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    Garcinol promotes neurogenesis in rat cortical progenitor cells through the duration of extracellular signal-regulated kinase signaling. Weng Meng-Shih,Liao Chiung-Ho,Yu Sheng-Yung,Lin Jen-Kun Journal of agricultural and food chemistry Garcinol is a polyisoprenylated benzophenone derivative found in Garcinia indica fruit rind and other species. The potential antioxidative and neuroprotective effects of garcinol in rat cortical astrocyte were demonstrated in our laboratory recently. Here, the effects of garcinol on the neuritogenesis process in cultured cortical progenitor cells were investigated to understand the roles of garcinol in neuronal survival and differentiation. These cells, derived from embryonic day 17 rats, differentiated into EGF-responsive neural precursor cells, would further form neurospheres. Our data exhibited garcinol induced neurite outgrowth in early developing EGF-treated neurospheres and significantly enhanced the expression of neuronal proteins, microtubule-associated protein 2 (MAP-2), and glial fibrillary acidic protein (GFAP). Furthermore, the neuronal marker, high-molecular-weight subunit of neurofilaments (NFH), was highly expressed after 5 μM garcinol treatment in neural precursor cells for 20 days. To identify the extracellular mechanism, rat cortical progenitor cells were treated garcinol and accordingly mediated the sustained activation of extracellular signal-regulated kinase (ERK) for different periods up to 20 h. In this regard, NMDA receptor-mediated calcium influx led to excitotoxic death and activated tyrosine phosphatase which limited the duration of ERK in cultured neurons. MK801, the NMDA receptor antagonist, treatment also induced the sustained phosphorylation of ERK and therefore enhanced neuronal survival. In our observation, garcinol treatment reduced growth factor deprivation-mediated cell death and nuclear import of C/EBPβ levels. Noteworthy, garcinol could promote neurite outgrowth in EGF-responsive neural precursor cells and modulate the ERK pathway in the enhancement of neuronal survival. 10.1021/jf104263s
    Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol. Chen Xin,Zhang Xinyan,Lu Ye,Shim Joong-Youn,Sang Shengmin,Sun Zheng,Chen Xiaoxin Nutrition and cancer Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis. 10.1080/01635581.2012.718032
    Novel Combinatorial Regimen of Garcinol and Curcuminoids for Non-alcoholic Steatohepatitis (NASH) in Mice. Majeed Muhammed,Majeed Shaheen,Nagabhushanam Kalyanam,Lawrence Lincy,Mundkur Lakshmi Scientific reports Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), a chronic liver disease with a significant unmet clinical need. In this study, we examined the protective effects of Garcinia indica extract standardized to contain 20% w/w of Garcinol (GIE) and 95% Curcuminoids w/w from Curcuma longa (Curcuminoids) in a Stelic animal model (STAM) of NASH. The STAM mice developed steatosis, hepatocyte ballooning, and inflammation, which were significantly reduced by the combination of GIE and Curcuminoids, resulting in a lower NAFLD activity score. The treatment reduced fibrosis as observed by Sirius red staining, liver hydroxyproline content and mRNA levels of TGF- β and collagen in the liver. Immunostaining with alpha-smooth muscle actin (α SMA) revealed a significant reduction in hepatic stellate cells. Intriguingly, the combination regimen markedly decreased the mRNA levels of MCP1 and CRP and both mRNA and protein levels of TNF-α. NF-kB, reduced the hepatic and circulating FGF21 levels and altered the nonenzymatic (glutathione) and enzymatic antioxidant markers (Glutathione peroxidase, and superoxide dismutase). Our results suggest that the combination of GIE and Curcuminoids can reduce the severity of NASH by reducing steatosis, fibrosis, oxidative stress, and inflammation. The results suggest that the combinatorial regimen could be an effective supplement to prevent the progression of liver steatosis to inflammation and fibrosis in NASH. 10.1038/s41598-020-64293-w
    Inhibitory effects of garcinol and pterostilbene on cell proliferation and adipogenesis in 3T3-L1 cells. Hsu Chin-Lin,Lin Yu-Jyun,Ho Chi-Tang,Yen Gow-Chin Food & function The aim of this work was to study the effects of garcinol and pterostilbene on cell proliferation and adipogenesis in 3T3-L1 cells. The results showed that garcinol and pterostilbene decreased the cell population growth and caused cell cycle arrest at the G2/M phase in 3T3-L1 preadipocytes. During adipocyte differentiation, both garcinol and pterostilbene had inhibitory effects on fat droplet formation and triacylglycerol accumulation. The data indicated that garcinol and pterostilbene could inhibit the glycerol-3-phosphate dehydrogenase (GPDH) activity by 97.8 and 61.5%, respectively, as compared to the control. Both garcinol and pterostilbene significantly attenuated the protein expressions of PPARγ and C/EBPα during 3T3-L1 adipocyte differentiation. Moreover, garcinol and pterostilbene caused an inhibition of lipid accumulation in the 3T3-L1 adipocyte differentiation phase. Garcinol and pterostilbene also significantly up-regulated the gene expression of adiponectin as well as down-regulated the gene expressions of leptin, resistin, and fatty acid synthase (FAS) in 3T3-L1 adipocyte differentiation. In 3T3-L1 adipocytes, garcinol significantly down-regulated the protein expressions of PPARγ and FAS as well as up-regulated the protein expressions of adipose triglyceride lipase (ATGL) and adiponectin. Garcinol also significantly up-regulated the gene expression of adiponectin as well as down-regulated the gene expressions of leptin and FAS. These results suggest that garcinol and pterostilbene have anti-adipogenic effects on preadipocytes and adipocytes. 10.1039/c1fo10209e
    Garcinol sensitizes breast cancer cells to Taxol through the suppression of caspase-3/iPLA and NF-κB/Twist1 signaling pathways in a mouse 4T1 breast tumor model. Tu Shih-Hsin,Chiou Yi-Shiou,Kalyanam Nagabhushanam,Ho Chi-Tang,Chen Li-Ching,Pan Min-Hsiung Food & function Breast cancer is a significant threat to women's health and has high incidence and mortality. Metastasis in breast cancer patients is a major cause of cancer deaths among women worldwide. Clinical experience suggests that patients with metastatic triple-negative breast cancer (TNBC) relapse quickly and often have chemotherapy resistance. Taxol (paclitaxel) is an effective chemotherapeutic agent for treating metastatic breast cancer, but Taxol at high doses can cause adverse effects and recurrent resistance. Thus, the selection of a synergistic combination therapy is recommended, which is safer and has a more significant response rate than monotherapy. In this study, our strategy is to combine a low dose of Taxol (5 mg kg, i.p.) and garcinol (1 mg kg, i.g.) to investigate the synergistic antitumor and anti-metastasis effects and to determine the underlying mechanisms of these effects in vivo. For the in vivo study, metastasis-specific mouse mammary carcinoma 4T1 cells were inoculated in Balb/c mice to establish an orthotopic primary tumor and spontaneous metastasis model. Tumor growth and metastases were monitored. The mechanisms of synergistic efficacies were evaluated at different signaling pathways, including proliferation, survival, and epithelial-mesenchymal transition (EMT)-regulated metastatic propensity. We demonstrated that garcinol combined with Taxol significantly increased the therapeutic efficacy when compared with either treatment alone. The synergistic antitumor and anti-metastasis effects were enhanced primarily through the induction of Taxol-stimulated G2/M phase arrest and the inhibition of caspase-3/cytosolic Ca-independent phospholipase A2 (iPLA) and nuclear factor-κB (NF-κB)/Twist-related protein 1 (Twist1) drive downstream events including tumor cell repopulation, survival, inflammation, angiogenesis, invasion, and EMT. Our current findings provide the first experimental evidence that a combination of a low dose of Taxol and garcinol is a promising therapeutic strategy for controlling advanced or metastatic breast cancer. Finally, our results also point to the possible role of NF-κB/Twist1 and caspase-3/iPLA signaling pathways as biomarkers to predict the tumor response to treatment. 10.1039/c6fo01588c
    Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Ahmad Aamir,Sarkar Sanila H,Bitar Bassam,Ali Shadan,Aboukameel Amro,Sethi Seema,Li Yiwei,Bao Bin,Kong Dejuan,Banerjee Sanjeev,Padhye Subhash B,Sarkar Fazlul H Molecular cancer therapeutics Anticancer properties of Garcinia indica-derived garcinol are just beginning to be elucidated. We have earlier reported its cancer cell-specific induction of apoptosis in breast cancer cells, which was mediated through the downregulation of NF-κB signaling pathway. To gain further mechanistic insight, here, we show for the first time that garcinol effectively reverses epithelial-to-mesenchymal transition (EMT), that is, it induces mesenchymal-to-epithelial transition (MET) in aggressive triple-negative MDA-MB-231 and BT-549 breast cancer cells. This was associated with upregulation of epithelial marker E-cadherin and downregulation of mesenchymal markers vimentin, ZEB-1, and ZEB-2. We also found that garcinol upregulates the expression of miR-200 and let-7 family microRNAs (miRNAs), which provides a molecular mechanism for the observed reversal of EMT to MET. Transfection of cells with NF-κB p65 subunit attenuated the effect of garcinol on apoptosis induction through reversal of MET to EMT. Forced transfection of p65 and anti-miR-200s could also reverse the inhibitory effect of garcinol on breast cancer cell invasion. Moreover, treatment with garcinol resulted in increased phosphorylation of β-catenin concomitant with its reduced nuclear localization. The results were also validated in vivo in a xenograft mouse model where garcinol was found to inhibit NF-κB, miRNAs, vimentin, and nuclear β-catenin. These novel findings suggest that the anticancer activity of garcinol against aggressive breast cancer cells is, in part, due to reversal of EMT phenotype, which is mechanistically linked with the deregulation of miR-200s, let-7s, NF-κB, and Wnt signaling pathways. 10.1158/1535-7163.MCT-12-0232-T
    Garcinol, a histone acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting non-homologous end joining. Oike Takahiro,Ogiwara Hideaki,Torikai Kohta,Nakano Takashi,Yokota Jun,Kohno Takashi International journal of radiation oncology, biology, physics PURPOSE:Non-homologous end joining (NHEJ), a major pathway used to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through the acetylation of histones by histone acetyltransferases (HATs). However, the effect of compounds with HAT inhibitory activities on the DNA damage response (DDR), including the NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells, remains largely unclear. Here, we investigated whether garcinol, a HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR, and whether it can be used for radiosensitization. METHODS AND MATERIALS:The following assays were used to examine the effect of garcinol on the inhibition of DSB repair, including the following: a conventional neutral comet assay; a cell-based assay recently developed by us, in which NHEJ repair of DSBs on chromosomal DNA was evaluated; the micrococcal nuclease sensitivity assay; and immunoblotting for autophosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We assessed the effect of garcinol on the cell cycle checkpoint after IR treatment by analyzing the phosphorylation levels of checkpoint kinases CHK1 and CHK2 and histone H3, and by cell cycle profile analysis using flow cytometry. The radiosensitizing effect of garcinol was assessed by a clonogenic survival assay, whereas its effects on apoptosis and senescence were examined by annexin V and senescence-associated β-galactosidase (SA-β-Gal) staining, respectively. RESULTS:We found that garcinol inhibits DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with dose enhancement ratios (at 10% surviving fraction) of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. CONCLUSION:These results suggest that garcinol is a radiosensitizer that inhibits NHEJ and facilitates senescence without impairing activation of the cell cycle checkpoint. 10.1016/j.ijrobp.2012.01.017
    Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling. Ahmad Aamir,Sarkar Sanila H,Aboukameel Amro,Ali Shadan,Biersack Bernhard,Seibt Sebastian,Li Yiwei,Bao Bin,Kong Dejuan,Banerjee Sanjeev,Schobert Rainer,Padhye Subhash B,Sarkar Fazlul H Carcinogenesis Garcinol, obtained from Garcinia indica, has exhibited some promising anticancer activity. In particular, our earlier work has demonstrated its ability to inhibit cell proliferation and induction of apoptosis in multiple cancer cell lines representative of breast, prostate, as well as pancreatic cancers. However, its exact mechanism of action remains largely unclear. Here we show that garcinol also targets signal transducer and activator of transcription-3 (STAT-3) signaling pathway. STAT-3 is frequently found to be activated in many cancer types and this is the first report on such action of garcinol leading to its anticancer effects. Garcinol inhibited total, as well as phosphorylated, STAT-3 in breast, prostate and pancreatic cancer cell lines and was also found to inhibit cell invasion of all the cancer cell lines tested. STAT-3 phosphorylation was inhibited by garcinol in a dose-dependent manner. We also observed an inhibitory effect of garcinol on IL-6-induced STAT-3 phosphorylation and production of urokinase-type plasminogen activator, vascular endothelial growth factor and matrix metalloproteinase-9, which might explain the reduced invasion and aggressiveness of cells treated with garcinol. The results were further verified in vivo using MDA-MB-231 breast cancer mouse xenograft model where administration of garcinol significantly inhibited tumor growth, and western blot analysis of remnant tumor lysates showed reduced STAT-3 expression and activation. These results suggest that garcinol may have translational potential as chemopreventive or therapeutic agent against multiple cancers and inhibition of STAT-3 signaling pathway is one of the mechanisms by which garcinol exerts its anticancer effects. 10.1093/carcin/bgs290
    Modulatory effect of garcinol in streptozotocin-induced diabetic Wistar rats. Madhuri Kodikonda,Naik Prakash Ramachandra Archives of physiology and biochemistry The objective of the study was to evaluate the efficacy of garcinol as an antidiabetic candidate in streptozotocin-induced diabetic Wistar rats. Diabetic rats showed a significant increase in the biochemical parameters such as fasting blood glucose, glycated haemoglobin, urea, alanine aminotransferase and aspartate aminotransferase, malondialdehyde, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, atherogenic index and a significant decrease in plasma insulin, HOMA-β-cell functioning index, glycogen, high-density lipoprotein cholesterol, body weight and antioxidant enzyme activities, viz. superoxide dismutase, catalase and reduced glutathione. Oral administration of garcinol (10 and 20 mg/kg body weight/day) for 30 days improved the above-mentioned alterations. The effect produced by the drug was compared with that of glibenclamide, a standard hypoglycaemic drug. These findings reveal that garcinol can be a promising antidiabetic candidate in the future. 10.1080/13813455.2017.1336632
    Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells. Collins Hilary M,Abdelghany Magdy K,Messmer Marie,Yue Baigong,Deeves Sian E,Kindle Karin B,Mantelingu Kempegowda,Aslam Akhmed,Winkler G Sebastiaan,Kundu Tapas K,Heery David M BMC cancer BACKGROUND:Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7. METHODS:Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR. RESULTS:Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as γH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2. CONCLUSION:In summary, although garcinol and curcumin can both inhibit histone acetyltransferase activities, our results show that these compounds have differential effects on cancer cells in culture. Garcinol treatment alters expression of chromatin modifying enzymes in MCF7 cells, resulting in reprogramming of key histone and p53 PTMs and growth arrest, underscoring its potential as a cancer chemopreventive agent. 10.1186/1471-2407-13-37
    HAT inhibitor, garcinol, exacerbates lipopolysaccharide‑induced inflammation in vitro and in vivo. Wang Bin,Lin Ling,Ai Qing,Zeng Tao,Ge Pu,Zhang Li Molecular medicine reports Acetylation modification catalyzed by histone acetyl transferases (HATs) is important for transcriptional regulation. The present study investigated the effects of the HAT inhibitor garcinol on the expression of inflammation‑associated genes in lipopolysaccharide (LPS)‑stimulated RAW264.7 murine macrophages and LPS‑challenged mice. The levels of pro‑inflammatory cytokines were determined by reverse transcription‑quantitative polymerase chain reaction and enzyme‑linked immunosorbent assay. The degree of multi‑organ injury was evaluated by histopathological examination of the lung, determination of the alanine aminotransferase and blood urea nitrogen in plasma samples and by monitoring the survival rate of the experimental animals. The results of the current study demonstrated that garcinol promoted LPS‑induced expression of tumor necrosis factor‑α (TNF‑α) and interleukin‑6 (IL‑6) in RAW264.7 cells. These effects were associated with reduced acetylation of nuclear factor‑κB p65. Additionally, treatment with garcinol enhanced LPS‑induced expression of TNF‑α and IL‑6, exacerbated LPS‑induced lung injury, increased LPS‑induced elevation of plasma alanine aminotransferase and blood urea nitrogen, and reduced the survival rate of LPS‑challenged mice. These data indicated that the HAT inhibitor, garcinol, enhances LPS‑induced inflammation in vitro and in vivo, suggesting that acetylation modification has an important regulatory function during inflammation. 10.3892/mmr.2016.5189
    Garcinol, a polyisoprenylated benzophenone modulates multiple proinflammatory signaling cascades leading to the suppression of growth and survival of head and neck carcinoma. Li Feng,Shanmugam Muthu K,Chen Luxi,Chatterjee Snehajyoti,Basha Jeelan,Kumar Alan Prem,Kundu Tapas K,Sethi Gautam Cancer prevention research (Philadelphia, Pa.) Constitutive activation of proinflammatory transcription factors such as STAT3 and NF-κB plays a pivotal role in the proliferation and survival of squamous cell carcinoma of the head and neck (HNSCC). Thus, the agents that can modulate deregulated STAT3 and NF-κB activation have a great potential both for the prevention and treatment of HNSCC. In the present report, we investigated the potential effects of garcinol, an active component of Garcinia indica on various inflammatory mediators involved in HNSCC progression using cell lines and xenograft mouse model. We found that garcinol inhibited constitutively activated STAT3 in HNSCC cells in a time- and dose-dependent manner, which correlated with the suppression of the upstream kinases (c-Src, JAK1, and JAK2) in HNSCC cells. Also, we noticed that the generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol. Furthermore, garcinol exhibited an inhibitory effect on the constitutive NF-κB activation, mediated through the suppression of TGF-β-activated kinase 1 (TAK1) and inhibitor of IκB kinase (IKK) activation in HNSCC cells. Garcinol also downregulated the expression of various gene products involved in proliferation, survival, and angiogenesis that led to the reduction of cell viability and induction of apoptosis in HNSCC cells. When administered intraperitoneally, garcinol inhibited the growth of human HNSCC xenograft tumors in male athymic nu/nu mice. Overall, our results suggest for the first time that garcinol mediates its antitumor effects in HNSCC cells and mouse model through the suppression of multiple proinflammatory cascades. 10.1158/1940-6207.CAPR-13-0070
    Garcinol Is an HDAC11 Inhibitor. Son Se In,Su Dan,Ho Thanh Tu,Lin Hening ACS chemical biology Garcinol is a natural product from the fruit and is well-known as an antioxidant, anti-inflammatory, and anticancer agent. However, the understanding of its mechanism of action is still incomplete. It has been reported to be a histone acetyltransferase (HAT) inhibitor. Here, we surprisingly found that garcinol is a potent histone deacetylase 11 (HDAC11) inhibitor (IC ∼ 5 μM in vitro with the HPLC assay and IC ∼ 10 μM in the cellular SHMT2 fatty acylation assay), which is comparable to previously reported HDAC11 inhibitors. Additionally, among all the HDACs tested, garcinol specifically inhibits HDAC11 over other HDACs. HDAC11 is the only class IV HDAC, and there are very few inhibitors available for it. Therefore, this study provides a new HDAC11 inhibitor lead from natural products and may help explain the various biological activities of garcinol. 10.1021/acschembio.0c00719
    Protective effects of garcinol on dimethylnitrosamine-induced liver fibrosis in rats. Hung Wei-Lun,Tsai Mei-Ling,Sun Pei-Pei,Tsai Chen-Yu,Yang Chin-Chou,Ho Chi-Tang,Cheng An-Chin,Pan Min-Hsiung Food & function Garcinol, a polyisoprenylated benzophenone derivative, mainly isolated from Garcinia indica fruit rind, has been suggested to exhibit many biological benefits including antioxidative, anti-inflammatory, and anti-tumor activities. The aim of this study is to evaluate the protective effects of garcinol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. The administration of DMN for six consecutive weeks resulted in the decrease of body weights, the elevation of serum aminotransferases, as well as histological lesions in livers. However, oral administration of garcinol remarkably inhibited the elevation of aspartate transaminase (AST) and relieved liver damage induced by DMN. Furthermore, our results revealed that garcinol not only effectively reduced the accumulation of extracellular matrix (ECM) components but also inhibited the expression of α-smooth muscle actin (α-SMA) in livers. The expression of transforming growth factor-β1 (TGF-β1) and the phosphorylation of Smad 2 and Smad 3 were also suppressed by garcinol supplementation. In conclusion, our current study suggested that garcinol exerted hepatoprotective and anti-fibrotic effects against DMN-induced liver injury in rats. 10.1039/c4fo00342j
    Garcinol Blocks the Reconsolidation of Multiple Cocaine-Paired Cues after a Single Cocaine-Reactivation Session. Dunbar Amber B,Taylor Jane R Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Manipulations of memory reconsolidation can interfere with the ability of a drug-paired cue to drive drug-seeking behavior. However, the typical reconsolidation paradigm that reactivates the memory through the presentation of the cue (conditioned stimulus (CS)) only interferes with the memory of the reactivated CS while leaving other drug-paired CSs intact and able to continue driving drug-seeking behavior. Here, we used a novel unconditioned-stimulus (US) reactivation paradigm to interfere with the ability of multiple cues to drive drug-seeking behavior after just one reactivation and treatment session. Rats were trained to self-administer cocaine, during which time each active lever press resulted in an i.v. cocaine infusion paired with one of two cues that alternated within each session. The drug memory was later reactivated with either i.v. or i.p. cocaine presentation in the absence of any cue. The histone acetyltransferase (HAT) inhibitor garcinol or vehicle was injected following US reactivation to impair reconsolidation. Rats were later tested on cue-induced reinstatement to both cues. Garcinol administered after either i.v. or i.p. cocaine reactivation significantly decreased cue-induced reinstatement to both cues, indicative of reconsolidation impairment. In addition, garcinol administered in the absence of reconsolidation or at a 6 h delay when the memory should be restabilized had no effect on reinstatement, further suggesting that garcinol's effects on reinstatement are through reconsolidation-based mechanisms. Our results demonstrate that a US-reactivation paradigm may be preferable to traditional CS-reactivation paradigms for treating disorders that involve multiple CS-US associations and support investigations of garcinol as a therapeutic pharmacological agent. 10.1038/npp.2017.27
    Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo. Sethi Gautam,Chatterjee Snehajyoti,Rajendran Peramaiyan,Li Feng,Shanmugam Muthu K,Wong Kwong Fai,Kumar Alan Prem,Senapati Parijat,Behera Amit K,Hui Kam Man,Basha Jeelan,Natesh Nagashayana,Luk John M,Kundu Tapas K Molecular cancer BACKGROUND:Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been linked with proliferation, survival, invasion and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Thus, novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC. Here we report, garcinol, a polyisoprenylated benzophenone, could suppress STAT3 activation in HCC cell lines and in xenografted tumor of HCC in nude mice model. EXPERIMENTAL DESIGN:Different HCC cell lines have been treated with garcinol and the inhibition of STAT3 activation, dimerization and acetylation have been checked by immunoblotting, immuno-fluorescence, and DNA binding assays. Xenografted tumor model has been generated in nude mice using HCC cell line and effect of garcinol in the inhibition of tumor growth has been investigated. RESULTS:Garcinol could inhibit both constitutive and interleukin (IL-6) inducible STAT3 activation in HCC cells. Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppress its dimerization in vitro. Being an acetyltransferase inhibitor, garcinol also inhibits STAT3 acetylation and thus impairs its DNA binding ability. The inhibition of STAT3 activation by garcinol led to the suppression of expression of various genes involved in proliferation, survival, and angiogenesis. It also suppressed proliferation and induced substantial apoptosis in HCC cells. Remarkably, garcinol inhibited the growth of human HCC xenograft tumors in athymic nu/nu mice, through the inhibition of STAT3 activation. CONCLUSION:Overall, our results suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo. 10.1186/1476-4598-13-66
    Garcinol pacifies acrylamide induced cognitive impairments, neuroinflammation and neuronal apoptosis by modulating GSK signaling and activation of pCREB by regulating cathepsin B in the brain of zebrafish larvae. Sharma Chanchal,Kang Sun Chul Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association The presence of acrylamide (ACR) in food results in evident cognitive decline, accumulation of misfolded proteins, neurotoxicity, neuroinflammation, and neuronal apoptosis leading to progressive neurodegeneration. Here, we used 4 dpf zebrafish larvae exposed to ACR (1mM/3days) as our model, and neuronal proteins were analyzed. Next, we tested the effect of garcinol (GAR), a natural histone-acetylation inhibitor, whose neuroprotection mechanism of action remains to be fully elucidated. Our result revealed that ACR exposure significantly impaired cognitive behavior, downregulated oxidative repair machinery, and enhanced microglia-induced neuronal apoptosis. Moreover, ACR mediated cathepsin-B (CAT-B) translocation acted as the intracellular secretase for the processing of amyloid precursor protein (APP) and served as an additional risk factor for tau hyper-phosphorylation. Here, GAR suppresses ACR mediated CATB translocation as similar with standard inhibitor CA-074. And, this pharmacological repression helped in inhibiting amyloidogenic APP processing and downstream tau hyper-phosphorylation. GAR neuroprotection was accompanied by CREB, ATF1, and BDNF activation promoting neuronal survival. At the same time, GAR subdued cdk5 and GSK3β, the link between APP processing and tau hyper-phosphorylation. Taken together, our findings indicate that GAR rescued from ACR mediated behavioral defects, oxidative injury, neuroinflammation, undesirable APP processing, tau hyper-phosphorylation which in turn found to be CATB dependent. 10.1016/j.fct.2020.111246
    Protective effects of garcinol in mice with lipopolysaccharide/D-galactosamine-induced apoptotic liver injury. Jing Yuping,Ai Qing,Lin Ling,Dai Jie,Jia Mengying,Zhou Dan,Che Qian,Wan Jingyuan,Jiang Rong,Zhang Li International immunopharmacology Garcinol is a polyisoprenylated benzophenone derivative of Garcinia indica. Recent researches have revealed the antioxidant, anticancer and anti-inflammatory properties of garcinol. In the present study, the pharmacological effects of garcinol in lipopolysaccharide (LPS)-induced hepatic injury in D-galactosamine (D-Gal)-sensitized mice were investigated. We found that treatment with garcinol significantly decreased serum ALT and AST levels in LPS/D-Gal-exposed mice. These were accomplished with improved histological alterations in liver sections and reduced malondialdehyde (MDA) content in liver homogenates. Garcinol significantly reduced the acetylation level of NF-κB, but it had no obvious effects on the elevation of TNF-α or IL-6 in plasma or liver tissue. Garcinol significantly attenuated LPS/D-Gal-induced hepatic apoptosis as evidenced by reduced number of TUNEL-positive cells in liver sections. Our experiments also showed that garcinol markedly suppressed the cleavage of caspase-3 and significantly decreased the activities of caspase-3, -8, and -9 in liver tissues. In addition, garcinol obviously reduced the induction of Bax but did not alter the level of Bcl-2. These results indicated that garcinol might provide protective benefits in LPS/D-Gal-induced liver injury through suppressing apoptosis. 10.1016/j.intimp.2014.02.012
    Stimulation of Suicidal Erythrocyte Death by Garcinol. Fazio Antonella,Briglia Marilena,Faggio Caterina,Alzoubi Kousi,Lang Florian Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:The benzophenone garcinol from dried fruit rind of Garcinia indica counteracts malignancy, an effect at least in part due to stimulation of apoptosis. The proapototic effect of garcinol is attributed in part to inhibition of histone acetyltransferases and thus modification of gene expression. Moreover, garcinol triggers mitochondrial depolarisation. Erythrocytes lack gene expression and mitochondria but are nevertheless able to enter apoptosis-like suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, energy depletion and Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether and how garcinol induces eryptosis. METHODS:To this end, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence and cytosolic ATP levels utilizing a luciferin-luciferase-based assay. RESULTS:A 24 hours exposure of human erythrocytes to garcinol (2.5 or 5 µM) significantly increased the percentage of annexin-V-binding cells. Garcinol decreased (at 1 µM and 2.5 µM) or increased (at 5 µM) forward scatter. Garcinol (5 µM) further increased Fluo3-fluorescence, increased DCFDA fluorescence, and decreased cytosolic ATP levels. The effect of garcinol on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSIONS:Garcinol triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to stimulation of ROS formation, energy depletion and Ca2+ entry. 10.1159/000430397
    Garcinol inhibits the proliferation of endometrial cancer cells by inducing cell cycle arrest. Zhang Min,Lu Qinsheng,Hou Huomei,Sun Dingqian,Chen Miaojuan,Ning Fen,Wu Peihuang,Wei Dan,Duan Yaoyun,Pan Yue,Lash Gendie E Oncology reports Endometrial cancer (EC) is the most common gynecological cancer, and one of the most important causes of cancer‑related deaths in women worldwide. The long‑term survival rate is lower in advanced‑stage and recurrent EC, therefore it is important to identify new anticancer drugs. Garcinol, a polyisoprenylated benzophenone, is a promising anticancer drug for various cancer types but its effects on EC remain unclear. To investigate the anticancer effects of garcinol on EC, cell proliferation and cell cycle were assessed by real‑time cell proliferation, cell counting, and colony formation assays, flow cytometric analysis, and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assay, in EC Ishikawa (ISH) and HEC‑1B cell lines. Western blotting was used to evaluate the expression of cell cycle‑related protein cyclins, cyclin‑dependent kinase and tumor suppression proteins. Garcinol inhibited ISH and HEC‑1B cell proliferation in a dose‑dependent manner, and induced ISH and HEC‑1B cell cycle arrest at the G1 phase and G2/M phase, respectively, and decreased the S phase and DNA synthesis in these two cell lines. Following garcinol treatment the expression levels of p53 and p21 were increased, while the expression levels of CDK2, CDK4, cyclin D1 and cyclin B1 were gradually decreased in a dose‑dependent manner in both ISH and HEC‑1B cells. In addition, the expression levels of phosphorylated c‑JUN N‑terminal kinase (JNK) and p‑c‑JUN were significantly increased in both types of cells. Collectively, garcinol can induce EC cell cycle arrest and may be a promising candidate for EC chemotherapy. 10.3892/or.2020.7900
    Garcinol suppresses inflammation-associated colon carcinogenesis in mice. Tsai Mei-Ling,Chiou Yi-Shiou,Chiou Li-Yu,Ho Chi-Tang,Pan Min-Hsiung Molecular nutrition & food research SCOPE:Garcinol is a polyisoprenylated benzophenone derivative isolated from the fruit rind of Garcinia indica and has exhibited chemopreventive effects on azoxymethane)-induced colonic aberrant crypt foci in mice. In this study, we investigated whether garcinol protects against dextran sulfate sodium (DSS) induced colitis/inflammation and azoxymethane/DSS-induced inflammation-related colon tumorigenesis in male ICR mice. We also aimed to delineate the possible molecular mechanisms responsible for these effects. METHODS AND RESULTS:Treatment with garcinol prevented shortening of the colon length and the formation of aberrant crypt foci and improved the inflammation score in the mouse colon stimulated by DSS. Moreover, administration of garcinol markedly decreased DSS-induced inducible nitric oxide synthase, cyclooxygenase-2, and proliferating cell nuclear antigen protein expression. The dietary administration of garcinol effectively reduced the tumor size and incidence in the mouse colon. Western blot and immunohistochemical analysis revealed that administration of garcinol significantly downregulated cyclooxygenase-2, cyclin D1, and vascular endothelial growth factor expression via inhibition of the extracellular signal-regulated protein kinase 1/2, phosphatidylinositol 3 kinase/Akt/p70 ribosomal S6 kinase, and Wnt/β-catenin signaling pathways. CONCLUSION:Our results suggest that garcinol may merit further clinical investigation as a chemoprophylactic food that helps prevent colitis-associated colon cancer. 10.1002/mnfr.201400149
    Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments. Schobert Rainer,Biersack Bernhard Chemistry & biodiversity The natural polyisoprenylated benzophenone derivatives garcinol and isogarcinol are secondary plant metabolites isolated from various Garcinia species including Garcinia indica. This review takes stock of the recent chemical and biological research into these interesting natural compounds over the last five years. New biological sources and chemical syntheses are discussed followed by new insights into the activity of garcinol and isogarcinol against cancer, pathogenic bacteria, parasite infections and various inflammatory diseases. 10.1002/cbdv.201900366
    Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers. Li Feng,Shanmugam Muthu K,Siveen Kodappully Sivaraman,Wang Fan,Ong Tina H,Loo Ser Yue,Swamy Mahadeva M M,Mandal Somnath,Kumar Alan Prem,Goh Boon Cher,Kundu Tapas,Ahn Kwang Seok,Wang Ling Zhi,Hui Kam Man,Sethi Gautam Oncotarget Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated whether garcinol, a polyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin. We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines, enhanced the apoptotic effect of cisplatin, suppressed constitutive as well as cisplatin-induced NF-κB activation, and downregulated the expression of various oncogenic gene products (cyclin D1, Bcl-2, survivin and VEGF). In vivo study showed that administration of garcinol alone (0.5 mg/kg body weight, i.p. five times/week) significantly suppressed the growth of the tumor, and this effect was further increased by cisplatin. Both the markers of proliferation index (Ki-67) and microvessel density (CD31) were downregulated in tumor tissues by the combination of cisplatin and garcinol. The pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after i.p. administration of garcinol at 0.5 mg/kg and 2 mg/kg with mean peak concentration (Cmax) of 1825.4 and 6635.7 nM in the mouse serum, respectively. Overall, our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers. 10.18632/oncotarget.2881
    Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii. Jeffers Victoria,Gao Hongyu,Checkley Lisa A,Liu Yunlong,Ferdig Michael T,Sullivan William J Antimicrobial agents and chemotherapy Lysine acetylation is a critical posttranslational modification that influences protein activity, stability, and binding properties. The acetylation of histone proteins in particular is a well-characterized feature of gene expression regulation. In the protozoan parasiteToxoplasma gondii, a number of lysine acetyltransferases (KATs) contribute to gene expression and are essential for parasite viability. The natural product garcinol was recently reported to inhibit enzymatic activities of GCN5 and p300 family KATs in other species. Here we show that garcinol inhibits TgGCN5b, the only nuclear GCN5 family KAT known to be required forToxoplasmatachyzoite replication. Treatment of tachyzoites with garcinol led to a reduction of global lysine acetylation, particularly on histone H3 and TgGCN5b itself. We also performed transcriptome sequencing (RNA-seq), which revealed increasing aberrant gene expression coincident with increasing concentrations of garcinol. The majority of the genes that were most significantly affected by garcinol were also associated with TgGCN5b in a previously reported chromatin immunoprecipitation assay with microarray technology (ChIP-chip) analysis. The dysregulated gene expression induced by garcinol significantly inhibitsToxoplasmatachyzoite replication, and the concentrations used exhibit no overt toxicity on human host cells. Garcinol also inhibitsPlasmodium falciparumasexual replication with a 50% inhibitory concentration (IC50) similar to that forToxoplasma Together, these data support that pharmacological inhibition of TgGCN5b leads to a catastrophic failure in gene expression control that prevents parasite replication. 10.1128/AAC.03059-15
    13,14-Dihydroxy groups are critical for the anti-cancer effects of garcinol. Han Chao-Ming,Zhou Xin-Ying,Cao Jing,Zhang Xin-Yan,Chen Xin Bioorganic chemistry In the presence of K2CO3/Cs2CO3 (molar ratio 10:1), garcinol was subjected to methylation by reaction with iodomethane at room temperature to afford 13,14-dimethoxy garcinol. The methylated garcinol derivative was screened against oral cancer cell line SCC15 for cell proliferation and apoptosis. 13,14-Dimethoxy garcinol showed weaker inhibitory activity on SCC15 cell growth than garcinol, and had little effect on cell cycle and apoptosis of SCC15, whereas garcinol effectively induced cell cycle arrest and cell apoptosis. Meanwhile, the ELISA data showed that the inhibitory effect of garcinol on 5-Lox pathway was more potent than 13,14-dimethoxy garcinol (P<0.05). All these results have confirmed the important role of 13,14-dihydroxy groups for anti-cancer effects of garcinol. 10.1016/j.bioorg.2015.04.010
    Garcinol: Current status of its anti-oxidative, anti-inflammatory and anti-cancer effects. Liu Chaoqun,Ho Paul Chi-Lui,Wong Fang Cheng,Sethi Gautam,Wang Ling Zhi,Goh Boon Cher Cancer letters Garcinol is the main medicinal component of the dried fruit rind of Garcinia indica (G. indica), which has traditionally been extensively used to treat gastric ailments and skin irritation. In vitro studies of garcinol revealed its potential therapeutic effects, such as its anti-oxidative, anti-inflammatory and anti-cancer properties. Similarly, in vivo studies in animal models also demonstrated the efficacy of garcinol for the treatment of various inflammatory and cancerous conditions. Despite being well tolerated in preclinical studies, the toxicological profile of garcinol remains elusive. More importantly, systematic pharmacokinetics (PK) studies of garcinol to establish an appropriate route of administration and its effective concentration range under physiological conditions have not yet been performed. PK studies play an essential role in translating the preclinical findings of garcinol from cell line models and animal species to humans, thereby facilitating dose selection, the characterization of the therapeutic index, identification of a metabolic pathway, and the determination of garcinol's potency and tolerability. This paper reviews the current studies of garcinol as a potential anti-oxidant, anti-inflammatory and anti-cancer agent and highlights the importance of performing preclinical PK and toxicological studies on garcinol for its development pipeline. 10.1016/j.canlet.2015.03.019
    Antitumor Activity of Garcinol in Human Prostate Cancer Cells and Xenograft Mice. Wang Yu,Tsai Mei-Ling,Chiou Li-Yu,Ho Chi-Tang,Pan Min-Hsiung Journal of agricultural and food chemistry Garcinol, which is isolated from fruit rinds of Garcinia indica, is a polyisoprenylated benzophenone. It has been studied for its antitumor activity by inducing apoptosis and inhibiting autophagy in human prostate cancer cells. The Bax/Bcl-2 ratio increased when garcinol was applied to PC-3 cells indicating a presence of apoptosis. Meanwhile, procaspases-9 and -3 were suppressed with attenuating PARP and DFF-45. Autophagy was inhibited through activating p-mTOR and p-PI3 Kinase/AKT by garcinol, which as a result induced the cells to apoptosis directly. In addition, the apoptosis effect of garcinol in a xenograft mouse model was also tested, suggesting a consistent result with PC-3 cell model. The tumor size was reduced more than 80 percent after the mouse accepted the garcinol treatment. Garcinol was demonstrated to have a strong antitumor activity through inhibiting autophagy and inducing apoptosis, which was discovered for the first time. Based on these findings, our data suggests that garcinol deserves further investigation as a potent chemopreventive agent. 10.1021/acs.jafc.5b03851
    Anti-Arthritic Effect of Garcinol Enriched Fraction Against Adjuvant Induced Arthritis. Warriar Purnima,Barve Kalyani,Prabhakar Bala Recent patents on inflammation & allergy drug discovery BACKGROUND:Garcinia indica also known as kokum is used in traditional system of medicine for relieving inflammation and rheumatic pain. Garcinol, a benzophenone obtained from its fruit rind is reported to have anti-inflammatory effect via modulating arachidonic acid metabolism, suppressing iNOS expression, NF-κB activation and COX-2 expression. It has also been studied for antioxidant and anticancer activity. Apart from these, few patents claim that garcinol also has anti-obesity and hepatoprotective effect and has a potential to be used for the treatment of renal disorders, endometriosis and cardiac dysfunction. OBJECTIVE:Garcinol Enriched Fraction (GEF) from the fruit rind of Garcinia indica should be effective in the treatment of arthritis, one of the chronic inflammatory disorder owing to its anti-inflammatory property as indicated by earlier experiments. METHODS:GEF was prepared from the fruit rind of Garcinia indica and quantified using LC-MS/MS. It was found to contain 89.4% w/w of garcinol. GEF was evaluated at the dose of 10mg/kg for its efficacy against Complete Freund's Adjuvant (CFA) induced arthritis in Wistar albino rats. Paw volumes of both sides were measured by Plethysmometer and body weight was recorded on 0, 1, 5, 12 and 21st day. The hyperalgesic response was also measured by motility test and stair climbing test. RESULTS:GEF showed a significant reduction in paw swelling (p < 0.0001) and arthritis index (p < 0.0001) exhibiting anti-inflammatory potential. It also improves the motility and stair climbing ability of experimental animals (p < 0.05), thus reducing hyperalgesia. CONCLUSION:Garcinol enriched fraction shows anti-arthritic activity in experimental animals. 10.2174/1872213X12666181120091528
    Enhanced Hsa-miR-181d/p-STAT3 and Hsa-miR-181d/p-STAT5A Ratios Mediate the Anticancer Effect of Garcinol in -Addicted Glioblastoma. Liu Heng-Wei,Lee Peter Mingjui,Bamodu Oluwaseun Adebayo,Su Yu-Kai,Fong Iat-Hang,Yeh Chi-Tai,Chien Ming-Hsien,Kan I-Hung,Lin Chien-Min Cancers BACKGROUND:Glioblastoma (GBM), a malignant grade IV tumor, is the most malignant brain tumor due to its hyper-proliferative and apoptosis-evading characteristics. The signal transducer and activators of transcription (STAT) family genes, including and , have been indicated to play important roles in GBM progression. Increasing number of reports suggest that garcinol, a polyisoprenylated benzophenone and major bioactive component of contains potent anti-cancer activities. MATERIAL AND METHODS:The present study investigated the anti-GBM effects of garcinol, focusing on the activation, using a combination of bioinformatics, in vitro, and ex vivo assays. RESULTS:Our bioinformatics analysis of The Cancer Genome Atlas (TCGA)-GBM cohort ( = 173) showed that and are preferentially elevated in primary and recurrent GBM, compared to non-tumor brain tissues, and is significantly correlated with reduced overall survival. In support, our immunohistochemical staining of a GBM cohort ( = 45) showed an estimated 5.3-fold ( < 0.001) elevation in and protein expression in primary and recurrent GBM versus the non-tumor group. In vitro, garcinol treatment significantly suppressed the proliferative, invasive, and migratory potential of U87MG or GBM8401 cells, dose-dependently. In addition, garcinol anticancer effect significantly attenuated the GBM stem cell-like phenotypes, as reflected by diminished ability of U87MG or GBM8401 to form colonies and tumorspheres and suppressed expression of OCT4 and SOX2. Furthermore, analysis on GBM transcriptome revealed an inverse correlation between the level of and hsa-miR-181d. Garcinol-mediated anti-GBM effects were associated with an increased hsa-miR-181d/ and hsa-miR-181d/5A ratio. The results were further verified in vivo using U87MG mouse xenograft model where administration of garcinol significantly inhibited tumor growth. CONCLUSIONS:We present evidence of anti-GBM efficacy of garcinol mediated by enhancing the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratios in GBM cells. Our findings suggest a potential new therapeutic agent for combating aggressive GBM. 10.3390/cancers11121888
    Garcinol Upregulates GABAA and GAD65 Expression, Modulates BDNF-TrkB Pathway to Reduce Seizures in Pentylenetetrazole (PTZ)-Induced Epilepsy. Hao Fang,Jia Li-Hua,Li Xiao-Wan,Zhang Ying-Rui,Liu Xue-Wu Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Epilepsy is the most predominant neurological disorder characterized by recurrent seizures. Despite treatment with antiepileptic drugs, epilepsy still is a challenge to treat, due to the associated adverse effects of the drugs. Previous investigations have shown critical roles of BDNF-TrkB signalling and expression of glutamic acid decarboxylase 65 (GAD65) and GABAA in the brain during epilepsy. Thus, drugs that could modulate BDNF-TrkB signal and expression of GAD65 and GABAA could aid in therapy. Recent experimental data have focussed on plant-derived compounds in treatments. Garcinol (camboginol), is a polyisoprenylated benzophenone derived from the fruit of Garcinia indica. We investigated the effects of garcinol in pentylenetetrazole (PTZ)-induced epileptic models. MATERIAL AND METHODS Seizure scores were measured in epilepsy kindled mice. Neuronal degeneration and apoptosis were assessed by Nissl staining, TUNEL assay, and Fluoro-Jade B staining. Immunohistochemistry was performed to evaluate cleaved caspase-3 expressions. Expression of BDNF, TrkB, GABAA, GAD65, Bad, Bcl-2, Bcl-xL, and Bax were determined by western blots. RESULTS Significantly reduced seizure scores and mortality rates were observed with pretreatment with garcinol. Elevated expression of apoptotic proteins and caspase-3 in kindled mice were effectively downregulated by garcinol. Epileptogenic mice presented increased BDNF and TrkB with considerably decreased GABAA and GAD65 expression. Garcinol significantly enhanced GABAA and GAD65 while it suppressed BDNF and TrkB. Garcinol enhanced the performance of mice in Morris water maze tests. CONCLUSIONS Garcinol exerts neuroprotective effects via supressing apoptosis and modulating BDNF-TrkB signalling and GAD65/GABAA expressions and also enhanced cognition and memory of the mice. 10.12659/msm.897579
    Garcinol downregulates Notch1 signaling via modulating miR-200c and suppresses oncogenic properties of PANC-1 cancer stem-like cells. Huang Chi-Cheng,Lin Chien-Min,Huang Yan-Jiun,Wei Li,Ting Lei-Li,Kuo Chia-Chun,Hsu Cheyu,Chiou Jeng-Fong,Wu Alexander T H,Lee Wei-Hwa Biotechnology and applied biochemistry Pancreatic cancer represents one of the most aggressive types of malignancy due to its high resistance toward most clinically available treatments. The presence of pancreatic cancer stem-like cells (CSCs) has been attributed to the intrinsically high resistance and highly metastatic potential of this disease. Here, we identified and isolated pancreatic CSCs using the side population (SP) method from human pancreatic cancer cell line, PANC-1. We then compared the SP and non-SP PANC-1 cells genetically. PANC-1 SP cells exhibited CSC properties including enhanced self-renewal ability, increased metastatic potential, and resistance toward gemcitabine treatment. These cancer stem-like phenotypes were supported by their enhanced expression of ABCG2, Oct4, and CD44. A traditional plant-derived antioxidant, garcinol, has been implicated for its anticancer properties. Here, we found that garcinol treatment to PANC-1 SP cells significantly suppressed the stem-like properties of PANC-1 SP cells and metastatic potential by downregulating the expression of Mcl-1, EZH2, ABCG2, Gli-1, and Notch1. More importantly, garcinol treatment led to the upregulation of several tumor suppressor microRNAs, and miR-200c increased by garcinol treatment was found to target and downregulate Notch1. Thus, PANC-1 SP cells may serve as a model for studying drug-resistant pancreatic CSCs, and garcinol has the potential as an antagonist against pancreatic CSCs. 10.1002/bab.1446
    Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer. Aggarwal Sadhna,Das Satya N Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine Garcinol, a polyisoprenylated benzophenone is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Its ability to inhibit tumour growth has been demonstrated in certain cancers. In this study, we evaluated the potential anti-tumour effects of garcinol on oral squamous cell carcinoma (OSCC) cells. Three OSCC cell lines (SCC-4, SCC-9 and SCC-25) were treated with garcinol for 48 h and its effect on growth and proliferation, clonogenic survival, cell cycle and apoptosis was studied by MTT, clonogenic assay, propidium iodide (PI) staining and annexin-V binding assay, respectively. The alteration in expression of NF-κB and COX-2 was studied by western blot analysis and that of VEGF by ELISA. Garcinol treatment significantly (p < 0.001) inhibited the growth and proliferation and colony formation of OSCC cells with a concomitant induction of apoptosis and cell cycle arrest. It did not show toxic effect on normal cells. It significantly (p < 0.05) reduced the expression of NK-κB and COX-2 expression in treated cells as compared to untreated controls besides inhibiting VEGF expression. It appears that garcinol exerts anti-proliferative, pro-apoptotic, cell-cycle regulatory and anti-angiogenic effects on oral cancer cells through inhibition of NF-κB and COX-2. Thus, garcinol may be developed as a potential chemopreventive and/or chemotherapeutic agent for treatment of oral squamous cell carcinoma. 10.1007/s13277-015-4583-8
    Garcinol acts as an antineoplastic agent in human gastric cancer by inhibiting the PI3K/AKT signaling pathway. Zheng Yuanyuan,Guo Chuanyong,Zhang Xiaoping,Wang Xiaoli,Ma A'Huo Oncology letters Gastric cancer (GC) is one of the most common malignancies worldwide; however, treatment options other than surgery remain limited. Neoadjuvant chemotherapy has the potential to suppress of gastric tumorigenesis. Garcinol has been reported to exert inhibitory effects on the progression of numerous carcinomas. However, its effects in GC remain unclear. Therefore, the aim of the present study was to investigate the effects of garcinol on the proliferation, invasion and apoptosis of gastric carcinoma cells and then to explore the underlying mechanisms. Garcinol significantly decreased the proliferation and invasion of GC cells and increased apoptosis in a dose-dependent manner. Additionally, the expression of AKT, cyclin D1, Bcl-2, BAX, matrix metalloprotease (MMP-2) and MMP-9 in HGC-27 cells following treatment with garcinol. The results obtained in the present study suggested that garcinol may inhibit gastric tumorigenesis by suppressing the PI3K/AKT signaling pathway. 10.3892/ol.2020.11585
    Garcinol A Novel Inhibitor of Platelet Activation and Apoptosis. Cao Hang,Al Mamun Bhuyan Abdulla,Umbach Anja T,Ma Ke,Borst Oliver,Gawaz Meinrad,Zhang Shaqiu,Nürnberg Bernd,Lang Florian Toxins Garcinol, an anti-inflammatory and anti-carcinogenic polyisoprenylated benzophenone isolated from Garcinia plants, stimulates tumor cell apoptosis and suicidal erythrocyte death, but supports the survival of hepatocytes and neurons. The present study explored whether the substance influences platelet function and/or apoptosis. To this end, we exposed murine blood platelets to garcinol (33 µM, 30 min) without and with activation by collagen-related peptide (CRP) (2-5 µg/mL) or thrombin (0.01 U/mL); flow cytometry was employed to estimate cytosolic Ca-activity ([Ca]) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from αIIbβ3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, relative platelet volume from forward scatter, and aggregation utilizing staining with CD9-APC and CD9-PE. As a result, in the absence of CRP and thrombin, the exposure of the platelets to garcinol did not significantly modify [Ca], P-selectin abundance, activated αIIbβ3 integrin, annexin-V-binding, cell volume, caspase activity, and aggregation. Exposure of platelets to CRP or thrombin was followed by a significant increase of [Ca], P-selectin abundance, αIIbβ3 integrin activity, annexin-V-binding, caspase activity, and aggregation, as well as significant cell shrinkage. All effects of CRP were strong and significant; those of thrombin were only partially and slightly blunted in the presence of garcinol. In conclusion, garcinol blunts CRP-induced platelet activity, apoptosis and aggregation. 10.3390/toxins11070382
    Garcinol and Related Polyisoprenylated Benzophenones as Topoisomerase II Inhibitors: Biochemical and Molecular Modeling Studies. Di Micco Simone,Masullo Milena,Bandak Afif F,Berger James M,Riccio Raffaele,Piacente Sonia,Bifulco Giuseppe Journal of natural products Garcinol, a polyisoprenylated benzophenone isolated from genus, has been reported to inhibit eukaryotic topoisomerase I and topoisomerase II at concentrations comparable to that of etoposide (∼25-100 μM). With the aim to clarify the underlying molecular mechanisms by which garcinol inhibits human topoisomerase IIα and topoisomerase IIβ, biochemical assays along with molecular docking and molecular dynamics studies were carried out on garcinol and six congeners. The biochemical results revealed that garcinol derivatives appear to act as catalytic inhibitors of topoisomerase II and to inhibit ATP hydrolysis by topoisomerase II via some form of mixed inhibition. The computational investigation identified the structural elements responsible for binding to the biological target and also provided information for the eventual design of more selective and potent analogues. Collectively, our data suggest that garcinol-type agents may bind to the DNA binding surface and/or ATP domain of type II topoisomerases to antagonize function. 10.1021/acs.jnatprod.9b00382
    Garcinol, a multifaceted sword for the treatment of Parkinson's disease. Deb Satarupa,Phukan Banashree Chetia,Mazumder Muhammed Khairujjaman,Dutta Ankumoni,Paul Rajib,Bhattacharya Pallab,Sandhir Rajat,Borah Anupom Neurochemistry international Garcinol, the principal phytoconstituent of plants belonging to the genus Garcinia, is known for its anti-oxidant as well as anti-inflammatory properties, which can be extended to its possible neuroprotective role. Recent reports disseminate the capacity of garcinol to influence neuronal growth and survival, alter the neurochemical status in brain, as well as regulate memory and cognition. The concomitant neuro-rescue property of garcinol may render it as an effective compound in Parkinson's disease (PD) therapeutics since it is capable of ameliorating the related pathophysiological changes. Emerging pieces of evidence linking histone acetylation defects to the progression of neurodegenerative diseases provide an effective basis for targeting PD. Hyperacetylation of histones has been reported in Parkinsonian brain, which demands the use of pharmacological inhibitors of histone acetyltransferases (HAT). Garcinol serves as a potent natural HAT inhibitor and has unveiled promising results in molecular interaction studies against Monoamine oxidase B (MAO-B) and Catechol-O-Methyltransferase (COMT), as well as in L-DOPA induced dyskinesia. This review highlights the prospective implications of garcinol as a novel anti-Parkinsonian agent, and establishes a bridge between histone acetylation defects and the pathological aspects of PD. 10.1016/j.neuint.2019.04.004
    Protective effects of Garcinol against neuropathic pain - Evidence from in vivo and in vitro studies. Wang Yi-Wei,Zhang Xiang,Chen Chun-Long,Liu Qing-Zhen,Xu Jia-Wen,Qian Qing-Qing,Li Wei-Yan,Qian Yan-Ning Neuroscience letters Neuroinflammatory processes have a vital role in the pathogenesis of neuropathic pain. Garcinol, harvested from Garcinia indica, is known to exert potent anti-inflammatory properties. Recent studies have indicated that Garcinol may inhibit activation of nuclear factor-κB (NF-κB) by inhibiting NF-κB/p65 acetylation. These findings prompted us to evaluate the protective effects of Garcinol in the lumbar fifth spinal nerve ligation (SNL)-induced rat model of neuropathic pain and Lipopolysaccharide(LPS)-stimulated primary cultured microglia. In the present study, we found that intrathecal administration of Garcinol significantly attenuated SNL-induced nociceptive behaviors. Garcinol suppressed microglial activation as well as the expression of interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) in the spinal cord of SNL rats. It also reduced the nuclear translocation of NF-κB by decreasing acetyl-p65 protein expression. Similarly, in the in vitro study, Garcinol decreased the production of NO/iNOS, PGE2/COX-2, and proinflammatory cytokines in LPS-exposed microglia. Likewise, Garcinol inhibited the NF-κB signaling pathway by downregulating acetyl-p65 levels in LPS-challenged microglia. Our findings suggest that Garcinol may have protective effects against neuropathic pain that are associated with the inhibition of neuroinflammation in microglia. Therefore, Garcinol could be a promising agent in the treatment of neuropathic pain. 10.1016/j.neulet.2017.03.015
    Regulation of Garcinol on Histone Acetylation in the Amygdala and on the Reconsolidation of a Cocaine-Associated Memory. Monsey Melissa S,Ruiz Sonia G,Taylor Jane R Frontiers in behavioral neuroscience Exposure to drug-related cues often disrupts abstinence from cocaine use by triggering memories of drug effects, leading to craving and possible relapse. One prospective method of treatment is weakening cocaine-associated memories impairment of memory reconsolidation. Previous experiments have shown that systemic injection of the amnestic agent garcinol impairs the reconsolidation of cocaine-cue memories in a temporally constrained, cue-specific, and persistent manner. Here, we investigated garcinol's effect on cocaine-cue memory reconsolidation when administered to the lateral nucleus of the amygdala (LA), as well as its epigenetic activity following systemic garcinol administration and also when given in conjunction with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor. Rats received 12 days of cocaine self-administration training during which time an active lever press resulted in an i.v. cocaine infusion that was concurrently paired with the presentation of a light/tone cue. After 8 days of lever extinction, rats received a memory reactivation session followed by a cue-induced reinstatement test. Intra-LA garcinol following memory reactivation significantly impaired reconsolidation only if the memory was reactivated. Additional studies revealed a significant reduction in histone H3 K27 acetylation and reduced expression of the immediate-early genes Arc and Egr-1 in the LA. When administered alone, TSA enhanced the reinstatement of a cocaine-cue memory, an effect that was prevented when garcinol was concurrently administered. These data indicate the LA is a key structure responsive to garcinol, suggest that one of garcinol's mechanisms of action is through the reduction of memory-related gene expression in the LA, implicate changes in histone acetylation in memory reconsolidation, and support garcinol as a potential therapeutic tool for sustaining abstinence. 10.3389/fnbeh.2019.00281
    The C8 side chain is one of the key functional group of Garcinol for its anti-cancer effects. Zhou Xin-Ying,Cao Jing,Han Chao-Ming,Li Shu-Wen,Zhang Chen,Du Yin-Duan,Zhou Qian-Qian,Zhang Xin-Yan,Chen Xin Bioorganic chemistry Garcinol from the fruit rind of Garcinia indica shows anti-carcinogenic and anti-inflammatory properties, but its mechanism and key functional groups were still need to be identified. Our previous computer modeling suggested that the C8 side chain of Garcinol is so large that it may influence the bioactivity of the compound. 8-Me Garcinol, a derivative of Garcinol in which the bulky side chain at the C8 position of Garcinol is replaced with a much smaller methyl group, was synthesized through a 12-step procedure starting from 1,3-cyclohexanedione. The antitumor activity of Garcinol and 8-Me Garcinol was evaluated in vitro by MTT, cell cycle and cell apoptosis assays. The results showed that 8-Me Garcinol had weaker inhibitory activity on cells proliferation, and little effects on cell cycle and apoptosis in oral cancer cell line SCC15 cells when compared with Garcinol. All of the results indicated 8-Me Garcinol exerts weaker antitumor activity than Garcinol, and the C8 side chain might be an important active site in Garcinol. Changing the C8 side chain will affect the inhibitory effect of Garcinol. 10.1016/j.bioorg.2017.01.013
    Garcinol from Garcinia indica Downregulates Cancer Stem-like Cell Biomarker ALDH1A1 in Nonsmall Cell Lung Cancer A549 Cells through DDIT3 Activation. Wang Jinhan,Wang Liwen,Ho Chi-Tang,Zhang Kunsheng,Liu Qiang,Zhao Hui Journal of agricultural and food chemistry Nonsmall cell lung cancer (NSCLC) is the predominant type of lung cancer. Patients with NSCLC show high mortality rates because of failure to clean up cancer stem cells (CSCs). The anticancer activity of phytochemical garcinol has been identified in various cancer cell models. However, the effect of garcinol on NSCLC cell lines is still lacking. Of the NSCLC cell lines we tested, A549 cells were the most sensitive to garcinol. Interestingly, Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) was preferentially expressed in A549 cells and downregulated by the addition of garcinol. We also found that garcinol enriched DNA damage-inducible transcript 3 (DDIT3) and then altered DDIT3-CCAAT-enhancer-binding proteins beta (C/EBPβ) interaction resulting in a decreased binding of C/EBPβ to the endogenous ALDH1A1 promoter. Furthermore, garcinol's inhibition of ALDH1A1 was identified in a xenograft mice model. Garcinol repressed ALDH1A1 transcription in A549 cells through alterations in the interaction between DDIT3 and C/EBPβ. Garcinol could be a potential dietary phytochemical candidate for NSCLCs patients whose tumors harbored high ALDH1A1 expression. 10.1021/acs.jafc.7b00346
    Garcinol exhibits anti-proliferative activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells. Ranjbarnejad T,Saidijam M,Tafakh M Sadat,Pourjafar M,Talebzadeh F,Najafi R Human & experimental toxicology BACKGROUND:Colorectal cancer is the fourth leading cause of death. Various natural compounds are known to have antitumor properties. Garcinol, a polyisoprenylated benzophenone, has antioxidant and anti-inflammatory properties. In the current study, we investigated the anticancer activity of garcinol on human colorectal adenocarcinoma cell line (HT-29) human colon cancer cells. METHODS:HT-29 cells were treated with various concentrations of garcinol for 24 h. The effect of garcinol on HT-29 cells proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; the mRNA expression of microsomal prostaglandin E synthase-1 (mPGES-1), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were examined by quantitative real-time polymerase chain reaction; apoptosis was detected by proportion of sub-G1 cell; caspase 3 activity and prostaglandin E2 (PGE2) level were determined by enzyme-linked immunosorbent assay and HT-29 cells migration was assessed using scratch test. RESULTS:Garcinol preconditioning markedly decreased the expression of mPGES-1, HIF-1α, VEGF, CXCR4, MMP-2, and MMP-9. The proportion of cells in sub-G1 phase and caspase 3 activity were increased by garcinol treatment whereas the cell proliferation, PGE2 level, and cell migration were decreased in these cells, compared to the control group. CONCLUSION:Our findings suggest that garcinol plays a critical role in elevating apoptosis and inhibiting HT-29 cells proliferation, angiogenesis, and invasion by suppressing the mPGES-1/PGE2/HIF-1α signaling pathways. 10.1177/0960327116660865
    Anti-proliferative and anti-invasive effects of garcinol from on gallbladder carcinoma cells. Duan Yi-Tao,Yang Xiao-Ang,Fang Lian-Ying,Wang Jin-Han,Liu Qiang Die Pharmazie Garcinol, a natural histone acetyltransferase inhibitor, has been reported to exhibit significant anti-proliferative activity in various cancer cell types. However, no information is available about the anti-cancer effects of garcinol on gallbladder carcinoma cells (GBC). In this study, GBC cells (GBC-SD and NOZ) were treated by garcinol and subjected to Cell Counting Kit-8 (CCK-8), and GBC-SD cells were selected for further transwell chamber assay, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Our results indicated that garcinol could significantly inhibit the growth of GBC cells in a dose- and time-dependent manner. It also inhibited the invasion of GBC-SD cells in a dose-dependent manner. Garcinol treatment decreased the activity of matrix metalloproteinase 2 (MMP2) and MMP9 by the downregulation of mRNA levels, and these two enzymes are critical to tumor invasion. Treatment with garcinol also decreased Stat3 and Akt activation in GBC-SD cells. Taken together, the effects of garcinol on GBC-SD cells may be associated with the suppression of Stat3 and Akt signaling pathways, which may contribute to inhibiting their downstream targets such as mRNA levels of MMP2 and MMP9. 10.1691/ph.2018.8366
    Opposite Effects of Garcinol on Tumor Energy Metabolism in Oral Squamous Cell Carcinoma Cells. Zhang Guilian,Fu Jie,Su Ying,Zhang Xinyan Nutrition and cancer Garcinol is a natural polyisoprenylated benzophenone extracted from the dried fruit rind of . The aim of this study was to investigate the roles of garcinol in oral squamous cell carcinoma (OSCC) cells and its action on cancer cell energy metabolisms. Cell cycle, apoptosis, migration and invasion assays were detected, and oxygen consumption and extracellular acidification rates were also measured with Extracellular Flux Analyzer. Our studies showed that garcinol represses OSCC cells proliferation, cell cycle, migration and invasion, and colony formation. Of note, garcinol directly targeted cancer cell energy producing pathway mitochondrial respiration by significantly inhibiting ATP production, maximal respiration, spare respiration capacity and basal respiration in a dose-dependent manner. But garcinol treatment reflexively boosted glycolysis presented by increased glycolysis and glycolytic capacity. The promotion of garcinol on glycolytic pathway is also confirmed presented by elevated lactic acid content and the activity of pyruvate kinase. Furthermore, the expression of glucose transporter1 and 4, and several important genes related to the glycolysis pathway, including HIF-1α, AKT, and PTEN, was also upregulated after garcinol treatment. Taken together, our results revealed that garcinol has opposite effects on tumor energy metabolism through inhibiting mitochondrial oxidative phosphorylation significantly, and reflexively enhancing glycolysis in OSCC cells. Abbreviations OSCC oral squamous cell carcinoma DMBA dimethylbenzanthracene OCR oxygen consumption rate OXPHOS oxidative phosphorylation ECAR extracellular acidification rate. 10.1080/01635581.2019.1607409
    Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas. Huang Wen-Chien,Kuo Kuang-Tai,Adebayo Bamodu Oluwaseun,Wang Chun-Hua,Chen Yu-Jen,Jin Ketao,Tsai Tung-Hu,Yeh Chi-Tai The Journal of nutritional biochemistry Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated β-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/β-catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent. 10.1016/j.jnutbio.2017.12.008
    Dietary garcinol supplementation improves diarrhea and intestinal barrier function associated with its modulation of gut microbiota in weaned piglets. Wang Tongxin,Yao Weilei,Li Juan,Shao Yafei,He Qiongyu,Xia Jun,Huang Feiruo Journal of animal science and biotechnology Background:The effects of dietary garcinol on diarrhea and intestinal barrier function associated with its modulation of gut microbiota in weaned piglets were investigated. Method:One hundred forty four weaned piglets (Duroc × Yorkshire × Landrace) from 16 pens (9 piglets per pen) were randomly divided into four treatment groups: controls (CON) or those supplemented with 200 mg/kg (LOW), 400 mg/kg (MID), or 600 mg/kg (HIGH) diet garcinol. After 14-day trial, three piglets per pen were chosen to collect plasma, intestinal tissue and colonic digesta samples. Results:We demonstrated for the first time that garcinol promoted growth performance, as increased average daily feed intake (ADFI) and decreased feed/gain ratio (F/G); and reduced diarrhea incidence ( < 0.05); and strengthened antioxidant capacity, as an increased antioxidative index ( < 0.05). Additionally, garcinol ameliorated intestinal barrier dysfunction, as an increased villus height to crypt depth ratio, increased zonula occludens protein 1 (ZO-1), occludin and claudin-1 expression in the jejunum and ileum ( < 0.05), and decreased intestinal permeability ( < 0.05); and reduced inflammation, as decreased cytokine interleukin (IL)-6, IL-10, IL-1β and tumor necrosis factor-α (TNF-α) levels in the mucosa of the jejunum and ileum, and NF-κB p65 translocation ( < 0.05). Moreover, garcinol inhibited the growth of most harmful bacteria in the gut, especially , and increased the growth of the beneficial bacteria Conclusion:This work provides a fundamental basis for the future development of garcinol-functional food use for improving diarrhea and intestinal barrier function in weaned piglets and for understanding the biological effects of garcinol and its potential as a functional feed additive. 10.1186/s40104-020-0426-6
    Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs. Farhan Mohd,Malik Arshi,Ullah Mohammad Fahad,Afaq Sarah,Faisal Mohd,Farooqi Ammad Ahmad,Biersack Bernhard,Schobert Rainer,Ahmad Aamir International journal of molecular sciences Garcinol, a dietary factor obtained from , modulates several key cellular signaling pathways as well as the expression of miRNAs. Acquired resistance to standard therapies, such as erlotinib and cisplatin, is a hallmark of non-small cell lung cancer (NSCLC) cells that often involves miRNA-regulated epithelial-to-mesenchymal transition (EMT). We used A549 cells that were exposed to transforming growth factor beta 1 (TGF-β1), resulting in A549M cells with mesenchymal and drug resistant phenotype, and report that garcinol sensitized resistant cells with mesenchymal phenotype to erlotinib as well as cisplatin with significant decrease in their IC values. It also potentiated the apoptosis-inducing activity of erlotinib in A549M and the endogenously mesenchymal H1299 NSCLC cells. Further, garcinol significantly upregulated several key EMT-regulating miRNAs, such as miR-200b, miR-205, miR-218, and let-7c. Antagonizing miRNAs, through anti-miRNA transfections, attenuated the EMT-modulating activity of garcinol, as determined by mRNA expression of EMT markers, E-cadherin, vimentin, and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). This further led to repression of erlotinib as well as cisplatin sensitization, thus establishing the mechanistic role of miRNAs, particularly miR-200c and let-7c, in garcinol-mediated reversal of EMT and the resulting sensitization of NSCLC cells to standard therapies. 10.3390/ijms20040800
    [Role of 8-allyl Garcinol in the Chemoprevention of Oral Squamous Cell Carcinoma]. Dong Hai Tao,Cao Jing,Han Chao Ming,Su Ying,Zhang Xin Yan,Chen Xin Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae Objective To evaluate the chemopreventive effects of 8-allyl garcinol on oral squamous cell carcinoma(OSCC).Methods OSCC cell line CAL27 were cultured and treated with different concentrations of garcinol or 8-allyl garcinol. Their effects on the biological behaviors of OSCC cell line CAL27 were measured by MTT assay,clony formation assay,scratch migration assay,and flow cytometry with Annexin V-FITC/PI staining assay. We established DMBA-induced hamster cheek pouch models of dysplasia. While the negative control group was not treated,the positive group was treated with 0.5% DMBA solution tropically to the left cheek pouch three times per week for three consecutive weeks. The other four groups received 0.5 mmol/L or 1.0 mmol/L garcinol or 8-allyl garcinol respectively three times within the following two weeks after DMBA treatment. Hamsters were sacrificed at the fifth week to obtain tissue samples of the left cheek pouch. The samples were examined by histopathology and BrdU immunohistochemisty.Results MTT assay showed that both garcinol and 8-allyl garcinol inhibited the proliferation of CAL27 cells in a concentration-and time-dependent manner. The half maximal inhibitory concentration(IC)of 8-allyl garcinol[(13.13±2.55)μmol/L] was significantly lower than garcinol[(32.20±3.24)μmol/L;t=8.008,P=0.001]. Comparing the two grougs of medicine in the same concentration,the inhibiting proliferation effects 8-allyl garcinol had significantly stronger effect in inhibiting proliferation than garcinol when the same dose was applied,and the difference was largest at the concentrations of 10(24 h:t=8.012,P=0.001;48 h:t=5.939,P=0.001;72 h:t=12.551,P=0.001)and 20 μmol/L(24 h:t=8.887,P=0.001;48 h:t=9.324,P=0.002;72 h:t=5.361,P=0.002). The clone formation assay showed the clone formation rates after the treatment with 20 μmol/L garcinol and 20 μmol/L 8-allyl garcinol were(44.1±0.4)% and(23.6±0.6)%,respectively,which were significantly lower than those after treatment with 10 μmol/L garcinol[(55.6±2.8)%;t=6.894,P=0.019] and 10 μmol/L 8-allyl garcinol[(31.0±0.6)%;t=15.556,P=0.001]. The inhibiting effects of 8-allyl garcinol at the concentrations of 10 μmol/L(t=14.682,P=0.003)and 20 μmol/L(t=51.514,P=0.001)were significantly stronger than garcinol.Scratch test showed the relative cell migration rates after treatment with 10 and 20 μmol/L garcinol for 12 hours were(16.00±4.55)%(t=3.139,P=0.026)and(3.00±3.16)%(t=6.608,P=0.001),respectively,which were lower than negative control [(30.33±7.64)%]. The relative cell migration rates after treatment with 10 and 20 μmol/L 8-allyl garcinol for 12 hours were(16.25±3.86)%(t=3.245,P=0.023)and(6.00±2.65)%(t=5.214,P=0.006),respectively,which were also lower than negative control[(30.33±7.64)%]. In addition,the relative cell migration rates after treatment with 10 and 20 μmol/L garcinol for 24 hours were(23.75±4.57)%(t=4.718,P=0.005)and(5.75±1.50)%(t=10.432,P=0.001),respectively,which were lower than negative control[(45.33±7.64)%]. The relative cell migration rates after treatment with 10 and 20 μmol/L 8-allyl garcinol for 24 hours were(23.50±2.38)%(t=5.529,P=0.003)and(11.67±2.31)%(t=7.308,P=0.002),respectively,which were also lower than negative control[(45.33±7.64)%]. Furthermore,the relative cell migration rate after treatment with 20 μmol/L garcinol for 24 hours was significantly lower than after treatment with 8-allyl garcinol(t=4.151,P=0.009). The apoptosis experiments showed that the early apoptosis rate of CAL27 cells was(5.00±0.10)% after treatment with 10 μmol/L garcinol,which was significantly higher than negative control[(1.57±0.21)%;F=70.950,P=0.001]. The early and late apoptosis rates of CAL27 cells were(5.90±0.78)%(t=39.384,P=0.001)and(9.73±1.67)%(t=10.101,P=0.001),respectively,after treatment with 20 μmol/L garcinol,which were also significantly higher than negative control. The early apoptosis rate of CAL27 cells was(4.63±1.16)% after treatment with 8-allyl garcinol,which was significantly higher than negative control(t=4.511,P=0.041). The effects of 8-allyl garcinol in promoting cell apoptosis were weaker than garcinol(10 μmol/L:t=5.982,P=0.004;20 μmol/L:t=8.578,P=0.001). The histopathological test also showed that the hyperplastic areas of oral mucosal epithelium in hamsters after treatment with 0.5 mmol/L garcinol(t=2.546,P=0.031),0.5 mmol/L 8-allyl garcinol(t=3.485,P=0.008),1.0 mmol/L garcinol(t=4.556,P=0.001),and 1.0 mmol/L 8-allyl garcinol(t=5.393,P=0.001)were significantly smaller than positive control. The dysplasia areas of oral mucosal epithelium in hamsters after treatment with 0.5 mmol/L 8-allyl garcinol(t=2.130,P=0.046),1.0 mmol/L garcinol(t=3.434,P=0.010),and 1.0 mmol/L 8-allyl garcinol(t=4.518,P=0.004)were also smaller than positive control;1.0 mmol/L garcinol group(t=2.793,P=0.023)and 1.0 mmol/L 8-allyl garcinol group(t=4.997,P=0.001)were smaller than 0.5 mmol/L garcinol treatment group. Immunohistochemical staining of BrdU showed that the BrdU-labeled indicators were significantly lower in negative control group(t=7.563,P=0.001),0.5 mmol/L garcinol(t=2.862,P=0.029),0.5 mmol/L 8-allyl garcinol(t=4.693,P=0.002),1.0 mmol/L garcinol(t=5.071,P=0.002),and 1.0 mmol/L 8-allyl garcinol(t=5.133,P=0.001)when compared with the positive control. The BrdU-labeled indicators in 0.5 mmol/L 8-allyl garcinol(t=3.724,P=0.007),1.0 mmol/L garcinol(t=7.000,P=0.001),and 1.0 mmol/L 8-allyl garcinol(t=4.413,P=0.003)were also significantly lower than in 0.5 mmol/L garcinol group.Conclusions 8-allyl garcinol could inhibit the proliferation and migration of OSCC cell line CAL27 and promotes apoptosis. It also has prominent inhibitory effects on DMBA-induced hamster cheek pouch dysplasia. However,the specific effects are slightly different from garcinol. 10.3881/j.issn.1000-503X.10735
    Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells. Aggarwal Vaishali,Tuli Hardeep Singh,Kaur Jagjit,Aggarwal Diwakar,Parashar Gaurav,Chaturvedi Parashar Nidarshana,Kulkarni Samruddhi,Kaur Ginpreet,Sak Katrin,Kumar Manoj,Ahn Kwang Seok Biomedicines Garcinol, a polyisoprenylated benzophenone, is the medicinal component obtained from fruits and leaves of () and has traditionally been extensively used for its antioxidant and anti-inflammatory properties. In addition, it has been also been experimentally illustrated to elicit anti-cancer properties. Several in vitro and in vivo studies have illustrated the potential therapeutic efficiency of garcinol in management of different malignancies. It mainly acts as an inhibitor of cellular processes via regulation of transcription factors NF-κB and JAK/STAT3 in tumor cells and have been demonstrated to effectively inhibit growth of malignant cell population. Numerous studies have highlighted the anti-neoplastic potential of garcinol in different oncological transformations including colon cancer, breast cancer, prostate cancer, head and neck cancer, hepatocellular carcinoma, etc. However, use of garcinol is still in its pre-clinical stage and this is mainly attributed to the limitations of conclusive evaluation of pharmacological parameters. This necessitates evaluation of garcinol pharmacokinetics to precisely identify an appropriate dose and route of administration, tolerability, and potency under physiological conditions along with characterization of a therapeutic index. Hence, the research is presently ongoing in the dimension of exploring the precise metabolic mechanism of garcinol. Despite various lacunae, garcinol has presented with promising anti-cancer effects. Hence, this review is motivated by the constantly emerging and promising positive anti-cancerous effects of garcinol. This review is the first effort to summarize the mechanism of action of garcinol in modulation of anti-cancer effect via regulation of different cellular processes. 10.3390/biomedicines8050103
    Garcinol Enhances TRAIL-Induced Apoptotic Cell Death through Up-Regulation of DR5 and Down-Regulation of c-FLIP Expression. Kim Seok,Seo Seung Un,Min Kyoung-Jin,Woo Seon Min,Nam Ju-Ock,Kubatka Peter,Kim Shin,Park Jong-Wook,Kwon Taeg Kyu Molecules (Basel, Switzerland) Garcinol is a polyisoprenylated benzophenone derived from the fruit that possess potential therapeutic effects such as inhibition of inflammation and tumor expansion. Here, we investigated whether garcinol induces TRAIL sensitization in renal carcinoma cells. Single treatment with garcinol or TRAIL did not effect on apoptosis. However, combined treatment with garcinol plus TRAIL significantly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung carcinoma (A549), and hepatoma (SK-Hep1) cells. In contrast, garcinol plus TRAIL did not alter cell viability in normal cells. Garcinol plus TRAIL induced up-regulation of DR5 and down-regulation of c-FLIP expression at post-translational levels. Furthermore, knock-down of DR5 by siRNA and ectopic expression of c-FLIP blocked apoptotic cell death induced by garcinol plus TRAIL. Overall, our study provides evidence that garcinol can be exploited as a potential TRAIL sensitizer. 10.3390/molecules23071614
    Garcinol Alone and in Combination With Cisplatin Affect Cellular Behavior and PI3K/AKT Protein Phosphorylation in Human Ovarian Cancer Cells. Zhang Jie,Fang Huan,Zhang Jinguo,Guan Wencai,Xu Guoxiong Dose-response : a publication of International Hormesis Society Garcinol is a plant-derived compound that has some physiological benefits to human cells. However, the effect of garcinol on ovarian cancer (OC) cell proliferation and apoptosis is unknown. The current study aimed to examine the effects of garcinol alone and in combination with cisplatin (DDP) on cellular behavior and to explore the expression pattern of PI3K/AKT and nuclear factor-κB (NF-κB) in human OC cells. We found that OVCAR-3 cell viability was decreased after garcinol treatment. Garcinol alone and in combination with DDP significantly inhibited cell proliferation and had a synergistic effect evaluated by CompuSyn software. The cell cycle analysis showed the S phase arrest by garcinol. Furthermore, garcinol alone and in combination with DDP promoted cell apoptosis. The garcinol-induced apoptosis was further confirmed by the detection of cleavage forms of PARP and caspase 3. An increase in proapoptotic factor Bax expression was also found in garcinol-treated cells. Moreover, garcinol significantly decreased the phosphorylation of PI3K and AKT proteins and downregulated the expression of NF-κB. Thus, our data demonstrated that garcinol has the potential to be used as an anticancer agent and may synergize the effect of DDP. These actions are most likely through the regulation of the PI3K/AKT and NF-κB pathways. 10.1177/1559325820926732
    Cardioprotective effects of garcinol following myocardial infarction in rats with isoproterenol-induced heart failure. Li Man,Li Xuewen,Yang Lifeng AMB Express Myocardial infarction is a clinical form of necrosis in the myocardium caused by an imbalance between the coronary blood supply and myocardial demand. Garcinol is a polyisoprenylated benzophenone found in the fruit of Garcinia indica, which is abundant in tropical regions. This fruit contains high levels of garcinol, isoxanthochymol, isogarcinol, hydroxycitric acid and xanthochymol. Garcinol and hydroxycitric acid have been shown to have antioxidant effects. In this study, rats were assigned to sham, control, low-dose, high-dose and positive control groups. Hemodynamic and apoptotic markers were evaluated, and histopathological analysis was conducted. The mRNA and protein levels of caspase-3, Bax, Bcl-2 and cleaved caspase-3 were quantified. Garcinol treatment increased the heart rate and improved the maximum rate of increase in left-ventricle (LV) pressure (+dp/dt), maximum rate of decrease in LV pressure (-dp/dt), LV ejection fraction and LV systolic pressure in rats with induced heart failure. Garcinol treatment reversed body, liver and heart weight changes, resulting in returns to near-normal levels. In the garcinol treatment group, the number of broken fibers, extent of inflammatory cell infiltration and rate of apoptosis remained within normal ranges. Garcinol reduced the cross-sectional areas of cardiomyocytes, and reduced interstitial fibrosis to a normal level. The mRNA and protein levels of cleaved caspase-3, caspase-3 and Bax were reduced, whereas those of Bcl-2 were increased, following high-dose (100 mg/kg) garcinol treatment. These findings suggest that garcinol effectively prevents apoptosis in rats with isoproterenol-induced heart failure and in cardiac H9C2 cells. 10.1186/s13568-020-01065-9
    Garcinol promotes hepatic gluconeogenesis by inhibiting P300/CBP-associated factor in late-pregnant sows. Yao Weilei,Xia Jun,Wang Tongxin,Li Juan,Huang Lu,Huang Feiruo The British journal of nutrition Disorder of hepatic glucose metabolism is the characteristic of late-pregnant sows. The purpose of our study was to look into the mechanism of garcinol on the improvement of hepatic gluconeogenic enzyme in late-pregnant sows. Thirty second- and third-parity sows (Duroc × Yorkshire × Landrace, n 10/diet) were fed a basal diet (control) or that diet supplemented with 100 mg/kg (Low Gar) or 500 mg/kg (High Gar) garcinol from day 90 of gestation to the end of farrowing. The livers were processed to measure enzymatic activity. Hepatocytes from pregnant sows were transfected with P300/CBP-associating factor (PCAF) small interfering RNA (siRNA) or treated with garcinol. Dietary garcinol had no effect on average daily feed intake, body weight (BW), backfat and BW gain of late-pregnant sows. Garcinol promoted plasma glucose levels in pregnant sows and newborn piglets. Garcinol up-regulated hepatic gluconeogenic enzyme expression and decreased PCAF activity. Garcinol had no effect on the expression of PPAR-γ co-activator 1α (PGC-1α) and Forkhead box O1 (FOXO1) but significantly increased their activity and decreased their acetylation in late-pregnant sows. Transfection of PCAF siRNA to hepatocytes of pregnant sows increased PGC-1α and FOXO1 activities. Furthermore, in hepatocytes of pregnant sows, garcinol treatment also up-regulated the activities of PGC-1α and FOXO1 and inhibited the acetylation of PGC-1α and FOXO1. Garcinol improves hepatic gluconeogenic enzyme expression in late-pregnant sows, and this may be due to the mechanism of down-regulating the acetylation of PGC-1α and FOXO1 induced by PCAF in isolated hepatocytes. 10.1017/S000711452000375X
    Garcinol exerts anti-cancer effect in human cervical cancer cells through upregulation of T-cadherin. Zhao Juan,Yang Ting,Ji Jing,Li Chen,Li Zhen,Li Long Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Garcinol, a polyisoprenylated benzophenone, has been demonstrated to exert anti-cancer effects in various tumor cells. However, the effect of garcinol on cervical cancer (CC) cell progression and the related molecular mechanism remains poorly understood. Accumulating evidence has verified that downregualtion of T-cadherin is closely associated with tumorigenesis, suggesting that T-cadherin might be a potential therapeutic target for cancer treatment. In the present study, Hela and SiHa cells were treated with different concentrations of garcinol (0, 5, 10, and 25 u M), and T-cadherin siRNA was synthesized and transfected into Hela and SiHa cells combined with garcinol (25 u M) treatment. We found that garcinol dose-dependently suppressed cell viability, colony formation, invasion, migration, cell cycle progression, and promoted cell apoptosis in CC cell lines, as well as inhibited tumor growth in xenograft model. Importantly, our results showed that garcinol treatment increased the expression of T-cadherin both in vitro and in vivo, and knockdown of T-cahderin partially reversed garcinol-induced inhibition of CC development via activating P13 K/AKT signaling pathway in CC cell lines. Thus, these findings demonstrated the tumor suppressive function of garcinol on CC progression, and emphasized that the T-cadherin/P13 K/AKT was a potential mechanism involved in the antumor effects of garcinol. 10.1016/j.biopha.2018.08.060
    Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice. Kim Jung-Yeon,Jo Jungmin,Leem Jaechan,Park Kwan-Kyu Antioxidants (Basel, Switzerland) Emerging evidence suggests that epigenetic mechanisms such as histone modification are crucially involved in the pathophysiology of acute kidney injury (AKI). The histone acetyltransferase p300 regulates several biological processes through the acetylation of histones or transcription factors. However, the role of p300 in cisplatin-induced AKI remains poorly understood. Therefore, we investigated the effects of garcinol, a potent p300 inhibitor, on cisplatin-induced AKI and explored the mechanisms. Administration of garcinol significantly reversed the upregulation of p300 and increased acetylation of histone H3, along with amelioration of renal dysfunction and histopathological injury in the kidneys of cisplatin-injected mice. Garcinol also attenuated oxidative stress and reduced expression of pro-oxidant enzymes. In addition, garcinol reduced the elevated production of cytokines and chemokines and suppressed immune cell accumulation together with downregulation of vascular adhesion molecules. These beneficial effects of garcinol were associated with a reduction in acetylation of the p65 subunit of nuclear factor kappa-B. Further, garcinol significantly inhibited apoptosis and caspase-3 activation, with a decrease in p53 acetylation in cisplatin-injected mice. Taken together, we demonstrated that the inhibition of p300 by garcinol ameliorated cisplatin-induced renal injury, presumably through epigenetic mechanisms. These results suggest that garcinol might be a potential preventive agent for cisplatin-induced AKI. 10.3390/antiox9121271
    Garcinol Reduces Obesity in High-Fat-Diet-Fed Mice by Modulating Gut Microbiota Composition. Lee Pei-Sheng,Teng Chia-Yi,Kalyanam Nagabhushanam,Ho Chi-Tang,Pan Min-Hsiung Molecular nutrition & food research SCOPE:Obesity has become a major health problem worldwide and is associated with low-grade chronic inflammation and intestinal dysbiosis. This study is conducted to investigate the chemopreventive effects of garcinol, a polyisoprenylated benzophenone derivative isolated from the fruit rind of Garcinia indica. How garcinol protects against obesity in high-fat diet (HFD)-induced mice is delineated and whether its anti-obesity effects are related to gut microbiota has been determined. METHODS AND RESULTS:The results show that garcinol reduces HFD-fed mice body weight gain and relative visceral adipose tissue fat weight in a dose-dependent manner. Furthermore, garcinol markedly reduces the plasma levels of glutamate pyruvate transaminase, total cholesterol, and triacylglycerol. The 16S rRNA gene sequence data indicate that garcinol not only reverses HFD-induced gut dysbiosis-as indicated by the decreased Firmicutes-to-Bacteroidetes ratios-but also controls inflammation by increasing the intestinal commensal bacteria, Akkermansia. In addition, the AMP-activated protein kinase α signaling pathway involved in adipocyte adipogenesis is also affected by garcinol. CONCLUSION:Taken together, these results demonstrate for the first time that garcinol can prevent HFD-induced obesity and may be used as a novel gut microbiota modulator to prevent HFD-induced gut dysbiosis and obesity-related metabolic disorders. 10.1002/mnfr.201800390
    Garcinol protects against cerebral ischemia-reperfusion injury in vivo and in vitro by inhibiting inflammation and oxidative stress. Kang Yingchao,Sun Yaping,Li Tiantian,Ren Zelin Molecular and cellular probes Garcinol, a polyisoprenylated benzophenone derivative, is isolated from fruit rind of Garcinia indica. It is known to exert potent anti-inflammatory and anti-oxidative properties. In the present study, we tried to investigate the neuroprotective effects of garcinol on a rat model with middle cerebral artery occlusion/reperfusion (MCAO/R) and a cell model subjected to oxygen glucose deprivation and reperfusion (OGD/R). In vivo, we found that the rats with garcinol treatment showed a lower neurological deficit score and a smaller infarct size compared with the rats with ischemia-reperfusion (I/R) injury alone. We further found that garcinol treatment decreased cerebral I/R-induced inflammatory cytokines and oxidative stress, including inhibiting the production of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), decreasing the levels of malonaldehyde (MDA) and nitric oxide (NO), and suppressing the decreased superoxide dismutase (SOD) activity. Moreover, the suppression of toll-like receptor (TLR) 4 and nuclear NF-κB (p65) expression by garcinol was found both in vivo and in vitro. In addition, NF-κB activator or TLR4 overexpression was employed to investigate its involvement in the effects of garcinol. The results showed that NF-κB activator or TLR4 overexpression at least in part reversed the anti-inflammatory and anti-oxidative properties of garcinol in vitro. Taken together, the data suggest that garcinol could protect against cerebral I/R injury through attenuating inflammation and oxidative stress, and improving neurological function. The molecular mechanism might be related to its suppression of TLR4/NF-ĸB signal pathway. 10.1016/j.mcp.2020.101672
    Garcinol suppresses RANKL-induced osteoclastogenesis and its underlying mechanism. Jia Yewei,Jiang Jiawei,Lu Xuanyuan,Zhang Tan,Zhao Kangxian,Han Weiqi,Yang Wanlei,Qian Yu Journal of cellular physiology Osteoclasts (OCs) are multinuclear giant cells responsible for bone resorption, and an excessive bone resorption by OCs plays an important role in osteoporosis. Commonly used drugs for the treatment of osteoporosis have severe side effects. As such, identification of alternative treatments is essential. Garcinol, a polyisoprenylated benzophenone extracted from the fruit of Garcinia indica, has shown a strong antitumor effect through the nuclear factor-κB (NF-κB) and mitogen-associated protein kinases (MAPK) signaling pathways. However, the role of garcinol in the osteoclastogenesis is still unclear. Here, we demonstrated that garcinol can inhibit the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, osteoclastogenesis-related gene expression, the f-actin ring, and resorption pit formation. In addition, garcinol abrogated RANKL-induced osteoclastogenesis by attenuating the degradation of the MAPK, NF-κB, and PI3K-AKT signaling pathway as well as downstream factors c-jun, c-fos, and NFATC1. In vivo, suppression of osteoclastogenesis by garcinol was evidenced by marked inhibition of lipopolysaccharide-induced bone resorption. In conclusion, our data demonstrated that garcinol inhibited the RANKL-induced osteoclastogenesis by suppressing the MAPK, NF-κB, and PI3K-AKT signaling pathways and thus has potential as a novel therapeutic option for osteolytic bone diseases. 10.1002/jcp.27511
    Garcinol Suppresses IL-1β-Induced Chondrocyte Inflammation and Osteoarthritis via Inhibition of the NF-κB Signaling Pathway. Jia Yewei,Pang Cong,Zhao Kangxian,Jiang Jiawei,Zhang Tan,Peng Jiaxuan,Sun Peng,Qian Yu Inflammation Osteoarthritis (OA), which is characterized as a common degenerative joint disease, is presently the most prevalent chronic degenerative joint disease. Accumulating evidence has shown a biological function for Garcinol in a variety of diseases; however, whether it could be used to treat OA remains unclear. In this study, we explored the protective effects of garcinol on the progression of OA and explored the underlying mechanism. In vitro, garcinol reduced the expression of pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor alpha (TNF-α). It also decreased the expression of inducible nitric oxide synthase (iNOS), as well as cyclooxygenase-2 (COX-2). Furthermore, garcinol inhibited the expression of thrombospondin motifs 5(ADAMTS5) and metalloproteinase (MMPs), both of which regulate extracellular matrix degradation. These changes could be attributed to garcinol-related suppression of the IL-1β-induced NF-κB signaling pathway. Moreover, we investigated the protective effects of garcinol on the surgical destabilization of the medial meniscus (DMM) of the mouse, an in vivo model of OA. Taken together, our data suggest garcinol as a potential future agent for the treatment of OA. 10.1007/s10753-019-01037-7
    Dietary supplementation with garcinol during late gestation and lactation facilitates acid-base balance and improves the performance of sows and newborn piglets1. Wang Tongxin,Yao Weilei,Xia Jun,Li Juan,Shao Yafei,Huang Feiruo Journal of animal science The present study was conducted to evaluate the effects of dietary garcinol supplementation during late gestation (from the 90th day of pregnancy; day 90) and lactation on the acid-base balance of the umbilical cord blood and performance of sows and piglets. Sixty sows (Duroc × Yorkshire × Landrace; second- or third-parity; n = 20) were randomly divided into 3 gestation (day 90 of pregnancy) or lactation treatments, control diet (CON; basal diet), basal diet with 200 mg garcinol, and basal diet with 600 mg garcinol per kg of feed. The body weight (BW); backfat thickness and litter size of the sows; and birth weight, weaning weight, and mortality of piglets were recorded. Sows' blood and piglets' umbilical cord blood were collected for the measurements of hematological parameters and antioxidative and immune indexes, and acid-base balance parameters, respectively. The colostrum and milk and fecal samples of the sows were also collected for analysis of milk composition and apparent total tract nutrient digestibility. Garcinol had no effect on the BW and backfat thickness of the sows but significantly increased the birth weight and weaning weight of piglets (P < 0.05) and decreased the mortality (P < 0.05). Moreover, the white blood cell counts and neutrophil count, mean cell hemoglobin, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity in the plasma of the sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group, whereas the malondialdehyde (MDA) content was decreased (P < 0.05). The garcinol treatment significantly increased the pH, HCO3- and base excess values (P < 0.05), whereas it decreased the pCO2 and lactate content (P < 0.05) in the umbilical blood. Dry matter (DM), ash, and ether extract in the colostrum were similar between groups (P > 0.05), whereas the garcinol significantly increased the crude protein (CP) in the milk. In addition, the content of immunoglobulin A (IgA) and immunoglobulin G (IgG) in the plasma of piglets and in colostrum and milk of sows were increased more significantly (P < 0.05) in the garcinol groups than that in the CON group. The apparent total tract nutrient digestibility was similar between treatments. Collectively, this study indicates that sows fed with garcinol in late gestation and lactation showed improved maternal health and antioxidative status, milk protein content, acid-base balance in the umbilical cord blood, and growth performance in piglets, showing promise in natural plant extract nutrition for sows. 10.1093/jas/skz292
    Garcinol inhibits esophageal cancer metastasis by suppressing the p300 and TGF-β1 signaling pathways. Wang Jing,Wu Man,Zheng Dan,Zhang Hong,Lv Yue,Zhang Li,Tan Hong-Sheng,Zhou Hua,Lao Yuan-Zhi,Xu Hong-Xi Acta pharmacologica Sinica Metastasis causes the main lethality in esophageal cancer patient. Garcinol, a natural compound extracted from Gambogic genera, is a histone acetyltransferase (HAT) inhibitor that has shown anticancer activities such as cell cycle arrest and apoptosis induction. In this study, we investigated the effects of garcinol on the metastasis of esophageal cancer in vitro and in vivo. We found that garcinol (5-15 μM) dose-dependently inhibited the migration and invasion of human esophageal cancer cell lines KYSE150 and KYSE450 in wound healing, transwell migration, and Matrigel invasion assays. Furthermore, garcinol treatment dose-dependently decreased the protein levels of p300/CBP (transcriptional cofactors and HATs) and p-Smad2/3 expression in the nucleus, thus impeding tumor cell proliferation and metastasis. Knockdown of p300 could inhibit cell metastasis, but CBP knockdown did not affect the cell mobility. It has been reported that TGF-β1 stimulated the phosphorylation of Smad2/3, which directly interact with p300/CBP in the nucleus, and upregulating HAT activity of p300. We showed that garcinol treatment dose-dependently suppressed TGF-β1-activated Smad and non-Smad pathway, inhibiting esophageal cancer cell metastasis. In a tail vein injection pulmonary metastasis mouse model, intraperitoneal administration of garcinol (20 mg/kg) or 5-FU (20 mg/kg) significantly decreased the number of lung tumor nodules and the expression levels of Ki-67, p300, and p-Smad2/3 in lung tissues. In conclusion, our study demonstrates that garcinol inhibits esophageal cancer metastasis in vitro and in vivo, which might be related to the suppression of p300 and TGF-β1 signaling pathways, suggesting the therapeutic potential of Garcinol for metastatic tumors. 10.1038/s41401-019-0271-3
    Dietary Garcinol Attenuates Hepatic Pyruvate and Triglyceride Accumulation by Inhibiting P300/CBP-Associated Factor in Mid-to-Late Pregnant Rats. Yao Weilei,Wang Tongxin,Xia Jun,Li Juan,Yu Xinhong,Huang Feiruo The Journal of nutrition BACKGROUND:Increased hepatic glycolysis and lipogenesis are characteristic of pregnancy. OBJECTIVES:The present study aimed to investigate the mechanism of garcinol on the amelioration of hepatic pyruvate and triglyceride (TG) accumulation in mid-to-late pregnant rats. METHODS:Forty Sprague-Dawley pregnant rats (aged 9 wk, n = 10/diet) were fed a basal diet (control) or that diet plus garcinol at 100 ppm (Low Gar), 300 ppm (Mid Gar), or 500 ppm (High Gar) for 14 d. The livers were processed for Western blotting analyses and measuring enzymatic activity and pyruvate and TG concentrations. Hepatocytes from other pregnant Sprague Dawley rats were transfected with P300/CBP associating factor (PCAF) short interfering (si)RNAs; hepatocytes from nonpregnant Sprague-Dawley rats with overexpression of PCAF were treated with garcinol (5 μM). The activity and acetylation of upstream stimulatory factor (USF-1) and glycolytic enzymes were analyzed. RESULTS:Dietary garcinol significantly decreased (P < 0.05) concentrations of hepatic and plasma TG (27.1-45.8%) and total cholesterol (25.3-49.5%), plasma free fatty acids (24.4-37.8%), and hepatic pyruvate (31.5-43.5%) and lactate (33.4-65.7%) in mid-to-late pregnant rats. Garcinol promoted (P < 0.05) antioxidant capacity in the liver and plasma by 27.4-32.1%. Garcinol downregulated (P < 0.05) lipid synthesis-related enzyme expression by 30.6-85.3% and decreased (P < 0.05) glycolytic enzyme activities by 22.5-74.6% and PCAF activity by 18.6-55.4%. Transfection of PCAF siRNAs to hepatocytes of pregnant rats decreased USF-1 and glycolytic enzyme activities by PCAF; garcinol treatment downregulated (P < 0.05) the acetylation and activities of USF-1 and glycolytic enzymes by 35.6-83.7%. CONCLUSIONS:Garcinol attenuates hepatic pyruvate and TG accumulation in the liver of mid-to-late pregnant rats, which may be due to downregulating the acetylation of USF-1 and the glycolytic enzymes induced by PCAF in isolated hepatocytes. 10.1093/jn/nxz238
    The effect of dietary garcinol supplementation on oxidative stability, muscle postmortem glycolysis and meat quality in pigs. Wang Tongxin,Li Juan,Shao Yafei,Yao Weilei,Xia Jun,He Qiongyu,Huang Feiruo Meat science The objective of this study was to evaluate the effects of dietary garcinol (0, 200, 400 and 600 mg/kg) on the growth performance, meat quality, postmortem glycolysis and antioxidative capacity of finishing pigs. Dietary garcinol increased pigs' average daily gain, pH , a* and myoglobin content of longissimus dorsi (LM) (P < 0.05), and decreased feed/gain ratio, the L*, glycolytic potential, drip loss, shear force, and backfat depth (P < 0.05). The glutathione peroxidase (GPx), catalase (CAT) and total antioxidative capacity (T-AOC) were significantly increased by garcinol (P < 0.05), while the activity of lactate dehydrogenase (LDH) and malonaldehyde (MDA) content were decreased (P < 0.05). Moreover, garcinol decreased the p300/CBP-associated factor (PCAF) activity, the acetylation level and activities of glycolysis enzymes phosphoglycerate kinase 1 (PGK1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3 (PFKFB3) (P < 0.05). The results of this study showed that garcinol decreased postmortem glycolysis, and this may be due to the mechanism of decreasing glycolytic enzyme acetylation induced by PCAF. The present study indicates that garcinol can facilitate the growth performance of pigs and improve pork quality by changing postmortem glycolysis and antioxidative capacity. 10.1016/j.meatsci.2019.107998