Salvianolic acid A alleviates chronic ethanol-induced liver injury via promotion of β-catenin nuclear accumulation by restoring SIRT1 in rats.
Shi Xue,Zhao Yan,Ding Chunchun,Wang Zhecheng,Ji Anlong,Li Zhenlu,Feng Dongcheng,Li Yang,Gao Dongyan,Zhou Junjun,Tian Xiaofeng,Yao Jihong
Toxicology and applied pharmacology
In recent years, alcoholic liver disease (ALD) has emerged as a growing public health problem worldwide. β-catenin plays an important role in the growth, development, regeneration and metabolic activity of the liver. Salvianolic acid A (SalA) is a water-soluble component from the root extract of Salvia miltiorrhiza Bunge, and its effect on ALD has not yet been investigated. This study aimed to investigate the effect of SalA on chronic alcohol-induced liver injury and to explore the role of SIRT1-mediated β-catenin deacetylation in such an effect. In this study, SalA treatment significantly alleviated the accumulation of lipid droplets and reduced the plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), alcohol and ammonia levels in rats. SalA enhanced ethanol and ammonia metabolism and maintained mitochondrial homeostasis. Moreover, SalA restored the activity of the major ethanol-metabolizing enzymes and oxidative stress functions in the liver. Importantly, we found that SalA treatment effectively inhibited the ethanol-mediated decrease in nuclear β-catenin by upregulating SIRT1 in the liver. SIRT1 then deacetylated β-catenin to promote its accumulation in the nucleus, thereby preventing alcohol-induced liver injury. The results demonstrate that the SIRT1/β-catenin pathway is a key therapeutic target in liver injury caused by chronic alcohol exposure and that SalA protects against alcohol-induced liver injury via the SIRT1-mediated deacetylation of β-catenin.
Pharmacological basis of tanshinone and new insights into tanshinone as a multitarget natural product for multifaceted diseases.
Li Zhibei,Zou Jing,Cao Dan,Ma Xiao
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Drug development has long included the systematic exploration of various resources. Among these, natural products are one of the most important resources from which novel agents are developed due to the multiple pharmacologic effects of these natural products on diseases. Tanshinone, a representative natural product, is the main compound extracted from the dried root and rhizome of Salvia miltiorrhiza Bge. Research on tanshinone began in the early 1930s. With the in-depth investigation of an increasing number of identified analogs, tanshinone has demonstrated a wide variety of bioactivities and contradicted the saying, 'You can't teach an old dog new tricks'. This review is focused on the pharmacological action of tanshinone and status of research on tanshinone in recent years. The mechanism of tanshinone has also drawn much attention, with the findings of representative targets and pathways of tanshinone. The most recent studies have comprehensively shown that tanshinone can be used to treat leukemia and solid carcinoma, protect against cardiovascular and cerebrovascular diseases, and alleviate liver- and kidney-related diseases, among its other effects. Multiple signaling pathways, including antiproliferative, antiapoptotic, anti-inflammatory, and antioxidative stress pathways, are involved in its actions.
[Advance in studies on hepatoprotective effect of Salvia miltiorrhiza and its main components].
Yuan Yuan,Wu Qin,Shi Jing-shan,Chen Xiu-ping
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Dried roots and rhizomes of Salvia miltiorrhiza (Danshen) are among the most commonly used traditional Chinese medicines in clinic. The material basis for its efficacy mainly includes hydrophobic tanshinones and hydrophilic salvianolic acids. The traditional effects of Danshen are "removing stasis and relieving pain, activating blood to promote menstruation, clearing heart fire and tranquilization". According to modern pharmacological studies, Danshen and its main components have cardiovascular and cerebrovascular protective effect. Recent studies showed that Danshen and its main components also demonstrated protective effects on liver injury models induced by carbon tetrachloride, D-galactosamine, acetaminophen and alcohol. In this paper, the hepatoprotective effect and mechanism of Danshen were summarized and studied.
Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocellular carcinoma progression via miR-145/miR-21 mediated Smad3 phosphorylation.
Wu Chao,Chen Weiyang,Fang Meng,Boye Alex,Tao Xiangming,Xu Yuanyuan,Hou Shu,Yang Yan
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Compound Astragalus and Salvia miltiorrhiza extract (CASE), containing astragalosides, astragalus polysaccharide extracted from Astragalus membranaceus (Fisch.) Bge. and salvianolic acids from Salvia miltiorhiza Bge., has been found to inhibit hepatocarcinogenesis via mediating transforming growth factor-β (TGF-β)/Smad signaling, especially Smad3 phosphorylation. The crucial interaction between microRNA-145/microRNA-21 (miR-145/miR-21) and Smad3 phosphorylation is implicated in the pathogenesis and progression of hepatocellular carcinoma (HCC). However, effects of CASE on HCC progression involved in the expression of miR-145/miR-21 and their interaction with Smad3 phosphorylation downstream of TGF-β/MAPK/Smad pathway remain unclear. This study addressed above questions using in vitro (HepG2 cells) and in vivo (Xenografts of nude mice) models of HCC. MATERIALS AND METHODS:In vivo [Diethylnitrosamine (DEN)-induced HCC in rats] and in vitro [TGF-β-stimulated HepG2 cells] models of HCC were established and co-administrated using graded doses/concentrations CASE (60, 120, 240 mg/kg used in rats; 20, 40, 80 µg/ml used in HepG2 cells), miR-145 and miR-21 were measured. HepG2 cells were transfected with miR-145 antagomir, miR-21 agomir and Smad3C/L plasmids (Smad3 EPSM, Smad3 3S-A and Smad3 WT related to up-regulated expression of pSmad3C, pSmad3L and pSmad3C/3L respectively) and then treated by CASE (80 µg/ml). Similarly, HepG2 cell xenografted nude mice were administered with miR-145 antagomir, miR-21 agomir and CASE (310 mg/kg); Smad3 WT, Smad3 EPSM and Smad3 3S-A plasmids stably transfected HepG2 cell lines were constructed respectively and their xenografted nude mice were established, and then treated by CASE (310 mg/kg). Cell proliferation, migration, apoptosis, tumor growth and histopathologic characteristics of xenografts were assessed; also, domain-specific Smad3 phosphorylation isoforms (pSmad3C/pSmad3L), activated MAPKs (pERK1/2, pJNK1/2, pp38) and miR-145, miR-21 were measured. RESULTS:CASE up-regulated miR-145 while down-regulated miR-21 expression in both rats with DEN-induced HCC and TGF-β-stimulated HepG2 cells; CASE inhibited cell migration, proliferation and tumor growth while facilitated cell apoptosis in TGF-β-stimulated HepG2 cells and xenografts of nude mice with miR-145 antagomir/miR-21 agomir treatment via increasing miR-145 and facilitating miR-145 modulated pSmad3L→pSmad3C signaling switch while decreasing miR-21 and inhibiting miR-21 modulated MAPK-dependent Smad3L phosphorylation. Also, up-regulated pSmad3C enhanced inhibited effect of CASE on tumor growth and facilitated effect of CASE on cell apoptosis involved in increased miR-145 while decreased miR-21 expression, however, inverse phenomena were observed when up-regulated pSmad3L. CONCLUSION:Our results suggest that CASE inhibits HCC progression via mediating the interaction of miR-145/miR-21 and Smad3 phosphorylation, especially miR-145/miR-21 mediated Smad3 phosphorylation, which maybe provides an important theoretical foundation for CASE's anti-HCC therapy used for patients in a near future.
Effects of Salvia miltiorrhiza and Radix astragali on the TGF-β/Smad/Wnt pathway and the pathological process of liver fibrosis in rats.
Cao Tingting,Lu Yuan,Zhu Minwei,Cheng Jiafei,Ye Bai,Fang Nanyuan,Cui Yueping,Xue Boyu,Lari Najafi Moslem,Kazemi Elham
Cellular and molecular biology (Noisy-le-Grand, France)
Traditional Chinese medicine has made some progress in the study of liver fibrosis, and provides valuable experience for clinical treatment of liver fibrosis. The aim of this study was to investigate the rationality of compatibility use of Salvia miltiorrhiza and Radix astragali on liver fibrosis in rats. For this purpose, the rat model of liver fibrosis was treated with single or different compatibilities of herbals extracts for 4 weeks. Saline and colchicine were set as a negative and positive control, respectively. Liver histopathology, liver function, and expressions of key proteins in the TGF-β/Smad/Wnt pathway were assessed. Results showed that compared with colchicine, herbal extracts showed better ability to reduce deposition of α-SMA and type I collagen, and improve liver function. The effect of R. astragali extracts and 1:1 compound on improving liver fibrosis and liver function was relatively better than other treatment options. The compound groups showed a particularly significant effect on reducing Cyclin D1 expression. It was concluded that the 1:1 compatibility use of S. miltiorrhiza extracts and R. astragali extracts can preferably attenuate liver fibrosis by regulating the expression of TGF-β1 and Cyclin D1.
Cryptotanshinone (Dsh-003) from Salvia miltiorrhiza Bunge inhibits prostaglandin E2-induced survival and invasion effects in HA22T hepatocellular carcinoma cells.
Chang Julia Huei-Mei,Lin Chih-Hsueh,Shibu Marthandam Asokan,Chou Yung-Chen,Liu Jer-Yuh,Chou Yen-Hong,Shen Chia-Yao,Yeh Yu-Lan,Viswanadha Vijaya Padma,Huang Chih-Yang
Human hepatocellular carcinoma (HCC) is currently the second most common cancer and one of the leading causes of cancer-related mortality in Taiwan. Previous reports show that the expression of (E-type prostaglandin 2) EP2 and (E-type prostaglandin 4) EP4 are elevated in HCC and further demonstrate that Prostaglandin E2 (PGE2) induces HA22T cell proliferation and metastasis through EP2 and EP4 receptor. Danshen (root of Salvia miltiorrhiza Bunge) is a very important and popular traditional Chinese herbal medicine which is widely and successfully used against breast cancer, leukemia, pancreatic cancer, and head and neck squamous carcinoma cells. In this study, we used Cryptotansinone (Dsh-003) (MW 269.14) from Danshen to investigate their effect and corresponding mechanism of action in PGE2-treated HA22T cells. Dsh-003 inhibited HA22T cell viability and further induced cell apoptosis in PGE2-treated HA22T cells. Furthermore, Dsh-003 inhibited EP2, EP4, and their downstream effector such as p-PI3K and p-Akt expression in HA22T hepatocellular carcinoma cells. We also observed that Dsh-003 blocked PGE2-induced cell migration by down-regulating PGE2-induced β-catenin expression and by up-regulating E-cadherin and GSK3-β expression. All these findings suggest that Dsh-003 inhibit human HCC cell lines and could potentially be used as a novel drug for HCC treatment.
Salvia miltiorrhiza compounds protect the liver from acute injury by regulation of p38 and NFκB signaling in Kupffer cells.
Yue Shuqiang,Hu Bin,Wang Zhipeng,Yue Zhenggang,Wang Fang,Zhao Yuan,Yang Zhifu,Shen Min
CONTEXT:Salvia miltiorrhiza Bunge is a traditional Asian medicine used to treat cerebral and cardiac ischemia. However, the effects of the active compounds of S. miltiorrhiza on liver damage are unclear. OBJECTIVE:In this study, we tested the effects on acute liver injury of crude S. miltiorrhiza extracts from roots as well as neotanshinone B, dehydromiltirone, tanshinol A, tanshinone I, dihydrotanshinono I, neotanshinone A, cryptanshinono, tanshinone II A, and salvianolie acid B from purified S. miltiorrhiza extracts. MATERIALS AND METHODS:Various compounds or ethanol extract of S. miltiorrhiza (50, 100, and 200 mg/kg, p.o.) were administered to rats for five consecutive days. After acute carbon tetrachloride (CCl4)-induced liver injury by treatment of rats with a single dose of CCl4 (0.75 mL/kg, p.o), rat liver function was tested by measuring serum biochemical parameters. Serum cytokine concentrations were assessed by enzyme-linked immunosorbent assay (ELISA). Expression of p38 and NFκB was evaluated by western blot. RESULTS:All S. miltiorrhiza components showed their effects on liver function from the dose from 50 to 200 mg/kg. At the dose of 200 mg/kg, they reduced serum levels of alkaline phosphatase (ALP) by 34-77%, alanine aminotransferase (ALT) by 30-57%, aspartate aminotransferase (AST) by 43-72%, creatine total bilirubin (BIL-T) by 33-81%, albumin (ALB) by 37-67%, indicating that S. miltiorrhiza extracts protected liver from CCl4-induced damage. Moreover, S. miltiorrhiza extracts at 200 mg/kg reduced the increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α) by 25-82%, interleukin-1 (IL-1) by 42-74% and interleukin-6 (IL-6) by 67-83%, indicating an effect on alleviating liver inflammation. Furthermore, in vitro, S. miltiorrhiza extracts inhibited p38 and NFκB signaling in Kupffer cells. This effect could be a main mechanism by which S. miltiorrhiza protects against acute liver toxicity. DISCUSSION AND CONCLUSION:Active compounds of S. miltiorrhiza protected the liver from CCl4-induced injury. Protection might have been due to inhibition of p38 and NFκB signaling in Kupffer cells, which subsequently reduced inflammation in the liver.
Cryptotanshinone from the Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways.
Nagappan Arulkumar,Kim Ji-Hyun,Jung Dae Young,Jung Myeong Ho
International journal of molecular sciences
Cryptotanshinone (CT), a diterpene that is isolated from Bunge, exhibits anti-cancer, anti-oxidative, anti-fibrosis, and anti-inflammatory properties. Here, we examined whether CT administration possess a hepatoprotective effect on chronic ethanol-induced liver injury. We established a chronic alcohol feeding mouse model while using C57BL/6 mice, and examined the liver sections with hematoxylin-eosin (H&E) and Oil Red O (ORO) staining. Further, we analyzed the lipogenesis, fatty acid oxidation, oxidative stress, and inflammation genes by using quantitative polymerase chain reaction (qPCR) and immunoblotting in in vivo, and in vitro while using HepG2 and AML-12 cells. CT treatment significantly ameliorated ethanol-promoted hepatic steatosis, which was consistent with the decreased hepatic triglyceride levels. Interestingly, CT activated the phosphorylation of AMP-activated protein kinase (), sirtuin 1 (), and nuclear factor E2-related factor 2 () proteins. Importantly, compound C ( inhibitor) significantly blocked the CT-mediated reduction in TG accumulation, but not Ex52735 ( inhibitor), which suggested that CT countering ethanol-promoted hepatic steatosis is mediated by activation. Furthermore, CT significantly inhibited cytochrome P450 2E1 () and enhanced both the expression of antioxidant genes and hepatic glutathione levels. Finally, CT inhibited the ethanol-induced inflammation in ethanol-fed mice and HepG2 cells. Overall, CT exhibits a hepatoprotective effect against ethanol-induced liver injury by the inhibition of lipogenesis, oxidative stress, and inflammation through the activation of and and the inhibition of . Therefore, CT could be an effective therapeutic agent for treating ethanol-induced liver injury.
Protective effect of Salvia miltiorrhiza and Carthamus tinctorius extract against lipopolysaccharide-induced liver injury.
Gao Li-Na,Yan Kuo,Cui Yuan-Lu,Fan Guan-Wei,Wang Yue-Fei
World journal of gastroenterology
AIM:To investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo. METHODS:C57BL/6J mice were randomly assigned to five groups and intraperitoneally administered 0.9% saline, Salvia miltiorrhiza and Carthamus tinctorius extract [Danhong injection (DHI), 0.75 and 3 g/kg mixed extract] or reduced glutathione for injection (RGI, 300 mg/kg) for 30 min before exposure to lipopolysaccharide (LPS, 16 mg/kg). After intraperitoneal LPS stimulation for 90 min or 6 h, the mice were sacrificed by ether anaesthesia, and serum and liver samples were collected. Histological analysis (H&E) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining were performed. Alanine transferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), glutathione-S-transferase (GST), malondialdehyde (MDA), tumour necrosis factor (TNF)-α, interleukin (IL)-6, and caspase-3 levels were measured. Bax, Bcl-2, P-IκBα, IκBα, P-NF-κB p65, and NF-κB p65 protein levels were determined by Western blot. TNF-α, IL-6, caspase-3, Bax and Bcl-2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS:Hematoxylin-eosin staining and TUNEL results suggested that DHI (3 g/kg) treatment alleviated inflammatory and apoptotic (P < 0.01) injury in the liver of mice. DHI treatment dose-dependently blunted the abnormal changes in biochemical parameters such as ALT (72.53 ± 2.83 for 3 g/kg, P < 0.01), AST (76.97 ± 5.00 for 3 g/kg, P < 0.01), TBil (1.17 ± 0.10 for 3 g/kg, P < 0.01), MDA (0.81 ± 0.36 for 3 g/kg, P < 0.01), and GST (358.86 ± 12.09 for 3 g/kg, P < 0.01). Moreover, DHI (3 g/kg) remarkably decreased LPS-induced protein expression of TNF-α (340.55 ± 10.18 for 3 g/kg, P < 0.01), IL-6 (261.34 ± 10.18 for 3 g/kg, P < 0.01), and enzyme activity of caspase-3 (0.93 ± 0.029 for 3 g/kg, P < 0.01). The LPS-induced mRNA expression of TNF-α, IL-6 and caspase-3 was also decreased by DHI. Western blot analysis revealed that DHI antagonised LPS-stimulated decrease of Bcl-2 and increase of Bax protein expression. Furthermore, DHI inhibited LPS-induced IκBα and NF-κB p65 phosphorylation. CONCLUSION:DHI may be a multi-function protectant against acute hepatic injury in mice through its anti-inflammatory, anti-oxidative and anti-apoptotic activities.
Protective effect of Salvia miltiorrhiza polysaccharides on liver injury in chickens.
Han Chao,Wei Yuanyuan,Wang Xiao,Ba Cuijing,Shi Wanyu
This study investigated the effects of Salvia miltiorrhiza polysaccharides (SMPs) on the injury of chicken hepatocytes in vitro and in vivo. In in vitro studies primary cultured hepatocytes were isolated by 2-step collagenase perfusion. Carbon tetrachloride (CCL4) was added to the hepatocytes to establish a hepatocyte injury model. Hepatocytes were treated with different concentrations of SMPs to detect the protective effects of SMPs on CCL4-induced hepatocyte injury. The results of the control group showed that chicken hepatocytes grew well and their morphology was normal. After CCL4 treatment, the activity of alanine transaminase (ALT) and aspartate transaminase (AST) of hepatocytes increased compared with the normal control group. SMPs treatment downregulated the contents of ALT, AST, and malondialdehyde (MDA), and upregulated the contents of glutathione (GSH) and cytochrome P450 (CYP450). An acute chicken liver injury model was established in vivo with 2.0 mL/kg 50% CCL4. Oral administration of SMP at different doses exhibited preventive success. The results showed that compared with the control group, the contents of total protein (TP), albumin (Alb), and GSH in the liver injury model group were significantly decreased and the levels of liver index, ALT, AST, and MDA were significantly increased. In contrast, in the SMP group the contents of TP, Alb, and GSH were significantly increased, and the levels of liver index, ALT, AST, and MDA were significantly decreased compared with the model group. Therefore, we conclude that SMPs have good protective effect on chicken liver damage in vivo and in vitro.
The Effect of Elephantopus scaber L. on Liver Regeneration after Partial Hepatectomy.
Tsai Chin-Chuan,Wu Jia-Ping,Lin Yueh-Min,Yeh Yu-Lan,Ho Tsung-Jung,Kuo Chia-Hua,Tzang Bor-Show,Tsai Fuu-Jen,Tsai Chang-Hai,Huang Chih-Yang
Evidence-based complementary and alternative medicine : eCAM
Liver regeneration after partial hepatectomy (PHx) is a physiological response for maintaining homeostasis. The aim of this study is to investigate effects of Elephantopus scaber L.- (ESL-) induced liver regeneration on growth factors (HGF and IGF-1), cell cycle regulation, and apoptosis suppressed. In this study, we fed five Chinese medicinal herbs (1 g/kg/day), Codonopsis pilosula (CP, Dangshen), Salvia miltiorrhiza Bunge (SMB, Danshen,), Bupleurum kasi (BK, Chaihu), Elephantopus scaber L. (ESL, Teng-Khia-U), and Silymarin (Sm, 25 mg/kg) for 7 days to male Spraue-Dawley rats. Then surgical 2/3 PHx was conducted and liver regeneration mechanisms were estimated on the following 24 hrs and 72 hrs. The activities of growth factors (HGF and IGF-I) and cell cycle proteins were measured by Western blot and RT-PCR. Histological analysis and apoptosis were detected by H&E stain and TUNEL. The results showed that extraction of Elephantopus scaber L. (ESL) and Silymarin (Sm, positive control) were increased protein expression levels of HGF and IGF-1 which leads into cell cycle. These results suggest that the ESL plays a crucial role in cell cycle-induced liver regeneration and apoptosis. These results suggested that the ESL plays a crucial role in cell cycle-induced liver regeneration and suppressed hepatocytes apoptosis.
[Meta-analysis on impact of Danshen on liver regeneration in rats].
Wu Qian-ni,Tian Hong-liang,Zhang Li-han,Tian Jin-hui,Xiong Hai-rui,Liu Ya-li,Yang Ke-hu
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
OBJECTIVE:To assess the effect of Danshen on liver regeneration capacity of carbon tetrachloride-induced liver injury rats. METHOD:Computer retrieval of data from CJFD, CBM, Chinese science & technology journal full-text database and Chinese medical association digital journals, and such foreign databases as PubMed, EMBASE and SCI was included in the randomized controlled trials (RCT) of rat liver injury induced by carbon tetrachloride,with the search as at May 2012. A Meta analysis was made using Rev-Man 5.1 software. Using the GRADE system to addess five outcomes in stuay. RESULT:Two hundred and fourteen rats got involved in seven randomized trials. Meta analysis showed there were statistical differences between the Danshen group and the control group in alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-alpha) and hyaluronic acid (HA) after rat liver injury induced by carbon tetrachloride. When we used system to each outcome, because of serious limitations and indirect, they are all very low quality. CONCLUSION:Danshen shows certain promoting effect to liver regeneration in carbon tetrachloride-induced liver injury rats.