquid chromatography with electrospray ionization tandem mass spectrometry.
Wang Ping,Yin Quan-Wei,Zhang Ai-Hua,Sun Hui,Wu Xiu-Hong,Wang Xi-Jun
Pharmacognosy magazine
BACKGROUND:Shaoyao-Gancao decoction (SGD), a traditional Chinese medicine formula, has been used for the treatment of abdominal pain and dysmenorrhea disease in Asia over long period of time. Its effectiveness has been confirmed in clinic, but its active constituents remain unclear. MATERIALS AND METHODS:In this paper, a rapid, sensitive and reliable ultra-performance liquid chromatography-electrospray ionization/quadrupole-time-of-flight high-definition mass spectrometry (UPLC-ESI-Q-TOF-MS) in positive and negative ion mode were established to characterize the active constituents of SGD in vitro. The analysis was performed on a Waters UPLCTM HSS T3 (2.1 × 100 mm, 1.8 µm) using gradient elution system. Automated MetaboLynxTM technique was employed to screen for the potentially bioactive components in rat plasma after oral administration of SGD. MS/MS fragmentation behavior was proposed for aiding the structural identification of the components. RESULTS:Based on the developed method of fingerprint analysis, an injection run of the plasma sample was finished in 15.0 min. A total of 12 compounds including 9 prototype components such as gallicacid, albiflorin, liquiritin, pallidiflorin, liquiritigenin, isoLiquiritigenin, formononetin, isolicoflavonol, licoricone, C9H10O3 and 2 metabolites such as liquiritigenin-4'-O-glucuronide, formononetin glucuronide were identified or tentatively characterized. Of note, 3 ingredients were identified from Radix Paeoniae Alba, and 9 were from Radix Glycyrrhizae. CONCLUSION:The compounds found in dosed plasma could be the effective substances of SGT for treating dysmenorrheal, and may provide important experimental data for further pharmacological and clinical research of SGD. Furthermore, this work has demonstrated that the feasibility of the UPLC-ESI-Q-TOF-MS for rapid and reliable characterization of identification and structural elucidation of the chemical constituents and their metabolites from herbal medicines.
10.4103/0973-1296.141774
Monitoring and evaluating the quality consistency of Compound Bismuth Aluminate tablets by a simple quantified ratio fingerprint method combined with simultaneous determination of five compounds and correlated with antioxidant activities.
Liu Yingchun,Liu Zhongbo,Sun Guoxiang,Wang Yan,Ling Junhong,Gao Jiayue,Huang Jiahao
PloS one
A combination method of multi-wavelength fingerprinting and multi-component quantification by high performance liquid chromatography (HPLC) coupled with diode array detector (DAD) was developed and validated to monitor and evaluate the quality consistency of herbal medicines (HM) in the classical preparation Compound Bismuth Aluminate tablets (CBAT). The validation results demonstrated that our method met the requirements of fingerprint analysis and quantification analysis with suitable linearity, precision, accuracy, limits of detection (LOD) and limits of quantification (LOQ). In the fingerprint assessments, rather than using conventional qualitative "Similarity" as a criterion, the simple quantified ratio fingerprint method (SQRFM) was recommended, which has an important quantified fingerprint advantage over the "Similarity" approach. SQRFM qualitatively and quantitatively offers the scientific criteria for traditional Chinese medicines (TCM)/HM quality pyramid and warning gate in terms of three parameters. In order to combine the comprehensive characterization of multi-wavelength fingerprints, an integrated fingerprint assessment strategy based on information entropy was set up involving a super-information characteristic digitized parameter of fingerprints, which reveals the total entropy value and absolute information amount about the fingerprints and, thus, offers an excellent method for fingerprint integration. The correlation results between quantified fingerprints and quantitative determination of 5 marker compounds, including glycyrrhizic acid (GLY), liquiritin (LQ), isoliquiritigenin (ILG), isoliquiritin (ILQ) and isoliquiritin apioside (ILA), indicated that multi-component quantification could be replaced by quantified fingerprints. The Fenton reaction was employed to determine the antioxidant activities of CBAT samples in vitro, and they were correlated with HPLC fingerprint components using the partial least squares regression (PLSR) method. In summary, the method of multi-wavelength fingerprints combined with antioxidant activities has been proved to be a feasible and scientific procedure for monitoring and evaluating the quality consistency of CBAT.
10.1371/journal.pone.0118223
New phenolic compounds from Coreopsis tinctoria Nutt. and their antioxidant and angiotensin i-converting enzyme inhibitory activities.
Wang Wei,Chen Wei,Yang Yingshi,Liu Tianxing,Yang Haiyan,Xin Zhihong
Journal of agricultural and food chemistry
Three new phenolic compounds, coretinphenol (1), coretincone (2), and coretinphencone (3), were isolated from the buds of Coreopsis tinctoria Nutt., together with nine known compounds, including butein (4), okanin (5), isoliquiritigenin (6), maritimetin (7), taxifolin (8), isookanin (9), marein (10), sachalinoside B (11), and 2-phenylethyl-β-d-glucoside (12). The chemical structures of these compounds were elucidated by extensive spectroscopic analysis and on the basis of their chemical reactivity. This work represents the first recorded example of the isolation of compounds 1–3, 6, 7, 9, 11, and 12 from C. tinctoria. Compounds 5–9 showed strong diphenyl(2,4,6-trinitrophenyl)iminoazanium (DPPH) radical-scavenging activity, with IC50 values of 3.35 ± 0.45, 9.6 ± 2.32, 4.12 ± 0.21, 6.2 ± 0.43, and 7.9 ± 0.53 μM, respectively. Compounds 2 and 8 exhibited angiotensin I-converting enzyme inhibitory activity, with IC50 values of 228 ± 4.47 and 145.67 ± 3.45 μM, respectively. The activities of phenolic compounds isolated from C. tinctoria support the medicinal use of this plant in the prevention of cardiovascular diseases.
10.1021/jf504289g
Antibacterial and Cytotoxic Activity of Compounds Isolated from Flourensia oolepis.
Joray Mariana Belén,Trucco Lucas Daniel,González María Laura,Napal Georgina Natalia Díaz,Palacios Sara María,Bocco José Luis,Carpinella María Cecilia
Evidence-based complementary and alternative medicine : eCAM
The antibacterial and cytotoxic effects of metabolites isolated from an antibacterial extract of Flourensia oolepis were evaluated. Bioguided fractionation led to five flavonoids, identified as 2',4'-dihydroxychalcone (1), isoliquiritigenin (2), pinocembrin (3), 7-hydroxyflavanone (4), and 7,4'-dihydroxy-3'-methoxyflavanone (5). Compound 1 showed the highest antibacterial effect, with minimum inhibitory concentration (MIC) values ranging from 31 to 62 and 62 to 250 μg/mL, against Gram-positive and Gram-negative bacteria, respectively. On further assays, the cytotoxic effect of compounds 1-5 was determined by MTT assay on acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) cell lines including their multidrug resistant (MDR) phenotypes. Compound 1 induced a remarkable cytotoxic activity toward ALL cells (IC50 = 6.6-9.9 μM) and a lower effect against CML cells (IC50 = 27.5-30.0 μM). Flow cytometry was used to analyze cell cycle distribution and cell death by PI-labeled cells and by Annexin V/PI staining, respectively. Upon treatment, 1 induced cell cycle arrest in the G2/M phase accompanied by a strong induction of apoptosis. These results describe for the first time the antibacterial metabolites of F. oolepis extract, with 1 being the most effective. This chalcone also emerges as a selective cytotoxic agent against sensitive and resistant leukemic cells, highlighting its potential as a lead compound.
10.1155/2015/912484
Natural product inhibitors of ocular angiogenesis.
Sulaiman Rania S,Basavarajappa Halesha D,Corson Timothy W
Experimental eye research
Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the importance of angiogenesis to many pathologies, numerous natural products have been explored as potential anti-angiogenic drugs. Ocular angiogenesis underlies blinding eye diseases such as retinopathy of prematurity (ROP) in children, proliferative diabetic retinopathy (DR) in adults of working age, and age-related macular degeneration (AMD) in the elderly. Despite the presence of effective therapy in many cases, these diseases are still a significant health burden. Anti-VEGF biologics are the standard of care, but may cause ocular or systemic side effects after intraocular administration and patients may be refractory. Many anti-angiogenic compounds inhibit tumor growth and metastasis alone or in combination therapy, but a more select subset of them has been tested in the context of ocular neovascular diseases. Here, we review the promise of natural products as anti-angiogenic agents, with a specific focus on retinal and choroidal neovascularization. The multifunctional curcumin and the chalcone isoliquiritigenin have demonstrated promising anti-angiogenic effects in mouse models of DR and choroidal neovascularization (CNV) respectively. The homoisoflavanone cremastranone and the flavonoid deguelin have been shown to inhibit ocular neovascularization in more than one disease model. The isoflavone genistein and the flavone apigenin on the other hand are showing potential in the prevention of retinal and choroidal angiogenesis with long-term administration. Many other products with anti-angiogenic potential in vitro such as the lactone withaferin A, the flavonol quercetin, and the stilbenoid combretastatin A4 are awaiting investigation in different ocular disease-relevant animal models. These natural products may serve as lead compounds for the design of more specific, efficacious, and affordable drugs with minimal side effects.
10.1016/j.exer.2014.10.002
Detection of reactive metabolites using isotope-labeled glutathione trapping and simultaneous neutral loss and precursor ion scanning with ultra-high-pressure liquid chromatography triple quadruple mass spectrometry.
Huang Ke,Huang Lingyi,van Breemen Richard B
Analytical chemistry
Metabolic activation of drugs to electrophilic species is responsible for over 60% of black box warnings and drug withdrawals from the market place in the United States. Reactive metabolite trapping using glutathione (GSH) and analysis using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) or HPLC with high resolution mass spectrometry (mass defect filtering) have enabled screening for metabolic activation to become routine during drug development. However, current MS-based approaches cannot detect all GSH conjugates present in complex mixtures, especially those present in extracts of botanical dietary supplements. To overcome these limitations, a fast triple quadrupole mass spectrometer-based approach was developed that can detect positively and negatively charged GSH conjugates in a single analysis without the need for advanced knowledge of the elemental compositions of potential conjugates and while avoiding false positives. This approach utilized UHPLC instead of HPLC to shorten separation time and enhance sensitivity, incorporated stable-isotope labeled GSH to avoid false positives, and used fast polarity switching electrospray MS/MS to detect GSH conjugates that form positive and/or negative ions. The general new method was then used to test the licorice dietary supplement Glycyrrhiza glabra, which was found to form multiple GSH conjugates upon metabolic activation. Among the GSH conjugates found in the licorice assay were conjugates with isoliquiritigenin and glabridin, which is an irreversible inhibitor of cytochrome P450 enzymes.
10.1021/ac504737x
[Anti-inflammatory mechanism research of flavonoid compounds in Dalbergiae Odoriferae Lignum by module-based network analysis].
Zheng Shi-chao,Ren Zhen-zhen,Zhang Yan-ling,Qiao Yan-jiang
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Dalbergiae Odoriferae Lignum as a traditional Chinese medicine (TCM) has been widely used for promoting blood circulation and removing blood stasis. Flavonoid compounds are main chemical constituents of Dalbergiae Odoriferae Lignum, which exert anti-inflammatory property. However, the underlying anti-inflammatory mechanisms of flavonoid compounds are incompletely understood. It has been reported that isoliquiritigenin, liquiritigenin, naringenin and butein possess anti-inflammatory property. The purpose of this study is to illuminate the anti-inflammatory mechanism of flavonoid compounds based on the protein interaction network (PIN) analysis on molecular network level. 130 targets of the main medicinal ingredients of flavonoid compounds were gained though database retrieval. A protein interaction network of flavonoid compounds was constructed with 589 nodes and 216 interactions. By a graph theoretic clustering algorithm Molecular Complex Detection (MCODE), 26 modules were identified and analyzed by Gene ontology (GO) enrichment. Two modules were associated with anti-inflammatory actions. The most interesting finding of this study was that the anti-inflammatory effect of flavonoid compounds may be partly attributable to inhibite FOS, PTGS2 expression, inhibite of IL-1beta release, and block the MAPK pathway and toll-like receptor pathway.
Transcriptome analysis highlights preformed defences and signalling pathways controlled by the prAe1 quantitative trait locus (QTL), conferring partial resistance to Aphanomyces euteiches in Medicago truncatula.
Badis Yacine,Bonhomme Maxime,Lafitte Claude,Huguet Stéphanie,Balzergue Sandrine,Dumas Bernard,Jacquet Christophe
Molecular plant pathology
To gain an insight into the molecular mechanisms of quantitative disease resistance in Medicago truncatula to the root-infecting oomycete Aphanomyces euteiches, we selected two near-isogenic lines (NILs), NR and NS, partially resistant and susceptible, respectively, differing in the allelic state of the quantitative resistance locus (QRL) prAe1 (partially resistant to A. euteiches 1). Complementary molecular and cytological phenotyping methods showed that prAe1 alone confers quantitative resistance to A. euteiches. Root and stem tissues were colonized in NS plants and 80% of NS plants died by 21 days post-inoculation (dpi). In contrast, A. euteiches mycelium was restricted to the root cortex and the spread of symptoms was arrested in aerial parts of NR plants. A transcriptome analysis performed at 0, 1 and 6 dpi identified 1198 differentially expressed genes (DEGs) between NR and NS lines. More than 87% of the DEGs were significantly more expressed in NR. The highest number of DEGs was found in control conditions, with 723 genes over-expressed in NR versus 85 in NS. Genes belonging to secondary metabolism, pathogenesis-related (PR) proteins and kinases were significantly enriched. The significant role of the flavonoid pathway in resistance was corroborated by the detection of larger amounts of flavonoids in NR roots and the inhibition of A. euteiches zoospore germination by 2'-O-methyl-isoliquiritigenin, a compound synthesized by enzymes specifically induced in NR. Our study revealed that prAe1-dependent resistance relies mainly on the constitutive expression of defence-related pathways and signalling elements, which can be re-amplified in later time points of the infection.
10.1111/mpp.12253
The comparative pharmacokinetics of four bioactive ingredients after administration of Ramulus Cinnamomi-Radix Glycyrrhizae herb pair extract, Ramulus Cinnamomi extract and Radix Glycyrrhizae extract.
Wang Shengnan,Sun Lijiao,Gu Liqiang,Zhang Yuanyuan,Zhao Simin,Zhao Long-Shan,Bi Kai-Shun,Chen Xiaohui
Biomedical chromatography : BMC
Ramulus Cinnamomi (RC)-Radix Glycyrrhizae (RG) is a classic herb pair, which is commonly used as a fixed form to treat cardiovascular disease in the clinic. Our work aimed to compare the pharmacokinetic difference of cinnamic acid, liquiritin, isoliquiritigenin and glycyrrhetinic acid in rats after oral administration of the RC-RG herb pair extracts [Guizhigancao Decoction (GGD) and Lingguizhugan Decoction (LGZGD)] and the single RC or RG extract. A HPLC-MS method was developed and validated to study comparative pharmacokinetics. The pharmacokinetic parameters (Cmax , AUC, MRT) of four compounds between the RC-RG herb pair group and the single herb (RC or RG) group showed significant differences (p < 0.05). Compared with the single herb (RC or RG) group, higher peak concentration, slower elimination and larger exposure could be observed after giving the RC-RG herb-pair extracts. The pharmacokinetic differences might indicate the relativity of remedy in the RC-RG herb pair and provide scientific information for rational administration of the drug in the clinic. Copyright © 2016 John Wiley & Sons, Ltd.
10.1002/bmc.3677
Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy.
Dandawate Prasad R,Subramaniam Dharmalingam,Jensen Roy A,Anant Shrikant
Seminars in cancer biology
Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3'-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.
10.1016/j.semcancer.2016.09.001
Identification and Chemical Standardization of Licorice Raw Materials and Dietary Supplements Using UHPLC-MS/MS.
Li Guannan,Nikolic Dejan,van Breemen Richard B
Journal of agricultural and food chemistry
Defined as the roots and underground stems of principally three Glycyrrhiza species, Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC., and Glycyrrhiza inflata Batalin, licorice has been used as a medicinal herb for millennia and is marketed as root sticks, powders, and extracts. Identity tests described in most pharmacopeial monographs enabled the distinction of Glycyrrhiza species. Accordingly, an ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay using the method of standard addition was developed to quantify 14 licorice components (liquiritin, isoliquiritin, liquiritin apioside, isoliquiritin apioside, licuraside, liquiritigenin, isoliquiritigenin, glycyrrhizin, glycyrrhetinic acid, glabridin, glycycoumarin, licoricidin, licochalcone A, and p-hydroxybenzylmalonic acid), representing several natural product classes including chalcones, flavanones, saponins, and isoflavonoids. Using this approach, G. glabra, G. uralensis, and G. inflata in a variety of forms including root powders and extracts as well as complex dietary supplements could be differentiated and chemically standardized without concerns due to matrix effects.
10.1021/acs.jafc.6b02954
Interactions of Three Chalcones with Human Serum Albumin Revealed by Spectroscopic Techniques.
Ma Ji,Fan Yunchang,Si Qingerile,Liu Yuan,Wang Xiangfeng,Liu Hailing,Xie Mengxia
Analytical sciences : the international journal of the Japan Society for Analytical Chemistry
Chalcones are the proverbial precursors of many naturally occurring compounds and possess a variety of biological activities and a broad spectrum of pharmacological properties. The interaction mechanism between three chalcones, 2',4',4-trihydroxyflavone (also called isoliquiritigenin, 2',4',4-triHC), 2',4'-dihydroxyflavone (2',4'-diHC), and 4-hydroxyflavone (4-HC) and human serum albumin (HSA) was investigated using fluorescence quenching, fluorescence enhancement and UV absorption spectra. The binding parameters of chalcone-HSA complexes were evaluated by fluorescence quenching measurements, and the results were consistent with those obtained from fluorescence enhancement methods. The binding affinities of three chalcones with HSA at pH 7.4 were ranked in the order (the binding constants in the range 0.28 - 2.39 × 10 L mol), 2',4',4-triHC > 2',4'-diHC > 4-HC, indicating that the three chalcones displayed tight affinities for HSA and the hydroxyl group in chalcones played a key role in their binding affinities with HSA. The results of the UV absorption and the fluorescence enhancement elucidated that the chalcones may lead to micro-environmental and conformational changes of HSA. The binding site of the chalcone 2',4',4-triHC on the HSA was explored by the spectroscopic properties of the 2',4',4-triHC-HSA complex at pH 7.4 and 3.5, and the results demonstrated that 2',4',4-triHC bound within the hydrophobic pockets of subdomain IIA of HSA, namely site I, and the electrostatic force and ionic interactions played a crucial role in the binding interaction between chalcones and protein. The obtained results provided scientific evidence for the binding property of the chalcones and protein, which would be helpful for development of novel drugs with the skeleton of chalcones.
10.2116/analsci.33.493
Simultaneous Determination of 8 Compounds in Gancao-Ganjiang-Tang by HPLC-DAD and Analysis of the Relations between Compatibility, Dosage, and Contents of Medicines.
Yang Yanfang,Zhang Guijun,Sun Qiyu,Liu Liang,Peng Hui,Wang Jingjuan,Xiang Li
Evidence-based complementary and alternative medicine : eCAM
Gancao-Ganjiang-Tang (GGT) is a traditional Chinese medicine (TCM) prescription and is a representative prescription for recuperating depleted Yang in Treatise on Febrile Diseases. The TCM theory believes that the efficacy of medicinal herbs is decided by the multicompounds which consist of different kinds of chemical constituents with bioactivities, but not by a monomeric constituent. From ancient times until today, GGT have 5 different kinds of compatibilities that can be verified. In this study, a HPLC-DAD method was established for the simultaneous determination of 8 compounds including 6-gingerol, 8-gingerol, 6-shogaol, liquiritin, liquiritigenin, isoliquiritin, isoliquiritigenin, and glycyrrhizic acid in the five GGT. The total contents of the 8 compounds in GGT varied from 555.56 to 956.33 g/mL. The effects showed that the dosage and compatibility of medicinal herbs have influenced the content of chemical compounds of TCM prescription while the content of chemical compounds has acted on clinical efficacy. Quality evaluation and active essence screening of TCM (including single herb and prescription) should be based on the TCM theory and clinical effectiveness. The method was proven to be suitable for quality control of GGT.
10.1155/2017/4703632
Simultaneous Determination of 11 Compounds in Gualou Guizhi Granule and Pharmacokinetics Study by UPLC-MS/MS.
Sun Chengtao,Xu Wen,Zhang Yuqin,Yu Lishuang,Ye Miao,Chu Kedan,Xu Wei,Lin Yu
Journal of analytical methods in chemistry
A rapid and sensitive ultrafast performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) was developed for the simultaneous determination of 11 compounds in Gualou Guizhi Granule (GLGZG), including liquiritin, isoliquiritin, liquirtin apioside, isoliquiritin apioside, liquiritigenin, isoliquiritigenin, glycyrrhizic acid, glycyrrhetinic acid, paeoniflorin, albiflorin, and paeoniflorin sulfonate in rat plasma. UPLC-MS/MS assay with negative ion mode was performed on a Waters CORTECS C18 (2.1 × 100 mm, 1.6 m) with the mobile phase consisting of 0.1% aqueous formic acid (A) and acetonitrile (B) in gradient elution at a flow rate of 0.25 mL·min. The method was linear for all analytes within the detection range ( ≥ 0.9597). The inter- and intraday precision (RSD) were 2.21-6.41% and 1.67-6.18%; the inter- and intraday accuracy (recover) were 92.48-114.03% and 90.23-112.04%. And the recovery rate ranged from 81.30% to 108.22%. The matrix effect values obtained for analytes ranged from 88.91% to 113.32%. This validated method was successfully applied to a pharmacokinetics study in rats after oral administration of GLGZG.
10.1155/2017/8451383
[Study on in vitro anti-inflammatory activity of total flavonoids from Glycyrrhizae Radix et Rhizoma and its ingredients].
Yang Xiao-Lu,Liu Duo,Bian Ka,Zhang Dan-Dan
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
OBJECTIVE:To examine the anti-inflammatory mechanism of total flavonoids of Glycyrrhizae Radix et Rhizoma (TFGR) and its ingredient on IFN-gamma and LPS-induced macrophage RAW264.7. METHOD:Solvent extraction and macroporous resin enrichment were adopted for preparing ethanol extracts of Glycyrrhizae Radix et Rhizoma, components and total flavonoids. Ultraviolet spectroscopy was used to determine the content of total flavonoids. An IFN-gamma and LPS-induced cell inflammatory model was established. Griess reaction was used for detecting the effect of extracts at all levels and flavonoid monomers on nitrite content in cell culture supernatant. FRAP was used for measuring anti-oxidation capacity. RT-PCR was used for determining the effect of TFGR and isoliquiritigenins on intracellular inducible nitric oxide synthase iNOS, COX-2, IL-6 and PPAR-gamma. Western blot was used for detecting the effect of TFGR and isoliquiritigenins on iNOS, COX-2 and MAPK signal transduction pathways. RESULT:Compared with other extracts, ethyl acetate fractions from Glycyrrhizae Radix et Rhizoma showed the highest inhibition ratio on nitrite content at the same concentration. After being enriched with macroporous resin, TFGR (60. 08% of liquiritin) of ethyl acetate extracts from Glycyrrhizae Radix et Rhizoma showed dose-dependence, and inhibited the nitrite content in cell culture supernatant, which was superior to ethyl acetate extracts, and had the protective effect on post-stimulated cell activity, with a stronger total anti-oxidation than other extracts. TFGR inhibited iNOS, IL-6 mRNA, protein expressions of iNOS, COX-2 and IL-6. Isoliquiritigenin, a flavonoid monomer, could inhibited iNOS, COX-2 gene and protein expression and gene expressions of IL-1beta and IL-6, and upside-regulated gene expression of PPAR-gamma. CONCLUSION:Activity-oriented extraction suggests that ethyl acetate fractions from Glycyrrhizae Radix et Rhizoma is one of components with anti-inflammatory activity. TFGR obtained by enriching the active component showed dose-dependence, and inhibited the nitrite content in cell culture supernatant. The anti-inflammatory effect is partially achieved by regulating ERK signal pathway and inhibiting iNOS and COX-2 gene and protein expressions through extracellular signals of mitogen activated protein kinases (MAPKs). Specifically, isoliquiritigenin may be a component with TFGR anti-inflammatory activity.
Influence of Jiegeng on Pharmacokinetic Properties of Flavonoids and Saponins in Gancao.
Mao Yancao,Peng Linxiu,Kang An,Xie Tong,Xu Jianya,Shen Cunsi,Ji Jianjian,Di Liuqing,Wu Hao,Shan Jinjun
Molecules (Basel, Switzerland)
Jiegeng Gancao decoction, which is composed of Jiegeng and Gancao at a weight ratio of 1:2, was widely used for treating pharyngalgia and cough for thousands of years. Our previous work indicated that Gancao could increase the systemic exposure of platycodin D and deapio-platycodin D, two main components in Jiegeng. However, whether Jiegeng could alter the pharmacokinetics of the main compounds in Gancao is still unknown. Thus, the purpose of this study was to compare the oral pharmacokinetics of flavonoids and saponins from Gancao alone vs. after co-administration with Jiegeng. Furthermore, Caco-2 cell transport and fecal hydrolysis were investigated to explain the altered pharmacokinetic properties. Pharmacokinetics results suggested that the bioavailability of liquiritin, isoliquiritin, glycyrrhizin and its metabolite, glycyrrhetinic acid, could be improved while bioavailability of liquiritigenin and isoliquiritigenin deteriorated when co-administered with Jiegeng. The Caco-2 transport study showed no significant difference of the P values of the main components in Jiegeng Gancao decoction when compared with those in Gancao decoction ( > 0.05). The in vitro metabolism study suggested that saponins and flavonoids glycosides in Gancao were influenced and the metabolic characteristics of most ingredients were consistent with pharmacokinetic results, such as liquiritin and glycyrrhetinic acid. The hydrolysis of liquiritigenin and glycyrrhizin observed with fecal lysate in vitro appeared consistent with the oral pharmacokinetics. Based on experiments, the pharmacokinetic profiles of six components in Gancao were influenced by Jiegeng. The metabolic process might partially contribute to the altered pharmacokinetic behavior. The metabolism of some components of Gancao appeared to be inhibited when coadministered with Jiegeng, possibly by the Jiegeng constituent platycodin.
10.3390/molecules22101587
[Chemical constituents from roots of Caragana stenophylla and their anti-tumor activities].
Subinuer Maiwulan,Pan Lan,Jia Xin-Yue,Zhang Tao,Jia Xiao-Guang,Zou Zhong-Mei
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Fourteen compounds were isolated from the 80% ethanol extract of Caragana stenophylla root, by using a combination of various chromatographic approaches, including silica gel sephadex LH-20 column chromatography, and preparative HPLC. On the basis of their physical and chemical properties and spectroscopic data, their structures were elucidated as 2-(4-hydroxy-3-methoxy lphenyl)-3-methoxyl benzofuran-6-ol (1), mucodianin C (2), isopterofuran (3), formononetin (4), afromosin (5), calycosin (6), acacetin (7), 3-O-methylkaempferol (8), liquiritigenin (9), isoliquiritigenin (10), variabilin (11), resveratrol (12), zhebeiresinol (13), and 2, 3-dicarboxy-6, 7-dihydroxy-1-(3', 4'-dihydroxy)-phenyl-1, 2-dihydronaphthalen (14). Compound 1 is a new benzofuran derivative, named as mucodianin S; compounds 2, 3, 11, 13, 14 were isolated from the genus Caragana for the first time, and compounds 4-10 were firstly isolated from Caragana stenophylla. MTT assay was used to determine their cytotoxicity of the isolated compounds against human tumor cell lines, and 2 showed cytotoxicity against human hepato cellular cancer (HepG2) and human cervical (HeLa) lines, with IC₅₀ values of (16.18±0.95), (3.75±0.08) μmol•L ⁻¹, respectively.
10.19540/j.cnki.cjcmm.20170512.007
Simultaneous quantitative determination of nine active chemical compositions in traditional Chinese medicine Glycyrrhiza by RP-HPLC with full-time five-wavelength fusion method.
Wu Yin-Ping,Meng Xian-Sheng,Bao Yong-Rui,Wang Shuai,Kang Ting-Guo
The American journal of Chinese medicine
A new, simple, accurate and reliable full-time five-wavelength fusion method for the simultaneous separation and determination of nine active chemical compositions (liquiritin apioside, liquiritin, isoliquiritin apioside, ononin, isoliquiritin, liquiritigenin, calycosin, isoliquiritigenin, Glycyrrhizic acid monoammonium salt) in traditional Chinese medicine Glycyrrhiza was developed using reverse phase high-performance liquid chromatography (RP-HPLC) coupled with a diode-array detector (DAD). The chromatographic separation was performed on an Agilent TC-C18 column with gradient elution using 0.04% methanoic acid (A) and acetonitrile (B) at a flow rate of 1.0 mL min(-1) and UV detection at 248 nm, 250 nm, 276 nm, 362 nm, 370 nm. The standard curves were linear over the range of 2.1379-12.8272 μg for liquiritin apioside, 3.9299-23.5794 μg for liquiritin, 1.0432-6.2592 μg for isoliquiritin apioside, 0.8764-5.8584 μg for ononin, 1.0701-6.4205 μg for isoliquiritin, 1.3685-8.2111 μg for liquiritigenin, 0.3927-2.3563 μg for calycosin, 0.2498- 1.4986 μg for isoliquiritigenin, 2.0094-12.0564 μg for Glycyrrhizic acid monoammonium salt, respectively (r(2) > 0.9997). The recoveries and relative standard deviation (RSD) varied from 95.09% to 103.54% and 1.09% to 2.36%, respectively. The precision for all the analytes was less than 2.52%. The method indicated good performance in terms of precision, accuracy and linearity. The method enabled the simultaneous determination of nine active chemical compositions for quality control of Glycyrrhiza.
10.1142/S0192415X13500158
[Study on correlation between color and effective components contents of Glycyrrhiza uralensis].
Ma Ting-Ting,Gong Mu-Xin,Wang Zhi-Min,He Rui,Wu Sha,Zhang Cun,Li Jing,Li Zhao-Xia,Lu Yun,Xu Yong-Song
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
To explore the correlation between color of Glycyrrhiza uralensis and its quality evaluation,the colors of root bark and transverse section were determined by Precision Color Reader and Visual Analyzer,and the contents of six flavonoids and two saponins in G.uralensis were determined by high performance liquid chromatography（HPLC）.The partial least squares regression（PLSR）method was employed to correlate the colors with component contents in G.uralensis. The results showed that there were no significant differences in the colors of root bark but significant or very significant differences（P<0.05,P<0.01）in the colors of transverse section between the wild and cultivated G. uralensis. Compared with those in the cultivated G. uralensis, the contents of liquiritin, isoliquiritin isoliquiritigenin and the contents of ammonium glycyrrhizinate, glycyrrhetinic acid were obviously significant or remarkably significant in the wild G. uralensis.The correlation results showed that there was a significant or very significant correlation between the colors and the effective component contents. This study provides a scientific basis to evaluate the quality of G.uralensis by color and a new reference for the traditional evaluation methods for Chinese drugs.
10.19540/j.cnki.cjcmm.20170807.006
A comparative pharmacokinetic study of three flavonoids and three anthraquinones in normal and gastrointestinal motility disorders rat plasma after the oral administration of Wei-Chang-Shu tablet using high-performance liquid chromatography-tandem mass spectrometry.
Ren Yan,Zhao Weiwei,Zhao Juanjuan,Chen Xiangming,Yu Chen,Liu Mengan
Biomedical chromatography : BMC
A simple, fast and reliable high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification and pharmacokinetic study of three flavonoids (liquiritigenin, isoliquiritigenin and formononetin) and three anthraquinones (emodin, rhein and aloe-emodin), which are the bioactive ingredients of Wei-Chang-Shu tablet found in rat plasma. After extraction by liquid-liquid extraction with ethyl acetate, chromatographic separation was achieved on an Agilent Zorbax SB-C column (4.6 × 150 mm, 5 μm) at a flow rate of 1 mL/min by gradient elution using 0.1% aqueous acetic acid and acetonitrile. The detection was performed using a triple quadrupole mass spectrometer equipped with electrospray ionization source in the negative ionization and selected reaction monitoring mode. Method validation was performed in terms of specificity, carryover, linearity (r > 0.99), intra-/inter-day precision (1.0-10.1%), accuracy (relative error, <7.6%), stability (0.6-13.2%), extract recovery (74.9-91.9%) and matrix effect (89.1-109%). The lower limits of quantification of the six analytes varied from 0.92 to 10.4 ng/mL. The validated method was successfully applied to compare the pharmacokinetic properties of Wei-Chang-Shu tablet in normal rats and in rats with gastrointestinal motility disorders. The results indicated that there were obvious differences in the pharmacokinetic behavior between normal and model rats. This study will be helpful in the clinical application of Wei-Chang-Shu tablet.
10.1002/bmc.3997
Simultaneous quantification of multiple components in rat plasma by UPLC-MS/MS and pharmacokinetic study after oral administration of Huangqi decoction.
Zeng Jia-Kai,Li Yuan-Yuan,Wang Tian-Ming,Zhong Jie,Wu Jia-Sheng,Liu Ping,Zhang Hua,Ma Yue-Ming
Biomedical chromatography : BMC
A rapid, sensitive and accurate UPLC-MS/MS method was developed for the simultaneous quantification of components of Huangqi decoction (HQD), such as calycosin-7-O-β-d-glucoside, calycosin-glucuronide, liquiritin, formononetin-glucuronide, isoliquiritin, liquiritigenin, ononin, calycosin, isoliquiritigenin, formononetin, glycyrrhizic acid, astragaloside IV, cycloastragenol, and glycyrrhetinic acid, in rat plasma. After plasma samples were extracted by protein precipitation, chromatographic separation was performed with a C column, using a gradient of methanol and 0.05% acetic acid containing 4mm ammonium acetate as the mobile phase. Multiple reaction monitoring scanning was performed to quantify the analytes, and the electrospray ion source polarity was switched between positive and negative modes in a single run of 10 min. Method validation showed that specificity, linearity, accuracy, precision, extraction recovery, matrix effect and stability for 14 components met the requirements for their quantitation in biological samples. The established method was successfully applied to the pharmacokinetic study of multiple components in rats after intragastric administration of HQD. The results clarified the pharmacokinetic characteristics of multiple components found in HQD. This research provides useful information for understanding the relation between the chemical components of HQD and their therapeutic effects.
10.1002/bmc.4178
Chemical Profile and Anti-inflammatory Activity of Total Flavonoids from Fisch.
Yin Lei,Guan Enshuang,Zhang Yuanbin,Shu Zhiheng,Wang Bing,Wu Xiuli,Chen Jing,Liu Jingxia,Fu Xueyan,Sun Weihong,Liu Meifeng
Iranian journal of pharmaceutical research : IJPR
Fisch. () is one of the most widely used herbal medicines. This study was designed to enrich total flavonoids (TFF) from . The chemical profile of TFF was identified by HPLC and colorimetric assay. The TFF mainly contained liquiritin apioside, liquiritin, isoliquiritin apioside, liquiritigenin and isoliquiritigenin without glycyrrhizic acid. To study the anti-inflammatory activity of TFF, the DMB-induced ear vasodilatation assay and carrageenan-induced rat paw edema model have been utilized. Treatment with TFF showed significant anti-inflammatory activities in the two models. The two edema assays demonstrated that the TFF possesses significant dose-dependent anti-inflammatory activity, similar to that of indomethacin at a dose of 500 mg/kg. In rat paws with carrageenan, treatment with TFF (500 and 250 mg/kg) markedly inhibited the expression of IL-1β and iNOS. TFF at all doses noticeably decreased levels of NO and MDA at the site of inflammation, while only i.g. TFF at a dose of 500 mg/kg significantly decreased TNF-α levels in the carrageenan-injected paws. In addition, an increase in SOD activity was induced by TFF at all doses. These results revealed that TFF exhibited significant anti-inflammatory activity in acute inflammatory models.
Mechanical and aesthetics compatibility of Brazilian red propolis micellar nanocomposite as a cavity cleaning agent.
Celerino de Moraes Porto Isabel Cristina,Chaves Cardoso de Almeida Dayse,Vasconcelos Calheiros de Oliveira Costa Gabriela,Sampaio Donato Tayná Stéphanie,Moreira Nunes Letícia,Gomes do Nascimento Ticiano,Dos Santos Oliveira José Marcos,Batista da Silva Carolina,Barbosa Dos Santos Natanael,de Alencar E Silva Leite Maria Luísa,Diniz Basílio-Júnior Irinaldo,Braga Dornelas Camila,Barnabé Escodro Pierre,da Silva Fonseca Eduardo Jorge,Umeko Kamiya Regianne
BMC complementary and alternative medicine
BACKGROUND:Propolis is a natural substance produced by bees and is known to have antimicrobial activity. Our aim was to evaluate the antimicrobial effect of micellar nanocomposites loaded with an ethyl acetate extract of Brazilian red propolis as a cavity cleaning agent and its influence on the color and microtensile bond strength (μTBS) of the dentin/resin interface. METHODS:An ultra-performance liquid chromatography coupled with a diode array detector (UPLC-DAD) assay was used to determine the flavonoids and isoflavones present in an ethyl acetate extract of Brazilian red propolis (EARP) and micellar nanocomposites loaded with EARP (MNRP). The antimicrobial activity of EARP and MNRP was tested against Streptococcus mutans, Lactobacillus acidophilus, and Candida albicans. One of the following experimental treatments was applied to etched dentin (phosphoric acid, 15 s): 5 μL of MNRP (RP3, 0.3%; RP6, 0.6%; or RP1, 1.0% w/v), placebo, and 2% chlorhexidine digluconate. Single Bond adhesive (3 M/ESPE) was applied and a 4-mm-thick resin crown (Z350XT, 3 M/ESPE) was built up. After 24 h, the teeth were sectioned into sticks for the μTBS test and scanning electron microscopy. Spectrophotometry according to the CIE L*a*b* chromatic space was used to evaluate the color. Data were analyzed using one-way ANOVA and the Tukey test or Kruskal-Wallis test and the same test for pairwise comparisons between the means (P < 0.05). RESULTS:The UPLC-DAD assay identified the flavonoids liquiritigenin, pinobanksin, pinocembrin, and isoliquiritigenin and the isoflavonoids daidzein, formononetin, and biochanin A in the EARP and micellar nanocomposites. EARP and MNRP presented antimicrobial activity against the cariogenic bacteria Streptococcus mutans and Lactobacillus acidophilus, and for Candida albicans. ΔE values varied from 2.31 to 3.67 (P = 0.457). The mean μTBS for RP1 was significantly lower than for the other groups (P < 0.001). Dentin treated with RP1 showed the shortest resin tags followed by RP6 and RP3. CONCLUSIONS:The EARP and (MNRP) showed antimicrobial activity for the main agents causing dental caries (Streptococcus mutans and Lactobacillus acidophilus) and for Candida albicans. MNRP at concentrations of 0.3 and 0.6% used as a cavity cleaner do not compromise the aesthetics or μTBS of the dentin/resin interface.
10.1186/s12906-018-2281-y
Chitosan elicitation of L. hairy root cultures for enhancing flavonoid productivity and gene expression and related antioxidant activity.
Industrial crops and products
Elicitation for phytochemical enhancement cost-effective elicitors can overcome the limitation of commercial application faced by plant cell and organ culture technology. Chitosan is a natural, low-cost, and nontoxic elicitor that can trigger plant defense responses with the concomitant enhancement in phytochemical biosynthesis. In this work, the elicitation of L. hairy root cultures by chitosan was conducted to enhance the production of pharmacologically active flavonoids. In comparison with control (2.31 ± 0.29 mg/g DW), a 7.08-fold enhancement of total flavonoids (16.35 ± 0.88 mg/g DW) was achieved in 24 day-old hairy root cultures elicited by 150 mg/L chitosan for 36 h. Interestingly, the multiple hydroxyl-substituted flavonoids (rutin, quercetin, isorhamnetin, and isoliquiritigenin) were noticed to increase significantly in chitosan-elicited hairy root cultures. Moreover, the transcription of associated genes involved in flavonoid biosynthesis pathway was significantly up-regulated underlying chitosan elicitation, among which and might play an important role in flavonoid enhancement. Additionally, extracts from chitosan-elicited hairy root cultures exhibited higher antioxidant activities with lower IC values as compared with control. Overall, a cost-effective strategy the simple chitosan elicitation is provided here to enhance the production of high-added value flavonoids in hairy root cultures, which paves the way toward the successful commercialization of this culture system in the future.
10.1016/j.indcrop.2018.07.056
Anti-hepatitis C virus compounds obtained from Glycyrrhiza uralensis and other Glycyrrhiza species.
Adianti Myrna,Aoki Chie,Komoto Mari,Deng Lin,Shoji Ikuo,Wahyuni Tutik Sri,Lusida Maria Inge,Soetjipto ,Fuchino Hiroyuki,Kawahara Nobuo,Hotta Hak
Microbiology and immunology
Development of complementary and/or alternative drugs for treatment of hepatitis C virus (HCV) infection is still much needed from clinical and economic points of view. Antiviral substances obtained from medicinal plants are potentially good targets to study. Glycyrrhiza uralensis and G. glabra have been commonly used in both traditional and modern medicine. In this study, extracts of G. uralensis roots and their components were examined for anti-HCV activity using an HCV cell culture system. It was found that a methanol extract of G. uralensis roots and its chloroform fraction possess anti-HCV activity with 50%-inhibitory concentrations (IC(50)) of 20.0 and 8.0 μg/mL, respectively. Through bioactivity-guided purification and structural analysis, glycycoumarin, glycyrin, glycyrol and liquiritigenin were isolated and identified as anti-HCV compounds, their IC(50) being 8.8, 7.2, 4.6 and 16.4 μg/mL, respectively. However, glycyrrhizin, the major constituent of G. uralensis, and its monoammonium salt, showed only marginal anti-HCV activity. It was also found that licochalcone A and glabridin, known to be exclusive constituents of G. inflata and G. glabra, respectively, did have anti-HCV activity, their IC(50) being 2.5 and 6.2 μg/mL, respectively. Another chalcone, isoliquiritigenin, also showed anti-HCV activity, with an IC(50) of 3.7 μg/mL. Time-of-addition analysis revealed that all Glycyrrhiza-derived anti-HCV compounds tested in this study act at the post-entry step. In conclusion, the present results suggest that glycycoumarin, glycyrin, glycyrol and liquiritigenin isolated from G. uralensis, as well as isoliquiritigenin, licochalcone A and glabridin, would be good candidates for seed compounds to develop antivirals against HCV.
10.1111/1348-0421.12127
Simultaneous determination of five bioactive components of Gancao in rat plasma by UHPLC-MS/MS and its application to comparative pharmacokinetic study of incompatible herb pair Gansui-Gancao and Gansuibanxia Decoction.
Cui Yue,Liu Ting,Zhang Ye,Wang Roujia,Liu Xiaozhou,Zhang Qili,Yu Peipei,Zhao Yunli,Yu Zhiguo
Journal of pharmaceutical and biomedical analysis
Incompatible herb pair Gansui-Gancao is recorded in "eighteen incompatible" medicaments in many monographs of TCM (Traditional Chinese Medicine) which means the two herbs can not be co-used in most cases. However, Gansuibanxia decoction composed of Gansui(Kansui), Banxia(Pinellia), Shaoyao(Peony) and Gancao(Liquorice) is a traditional Chinese formula which has been clinically employed for the treatment of cancerous ascites, pleural effusion, peritoneal effusion, etc. The purpose of the study was to investigate the pharmacokinetics of main bioactive components in Gancao to explore the reasons why Gansui-Gancao can be used in Gansuibanxia decoction. A simple, rapid and sensitive UHPLC-MS/MS method for simultaneous determination of liquiritigenin, isoliquiritigenin, liquiritin, glycyrrhetinic acid and glycyrrhizic acid of liquorice in rat plasma was developed and validated. After extraction from plasma, the analytes and internal standard were separated on a C18 column with the mobile phase consisting of 0.1% acetic acid containing 0.2 mM ammonium acetate in water and acetonitrile via gradient elution. The electrospary ionization source was adopted under the multiple reaction monitoring mode. The method was succesfully applied to a comparative pharmacokinetic study of main bioactive components of Gancao in rat plasma after oral administration of the extracts of Gancao (GC), Gansui-Gancao (GS-GC), Shaoyao-Gancao (SY-GC), Gansui-Shaoyao-Gancao (GS-SY-GC) and Gansuibanxia decoction (GSBXD), respectively. The pharmacokinetic parameters had significant differences (P < 0.05) in different groups which showed that Gansui decreased the bioavailability of Gancao, while Shaoyao increased the bioavailability of Gancao. Hence, these may be the pharmacokinetic mechanism of incompatible herb pair Gansui-Gancao and the reasons why the herb pair can be used in Gansuibanxia decoction.
10.1016/j.jpba.2018.07.014
UPLC-MS/MS Method for the Determination of 14 Compounds in Rat Plasma and Its Application in a Pharmacokinetic Study of Orally Administered Xiaoyao Powder.
Xu Mingyue,Xu Zhanling,Xu Qingxuan,Zhang Hongyue,Liu Mingyang,Geng Fang,Zhang Ning
Molecules (Basel, Switzerland)
Xiaoyao Powder (XYP), a common Chinese medicine, comprises eight traditional Chinese herbs and has been widely used clinically to treat liver damage and mental disorders. An ultra-performance liquid chromatography⁻tandem mass spectrometry method was developed to investigate the pharmacokinetics of 14 compounds (albiflorin, paeoniflorin, ferulic acid, senkyunolide I, quercetin, isoliquiritigenin, atractylenolide III, ligustilide, atractylenolide II, liquiritin, liquiritigenin, saikosaponin c, glycyrrhizic acid, and saikosaponin a) in XYP. Naringenin was used as the internal standard. The compounds were separated using an ACQUITY UPLC BEH C18 column (1.7 μm, 50 × 2.1 mm) with a mobile phase consisting of acetonitrile and 0.1% formic acid in water at a flow rate of 0.3 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometer using multiple reaction monitoring and an electrospray ionization source in both positive and negative ionization modes. All calibration curves exhibited good linearity (r² > 0.9974) over the measured ranges. The intra- and inter-day precisions were within 12%, and the accuracy ranged from 89.93% to 106.64%. Extraction recovery and matrix effect results were satisfactory. The method was successfully applied in a pharmacokinetic study of the 14 compounds in rat plasma after the oral administration of XYP.
10.3390/molecules23102514
Inflammation, a Double-Edge Sword for Cancer and Other Age-Related Diseases.
Gupta Subash Chandra,Kunnumakkara Ajaikumar B,Aggarwal Sadhna,Aggarwal Bharat B
Frontiers in immunology
Increasing evidence from diverse sources during the past several years has indicated that long-term, low level, chronic inflammation mediates several chronic diseases including cancer, arthritis, obesity, diabetes, cardiovascular diseases, and neurological diseases. The inflammatory molecules and transcription factors, adhesion molecules, AP-1, chemokines, C-reactive protein (CRP), cyclooxygenase (COX)-2, interleukins (ILs), 5-lipooxygenase (5-LOX), matrix metalloproteinases (MMPs), nuclear factor (NF)-kB, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) are molecular links between inflammation and chronic diseases. Thus, suppression of inflammatory molecules could be potential strategy for the prevention and therapy of chronic diseases. The currently available drugs against chronic diseases are highly expensive, minimally effective and produce several side effects when taken for long period of time. The focus of this review is to discuss the potential of nutraceuticals derived from "Mother Nature" such as apigenin, catechins, curcumin, ellagic acid, emodin, epigallocatechin gallate, escin, fisetin, flavopiridol, genistein, isoliquiritigenin, kaempferol, mangostin, morin, myricetin, naringenin, resveratrol, silymarin, vitexin, and xanthohumol in suppression of these inflammatory pathways. Thus, these nutraceuticals offer potential in preventing or delaying the onset of chronic diseases. We provide evidence for the potential of these nutraceuticals from pre-clinical and clinical studies.
10.3389/fimmu.2018.02160
The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb.
Wang Liqiang,Yang Rui,Yuan Bochuan,Liu Ying,Liu Chunsheng
Acta pharmaceutica Sinica. B
Licorice is a common herb which has been used in traditional Chinese medicine for centuries. More than 20 triterpenoids and nearly 300 flavonoids have been isolated from licorice. Recent studies have shown that these metabolites possess many pharmacological activities, such as antiviral, antimicrobial, anti-inflammatory, antitumor and other activities. This paper provides a summary of the antiviral and antimicrobial activities of licorice. The active components and the possible mechanisms for these activities are summarized in detail. This review will be helpful for the further studies of licorice for its potential therapeutic effects as an antiviral or an antimicrobial agent.
10.1016/j.apsb.2015.05.005
20S proteasome inhibitory activity of flavonoids isolated from Spatholobus suberectus.
Shim Sang Hee
Phytotherapy research : PTR
The promising biological role of the ubiquitin proteasome pathway (UPP) in cancer therapy has recently emerged. Inhibition of proteasome has been proposed as a new therapeutic target for treatment of cancer. Bioassay-guided fractionation of a MeOH extract of the stems of Spatholobus suberectus resulted in seven compounds, liquiritigenin (1), isoliquiritigenin (2), genistein (3), daidzein (4), medicarpin (5), 7-hydroxyflavanone (6) and formononetin (7), which were evaluated for the first time for their inhibitory effect on 20S proteasome. Among the isolated compounds, 2, 3 and 6 exhibited inhibitory activities on human 20S proteasome with IC(50) values of 4.88 ± 1.5, 9.26 ± 1.2 and 5.21 ± 1.5 µm, respectively.
10.1002/ptr.3342
The role of chalcones in suppression of NF-κB-mediated inflammation and cancer.
Yadav Vivek R,Prasad Sahdeo,Sung Bokyung,Aggarwal Bharat B
International immunopharmacology
Although consumption of fruits, vegetables, spices, cereals and pulses has been associated with lower incidence of cancer and other chronic diseases, how these dietary agents and their active ingredients minimize these diseases, is not fully understood. Whether it is oranges, kawa, hops, water-lilly, locorice, wax apple or mulberry, they are all connected by a group of aromatic ketones, called chalcones (1,3-diaryl-2-propen-1-ones). Some of the most significant chalcones identified from these plants include flavokawin, butein, xanthoangelol, 4-hydroxyderricin, cardamonin, 2',4'-dihydroxychalcone, isoliquiritigenin, isosalipurposide, and naringenin chalcone. These chalcones have been linked with immunomodulation, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, anticancer, and antidiabetic activities. The current review, however, deals with the role of various chalcones in inflammation that controls both the immune system and tumorigenesis. Inflammatory pathways have been shown to mediate the survival, proliferation, invasion, angiogenesis and metastasis of tumors. How these chalcones modulate inflammatory pathways, tumorigenesis and immune system is the focus of this review.
10.1016/j.intimp.2010.12.006
Nanosuspensions of a new compound, ER-β005, for enhanced oral bioavailability and improved analgesic efficacy.
Ye Ling,Miao Mingxing,Li Suning,Hao Kun
International journal of pharmaceutics
Estrogen receptor-β005 (ER-β005) is a novel compound developed by our group; however, its application has been greatly hindered due to its low solubility. A nanosuspension of insoluble drugs is a nanoscale colloidal dispersion that has extremely higher drug-loading compared with other nanomedicines. In this study, nanosuspensions of ER-β005 (Nano-ER-β005) stabilized by a food protein, β-casein (β-CN), were prepared via an antisolvent-precipitation method to improve oral absorption and thus promote therapeutic efficacy. Nano-ER-β005, which has a diameter of 110nm and drug-loading of 50%, was developed. Analyses of fluorescence and circular dichroism (CD) spectra demonstrated a strong interaction between β-CN and drug particles in Nano-ER-β005, indicating that β-CN is a potent nanosuspension stabilizer. The oral bioavailability of Nano-ER-β005 was 1.6-fold greater than that of raw drug particles. Additionally, ER-β005 was confirmed to have a strong therapeutic effect against pain reactions in animal models, and inhibition of this effect was significantly increased with Nano-ER-β005 treatment. In conclusion, by using β-CN as a stabilizer, nanosuspensions of ER-β005 were developed and oral absorption was enhanced. Moreover, ER-β005 is a powerful drug that inhibits pain reactions, and its therapeutic efficacy was markedly increased in the Nano-ER-β005.
10.1016/j.ijpharm.2017.08.103
Inhibitory effects of flavonoids extracted from Nepalese propolis on the LPS signaling pathway.
Funakoshi-Tago Megumi,Ohsawa Kentaro,Ishikawa Toshiyuki,Nakamura Fumika,Ueda Fumihito,Narukawa Yuji,Kiuchi Fumiyuki,Tamura Hiroomi,Tago Kenji,Kasahara Tadashi
International immunopharmacology
Flavonoids, particularly those derived from plants, harbor biological effects such as anti-inflammation and the inhibition of cancer progression. In the present study, we investigated the effects of 10 kinds of flavonoids isolated from Nepalese propolis on the LPS signaling pathway in order to clarify their anti-inflammatory activities. Five types of flavonoids: isoliquiritigenin, chrysin, 3',4'-dihydroxy-4-methoxydalbergione, 4-methoxydalbergion, and cearoin, markedly inhibited inflammatory responses including LPS-induced NO production by suppressing the expression of iNOS mRNA and LPS-induced mRNA expression of TNFα and CCL2. Their inhibitory effects on LPS-induced inflammatory responses correlated with the intensities of these flavonoids to suppress the LPS-induced activation of nuclear factor κB (NF-κB), an essential transcription factor for the mRNA expression of iNOS, TNFα, and CCL2. Among these flavonoids, 3',4'-dihydroxy-4-methoxydalbergione and 4-methoxydalbergion markedly inhibited the LPS-induced activation of IKK, thereby abrogating the degradation of IκBα and nuclear localization of NF-κB. On the other hand, isoliquiritigenin, chrysin, and cearoin failed to inhibit these signaling steps, but suppressed the transcriptional activity of NF-κB, which caused their anti-inflammatory effects. The results of the present study revealed that these five kinds of flavonoids are the components of Nepalese propolis that exhibit anti-inflammatory activities with a different regulatory mechanism for the activation of NF-κB.
10.1016/j.intimp.2016.10.008
Regulatory Roles of Flavonoids on Inflammasome Activation during Inflammatory Responses.
Yi Young-Su
Molecular nutrition & food research
Inflammation is an innate immune response to noxious stimuli to protect the body from pathogens. Inflammatory responses consist of two main steps: priming and triggering. In priming, inflammatory cells increase expressions of inflammatory molecules, while in triggering, inflammasomes are activated, resulting in cell death and pro-inflammatory cytokine secretion. Inflammasomes are protein complexes comprising intracellular pattern recognition receptors (PRRs) (e.g., nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2), and caspases-4/5/11) and pro-caspase-1 with or without a bipartite adaptor molecule ASC. Inflammasome activation induces pyroptosis, inflammatory cell death, and stimulates caspase-1-mediated secretion of interleukin (IL)-1b and IL-18. Flavonoids are secondary metabolites found in various plants and are considered as critical ingredients promoting health and ameliorating various disease symptoms. Anti-inflammatory activity of flavonoids and underlying mechanisms have been widely studied. This review introduces current knowledge on different types of inflammasomes and their activation during inflammatory responses and discusses recent studies regarding anti-inflammatory roles of flavonoids as suppressors of inflammasomes in inflammatory conditions. Understanding the regulatory effects of flavonoids on inflammasome activation will increase our knowledge of flavonoid-mediated anti-inflammatory activity and provide new insights into the development of flavonoid preparations to prevent and treat human inflammatory diseases.
10.1002/mnfr.201800147
A Comparative Pharmacokinetic Study by UHPLC-MS/MS of Main Active Compounds after Oral Administration of Zushima-Gancao Extract in Normal and Adjuvant-Induced Arthritis Rats.
Shan Jinjun,Qian Wenjuan,Peng Linxiu,Chen Lianghui,Kang An,Xie Tong,Di Liuqing
Molecules (Basel, Switzerland)
A sensitive and rapid ultra high-performance liquid-chromatography tandem mass spectrometry (UHPLC-MS/MS) method has been applied to investigate the influence of rheumatoid arthritis (RA) on the pharmacokinetics of nine analytes (daphnetin, daphnoretin, 7-hydroxycoumarin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, glycyrrhizin, and glycyrrhetinic acid), which are major active components in Zushima-Gancao extract. The analytes and internal standard (IS) were separated in a Hypersil Gold C column and detected on a triple-stage quadrupole mass spectrometer using the validated method. All analytes exhibited good linearities (² > 0.98), and the lower limit of quantification (LLOQs) were sufficient for quantitative analysis. Intra- and inter-batch precision were all within 14.96% while the accuracy of nine analytes ranged from -17.99 to 14.48%, and these results were all within acceptance criteria. The extraction recoveries, matrix effects, and stabilities were all satisfactory. Main pharmacokinetic parameters of each compound were compared, and significant differences were found in parameters of daphnetin, daphnoretin, liquiritin, isoliquiritin, isoliquiritigenin, glycyrrhizin, and glycyrrhetinic acid, especially the last one, between the two groups. Therefore, adjuvant-induced arthritis has different effects on the pharmacokinetics of ingredients in Zushima-Gancao extract. The comparative pharmacokinetic study between normal and adjuvant-induced arthritis rats might provide more comprehensive information to guide the clinical usage of Zushima-Gancao extract for treating RA.
10.3390/molecules23010227
Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma.
Sun Chao,Wang Zhen-Hua,Liu Xiong-Xiong,Yang Li-Na,Wang Yali,Liu Yang,Mao Ai-Hong,Liu Yuan-Yuan,Zhou Xin,Di Cui-Xia,Gan Lu,Zhang Hong
American journal of cancer research
AIMS:High constitutive expression of Nrf2 has been found in many types of cancers, and this high level of Nrf2 also favors resistance to drugs and radiation. Here we investigate how isoliquiritigenin (ISL), a natural antioxidant, inhibits the Nrf2-dependent antioxidant pathway and enhances the radiosensitivity of HepG2 cells and HepG2 xenografts. RESULTS:Treatment of HepG2 cells with ISL for 6 h selectively enhanced transcription and expression of Keap1. Keap1 effectively induced ubiquitination and degradation of Nrf2, and inhibited translocation of Nrf2 to the nucleus. Consequently, expression of Nrf2 downstream genes was reduced, and the Nrf2-dependent antioxidant system was suppressed. Endogenous ROS was higher than before ISL treatment, causing redox imbalance and oxidative stress in HepG2 cells. Moreover, pretreatment with ISL for 6 h followed by X-ray irradiation significantly increased γ-H2AX foci and cell apoptosis, and reduced clonogenic potential compared with cells irradiated with X-rays alone. In addition, HepG2 xenografts, ISL, and X-ray co-treatments induced greater apoptosis and tumor growth inhibition, when compared with X-ray treatments alone. Additionally, HepG2 xenografts, in which Nrf2 was expressed at very low levels due to ectopic expression of Keap1, showed that ISL-mediated radiosensitization was Keap1 dependent. INNOVATION AND CONCLUSIONS:ISL inhibited the Nrf2-antioxidant pathway by increasing the levels of Keap1 and ultimately inducing oxidative stress via disturbance of the redox status. The antioxidant ISL possessed pro-oxidative properties, and enhanced the radiosensitivity of liver cancer cells, both in vivo and in vitro. Taken together, these results demonstrated the effectiveness of using ISL to decrease radioresistance, suggesting that ISL could be developed as an adjuvant radiosensitization drug. Disturbance of redox status could be a potential target for radiosensitization.
Decrease of microRNA-122 causes hepatic insulin resistance by inducing protein tyrosine phosphatase 1B, which is reversed by licorice flavonoid.
Yang Yoon Mee,Seo So Yeon,Kim Tae Hyun,Kim Sang Geon
Hepatology (Baltimore, Md.)
UNLABELLED:Protein tyrosine phosphatase 1B (PTP1B) inhibits hepatic insulin signaling by dephosphorylating tyrosine residues in insulin receptor (IR) and insulin receptor substrate (IRS). MicroRNAs may modulate metabolic functions. In view of the lack of understanding of the regulatory mechanism of PTP1B and its chemical inhibitors, this study investigated whether dysregulation of specific microRNA causes PTP1B-mediated hepatic insulin resistance, and if so, what the underlying basis is. In high-fat-diet-fed mice or hepatocyte models with insulin resistance, the expression of microRNA-122 (miR-122), the most abundant microRNA in the liver, was substantially down-regulated among those predicted to interact with the 3'-untranslated region of PTP1B messenger RNA (mRNA). Experiments using miR-122 mimic and its inhibitor indicated that miR-122 repression caused PTP1B induction. Overexpression of c-Jun N-terminal kinase 1 (JNK1) resulted in miR-122 down-regulation with the induction of PTP1B. A dominant-negative mutant of JNK1 had the opposite effect. JNK1 facilitated inactivating phosphorylation of hepatocyte nuclear factor 4α (HNF4α) responsible for miR-122 expression, as verified by the lack of HNF4α binding to the gene promoter. The regulatory role of JNK1 in PTP1B induction by a decrease in miR-122 level was strengthened by cell-based assays using isoliquiritigenin and liquiritigenin (components in Glycyrrhizae radix) as functional JNK inhibitors; JNK inhibition enabled cells to restore IR and IRS1/2 tyrosine phosphorylation and insulin signaling against tumor necrosis factor alpha, and prevented PTP1B induction. Moreover, treatment with each of the agents increased miR-122 levels and abrogated hepatic insulin resistance in mice fed a high-fat diet, causing a glucose-lowering effect. CONCLUSION:Decreased levels of miR-122 as a consequence of HNF4α phosphorylation by JNK1 lead to hepatic insulin resistance through PTP1B induction, which may be overcome by chemical inhibition of JNK.
10.1002/hep.25912
Novel plant-derived target drugs: a step forward from licorice?
Lorusso Vito,Marech Ilaria
Expert opinion on therapeutic targets
Isoliquiritigenin (ISL) is a chalcone compound with valuable pharmacological properties such as antioxidant, anti-inflammatory, anticancer and anti-allergic activities. With regard to anticancer property, ISL was able to suppress HIF-1α level, VEGF expression and secretion, cell migration and to decrease the expression and secretion of MMP-9/-2. These effects may be mediated through inhibition of p38, PI3K/Akt and NF-κB signaling pathways. Thus, low concentration of ISL may have therapeutic potential in the treatment of aggressive breast carcinoma and other neoplasms.
10.1517/14728222.2013.773312
Isoliquiritigen enhances the antitumour activity and decreases the genotoxic effect of cyclophosphamide.
Molecules (Basel, Switzerland)
The aim of this study was to evaluate the antitumour activities and genotoxic effects of isoliquiritigenin (ISL) combined with cyclophosphamide (CP) in vitro and in vivo. U14 cells were treated with either of ISL (5-25 μg/mL) or CP (0.25-1.25 mg/mL) alone or with combination of ISL (5-25 μg/mL) and CP (1.0 mg/mL) for 48 h. The proliferation inhibitory effect in vitro was evaluated by MTT and colony formation assays. KM mice bearing U14 mouse cervical cancer cells were used to estimate the antitumour activity in vivo. The genotoxic activity in bone marrow polychromatic erythrocytes was assayed by frequency of micronuclei. The DNA damage in peripheral white blood cells was assayed by single cell gel electrophoresis. The results showed that ISL enhanced antitumour activity of CP in vitro and in vivo, and decreased the micronucleus formation in polychromatic erythrocytes and DNA strand breaks in white blood cells in a dose-dependent way.
10.3390/molecules18088786
Liquiritigenin derivatives and their hepatotoprotective activity.
Gaur Rashmi,Kumar Sunil,Trivedi Priyanka,Bhakuni Rajendra Singh,Bawankule Dnyaneshwar Umrao,Pal Anirban,Shanker Karuna
Natural product communications
Liquiritigenin (7,4'-dihydroxyflavanone), isolated from the roots of Glycyrrhiza glabra, was derivatized to liquiritigenin 7, 4'-diacetate, liquiritigenin 4'-acetate, isoliquiritigenin, and liquiritigenin 7, 4'-dibenzoate. All these derivatives were evaluated for in vitro hepatoprotective activity against D-galactosamine-lipopolysaccharide(GalN/LPS) induced toxicity. In-vitro hepatotoxicity was manifested by a significant increase (P < 0.05) in liver toxicity biomarkers (SGPT, SGOT, ALKP, triglyceride, LPO, NO and LDH). The level of biomarkers in the treatment groups was significantly decreased (P < 0.05) when compared with the GalN/LPS group. The results revealed that isoliquiritigenin exhibited better hepatoprotective activity than liquiritigenin and its derivatives.
The inhibitory effect of roasted licorice extract on human metastatic breast cancer cell-induced bone destruction.
Lee Sun Kyoung,Park Kwang-Kyun,Park Jung Han Yoon,Lim Soon Sung,Chung Won-Yoon
Phytotherapy research : PTR
The aim of this study was to determine whether the ethanol extract of roasted licorice (rLE) could inhibit breast cancer-mediated bone destruction. rLE treatment reduced the viability of MDA-MB-231 human metastatic breast cancer cells but did not show any cytotoxicity in hFOB1.19 human osteoblastic cells and murine bone marrow-derived macrophages (BMMs). rLE inhibited expression and secretion of receptor activator of nuclear factor κB ligand (RANKL) as well as the mRNA and protein expression of cyclooxygenase-2 in osteoblastic cells exposed to the conditioned medium of breast cancer cells. rLE dramatically inhibited RANKL-induced osteoclastogenesis in BMMs, thereby reducing osteoclast-mediated pit formation. Moreover, treatment with licochalcone A and isoliquiritigenin as the active components, whose contents are increased by the roasting process, remarkably suppressed RANKL-induced osteoclast formation in BMMs, respectively. Furthermore, orally administered rLE substantially blocked tumor growth and bone destruction in mice inoculated with breast cancer cells in the tibiae. Serum levels of tartrate-resistant acid phosphatase and C-terminal cross-linking telopeptide of type I collagen and trabecular bone morphometric parameters were reversed to almost the same levels as the control mice by the rLE treatment. In conclusion, rLE may be a beneficial agent for preventing and treating bone destruction in patients with breast cancer.
10.1002/ptr.4930
biosynthesis of liquiritin in .
Yin Yan,Li Yanpeng,Jiang Dan,Zhang Xianan,Gao Wei,Liu Chunsheng
Acta pharmaceutica Sinica. B
Liquiritigenin (LG), isoliquiritigenin (Iso-LG), together with their respective glycoside derivatives liquiritin (LN) and isoliquiritin (Iso-LN), are the main active flavonoids of , which is arguably the most widely used medicinal plant with enormous demand on the market, including Chinese medicine prescriptions, preparations, health care products and even food. Pharmacological studies have shown that these ingredients have broad medicinal value, including anti-cancer and anti-inflammatory effects. Although the biosynthetic pathway of glycyrrhizin, a triterpenoid component from , has been fully analyzed, little attention has been paid to the biosynthesis of the flavonoids of this plant. To obtain the enzyme-coding genes responsible for the biosynthesis of LN, analysis and screening were carried out by combining genome and comparative transcriptome database searches of and homologous genes of known flavonoid biosynthesis pathways. The catalytic functions of candidate genes were determined by or characterization. This work characterized the complete biosynthetic pathway of LN and achieved the biosynthesis of liquiritin in using endogenous yeast metabolites as precursors and cofactors for the first time, which provides a possibility for the economical and sustainable production and application of flavonoids through synthetic biology.
10.1016/j.apsb.2019.07.005
Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds.
Denzer Isabel,Münch Gerald,Friedland Kristina
Pharmacological research
Oxidative stress and mitochondrial dysfunction are early events in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Mitochondria are important key players in cellular function based on mitochondrial energy production and their major role in cell physiology. Since neurons are highly depending on mitochondrial energy production due to their high energy demand and their reduced glycolytic capacity mitochondrial dysfunction has fatal consequences for neuronal function and survival. The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) is the major regulator of cellular response to oxidative stress. Activation of Nrf2 induces the transcriptional regulation of antioxidant response element (ARE)-dependent expression of a battery of cytoprotective and antioxidant enzymes and proteins. Moreover, activation of Nrf2 protects mitochondria from dysfunction and promotes mitochondrial biogenesis. Therefore, the Nrf2/ARE pathway has become an attractive target for the prevention and treatment of oxidative stress-related neurodegenerative diseases. Small food-derived inducers of the Nrf2/ARE pathway including l-sulforaphane from broccoli and isoliquiritigenin from licorice displayed promising protection of mitochondrial function in models of oxidative stress and neurodegenerative diseases and represent a novel approach to prevent and treat aging-associated neurodegenerative diseases.
10.1016/j.phrs.2015.11.019
Promotion of regulatory T cell induction by immunomodulatory herbal medicine licorice and its two constituents.
Guo Ao,He Dongming,Xu Hong-Bo,Geng Chang-An,Zhao Jian
Scientific reports
Regulatory T cells (Treg) play a critical role to control immune responses and to prevent autoimmunity, thus selective increase of Treg cells in vivo has broad therapeutic implications for autoimmune and inflammatory diseases. Licorice is a well-known herbal medicine used worldwide for over thousands of years, and accumulating evidence has shown its immunomodulatory potential. However, it is not clear whether licorice could regulate the induction and function of Treg cells. Here we found licorice extract could promote Treg cell induction, and then we used a rational approach to isolate its functional fractions and constituents. The results showed that two constituents, isoliquiritigenin and naringenin, promoted Treg cell induction both in vitro and in vivo. The effective fractions and two constituents of licorice also enhanced immune suppression of Treg cells, and they further reduced severity of DSS-induced colitis in mice. This study suggested that promotion of regulatory T cell induction could be an underlying mechanism of the historically and widely used herbal medicine licorice, providing its two effective molecules against autoimmune and inflammatory diseases.
10.1038/srep14046
Combination of liquiritin, isoliquiritin and isoliquirigenin induce apoptotic cell death through upregulating p53 and p21 in the A549 non-small cell lung cancer cells.
Zhou Yanling,Ho Wing Shing
Oncology reports
Liquiritin, isoliquiritin and isoliquirigenin are the active polyphenols present in Glycyrrhiza uralensis which has been used for the treatment of cancer and its complications. The present study was conducted to evaluate the cytotoxicity and antitumor activity of liquiritin, isoliquiritin and isoliquirigenin on human non-small lung cancer cells including apoptosis-induction, inhibition of apoptotic pathways and to explore the underlying mechanism. Lactate dehydrogenase assays, FITC Annexin V staining assay were performed to evaluate cellular cytotoxicity and apoptosis activity. The results showed that pretreatment with these polyphenols induced apoptosis in A549 cells. Liquiritin, isoliquiritin and isoliquirigenin significantly increased cytotoxicity of, and upregulated p53 and p21 and downregulated the apoptotic pathways. Furthermore, it inhibited cell cycle at the G2/M phase. Western blot analysis showed it significantly decreased the protein expression of PCNA, MDM2, p-GSK-3β, p-Akt, p-c-Raf, p-PTEN, caspase-3, pro-caspase-8, pro-caspase-9 and PARP, Bcl-2 in a concentration-dependent manner while the protein expression of p53, p21 and Bax was increased. In addition, Akt pathway was downregulated. These findings suggest that liquiritin, isoliquiritin and isoliquirigenin inhibited the p53-dependent pathway and showed crosstalk between Akt activities. These active polyphenols can be an alternative agent for the treatment of lung cancer.
10.3892/or.2013.2849
Pharmacokinetic study of four flavones of Glycyrrhiza in rat plasma using HPLC-MS.
Wu Yin-Ping,Meng Xian-Sheng,Bao Yong-Rui,Wang Shuai
Journal of ethnopharmacology
AIM OF THE STUDY:This study aimed to develop a specific HPLC-MS method for simultaneous quantification of four flavones of Glycyrrhiza in rat plasma after oral administration and to describe the pharmacokinetics of four flavones in rat plasma. MATERIALS AND METHODS:A simple, sensitive and selective method for simultaneous determination of four flavones of Glycyrrhiza in rat plasma, i.e., liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS) with negative electrospray ionization mode, was developed and validated. The method was applied to investigate the pharmacokinetics of four flavones in rat plasma after oral administration of Glycyrrhiza flavones. Chromatographic separation was accomplished on an Agilent TC-C18 column (4.6mm×250mm, and 5μm), with gradient elution by using a mixture of methanoic acid (A) and acetonitrile (B) as the mobile phase at a flow rate of 0.8mL/min. RESULTS:The calibration curves for four flavones had good linearity higher than 0.997 in the measured range. Relative standard deviations (RSDs) of the intra- and inter-day precision at different levels were all less than 4.8%. The pharmacokinetic profile of four flavones in rat plasma was fitted with a two-compartment model detected by a simple, rapid and accurate HPLC-MS method. Time (h) to reach peak concentration (μg/mL) of liquiritin (2.69±0.04), isoliquiritin (10.16±0.02), liquiritigenin (2.83±0.02), and isoliquiritigenin (0.28±0.01) was 2.02±0.23, 1.97±0.20, 0.48±0.02, and 1.93±0.36, respectively. The distribution and elimination half-life (h) and area under the concentration-time curve (μg/mL-h) from t=0 to last time of liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin were 1.02±0.48/2.27±0.53/16.97±0.43, 2.04±1.01/2.38±0.80/69.20±5.24, 0.35±0.10/4.26±0.16/14.83±0.11, and 1.18±0.32/3.04±0.22/2.10±0.09, respectively. Isoliquiritin presented the phenomenon of double peaks and the others appeared together in a single and plateau absorption phase. Isoliquiritigenin had the lowest oral bioavailability because of Cmax and AUC0-∞. Liquiritigenin had the fastest absorption and distribution rate and the lowest elimination rate according to Tmax, t1/2α, and t1/2β. CONCLUSIONS:This paper first reported on identification and determination of four flavones of Glycyrrhiza in rat plasma and their respective pharmacokinetic characteristics. The results provided a meaningful basis for better understanding the absorption mechanism of Glycyrrhiza and evaluating the clinical application of this medicine.
10.1016/j.jep.2013.04.024
Transport of active flavonoids, based on cytotoxicity and lipophilicity: an evaluation using the blood-brain barrier cell and Caco-2 cell models.
Yang Yuya,Bai Lu,Li Xiaorong,Xiong Jie,Xu Pinxiang,Guo Chenyang,Xue Ming
Toxicology in vitro : an international journal published in association with BIBRA
This in vitro study aims to evaluate and compare transmembrane transport of eight cardio-cerebrovascular protection flavonoids including puerarin, rutin, hesperidin, quercetin, genistein, kaempferol, apigenin and isoliquiritigenin via the rat blood-brain barrier cell and Caco-2 cell monolayer models, based on the data of cytotoxicity and lipophilicity. The cytotoxicity of the flavonoids to rat brain microvessel endothelial cell was determined by the MTT assay. The apparent permeability coefficients (Papp) of the flavonoids were calculated from the unilateral transport assays in Transwell system with simultaneous determination using a high performance liquid chromatography. The results showed that the cytotoxicity and oil-water partition coefficient of the flavonoids modified by the number and position of the glycoside and hydroxyl group were the key determinant for the transmembrane transport. The Papp values of the flavonoids reduced adversely when the numbers of glycoside and hydroxyl groups of the flavonoids increased accordingly. The tested flavonoids exhibited time-dependent Papp values in these models. The efflux mechanism related with P-glycoprotein also existed with the polar flavonoids; verapamil could enhance the permeation of rutin and quercetin via inhibition of P-glycoprotein. We propose that genistein and isoliquiritigenin with the permeation priority in vitro Caco-2 and BBB cell model could be better as the drug candidates for cardio-cerebral vascular protection. These findings provided important information for establishing the transport relationship for the flavonoid compounds and evaluating the potential oral bioavailability and brain distribution of the flavonoids.
10.1016/j.tiv.2013.12.002
The genetic and chemical diversity in three original plants of licorice, Glycyrriza uralensis Fisch., Glycyrrhiza inflata Bat. and Glycyrrhiza glabra L.
Yang Rui,Li Wendong,Yuan Bochuan,Ren Guangxi,Wang Liqiang,Cheng Ting,Liu Ying
Pakistan journal of pharmaceutical sciences
Licorice is one of the most frequently used Chinese herbs, mainly containing triterpenoids and flavonoids. Three original plants, Glycyrrhiza glabra L., Glycyrrhiza uralensis Fisch., and Glycyrrhiza inflata Bat., are defined as licorice in Chinese pharmacopeia. In this study, 40 G. uralensis samples (Group A), 60 G. glabra samples (Group B, C and D) and 40 G. inflata samples (Group E and F), were used as plant materials, the genetic diversity of samples were determined by gene sequencing technology and the chemotypic diversity were detected by HPLC. The chemotypic diversity analysis showed that contents of triterpenoids in G. glabra (isoglycyrrhizin: 2.483±0.0671 mg∙g, glycyrrhizin: 34.660±0.8591 mg∙g) were obviously higher than that in G. uralensis and G. inflata. However, the contents of flavonoids (liquiritin: 21.996±0.6396 mg∙g-1, isoliquiritin: 4.556±0.1252 mg∙g-1, liquiritigenin: 0.623±0.0200 mg∙g-1, isoliquiritigenin: 0.281±0.008 mg∙g-1) in G. uralensis were higher than that in G. glabra and G. inflata. And contents of triterpenoids and flavonoids were both lowest in G. inflata. The genetic diversity analysis showed that the psbA-trnH intergenic regions on chloroplast DNA sequences were same in the same species, and significantly different between any two species. These findings will lay a solid foundation for the identification and quality control of licorice. Furthermore, recently the activity of isoglycyrrhizin has attracted more and more attentions and researches. The HPLC method established in this paper for the simultaneous assay of isoglycyrrhizin and glycyrrhizin will be helpful for the screening of superior quality licorice with a high content of isoglycyrrhizin.
The constituents of licorice () differentially suppress nitric oxide production in interleukin-1β-treated hepatocytes.
Tanemoto Ryunosuke,Okuyama Tetsuya,Matsuo Hirotaka,Okumura Tadayoshi,Ikeya Yukinobu,Nishizawa Mikio
Biochemistry and biophysics reports
Licorice (Glycyrrhizae radix) is the roots and stolons of Fischer or Linnaeus in the Japanese Pharmacopoeia. Glycyrrhizae radix has been widely used as a sweetener and a traditional medicine. A Glycyrrhizae radix extract contains many constituents and has antispasmodic, antitussive, anti-ulcer, and anti-inflammatory effects. However, reports comparing the anti-inflammatory effects of these constituents are very few. Here, we purified several constituents from the roots and stolons of and examined and compared their anti-inflammatory effects by monitoring the levels of the inflammatory mediator, nitric oxide (NO), in interleukin (IL)-1β-treated rat hepatocytes. From the extract, we purified the main constituent glycyrrhizin and the constituents that are characteristic of (chalcones and flavanones). These constituents suppressed NO production in IL-1β-treated rat hepatocytes, and isoliquiritigenin showed the greatest suppression activity. Isoliquiritigenin, isoliquiritin, and liquiritigenin significantly decreased both protein and mRNA for the inducible nitric oxide synthase. These constituents reduced the levels of mRNAs encoding tumor necrosis factor α and IL-6. In contrast, although glycyrrhizin is abundant, it showed a 100-fold lower potency in NO suppression. Therefore, both glycyrrhizin and the minor constituents (isoliquiritigenin, isoliquiritin, and liquiritigenin) may be responsible for the anti-inflammatory effects of . It is also implied that these constituents may have a therapeutic potential for inflammatory hepatic disorders.
10.1016/j.bbrep.2015.06.004
Screening of hepatoprotective compounds from licorice against carbon tetrachloride and acetaminophen induced HepG2 cells injury.
Kuang Yi,Lin Yan,Li Kai,Song Wei,Ji Shuai,Qiao Xue,Zhang Qingying,Ye Min
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Licorice and its constituents, especially licorice flavonoids have been reported to possess significant hepatoprotective activities. However, previous studies mainly focus on the extract and major compounds, and few reports are available on other licorice compounds. PURPOSE:This work aims to evaluate the in vitro hepatoprotective activities of licorice compounds and screen active compounds, and to establish the structure-activity relationship. METHODS:A compound library consisting of 180 compounds from three medicinal licorice species, Glycyrrhiza uralensis, G. glabra and G. inflata was established. HepG2 cells were incubated with the compounds, together with the treatment of 0.35% CCl for 6 h and 14 mM APAP for 24 h, respectively. RESULTS:A total of 62 compounds at 10 µM showed protective effects against CCl to improve cell viability from 52.5% to >60%, and compounds 5 (licoflavone A), 104 (3,4-didehydroglabridin), 107 (isoliquiritigenin), 108 (3,4,3',4'-tetrahydroxychalcone), and 111 (licochalcone B) showed the most potent activities, improving cell viability to >80%. And 64 compounds showed protective effects against APAP to improve cell viability from 52.0% to >60%, and compounds 47 (derrone), 76 (xambioona), 77 ((2S)-abyssinone I), 107 (isoliquiritigenin), 118 (licoagrochalcone A), and 144 (2'-O-demethybidwillol B) showed the most potent activities, improving cell viability to >80%. Preliminary structure-activity analysis indicated that free phenolics compounds especially chalcones showed relatively stronger protective activities than other types of compounds. CONCLUSION:Compounds 5, 76, 104, 107, 111, 118 and 144 possess potent activities against both CCl and APAP, and 5, 76 and 118 were reported for the first time. They could be the major active compounds of licorice for the treatment of liver injury.
10.1016/j.phymed.2017.08.005
Flavonoids derived from liquorice suppress murine macrophage activation by up-regulating heme oxygenase-1 independent of Nrf2 activation.
Wang Rui,Zhang Cheng Yue,Bai Li Ping,Pan Hu Dan,Shu Li Min,Kong Ah-Ng Tony,Leung Elaine Lai-Han,Liu Liang,Li Ting
International immunopharmacology
Liquiritigenin (LQG), isoliquiritin (ILQ) and isoliquiritigenin (ILG) are flavonoids derived from liquorice and all possess a similar chemical structural backbone. In the current study, we found that ILQ and ILG had suppressive effects on lipopolysaccharide (LPS)-induced inflammatory responses in murine macrophage by suppressing the iNOS and COX-2 proteins and mRNA expression. A mechanistic study indicated that the effect was associated with an induction of antioxidant and detoxification enzymes, including UGT1A1, NQO1, and heme oxygenase-1 (HO-1) mRNA expression. The regulator of these enzymes, nuclear factor-erythroid 2-related factor 2 (Nrf2), which plays a critical role in LPS-induced inflammatory responses, could be activated by ILQ and ILG. Additionally, ILQ and ILG promoted Nrf2 signaling activation by inhibiting the Kelch-like ECH-associated protein 1 (Keap1) and increasing Nrf2 translocation, inducing the expression of these antioxidant enzymes. We further found that ILQ and ILG induced HO-1 expression independent of Nrf2 expression. With respect to the effect of these compounds on NF-κB signaling, ILG was found to markedly inhibit IκBα degradation and phosphorylation, while LQG and ILQ had no significant effects. These results indicate that there are correlations between the anti-inflammatory responses and the chemical structural properties of these flavonoids.
10.1016/j.intimp.2015.03.040
Isoliquiritigenin, from Dalbergia odorifera, up-regulates anti-inflammatory heme oxygenase-1 expression in RAW264.7 macrophages.
Lee S H,Kim J Y,Seo G S,Kim Y-C,Sohn D H
Inflammation research : official journal of the European Histamine Research Society ... [et al.]
OBJECTIVES:Isoliquiritigenin (ISL), one of the major constituents of Dalbergia odorifera T. Chen (Leguminosae), is reported to exert anti-inflammatory effects, but the relevant anti-inflammatory mechanisms are not completely understood. Heme oxygenase-1 (HO-1) has been proven to be involved in the resolution of inflammatory responses. In this study, we investigated whether ISL could induce HO-1 expression in RAW264.7 macrophages, and if so, whether HO-1 could mediate the anti-inflammatory effects of ISL. METHODS:The protein expression of inducible nitric oxide synthase and HO-1 was analyzed by western blot analysis. The production of nitric oxide (NO) and interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) was assayed by Griess and ELISA, respectively. The TNF-alpha and HO-1 mRNA expression was analyzed by northern blot analysis. RESULTS:ISL markedly suppressed LPS-induced NO, IL-1beta, and TNF-alpha production. ISL induced HO-1 expression through the extracellular signal-regulated kinase1/2 pathway in RAW264.7 macrophages. The effects of ISL on LPS-induced NO and TNF-alpha production were reversed by the HO-1 inhibitor, tin protoporphyrin. CONCLUSIONS:ISL is an effective HO-1 inducer capable of inhibiting macrophage-derived inflammation.
10.1007/s00011-008-8183-6
AMPK-mediated GSK3beta inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress.
Choi Song Hwa,Kim Young Woo,Kim Sang Geon
Biochemical pharmacology
Isoliquiritigenin (ILQ), a flavonoid compound originated from Glycyrrhiza species, is known to activate SIRT1. Arachidonic acid (AA) in combination with iron (a catalyst of auto-oxidation) leads cells to produce excess reactive species with a change in mitochondrial permeability transition. In view of the importance of oxidative stress in cell death and inflammation, this study investigated the potential of ILQ to protect cells against the mitochondrial impairment induced by AA+iron and the underlying basis for this cytoprotection. Treatment with ILQ inhibited apoptosis induced by AA+iron, as evidenced by alterations in the levels of the proteins associated with cell viability: ILQ prevented a decrease in Bcl-x(L), and cleavage of poly(ADP-ribose)polymerase and procaspase-3. Moreover, ILQ inhibited the ability of AA+iron to elicit mitochondrial dysfunction. In addition, superoxide generation in mitochondria was attenuated by ILQ treatment. Consistently, ILQ prevented cellular H2O2 production increased by AA+iron, thereby enabling cells to restore GSH content. ILQ treatment enhanced inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3beta), and prevented a decrease in the GSK3beta phosphorylation elicited by AA+iron, which contributed to protecting cells and mitochondria. GSK3beta phosphorylation by ILQ was preceded by AMP-activated protein kinase (AMPK) activation, which was also responsible for mitochondrial protection, as shown by reversal of its effect in the experiments using a dominant negative mutant of AMPK and compound C. Moreover, the AMPK activation led to GSK3beta phosphorylation. These results demonstrate that ILQ has the ability to protect cells from AA+iron-induced H2O2 production and mitochondrial dysfunction, which is mediated with GSK3beta phosphorylation downstream of AMPK.
10.1016/j.bcp.2009.12.011
Cancer chemopreventive activity and metabolism of isoliquiritigenin, a compound found in licorice.
Cuendet Muriel,Guo Jian,Luo Yan,Chen Shaonong,Oteham Carol P,Moon Richard C,van Breemen Richard B,Marler Laura E,Pezzuto John M
Cancer prevention research (Philadelphia, Pa.)
Isoliquiritigenin (2',4',4-trihydroxychalcone; ILG), a chalcone found in licorice root and many other plants, has shown potential chemopreventive activity through induction of phase II enzymes such as quinone reductase-1 in murine hepatoma cells. In this study, the in vivo metabolism of ILG was investigated in rats. In addition, ILG glucuronides and ILG-glutathione adducts were observed in human hepatocytes and in livers from rats treated with ILG. ILG glucuronides were detected in both plasma and rat liver tissues. In addition, in a full-term cancer chemoprevention study conducted with 7,12-dimethylbenz(a)anthracene-treated female Sprague-Dawley rats, dietary administration of ILG slightly increased tumor latency but had a negative effect on the incidence of mammary tumors starting at approximately 65 days after 7,12-dimethylbenz(a)anthracene administration. Further, no significant induction of phase II enzymes was found in mammary glands, which is consistent with the low level of ILG observed in these tissues. However, ILG significantly induced quinone reductase-1 activity in the colon, and glutathione as well as glutathione S-transferase in the liver. Analysis of mRNA expression in tissues of rats treated with ILG supported these findings. These results suggest that ILG should be tested for chemopreventive efficacy in nonmammary models of cancer.
10.1158/1940-6207.CAPR-09-0049
Mammalian target of rapamycin pathway promotes tumor-induced angiogenesis in adenoid cystic carcinoma: its suppression by isoliquiritigenin through dual activation of c-Jun NH2-terminal kinase and inhibition of extracellular signal-regulated kinase.
Sun Zhi-Jun,Chen Gang,Zhang Wei,Hu Xiang,Huang Cong-Fa,Wang Yu-Fan,Jia Jun,Zhao Yi-Fang
The Journal of pharmacology and experimental therapeutics
Tumor-induced angiogenesis is essential for invasive growth and hematogenous metastasis of adenoid cystic carcinoma (ACC), a highly aggressive neoplasm mostly occurring in salivary glands. Previous studies have indicated that strategies directed against angiogenesis will help develop new therapeutic agents for ACC. The Chinese folk medicine licorice has been used for years as a natural remedy for angiogenesis-related diseases. In this study, we examined the effects of isoliquiritigenin (ISL), a flavonoid isolated from licorice, on the growth and viability of ACC cells and observed a concentration-dependent (0-20 microM) inhibition of cell growth without cell death at 24 h. In a further mimic coculture study, ISL effectively suppressed the ability of ACC cells to induce in vitro proliferation, migration, and tube formation of human endothelial hybridoma (EAhy926) cells as well as ex vivo and in vivo angiogenesis, whereas it exerted no effect on EAhy926 cells when added directly or in the presence of vascular endothelial growth factor (VEGF). The data also showed that the specific suppression of tumor angiogenesis by ISL was caused by down-regulation of mammalian target of rapamycin (mTOR) pathway-dependent VEGF production by ACC cells, correlating with concurrent activation of c-Jun NH(2)-terminal kinase (JNK) and inhibition of extracellular signal-regulated kinase (ERK). Most importantly, ISL also significantly decreased microvessel density within xenograft tumors, associating with the reduction of VEGF production and suppression of the mTOR pathway coregulated by JNK and ERK, as revealed by immunohistochemical studies and clustering analysis. Taken together, our results highlight the fact that ISL is a novel inhibitor of tumor angiogenesis and possesses great therapeutic potential for ACC.
10.1124/jpet.110.167692
Sensitivity and resistance towards isoliquiritigenin, doxorubicin and methotrexate in T cell acute lymphoblastic leukaemia cell lines by pharmacogenomics.
Youns Mahmoud,Fu Yu-Jie,Zu Yuan-Gang,Kramer Anne,Konkimalla V Badireenath,Radlwimmer Bernhard,Sültmann Holger,Efferth Thomas
Naunyn-Schmiedeberg's archives of pharmacology
The development of drug resistance in cancer cells necessitates the identification of novel agents with improved activity towards cancer cells. In the present investigation, we compared the cytotoxicity of the chalcone flavonoide, isoliquiritigenin (ISL), with that of doxorubicin (DOX) and methotrexate (MTX) in five T cell acute lymphoblastic leukaemia (T-ALL) cell lines (Jurkat, J-Jhan, J16, HUT78 and Karpas 45). To gain insight into the molecular mechanisms which determine the response of T-ALL cells towards ISL, DOX and MTX, we applied array-based matrix comparative genomic hybridisation and microarray-based mRNA expression profiling and compared the genomic and transcriptomic profiles of the cell lines with their 50% inhibition (IC(50)) values for these three drugs. The IC(50) values for ISL did not correlate with those for DOX or MTX, indicating that ISL was still active in DOX- or MTX-unresponsive cell lines. Likewise, the genomic imbalances of chromosomal clones and mRNA expression profile significantly correlating with IC(50) values for ISL were different from thoses correlating with IC(50) values for DOX and MTX. In conclusion, ISL represents a cytotoxic natural product with activity towards T-ALL cell lines. There was no cross-resistance between ISL and DOX or MTX, and the genomic and transcriptomic profiles pointed to different molecular modes of action of ISL as compared to DOX and MTX, indicating that ISL may be a valuable adjunct for cancer therapy to treat otherwise drug-resistant tumours.
10.1007/s00210-010-0541-6
Isoliquiritigenin, a flavonoid from licorice, plays a dual role in regulating gastrointestinal motility in vitro and in vivo.
Chen Gang,Zhu Lingxin,Liu Yang,Zhou Qian,Chen Hao,Yang Jing
Phytotherapy research : PTR
Licorice root has been used for years to regulate gastrointestinal function in traditional Chinese medicine. This study reveals the gastrointestinal effects of isoliquiritigenin, a flavonoid isolated from the roots of Glycyrrhiza glabra (a kind of Licorice). In vivo, isoliquiritigenin produced a dual dose-related effect on the charcoal meal travel, inhibitory at the low doses, while prokinetic at the high doses. In vitro, isoliquiritigenin showed an atropine-sensitive concentration-dependent spasmogenic effect in isolated rat stomach fundus. However, a spasmolytic effect was observed in isolated rabbit jejunums, guinea pig ileums and atropinized rat stomach fundus, either as noncompetitive inhibition of agonist concentration-response curves, inhibition of high K(+) (80 mM)-induced contractions, or displacement of Ca(2+) concentration-response curves to the right, indicating a calcium antagonist effect. Pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME; 30 microM), indomethacin (10 microM), methylene blue (10 microM), tetraethylammonium chloride (0.5 mM), glibenclamide (1 microM), 4-aminopyridine (0.1 mM), or clotrimazole (1 microM) did not inhibit the spasmolytic effect. These results indicate that isoliquiritigenin plays a dual role in regulating gastrointestinal motility, both spasmogenic and spasmolytic. The spasmogenic effect may involve the activating of muscarinic receptors, while the spasmolytic effect is predominantly due to blockade of the calcium channels.
10.1002/ptr.2660
Inhibition of liver X receptor-α-dependent hepatic steatosis by isoliquiritigenin, a licorice antioxidant flavonoid, as mediated by JNK1 inhibition.
Kim Young Mi,Kim Tae Hyun,Kim Young Woo,Yang Yoon Mee,Ryu Da Hye,Hwang Se Jin,Lee Jong Rok,Kim Sang Chan,Kim Sang Geon
Free radical biology & medicine
Isoliquiritigenin (ILQ), a flavonoid obtained from Glycyrrhizae species, has an antioxidant effect. This study investigated the potential of ILQ for inhibiting liver X receptor-α (LXRα)-mediated lipogenesis and steatosis in hepatocytes and its underlying molecular basis. Treatment with ILQ antagonized the ability of an LXRα agonist (T0901317) to activate sterol regulatory element binding protein-1c (SREBP-1c), thereby repressing transcription of fatty acid synthase, acetyl-CoA carboxylase, ATP-binding cassette transporter-A1, and stearoyl-CoA desaturase-1. ILQ treatment inhibited activating phosphorylation of JNK1 elicited by palmitate or TNFα. JNK1, but not JNK2, increased LXRα phosphorylation at serine residues, promoting LXRα activation. The ability of ILQ to inhibit JNK1 downstream of ASK1-MKK7 led to the repression of T0901317-inducible LXRα and SREBP-1c activation. In mice fed a high-fat diet, ILQ treatment inhibited hepatic steatosis, as shown by a decrease in fat accumulation and repression of lipogenic genes. The results of blood biochemistry and histopathology confirmed attenuation of high-fat diet-induced liver injury by ILQ. Moreover, ILQ inhibited oxidative stress, as indicated by decreases in thiobarbituric acid-reactive substance formation, iNOS and COX2 induction, and nitrotyrosinylation. Our results demonstrate that ILQ has the ability to repress LXRα-dependent hepatic steatosis through JNK1 inhibition and protect hepatocytes from oxidative injury inflicted by fat accumulation.
10.1016/j.freeradbiomed.2010.09.001
Isoliquiritigenin treatment induces apoptosis by increasing intracellular ROS levels in HeLa cells.
Yuan Xuan,Zhang Bo,Chen Na,Chen Xiao-Yu,Liu Liang-Liang,Zheng Qiu-Sheng,Wang Zhi-Ping
Journal of Asian natural products research
This study focuses on the relationship between the apoptosis induced by isoliquiritigenin (ISL) and the production of reactive oxygen species (ROS). Cell viability was evaluated using sulforhodamine B assay. The apoptotic rate was determined via flow cytometry. Intracellular ROS level was assessed using the 2,7-dichlorofluorescein probe assay. Poly-ADP-ribose polymerase (PARP) protein expression was examined using Western blot analysis. The results showed that ISL treatment inhibited cell proliferation by inducing apoptosis. The increased apoptotic rate and ROS production induced by ISL were inhibited by the co-treatment of ISL and free radical scavenger N-acetyl-cysteine (NAC), catalase (CAT), and 4,5-dihydroxyl-1,3-benzededisulfonic acid (Tiron). On the contrary, the increased apoptotic rate and the ROS production were compensated by the co-treatment of ISL and l-buthionine-(S,R)-sulfoximine (BSO). ISL treatment increased the degradation of PARP, which was counteracted by antioxidants (NAC or CAT), whereas the combination treatment of ISL and pro-oxidant (BSO) enhanced the PARP degradation induced by ISL. Our findings suggested that ISL treatment induced apoptosis by increasing intracellular ROS levels in HeLa cells.
10.1080/10286020.2012.694873
Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cells.
Zhang Xiaoyu,Yeung Eddie D,Wang Jingying,Panzhinskiy Evgeniy E,Tong Chao,Li Wenguang,Li Ji
Clinical and experimental pharmacology & physiology
1. Isoliquiritigenin (ISL) is a simple chalcone-type flavonoid derived from liquorice compounds. It has been reported to have anti-oxidative and antitumour activities. The aim of the present study was to investigate the antitumour effect of ISL on prostate cancer cells and to explore the possible signalling mechanisms involved. 2. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The fluorescent probe 2',7'-dichlorofluorescein diacetate (H(2)DCF-DA) was used to measure intracellular levels of reactive oxygen species (ROS). Mitochondrial membrane potential (Psi(m)) was measured using the mitochondrial probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC-1). 3. Isoliquiritigenin treatment (10-100 micromol/L for 24 h) markedly inhibited the proliferation of both C4-2 and LNCaP prostate cancer cells in a dose-dependent manner. Intriguingly, ISL treatment (10-100 micromol/L for 24 h) had no effect on the viability of IEC-6 normal epithelial cells. Treatment of C4-2 and IEC-6 cells with 87.0 micromol/L ISL significantly decreased ROS levels and the Psi(m) of C4-2 cells, but had no effect on either parameter in IEC-6 cells. Furthermore, AMP-activated protein kinase (AMPK) and extracellular-signal regulated kinase (ERK) levels were three to fourfold higher in IEC-6 cells than in C4-2 cells (P < 0.05). 4. The results of the present study suggest that ISL, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer C4-2 cells, which may be attributed, in part, to defective AMPK and ERK signalling pathways in C4-2 compared with IEC-6 cells.
10.1111/j.1440-1681.2010.05395.x
Isoliquiritigenin isolated from licorice Glycyrrhiza uralensis prevents 6-hydroxydopamine-induced apoptosis in dopaminergic neurons.
Hwang Cheol Kyu,Chun Hong Sung
Bioscience, biotechnology, and biochemistry
Licorice (Glycyrrhiza uralensis) is a medicinal herb containing various bioactive components implicated in antioxidative, anti-inflammatory, antiviral, and neuroprotective effects, but the effects of licorice against Parkinson's disease (PD)-related dopaminergic cell death have not been studied. In this study, we investigated the protective effects of isoliquiritigenin (ISL) isolated from Glycyrrhiza uralensis on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in a dopaminergic cell line, SN4741. ISL (1 µM) significantly attenuated 6-OHDA (50 µM)-induced reactive oxygen species (ROS) and nitric oxide (NO) generation and apoptotic cell death. ISL pretreatment effectively suppressed 6-OHDA-mediated upregulation of Bax, p-c-Jun N-terminal kinase (JNK), p-p38 mitogen-activated protein (MAP) kinase, cytochrome c release, and caspase 3 activation. In addition, ISL significantly attenuated 6-OHDA-induced Bcl-2, brain-derived neurotrophic factor (BDNF), and mitochondrial membrane potential (MMP) reduction. Pharmacological inhibitors of the phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway reversed ISL-mediated neuroprotection against 6-OHDA toxicity in SN4741 cells. These results provide the first evidence that ISL can protect dopaminergic cells under oxidative stress conditions by regulating the apoptotic process.
10.1271/bbb.110842
Isoliquiritigenin Attenuates Monocrotaline-Induced Pulmonary Hypertension via Inhibition of the Inflammatory Response and PASMCs Proliferation.
Jin Haifeng,Jiang Yang,Du Fengxia,Guo Linna,Wang Guan,Kim Sang Chan,Lee Chul Won,Shen Lei,Zhao Rongjie
Evidence-based complementary and alternative medicine : eCAM
Pulmonary hypertension (PH) is a progressive and serious disease, where exacerbated inflammatory response plays a critical role. Isoliquiritigenin (ISL), an important flavonoid isolated from Glycyrrhizae radix, exhibits a wide range of pharmacological actions including anti-inflammation. Previously we found ISL alleviated hypoxia-induced PH; in the present study, to extend this, we evaluated the effects of ISL on monocrotaline (MCT)-induced PH and the relevant mechanisms. Rats received a single intraperitoneal injection of MCT, followed by intragastric treatments with ISL (10 mg/kg/d or 30 mg/kg/d) once a day for 28 days. The MCT administration increased the right ventricular systolic pressure (RVSP) ( < 0.001), the median width of pulmonary arteries ( < 0.01), and the weight ratio of the right ventricular wall/left ventricular wall plus septum (Fulton index) ( < 0.01) in rats; however, these changes were inhibited by both doses of ISL ( < 0.05). In addition, treatment with ISL suppressed the upregulated production of serum interleukin-6 ( < 0.01) and tumor necrosis factor- ( < 0.05) by MCT and reversed the increases in the numbers of proliferating cell nuclear antigen (PCNA)-positive cells ( < 0.01) in the medial wall of pulmonary arteries. In in vitro experiments, ISL (10 M, 30 M, and 100 M) inhibited excessive proliferation of cultured primary pulmonary artery smooth muscle cells (PASMCs) ( < 0.05, < 0.01, and < 0.001) in a dose-dependent manner and prevented an increase in the expressions of PCNA ( < 0.01) and phospho-Akt ( < 0.05) in PASMCs induced by hypoxia. These results suggest that ISL can attenuate MCT-induced PH via its anti-inflammatory and antiproliferative actions.
10.1155/2019/4568198
The Protective Effects of Isoliquiritigenin and Glycyrrhetinic Acid against Triptolide-Induced Oxidative Stress in HepG2 Cells Involve Nrf2 Activation.
Cao Ling-Juan,Li Huan-De,Yan Miao,Li Zhi-Hua,Gong Hui,Jiang Pei,Deng Yang,Fang Ping-Fei,Zhang Bi-Kui
Evidence-based complementary and alternative medicine : eCAM
Triptolide (TP), an active ingredient of Tripterygium wilfordii Hook f., possesses a wide range of biological activities. Oxidative stress likely plays a role in TP-induced hepatotoxicity. Isoliquiritigenin (ISL) and glycyrrhetinic acid (GA) are potent hepatoprotection agents. The aim of the present study was to investigate whether Nrf2 pathway is associated with the protective effects of ISL and GA against TP-induced oxidative stress or not. HepG2 cells were treated with TP (50 nM) for 24 h after pretreatment with ISL and GA (5, 10, and 20 μM) for 12 h and 24 h, respectively. The results demonstrated that TP treatment significantly increased ROS levels and decreased GSH levels. Both ISL and GA pretreatment decreased ROS and meanwhile enhanced intracellular GSH content. Additionally, TP treatment obviously decreased the protein expression of Nrf2 and its target genes including HO-1 and MRP2 except NQO1. Moreover, both ISL and GA displayed activities as inducers of Nrf2 and increased the expression of HO-1, NQO1, and MRP2. Taken together the current data confirmed that ISL and GA could activate the Nrf2 antioxidant response in HepG2 cells, increasing the expression of its target genes which may be partly associated with their protective effects in TP-induced oxidative stress.
10.1155/2016/8912184
The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells.
Alshangiti Amnah M,Togher Katie L,Hegarty Shane V,Sullivan Aideen M,O'Keeffe Gerard W
Neuronal signaling
Neuroblastoma (NB) is the most common extracranial solid tumor of early childhood; it accounts for approximately 8-10% of all childhood cancers and is the most common cancer in children in the first year of life. Patients in the high-risk group have a poor prognosis, with relapses being common and often refractory to drug treatment in those that survive. Moreover, the drug treatment itself can lead to a range of long-term sequelae. Therefore, there is a critical need to identify new therapeutics for NB. Isoliquiritigenin (ISLQ) is a naturally-occurring, dietary chalcone-type flavonoid with a range of biological effects that depend on the cell type and context. ISLQ has potential as an anticancer agent. Here we show that ISLQ has potent cytotoxic effects on SK-N-BE(2) and IMR-32 human NB cells, which carry amplification of the gene, the main prognostic marker of poor survival in NB. ISLQ was found to increase cellular reactive oxygen species (ROS). The cytotoxic effect of ISLQ was blocked by small molecule inhibitors of oxidative stress-induced cell death, and by the antioxidant N-acetyl-l-cysteine (NAC). Combined treatment of either SK-N-B-E(2) or IMR-32 cells with ISLQ and the anticancer agent cisplatin resulted in loss of cell viability that was greater than that induced by cisplatin alone. This study provides proof-of-principle that ISLQ is a potent cytotoxin for MYCN-amplified human NB cells. This is an important first step in rationalizing the further study of ISLQ as a potential adjunct therapy for high-risk NB.
10.1042/NS20180201
Isoliquiritigenin inhibits the growth of multiple myeloma via blocking IL-6 signaling.
Chen Xiangzheng,Wu Yangping,Jiang Yangfu,Zhou Yan,Wang Yuxi,Yao Yuqin,Yi Cheng,Gou Lantu,Yang Jinliang
Journal of molecular medicine (Berlin, Germany)
Previous studies have suggested that isoliquiritigenin (ISL) has anti-carcinogenic activity in several kinds of solid tumors, however, little is known about the effects of ISL on hematologic malignancies. In this study, we investigated the effects of ISL on multiple myeloma (MM) cells both in vitro and in vivo. The results showed that ISL could inhibit the growth of MM cells and induce their apoptosis in time- and dose-dependent manners. ISL exhibited significant anti-tumor activity in MM xenograft models and synergistically enhanced the anti-myeloma activity of adriamycin. Further analysis demonstrated that ISL not only downregulated IL-6 expression but also significantly decreased levels of phosphorylated ERK and STAT3 and could inhibit phosphorylation levels of ERK and STAT3 induced by recombinant human IL-6, which are critical signaling proteins in IL-6 signaling regulation networks. Taken together, our findings suggested that ISL could inhibit the growth of MM via blocking IL-6 signaling and might serve as a promising therapeutic agent for treatment of MM.
10.1007/s00109-012-0910-3
Isoliquiritigenin enhances radiosensitivity of HepG2 cells via disturbance of redox status.
Sun Chao,Zhang Hong,Ma Xiao-fei,Zhou Xin,Gan Lu,Liu Yuan-yuan,Wang Zhen-hua
Cell biochemistry and biophysics
Redox balance plays an important role in the maintenance of cell growth and survival. Disturbance of this equilibrium can alter normal cellular processes. Excessive reactive oxygen species (ROS) are often found in cancer cells. However, cancer cells have an efficient antioxidant system to counteract the increased generation of ROS. This high antioxidant capacity also favors resistance to drugs and radiation. Here, we show that isoliquiritigenin (ISL), a natural antioxidant, effectively decreased ROS in HepG2 cells in a time-dependant manner at 0.5, 1, and 2 h of treatment. The decreased ROS caused redox imbalance and reductive stress. To adapt to this state, nuclear factor erythroid-2-related factor 2, which regulates the antioxidant enzyme system, was significantly decreased. Antioxidant enzymes reached their lowest level at 6 h after ISL treatment. Endogenous ROS were still being generated so after 6 h of ISL treatment, ROS were clearly higher than before ISL treatment, causing redox imbalance in the HepG2 cells which changed from reductive to oxidative stress. At this stage, cells were irradiated with X-rays. The excess ROS induced serious oxidative stress, resulting in radiosensitization. Therefore, we concluded that ISL induced oxidative stress by disturbing the redox status and ultimately enhancing the radiosensitivity of HepG2 cells.
10.1007/s12013-012-9447-x
A new approach for pharmacokinetic studies of natural products: measurement of isoliquiritigenin levels in mice plasma, urine and feces using modified automated dosing/blood sampling system.
Han Seung Yon,Chin Young-Won,Choi Young Hee
Biomedical chromatography : BMC
The present study was undertaken to investigate the pharmacokinetics of isoliquiritigenin (isoLQ) as determined by the automated dosing/blood sampling (ABS) and traditional manual blood sampling techniques in awake and freely moving mice using combined liquid chromatography tandem mass spectrometry. Pharmacokinetic comparison was conducted by allocating mice into two groups; an ABS group (intravenous study and oral studies, n = 5 each) and a manual group (intravenous and oral studies; n = 5 each). Significant differences in pharmacokinetic parameters (area under the curve and clearances) were observed between ABS and manual groups. This could be mainly due to the blood sampling site difference (via heart puncture in traditional manual group and via carotid artery in ABS groups). The low F of isoLQ could be mainly due to a considerable gastrointestinal and/or hepatic first-pass effect and not to incomplete absorption. The driving force for distribution and elimination of drugs is its concentration in the arterial blood. Therefore, the ABS method was found to be a useful drug development tool for accelerating the process of preclinical in vivo studies and for obtaining reliable and accurate pharmacokinetic parameters in mice.
10.1002/bmc.2854
Isoliquiritigenin Inhibits Metastatic Breast Cancer Cell-induced Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin Ratio in Human Osteoblastic Cells.
Lee Sun Kyoung,Park Kwang-Kyun,Kim Ki Rim,Kim Hyun-Jeong,Chung Won-Yoon
Journal of cancer prevention
Bone destruction induced by the metastasis of breast cancer cells is a frequent complication that is caused by the interaction between cancer cells and bone cells. Receptor activator of nuclear factor kappa-B ligand (RANKL) and the endogenous soluble RANKL inhibitor, osteoprotegerin (OPG), directly play critical roles in the differentiation, activity, and survival of osteoclasts. In patients with bone metastases, osteoclastic bone resorption promotes the majority of skeletal-related events and propagates bone metastases. Therefore, blocking osteoclast activity and differentiation via RANKL inhibition can be a promising therapeutic approach for cancer-associated bone diseases. We investigated the potential of isoliquiritigenin (ISL), which has anti-proliferative, anti-angiogenic, and anti-invasive effects, as a preventive and therapeutic agent for breast cancer cell-induced bone destruction. ISL at non-toxicity concentrations significantly inhibited the RANKL/OPG ratio by reducing the production of RANKL and restoring OPG production to control levels in hFOB1.19 cells stimulated with conditioned medium (CM) of MDA-MB-231 cells. In addition, ISL reduced the expression of cyclooxygenase-2 in hFOB1.19 cells stimulated by CM of MDA-MB-231 cells. Therefore, ISL may have inhibitory potential on breast cancer-induced bone destruction.
10.15430/JCP.2015.20.4.281
The Flavonoid Isoliquiritigenin Reduces Lung Inflammation and Mouse Morbidity during Influenza Virus Infection.
Traboulsi Hussein,Cloutier Alexandre,Boyapelly Kumaraswamy,Bonin Marc-André,Marsault Éric,Cantin André M,Richter Martin V
Antimicrobial agents and chemotherapy
The host response to influenza virus infection is characterized by an acute lung inflammatory response in which intense inflammatory cell recruitment, hypercytokinemia, and a high level of oxidative stress are present. The sum of these events contributes to the virus-induced lung damage that leads to high a level of morbidity and mortality in susceptible infected patients. In this context, we identified compounds that can simultaneously reduce the excessive inflammatory response and the viral replication as a strategy to treat influenza virus infection. We investigated the anti-inflammatory and antiviral potential activities of isoliquiritigenin (ILG). Interestingly, we demonstrated that ILG is a potent inhibitor of influenza virus replication in human bronchial epithelial cells (50% effective concentration [EC50] = 24.7 μM). In addition, our results showed that this molecule inhibits the expression of inflammatory cytokines induced after the infection of cells with influenza virus. We demonstrated that the anti-inflammatory activity of ILG in the context of influenza virus infection is dependent on the activation of the peroxisome proliferator-activated receptor gamma pathway. Interestingly, ILG phosphate (ILG-p)-treated mice displayed decreased lung inflammation as depicted by reduced cytokine gene expression and inflammatory cell recruitment. We also demonstrated that influenza virus-specific CD8(+) effector T cell recruitment was reduced up to 60% in the lungs of mice treated with ILG-p (10 mg/kg) compared to that in saline-treated mice. Finally, we showed that administration of ILG-p reduced lung viral titers and morbidity of mice infected with the PR8/H1N1 virus.
10.1128/AAC.01098-15
Isoliquiritigenin Inhibits Proliferation and Induces Apoptosis via Alleviating Hypoxia and Reducing Glycolysis in Mouse Melanoma B16F10 Cells.
Wang Yanming,Ma Jun,Yan Xinyan,Chen Xiaoyu,Si Lingling,Liu Ying,Han Jichun,Hao Wenjin,Zheng Qiusheng
Recent patents on anti-cancer drug discovery
BACKGROUND:Isoliquiritigenin (ISL) is a licorice chalcone. According to CN104758274, CN101658513 and US009089546, it is claimed that ISL has anti-inflammatory, anti-oxidative, and anti-tumoral effects. OBJECTIVE:This study aimed to investigate the potential therapeutic effect of ISL in mouse melanoma B16F10 cells. METHODS:Sulforhodamine B (SRB) colorimetric assay was used to test the effects of ISL on proliferation. Commercial assay kits were applied to assess glucose uptake, lactate production and ATP levels. Measurement of apoptosis was involved with Hoechst 33258, JC-1 and annexin V-FITC/PI staining. H2DCFDA probe was employed to detect ROS generation. Quantitative RT-PCR and western blot were utilized to measure the mRNA and protein levels. RESULTS:ISL abated hypoxia-inducible factor 1α (HIF-1α) stability and reduced a series of glycolysis-relevant enzymes expression, including glucose transporters 1/4 (GLUT 1/4), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Exposure to ISL induced the mitochondrial membrane potential depolarization and increased intracellular reactive oxygen species (ROS) level. ISL could effectively inhibit proliferation and alleviate hypoxia in mouse melanoma B16F10 cells via inducing apoptosis and reducing the expression of significant enzymes in the glycolysis. ISL significantly inhibited B16F10 cell proliferation via inducing apoptosis, and alleviated hypoxia by recovering mitochondrial function and reversing high glycolysis. CONCLUSION:Our findings propose that ISL can be a promising therapeutic agent for the melanoma via reliving hypoxia of microenvironment and targeting energy metabolism system of cancer cells. Consistent with WO2015079213 and WO2014084494, targeting glycolysis can be an effective means to anti-cancer.
10.2174/1573406412666160307151904
Synthesis and anti-tumor activity of novel aminomethylated derivatives of isoliquiritigenin.
Fu Haoran,Zhang Yuhang,Wang Xiqing,Han Yingzhi,Peng Xiao,Efferth Thomas,Fu Yujie
Molecules (Basel, Switzerland)
A series of new aminomethylated derivatives of isoliquiritigenin was synthesized. The structures of the compounds were confirmed by IR, MS, NMR, 13C-NMR and elemental analyses. Cytotoxic activities of these derivatives towards the human prostatic cell line PC-3, human mammary cancer cell line MCF-7 and human oophoroma cell line HO-8910 in vitro were tested. The IC50 values showed cytotoxic activities of some of these new derivatives were relatively strong. Furthermore, tumor growth inhibition in vivo of aminomethylated derivatives of isoliquiritigenin 15 was superior to that of isoliquritigenin and reached inhibition rates of 71.68%. The detailed synthesis, spectroscopic data, biological and pharmacologicalactivities of the synthesized compounds were provided.
10.3390/molecules191117715
Pharmacokinetics, biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration.
Qiao Hua,Zhang Xiaoyun,Wang Ting,Liang Li,Chang Wei,Xia Huxiong
Pharmaceutical biology
CONTEXT:Isoliquiritigenin (ISL) has been shown to exhibit a variety of biological activities. However, there is little research on the pharmacokinetic behavior and tissues distribution of ISL. OBJECTIVE:Pharmacokinetics, biodistribution and bioavailability of ISL after intravenous and oral administration were determined by systematic investigation in Sprague-Dawley rats. MATERIALS AND METHODS:ISL was dissolved in medicinal ethanol-Tween 80-0.9% sodium chloride saline in a volume ratio of 10:15:75. The ISL solution was injected in rats via a tail vein at a single dose of 10, 20 and 50 mg/kg and administered orally in rats at a single dose of 20, 50 and 100 mg/kg, respectively. Blood samples were collected at time intervals of 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8 and 12 h after intravenous injection. Tissues of interests in mice were collected immediately at each determined time point (0.5, 1, 2, 3 and 6 h) after cervical dislocation. RESULTS:The dose-normalized AUC values were 7.3, 7.6 and 8.7 μg × h/ml (calculated based on the dose of 10 mg/kg) for intravenous doses of 10, 20 and 50 mg/kg, respectively. The elimination half-lifes (t1/2λ) were 4.9, 4.6 and 4.8 h at 10, 20 and 50 mg/kg intravenous doses, respectively. The F values were 29.86, 22.70, 33.62% for oral doses of 20, 50 and 100 mg/kg, respectively. Liver, heart and kidney were major distribution tissues of ISL in mice. The plasma protein binding of ISL in rats was 43.72%. CONCLUSION:The work may useful for further study of the bioactive mechanism of ISL.
10.3109/13880209.2013.832334
Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters.
Hou Zhenyan,Chen Lei,Fang Pingfei,Cai Hualin,Tang Huaibo,Peng Yongbo,Deng Yang,Cao Lingjuan,Li Huande,Zhang Bikui,Yan Miao
Frontiers in pharmacology
Triptolide (TP), the main bioactive component of Hook F, can cause severe hepatotoxicity. Isoliquiritigenin (ISL) has been reported to be able to protect against TP-induced liver injury, but the mechanisms are not fully elucidated. This study aims to explore the role of nuclear transcription factor E2-related factor 2 (Nrf2) and hepatic transporters in TP-induced hepatotoxicity and the reversal protective effect of ISL. TP treatment caused both cytotoxicity in L02 hepatocytes and acute liver injury in mice. Particularly, TP led to the disorder of bile acid (BA) profiles in mice livers. Combined treatment of TP with ISL effectively alleviated TP-induced hepatotoxicity. Furthermore, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations and its downstream NAD(P)H: quinine oxidoreductase 1 (NQO1) expression. Expressions of hepatic P-gp, MRP2, MRP4, bile salt export pump, and OATP2 were also induced. In addition, transport assays identified that neither was TP exported by MRP2, OATP1B1, or OATP1B3, nor did TP influence the transport activities of P-gp or MRP2. All these results indicate that ISL may reduce the hepatic oxidative stress and hepatic accumulations of both endogenous BAs and exogenous TP as well as its metabolites by enhancing the expressions of Nrf2, NQO1, and hepatic influx and efflux transporters. Effects of TP on hepatic transporters are mainly at the transcriptional levels, and changes of hepatic BA profiles are very important in the mechanisms of TP-induced hepatotoxicity.
10.3389/fphar.2018.00226
Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin From Radix Glycyrrhizae in Human Health and Disease Models.
Ramalingam Mahesh,Kim Hyojung,Lee Yunjong,Lee Yun-Il
Frontiers in aging neuroscience
The increasing lifespan in developed countries results in age-associated chronic diseases. Biological aging is a complex process associated with accumulated cellular damage by environmental or genetic factors with increasing age. Aging results in marked changes in brain structure and function. Age-related neurodegenerative diseases and disorders (NDDs) represent an ever-growing socioeconomic challenge and lead to an overall reduction in quality of life around the world. Alzheimer's disease (AD) and Parkinson's disease (PD) are most common degenerative neurological disorders of the central nervous system (CNS) in aging process. The low levels of acetylcholine and dopamine are major neuropathological feature of NDDs in addition to oxidative stress, intracellular calcium ion imbalance, mitochondrial dysfunction, ubiquitin-proteasome system impairment and endoplasmic reticulum stress. Current treatments minimally influence these diseases and are ineffective in curing the multifunctional pathological mechanisms. Synthetic neuroprotective agents sometimes have negative reactions as an adverse effect in humans. Recently, numerous ethnobotanical studies have reported that herbal medicines for the treatment or prevention of NDDs are significantly better than synthetic drug treatment. Medicinal herbs have traditionally been used around the world for centuries. Radix Glycyrrhizae (RG) is the dried roots and rhizomes of or or from the Leguminosae/Fabaceae family. It has been used for centuries in traditional medicine as a life enhancer, for the treatment of coughs and influenza, and for detoxification. Diverse chemical constituents from RG have reported including flavanones, chalcones, triterpenoid saponins, coumarines, and other glycosides. Among them, flavanone liquiritigenin (LG) and its precursor and isomer chalcone isoliquiritigenin (ILG) are the main bioactive constituents of RG. In the present review, we summarize evidence in the literature on the structure and phytochemical properties and pharmacological applications of LG and ILG in age-related diseases to establish new therapeutics to improve human health and lifespan.
10.3389/fnagi.2018.00348
Isoliquiritigenin reduces oxidative damage and alleviates mitochondrial impairment by SIRT1 activation in experimental diabetic neuropathy.
Yerra Veera Ganesh,Kalvala Anil Kumar,Kumar Ashutosh
The Journal of nutritional biochemistry
Sirtuin (SIRT1) inactivation underlies the pathogenesis of insulin resistance and hyperglycaemia-associated vascular complications, but its role in diabetic neuropathy (DN) has not been yet explored. We have evaluated hyperglycaemia-induced alteration of SIRT1 signalling and the effect of isoliquiritigenin (ILQ) on SIRT1-directed AMP kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signalling in peripheral nerves of streptozotocin (STZ) (55 mg/kg, ip)-induced diabetic rats and in high glucose (30 mM)-exposed neuro2a (N2A) cells. Diabetic rats and high glucose-exposed N2A cells showed reduction in SIRT1 expression with consequent decline in mitochondrial biogenesis and autophagy. ILQ (10 & 20 mg/kg, po) administration to diabetic rats for 2 weeks and exposure to glucose-insulted N2A cells resulted in significant SIRT1 activation with concurrent increase in mitochondrial biogenesis and autophagy. ILQ administration also enhanced NAD/NADH ratio in peripheral sciatic nerves which explains its possible SIRT1 modulatory effect. Functional and behavioural studies show beneficial effect of ILQ as it alleviated nerve conduction and nerve blood flow deficits in diabetic rats along with improvement in behavioural parameters (hyperalgesia and allodynia). ILQ treatment to N2A cells reduced high glucose-driven ROS production and mitochondrial membrane depolarization. Further, ILQ-mediated SIRT1 activation facilitated the Nrf2-directed antioxidant signalling. Overall, results from this study suggest that SIRT1 activation by ILQ mimic effects of calorie restriction, that is, PGC-1α-mediated mitochondrial biogenesis, FOXO3a mediated stress resistance and AMPK mediated autophagy effects to counteract the multiple manifestations in experimental DN.
10.1016/j.jnutbio.2017.05.001
Syntheses and evaluation of novel isoliquiritigenin derivatives as potential dual inhibitors for amyloid-beta aggregation and 5-lipoxygenase.
Chen Yi-Ping,Zhang Zi-Ying,Li Yan-Ping,Li Ding,Huang Shi-Liang,Gu Lian-Quan,Xu Jun,Huang Zhi-Shu
European journal of medicinal chemistry
A series of new isoliquiritigenin (ISL) derivatives were synthesized and evaluated as dual inhibitors for amyloid-beta (Aβ) aggregation and 5-lipoxygenase (5-LO). It was found that all these synthetic compounds inhibited Aβ (1-42) aggregation effectively with their IC₅₀ values ranged from 2.2 ± 1.5 μM to 23.8 ± 2.0 μM. These derivatives also showed inhibitory activity to 5-LO with their IC50 values ranged from 6.1 ± 0.1 μM to 35.9 ± 0.3 μM. Their structure-activity relationships (SAR) and mechanisms of inhibitions were studied. This study provided potentially important information for further development of ISL derivatives as multifunctional agents for Alzheimer's disease (AD) treatment.
10.1016/j.ejmech.2013.05.015
A Review: The Pharmacology of Isoliquiritigenin.
Peng Fu,Du Qiaohui,Peng Cheng,Wang Neng,Tang Hailin,Xie Xiaoming,Shen Jiangang,Chen Jianping
Phytotherapy research : PTR
Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, Mongolian glycyrrhiza, Glycyrrhiza glabra, and so forth. Liquiritigenin is available in common foods and alternative medicine, and its derivative-ISL is applied into food additives and disease treatment like cancer therapy, antibiotic therapy, and so on. This review aims at providing a comprehensive summary of the pharmacological activities of ISL. The information published between 1972 and 2014 from a number of reliable sources including PubMed, ScienceDirect, Springer, and Wiley-Blackwell. The practical application of ISL on the various disease prevention and treatments may stem from its numerous pharmacological properties such as antiinflammatory, anti-microbial, anti-oxidative, anticancer activities, immunoregulatory, hepatoprotective, and cardioprotective effects. However, further studies are needed to verify the target-organ toxicity or side effects investigation.
10.1002/ptr.5348
Experimental and Theoretical Investigations on the Supermolecular Structure of Isoliquiritigenin and 6-O-α-D-Maltosyl-β-cyclodextrin Inclusion Complex.
Li Bin,Liu Benguo,Li Jiaqi,Xiao Huizhi,Wang Junyi,Liang Guizhao
International journal of molecular sciences
Isoliquiritigenin (ILTG) possesses many pharmacological properties. However, its poor solubility and stability in water hinders its wide applications. The solubility of bioactive compounds can often be enhanced through preparation and delivery of various cyclodextrin (CD) inclusion complexes. The 6-O-α-D-maltosyl-β-CD (G2-β-CD), as one of the newest developments of CDs, has high aqueous solubility and low toxicity, especially stable inclusion characteristics with bioactive compounds. In this work, we for the first time construct and characterize the supermolecular structure of ILTG/G2-β-CD by scanning electron microscopy (SEM), ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffractometry (XRD). The solubility of ILTG in water at 25 °C rises from 0.003 to 0.717 mg/mL by the encapsulation with G2-β-CD. Our experimental observations on the presence of the ILTG/G2-β-CD inclusion complex are further supported by the ONIOM(our Own N-layer Integrated Orbital molecular Mechanics)-based QM/MM (Quantum Mechanics/Molecular Mechanics) calculations, typically substantiating these supermolecular characteristics, such as detailed structural assignments, preferred binding orientations, selectivity, solvent effects, interaction energies and forces of the ILTG/G2-β-CD inclusion complex. Our results have elucidated how ILTG interacts with G2-β-CD, demonstrating the primary host-guest interactions between ILTG and G2-β-CD, characterized by hydrogen bonds, hydrophobic interactions, electrostatic forces, and conformational effects, are favored for the formation of the ILTG/G2-β-CD inclusion.
10.3390/ijms160817999
Preparation and evaluation of isoliquiritigenin-loaded F127/P123 polymeric micelles.
Xie Yu-Jiao,Wang Qi-Long,Adu-Frimpong Michael,Liu Jian,Zhang Kang-Yi,Xu Xi-Ming,Yu Jiang-Nan
Drug development and industrial pharmacy
Isoliquiritigenin (ISL) possesses a variety of pharmacological activities amid poor solubility in water which has restricted its clinical application. In this study, isoliquiritigenin-loaded F127/P123 polymeric micelles (ISL-FPM) were successfully prepared and evaluated and . The particle size, polydispersity index, and zeta potential of the selected formulation were 20.12 ± 0.72 nm, 0.183 ± 0.046, and -38.31 ± 0.33 mV, respectively, coupled with high encapsulation efficiency of 93.76 ± 0.31%. Drug-loading test showed the solubility of ISL after formulating into micelles was 232 times higher than its intrinsic solubility. Moreover, critical micelle concentration (CMC) was tested with fluorescence probe method and turned out to be quite low, which implied high stability of ISL-FPM. Release profile in HCl (pH 1.2), double distilled water, and PBS (pH 7.4) of ISL-FPM reached over 80%, while free ISL was around 40%. Pharmacokinetic research revealed that formulated ISL-FPM significantly increased bioavailability by nearly 2.23-fold compared to free ISL. According to the results of antioxidant activity, scavenging DPPH activity of ISL was significantly strengthened when it was loaded into polymeric micelles. Altogether, ISL-FPM can act as a promising approach to improve solubility as well as enhance bioavailability and antioxidant activity of ISL.
10.1080/03639045.2019.1574812
Isoliquiritigenin Ameliorates Acute Pancreatitis in Mice via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway.
Oxidative medicine and cellular longevity
Oxidative stress plays a crucial role in the pathogenesis of acute pancreatitis (AP). Isoliquiritigenin (ISL) is a flavonoid monomer with confirmed antioxidant activity. However, the specific effects of ISL on AP have not been determined. In this study, we aimed to investigate the protective effect of ISL on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, dynamic changes in oxidative stress injury of the pancreatic tissue were observed after AP onset. We found that ISL administration reduced serum amylase and lipase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. Meanwhile, ISL decreased the oxidative stress injury and increased the protein expression of the Nrf2/HO-1 pathway. In addition, after administering a Nrf2 inhibitor (ML385) or HO-1 inhibitor (zinc protoporphyrin) to block the Nrf2/HO-1 pathway, we failed to observe the protective effects of ISL on AP in mice. Furthermore, we found that ISL mitigated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by L-arginine. Taken together, our data for the first time confirmed the protective effects of ISL on AP in mice via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway.
10.1155/2018/7161592
Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin.
Boyapelly Kumaraswamy,Bonin Marc-André,Traboulsi Hussein,Cloutier Alexandre,Phaneuf Samuel C,Fortin Daniel,Cantin André M,Richter Martin V,Marsault Eric
Journal of natural products
Isoliquiritigenin (1) possesses a variety of biological activities in vitro. However, its poor aqueous solubility limits its use for subsequent in vivo experimentation. In order to enable the use of 1 for in vivo studies without the use of toxic carriers or cosolvents, a phosphate prodrug strategy was implemented relying on the availability of phenol groups in the molecule. In this study, a phosphate group was added to position C-4 of 1, leading to the more water-soluble prodrug 2 and its ammonium salt 3, which possesses increased stability compared to 2. Herein are reported the synthesis, characterization, solubility, and stability of phosphate prodrug 3 in biological medium in comparison to 1, as well as new results on its anti-inflammatory properties in vivo. As designed, the solubility of prodrug 3 was superior to that of the parent natural product 1 (9.6 mg/mL as opposed to 3.9 μg/mL). Prodrug 3 as an ammonium salt was also found to possess excellent stability as a solid and in aqueous solution, as opposed to its phosphoric acid precursor 2.
10.1021/acs.jnatprod.6b00600
Preparation, Properties and Preclinical Pharmacokinetics of Low Molecular Weight Heparin-modified Isoliquiritigenin-loaded Solid Lipid Nanoparticle.
Zhang Xiaoyun,Qiao Hua,Chen Ying,Li Lin,Xia Huxiong,Shi Yanbin
Iranian journal of pharmaceutical research : IJPR
Low molecular weight heparin-modified isoliquiritigenin-loaded solid lipid nanoparticle (LMWH-ISL-SLN) was developed for injective application. The morphological observation, particle diameter and zeta potential of LMWH-ISL-SLN were characterized using transmission electron microscopy (TEM) and a Malvern Zetasizer. Its entrapment efficiency (EE) and drug loading (DL) were determined by ultracentrifuge. The release experiments were performed by dialysis technique. The cytotoxic effects of LMWH-ISL-SLN on Hep-G2 cell lines were determined using an MTT assay. Pharmacokinetic and tissue distribution studies were conducted in kunming mice after intravenous administration of LMWH-ISL-SLN. The average drug entrapment efficiency for LMWH-ISL-SLN was (99.80 ± 3.27)%, drug loading was (18.68 ± 1.51)%, mean particle size was (217.53 ± 4.86) nm and zeta potential was (-18.24 ± 2.47) mV. The release experiments demonstrated isoliquiritigenin release from LMWH-ISL-SLN was in line with Weibull's distribution law. Hemolysis test and dose-related toxic effects proved that LMWH-ISL-SLN was a safe and non toxic product when given by intravenous injection. The pharmacokinetics results of LMWH-ISL-SLN showed that the area under the concentration-time curve (AUC)of LMWH-ISL-SLN was greater than that for the isoliquiritigenin solution in plasma. Tissue distribution study indicated that ISL were mainly distributed in the liver and lung. In conclusion, low molecular weight heparin-modified SLN system is a promising carrier for the intravenous delivery of ISL.
Differentiation-inducing and anti-proliferative activities of isoliquiritigenin and all-trans-retinoic acid on B16F0 melanoma cells: Mechanisms profiling by RNA-seq.
Chen Xiaoyu,Yang Ming,Hao Wenjin,Han Jichun,Ma Jun,Wang Caixia,Sun Shiguo,Zheng Qiusheng
Gene
Melanoma is a cancer that arises from melanocytes, specialized pigmented cells that are found predominantly in the skin. The incidence of malignant melanoma has significantly increased over the last decade. With the development of therapy, the survival rate of some kind of cancer has been improved greatly. But the treatment of melanoma remains unsatisfactory. Much of melanoma's resistance to traditional chemotherapy is believed to arise intrinsically, by virtue of potent growth and cell survival-promoting genetic alteration. Therefore, significant attention has recently been focused on differentiation therapy, as well as differentiation inducer compounds. In previous study, we found isoliquiritigenin (ISL), a natural product extracted from licorice, could induce B16F0 melanoma cell differentiation. Here we investigated the transcriptional response of melanoma differentiation process induced by ISL and all-trans-retinoic acid (RA). Results showed that 390 genes involves in 201 biochemical pathways were differentially expressed in ISL treatment and 304 genes in 193 pathways in RA treatment. Differential expressed genes (DGEs, fold-change (FC)≥10) with the function of anti-proliferative and differentiation inducing indicated a loss of grade malignancy characteristic. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated glutathione metabolism, glycolysis/gluconeogenesis and pentose phosphate pathway were the top three relative pathway perturbed by ISL, and mitogen-activated protein kinase (MAPK) signaling pathway was the most important pathway in RA treatment. In the analysis of hierarchical clustering of DEGs, we discovered 72 DEGs involved in the process of drug action. We thought Cited1, Tgm2, Xaf1, Cd59a, Fbxo2, Adh7 may have critical role in the differentiation of melanoma. The evidence displayed herein confirms the critical role of reactive oxygen species (ROS) in melanoma pathobiology and provides evidence for future targets in the development of next-generation biomarkers and therapeutics.
10.1016/j.gene.2016.07.052
Isoliquiritigenin attenuates lipopolysaccharide-induced cognitive impairment through antioxidant and anti-inflammatory activity.
Zhu Xiaobo,Liu Jiankun,Chen Shaojie,Xue Jiang,Huang Shanying,Wang Yibiao,Chen Ou
BMC neuroscience
BACKGROUND:Oxidative stress and neuroinflammation are central pathogenic mechanisms common to many neurological diseases. Isoliquiritigenin (ISL) is a flavonoid in licorice with multiple pharmacological properties, including anti-inflammatory activity, and has demonstrated protective efficacy against acute neural injury. However, potential actions against cognitive impairments have not been examined extensively. We established a rat model of cognitive impairment by intracerebroventricular injection of lipopolysaccharide (LPS), and examined the effects of ISL pretreatment on cognitive function, hippocampal injury, and hippocampal expression of various synaptic proteins, antioxidant enzymes, pro-inflammatory cytokines, and signaling factors controlling anti-oxidant and pro-inflammatory responses. RESULTS:Rats receiving LPS alone demonstrated spatial learning deficits in the Morris water maze test as evidenced by longer average escape latency, fewer platform crossings, and shorter average time in the target quadrant than untreated controls. ISL pretreatment reversed these deficits as well as LPS-induced decreases in the hippocampal expression levels of synaptophysin, postsynaptic density-95, brain-derived neurotrophic factor, superoxide dismutase, glutathione peroxidase, and BCL-2. ISL pretreatment also reversed LPS-induced increases in TUNEL-positive (apoptotic) cells, BAX/BCL-2 ratio, and expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 3. Pretreatment with ISL increased the expression levels of phosphorylated (p)-GSK-3β, nuclear NRF2, HO-1 mRNA, and NQO1 mRNA, and reversed LPS-induced nuclear translocation of nuclear factor (NF)-κB. CONCLUSIONS:ISL protects against LPS-induced cognitive impairment and neuronal injury by promoting or maintaining antioxidant capacity and suppressing neuroinflammation, likely through phosphorylation-dependent inactivation of GSK-3β, enhanced expression of NRF2-responsive antioxidant genes, and suppression of NF-κB-responsive pro-inflammatory genes.
10.1186/s12868-019-0520-x
Preparation, in vitro and in vivo evaluation of isoliquiritigenin-loaded TPGS modified proliposomes.
Liu Jian,Wang Qilong,Adu-Frimpong Michael,Wei Qiuyu,Xie Yujiao,Zhang Kangyi,Wei Chunmei,Weng Wen,Ji Hao,Toreniyazov Elmurat,Xu Ximing,Yu Jiangnan
International journal of pharmaceutics
Isoliquiritigenin (ISL) has a great variety of pharmacological effects especially liver cancer therapy, but its poor solubility, bioavailability and liver targeting have limited its clinical use. In order to solve the aforementioned shortcomings, the TPGS-modified proliposomes loaded with ISL (ISL-TPGS-PLP) was prepared in this study. ISL-TPGS-PLP was fabricated via thin-film dispersion method and was characterized by the appearance, particle size, zeta potential and morphology. HPLC was used to evaluate entrapment efficiency (EE), in vitro release and stability of ISL-TPGS-PLP single or combined while appropriate physicochemical parameters were measured with DLS. Meanwhile, the pharmacokinetics and tissue distribution were also studied after oral administration. The results demonstrated that ISL-TPGS-PLP had a mean size of 23.8 ± 0.9 nm, high EE of 97.33 ± 0.40%. More importantly, nearly 90% ISL was released from ISL-TPGS-PLP within 24 h while only 50% was released from ISL suspension. In the pharmacokinetics study, the area under the curve (AUC of ISL-TPGS-PLP was 1.53 times higher than that of ISL suspension. The Tissue distribution study showed that the ISL released from ISL-TPGS-PLP was higher in the liver than the free ISL suspension. Altogether, ISL-TPGS-PLP could ameliorate the ISL solubility, bioavailability and liver targeting ability, suggesting that ISL-TPGS-PLP could serve as a promising nanocarrier for liver cancer therapy.
10.1016/j.ijpharm.2019.03.034
Isoliquiritigenin decreases the incidence of colitis-associated colorectal cancer by modulating the intestinal microbiota.
Wu Minna,Wu Yaqi,Deng Baoguo,Li Jinsong,Cao Haiying,Qu Yan,Qian Xinlai,Zhong Genshen
Oncotarget
Imbalances in intestinal bacteria correlate with colitis-associated colorectal cancer (CAC). Traditional Chinese medicines have been used to adjust the gut microbiota, and isoliquiritigenin (ISL), a flavonoid extracted from licorice, has shown antitumor efficacy. In this study, the effects of ISL on CAC development and the gut microbiota were evaluated using an azoxymethane and dextran sulphate sodium (AOM/DSS)-induced mouse model of CAC (CACM). Histopathological analysis suggested that ISL reduced tumor incidence in vivo. Moreover, high-throughput sequencing and terminal restriction fragment length polymorphism (T-RFLP) studies of the bacterial 16S rRNA gene revealed that the structure of the gut microbial community shifted significantly following AOM/DSS treatment, and that effect was alleviated by treatment with high-dose ISL (150 mg/kg). Compared to the microbiota in the control mice (CK), the levels of Bacteroidetes decreased and the levels of Firmicutes increased during CAC development. ISL reversed the imbalance at the phylum level and altered the familial constituents of the gut microbiota. Specifically, the abundance of Helicobacteraceae increased after treatment with high-dose ISL, while the abundance of Lachnospiraceae and Rikenellaceae decreased. At the genus level, ISL reduced the abundance of opportunistic pathogens (Escherichia and Enterococcus), and increased the levels of probiotics, particularly butyrate-producing bacteria (Butyricicoccus, Clostridium, and Ruminococcus). Thus, ISL protects mice from AOM/DSS-induced CAC, and ISL and the gut microbiota may have synergistic anti-cancer effects.
10.18632/oncotarget.13347
Drug Resistance Reversal Potential of Isoliquiritigenin and Liquiritigenin Isolated from Glycyrrhiza glabra Against Methicillin-Resistant Staphylococcus aureus (MRSA).
Gaur Rashmi,Gupta Vivek Kumar,Singh Pooja,Pal Anirban,Darokar Mahendra Padurang,Bhakuni Rajendra Singh
Phytotherapy research : PTR
Isoliquiritigenin (ISL) and liquiritigenin (LTG) are structurally related flavonoids found in a variety of plants. Discovery of novel antimicrobial combinations for combating methicillin-resistant Staphylococcus aureus (MRSA) infections is of vital importance in the post-antibiotic era. The present study was taken to explore the in vitro and in vivo combination effect of LTG and ISL with β-lactam antibiotics (penicillin, ampicillin and oxacillin) against mec A-containing strains of MRSA. Minimum inhibitory concentration (MIC) of both LTG and ISL exhibited significant anti-MRSA activity (50-100 µg/mL) against clinical isolates of MRSA. The result of in vitro combination study showed that ISL significantly reduced MIC of β-lactam antibiotics up to 16-folds [∑ fractional inhibitory concentration (FIC) 0.312-0.5], while LTG reduced up to 8-folds (∑FIC 0.372-0.5). Time kill kinetics at graded MIC combinations (ISL/LTG + β-lactam) indicated 3.27-9.79-fold and 2.59-3.48-fold reduction in the growth of clinical isolates of S. aureus respectively. In S. aureus-infected Swiss albino mice model, combination of ISL with oxacillin significantly (p < 0.05, p < 0.01, p < 0.001) lowered the systemic microbial burden in blood, liver, kidney, lung and spleen tissues in comparison with ISL, oxacillin alone as well as untreated control. Considering its synergistic antibacterial effect, we suggest both ISL and LTG as promising compounds for the development of novel antistaphylococcal combinations. Copyright © 2016 John Wiley & Sons, Ltd.
10.1002/ptr.5677
Evidence for Anti-Inflammatory Activity of Isoliquiritigenin, 18β Glycyrrhetinic Acid, Ursolic Acid, and the Traditional Chinese Medicine Plants and , at the Molecular Level.
Zhou Jun-Xian,Wink Michael
Medicines (Basel, Switzerland)
We investigated the effect of root extracts from the traditional Chinese medicine (TCM) plants L., Pall., and the leaf extract of (Thunb.) Lindl., and their six major secondary metabolites, glycyrrhizic acid, 18β glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, paeoniflorin, and ursolic acid, on lipopolysaccharide (LPS)-induced NF-κB expression and NF-κB-regulated pro-inflammatory factors in murine macrophage RAW 264.7 cells. The cytotoxicity of the substances was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. RAW 264.7 cells were treated with LPS (1 μg/mL) or LPS plus single substances; the gene expression levels of NF-κB subunits (RelA, RelB, c-Rel, NF-κB1, and NF-κB2), and of ICAM-1, TNF-α, iNOS, and COX-2 were measured employing real-time PCR; nitric oxide (NO) production by the cells was quantified with the Griess assay; nuclear translocation of NF-κB was visualized by immunofluorescence microscopy with NF-κB (p65) staining. All the substances showed moderate cytotoxicity against RAW 264.7 cells except paeoniflorin with an IC above 1000 μM. extract and extract, as well as 18β glycyrrhetinic acid and isoliquiritigenin at low concentrations, inhibited NO production in a dose-dependent manner. LPS upregulated gene expressions of NF-κB subunits and of ICAM-1, TNF-α, iNOS, and COX-2 within 8 h, which could be decreased by 18β glycyrrhetinic acid, isoliquiritigenin and ursolic acid similarly to the anti-inflammatory drug dexamethasone. NF-κB translocation from cytoplasm to nucleus was observed after LPS stimulation for 2 h and was attenuated by extracts of and , as well as by 18β glycyrrhetinic acid, isoliquiritigenin, and ursolic acid. 18β glycyrrhetinic acid, isoliquiritigenin, and ursolic acid inhibited the gene expressions of ICAM-1, TNF-α, COX-2, and iNOS, partly through inhibiting NF-κB expression and attenuating NF-κB nuclear translocation. These substances showed anti-inflammatory activity. Further studies are needed to elucidate the exact mechanisms and to assess their usefulness in therapy.
10.3390/medicines6020055
Enhancement of Oral Bioavailability and Anti-hyperuricemic Activity of Isoliquiritigenin via Self-Microemulsifying Drug Delivery System.
Zhang Kangyi,Wang Qilong,Yang Qiuxuan,Wei Qiuyu,Man Na,Adu-Frimpong Michael,Toreniyazov Elmurat,Ji Hao,Yu Jiangnan,Xu Ximing
AAPS PharmSciTech
The aim of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for enhancement of the oral bioavailability of isoliquiritigenin (ISL) as well as evaluate its in vivo anti-hyperuricemic effect in rats. The ISL-loaded self-microemulsifying drug delivery system (ISL-SMEDDS) was comprised of ethyl oleate (EO, oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). The ISL-SMEDDS exhibited an acceptable narrow size distribution (44.78 ± 0.35 nm), negative zeta potential (- 10.67 ± 0.86 mV), and high encapsulation efficiency (98.17 ± 0.24%). The in vitro release study indicated that the release rates of the formulation were obviously higher in different release media (HCl, pH 1.2; PBS, pH 6.8; double-distilled water, pH 7.0) compared with the ISL solution. The oral bioavailability of the ISL-SMEDDS was enhanced by 4.71 times in comparison with the free ISL solution. More importantly, ISL-SMEDDS significantly reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in the model rats. Collectively, the prepared ISL-SMEDDS proved to be potential carriers for enhancing the solubility and oral bioavailability of ISL, as well as ameliorating its anti-hyperuricemic effect.
10.1208/s12249-019-1421-0