lignans and Liver-Diseases--Alcoholic

Alcoholic liver disease is one of the leading causes of liver-related morbidity and mortality worldwide, but effective treatments are still lacking. Honokiol, a lignin-type natural compound isolated from the leaves and bark of Magnolia plants, has been widely studied for its beneficial effects on several chronic diseases. Accumulating studies have revealed that honokiol displays a potential therapeutic effect on alcoholic liver disease. In this study, the protective activity of honokiol on alcoholic liver disease was confirmed due to its significant inhibitory activity on the expression levels of inflammatory cytokines (such as tumor necrosis factor-alpha, interleukin-6, and interleukin-1

Topics: Animals; Cytokines; Interleukin-1beta; Interleukin-6; Lignans; Lipid Metabolism; Lipid Metabolism Disorders; Liver; Liver Diseases, Alcoholic; Mice; NF-kappa B; PPAR alpha; Sterols; Tumor Necrosis Factor-alpha

Chemical hepatotoxicity, especially alcoholic liver injury (ALI), commonly occurs in young and middle-aged people who drink heavily. ALI is extremely harmful and can induce severe disease states, such as hepatitis, liver fibrosis, cirrhosis, or liver cancer, which are similar to CCl. This study sought to elucidate the mechanisms underlying SCDL-mediated hepatoprotection.. We first used in silico target prediction and computational simulation methods to identify putative lignan-binding targets relative to the hepatoprotective effect. A gene microarray analysis was performed to identify differently expressed genes that might have significance in the disease pathological process. We then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and a hepatocellular toxicity model to analyze the candidate-compound-mediated hepatoprotection and expression states of the key targets in vitro.. The in silico analysis results indicated that endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDL compound schisantherin D on the hepatoprotective effect; experimental studies showed that schisantherin D alleviated the EtOH- and ET-1-induced HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased the expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells). SCDLs ameliorated EtOH- and CCl. The findings indicated that SCDLs prevent hepatotoxicity via their anti-fibrotic, anti-oxidant, and anti-apoptosis properties. ETBR may be the key factor in promoting chemical hepatotoxicity.

Topics: Animals; Antioxidants; Apoptosis; Carbon Tetrachloride; Cell Line; Chemical and Drug Induced Liver Injury; Computer Simulation; Disease Models, Animal; Hepatic Stellate Cells; Hepatocytes; Humans; Lignans; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Receptor, Endothelin B; Schisandra

Schisantherin A (SinA), one of the most abundant active ingredients of Schisandra chinensis, was reported to protect and benefit the liver, however, its effect on alcohol-induced liver injury (ALI) was still not clear. In the present study, an ALI mice model was induced by feeding mice an alcohol-containing liquid diet for four weeks. Then, 100 mg/kg or 200 mg/kg SinA was administered to mice every day by gavage for the last two weeks. Histopathological analysis showed that alcohol-induced liver lipid vacuoles were reduced by SinA. The activities of aspartate aminotransferase (AST, 61.90 ± 14.65 vs. 93.65 ± 20.50, 50.46 ± 13.21 vs. 93.65 ± 20.50) and alanine transaminase (ALT, 41.29 ± 9.20 vs. 64.04 ± 18.13, 36.52 ± 7.71 vs. 64.04 ± 18.13) in the serum of ALI mice were significantly reduced by 100 mg/kg or 200 mg/kg SinA when compared with control mice. Alcohol-induced oxidative stress and the inflammatory response in the liver were suppressed by SinA in a dose-dependent manner. Meanwhile, treatment with SinA decreased alcohol dehydrogenase (ADH) activity and increased acetaldehyde dehydrogenase (ALDH) activity in ALI mice. Alcohol-induced upregulation of CYP2E1 and CYP1A2 in the liver was inhibited by SinA. Further, SinA suppressed activation of the NF-kB pathway in ALI mice. In conclusion, our findings demonstrate that SinA is able to protect against ALI, and this may be, at least in part, caused by regulation of alcohol metabolism and the NF-kB pathway. Our data suggest a therapeutic potential of SinA in the treatment of ALI.

Topics: Alanine Transaminase; Alcohol Dehydrogenase; Aldehyde Oxidoreductases; Animals; Aspartate Aminotransferases; Cyclooctanes; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2E1; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Lignans; Liver; Liver Diseases, Alcoholic; Male; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Phytotherapy; Schisandra; Signal Transduction

Alcoholic liver disease (ALD) is a leading cause of liver cirrhosis, liver cancer, and related mortality. The endocannabinoid system contributes to the development of chronic liver diseases, where cannabinoid receptor 2 (CB2) has been shown to have a protecting role. Thus, here, we investigated how CB2 agonism by 4'-O-methylhonokiol (MHK), a biphenyl from Magnolia grandiflora, affects chronic alcohol-induced liver fibrosis and damage in mice. A combination of alcohol (10% vol/vol) and CCl4 (1 ml/kg) was applied to C57BL/6 mice for 5 weeks. MHK (5 mg/kg) was administered daily, and liver damage assessed by serum AST and ALT levels, histology, gene, and protein expression. Endocannabinoids (ECs) and related lipid derivatives were measured by liquid chromatography and mass spectrometry (LC-MS) in liver tissues. In vitro, MHK was studied in TGFβ1-activated hepatic stellate cells (HSC). MHK treatment alleviated hepatic fibrosis, paralleled by induced expression of matrix metalloproteinases (MMP)-2, -3, -9, and -13, and downregulation of CB1 mRNA. Necrotic lesions and hepatic inflammation were moderately improved, while IL-10 mRNA increased and IFNγ, Mcl-1, JNK1, and RIPK1 normalized by MHK. Hepatic anandamide (AEA) and related N-acetylethanolamines (NAEs) were elevated in MHK group, whereas fatty acid synthase and diacylglycerol O-acyltransferase 2 expression reduced. In vitro, MHK prevented HSC activation and induced apoptosis via induction of bak1 and bcl-2. To conclude, MHK revealed hepatoprotective effects during alcohol-induced liver damage through the induction of MMPs, AEA, and NAEs and prevention of HSC activation, indicating MHK as a potent therapeutic for liver fibrosis and ALD.. Methylhonokiol improves liver damage and survival. Methylhonokiol reduces hepatic fibrosis and necroinflammation. Methylhonokiol prevents myofibroblast activation and induces apoptosis. Methylhonokiol upregulates endocannabinoids and related N-acylethanolamines. Methylhonokiol contributes to lipid hydrolysis via PPARα/γ.

Topics: Animals; Biphenyl Compounds; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Endocannabinoids; Lignans; Liver; Liver Cirrhosis; Liver Diseases, Alcoholic; Magnolia; Male; Mice, Inbred C57BL; Protective Agents

UHPLC-QTOF/MS technique was used to study the differences of lignans and their metabolites derived from Schisandra chinensis and vinegar Schisandra chinensis in rat plasma, bile, urine and faeces by the data processing techniques such as the dynamic background subtract(DBS), mass defect filtering(MDF) and enhance peak list (EPL) in analysis. In order to enhance accuracy for Schisandra chinensis hepatoprotective effect, we established rat acute alcoholic liver injury model in this experiment, and studied the prototype components and metabolisms of Schisandra lignans in vivo under pathological condition. The main ingredients of alcohol extract are lignans, including deoxyschizandrin, schisandrin B, schizandrin C, schizandrol, schizandrol B,schisantherin, schisantherin B, schisanhenol, gomisin G, gomisin J. The metabolic transformation of lignans in rats was mainly induced by methylation, hydroxyl, oxidation, and so on. Finally, we identified 6 kinds of prototype components and their 20 potential metabolites in Schisandra chinensis group and vinegar Schisandra chinensis group.

Topics: Acetic Acid; Animals; Bile; Chromatography, High Pressure Liquid; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Feces; Lignans; Liver Diseases, Alcoholic; Plasma; Polycyclic Compounds; Rats; Schisandra; Urine

This study aimed to investigate the liver protection effect of Schisandra chinensis (Turcz.) Baill. (SC) lignans and its combination with Rubus idaeus (RI) on chronic alcohol-induced mice. A low level of SC lignans (SL) was prepared from the clear juice of sarcocarp. Lignans were further extracted from the SC seeds and added to the SL to form high-level SC lignans (SH). Moreover, RI clear juice lyophilized powder was mixed with SL (SR), and the liver protection effects of SL, SH and SR were investigated. Male ICR mice were administered with the corresponding samples and gastrically infused with 50% alcohol (1 h later) once per day for 60 d. In the in vitro study, the characteristic lignans in the SC clear juice and the seed extract were analyzed by high performance liquid chromatography (HPLC). The total phenolic content (TPC) and antioxidant capability of SL, SH, and SR were determined. The results of the in vivo study showed that SC lignans exhibited a dose-dependent effect on the regulation of hepatic antioxidant status, serum transaminases levels, hyperlipidemia and hepatic fat deposition in mice. However, hepatic lesions were observed in the SH mice, which indicated a potential side effect caused by long-term consumption of SH under chronic alcohol administration. By contrast, SR exhibited a similar hepatoprotective effect as SH without any abnormality found in the histological analysis. After analysis with HPLC, Schizandrol A and Schizandrol B were identified in the SC clear juice, and two more kinds of lignans, Schisandrin A and Schisandrin B, were identified in the seed extracts. The SR sample had the highest TPC and exhibited the best antioxidant capability. In conclusion, RI strengthened the liver protection effect of SC lignans effectively and safely, which was probably achieved by enhancing the antioxidant status and the positive effect of their combination was possibly attributed to both lignans and polyphenols. This study demonstrated that the combination of low-level SC lignans and RI might be used as a potential safe formula for beverage development to alleviate the adverse effects of long-term alcohol consumption.

Topics: Animals; Antioxidants; Chromatography, High Pressure Liquid; Cyclooctanes; Dioxoles; Lignans; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred ICR; Plant Extracts; Polycyclic Compounds; Rubus; Schisandra