lignans and Chemical-and-Drug-Induced-Liver-Injury

Schisandra is the mature fruit of Schisandra chinensis(known as "north Schisandra") or S. shenanthera(known as "south Schisandra"). S. chinensis contains a variety of lignans, volatile oils, polysaccharides, organic acids and other chemical constituents; among them, lignans are recognized as the characteristic active components. Clinical studies have found that Schisandra and Schisandra-related products have a better effect in the prevention and treatment of viral hepatitis, drug-induced liver injury, liver cirrhosis, liver failure and other liver diseases. Modern pharmacological studies have demonstrated that Schisandra has a variety of pharmacological activities, such as anti-inflammation, antioxidation, anticancer, regulation of nuclear receptor, antivirus, regulation of cytochrome P450 enzyme, inhibition of liver cell apoptosis and promotion of liver regeneration. This paper reviews the studies about the applications and mechanism of Schisandra in the prevention and treatment of liver diseases, in the expectation of providing guidance for the development of hepatoprotective drugs from Schisandra and the clinical applications of Schisandra-related products.

Topics: Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Fruit; Humans; Lignans; Protective Agents; Schisandra

With increasing use of pharmaceuticals, drug-induced liver injury (DILI) has become a significant therapeutic challenge to physicians all over the world. Drugs based on Schisandra fruits (SF for short, the fruits of Schisandra chinensis or Schisandra sphenanthera) or synthetic analogues of schisandrin C, are commonly prescribed for treating DILI in China.. This review summarizes the literature regarding the application of SF-derived drugs in patients with DILI and current understanding of mechanisms underlying the protective effects of SF against liver injury.. Keywords related to drug-induced liver injury and Schisandra fruits were searched in the following databases: Pubmed, Cochrane Library, Google Scholar, LiverTox, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal database (VIP), and Wanfang database. All studies, published in English or Chinese, were included. Clinical study exclusion criteria: if patients received other Chinese herbal medicines in a study, the study will not be included in this review.. Clinical studies have shown that SF-derived drugs are effective in inhibiting drug-induced elevation of serum levels of alanine aminotransferase, aspartate transaminase and total bilirubin. Cellular and animal studies have demonstrated that crude SF extracts, lignan compounds found in SF, and SF-derived drugs are effective in protecting the liver against xenobiotic-induced injury. Regulation of cytochrome P450 enzyme activity, anti-oxidation, anti-inflammation and acceleration of liver regeneration are involved in the hepatoprotective mechanisms of SF.. SF-derived drugs are effective in ameliorating DILI in China. To verify the clinical efficacy of these drugs, high-quality clinical studies are needed.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; China; Cyclooctanes; Drugs, Chinese Herbal; Fruit; Humans; Lignans; Liver; Liver Regeneration; Phytotherapy; Polycyclic Compounds; Schisandra

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cytochrome P-450 Enzyme System; Drugs, Chinese Herbal; Lignans; Liver; Mitochondria, Liver; Polycyclic Compounds

Schisandrae Chinensis Fructus (SCF) was a Traditional Chinese Medicine for protecting liver. However, underlying therapeutic mechanisms of these bioactive lignans from SCF similar hepatoprotective effects against drug-induced liver injury (DILI) by acetaminophen (APAP) are still unclear. This study aims to discover the potential regulation mechanisms of Schisandrol A in the treatment of DILI by APAP. The integrated UPLC-Q-TOF/MS, pharmacodynamic study, histopathological combination with network pharmacology and molecular docking technology were used to explore the potential mechanisms. The results showed that Schisandrol A reduced the level of AST, ALT, MDA, PNP, TNF-α and IL-1β, increased the levels of the GSH against acute liver failure. Additionally, Schisandrol A could improve the morphological characteristics of DILI by APAP in mice with liver tissue. Molecular docking results had showed that Schisandrol A with high scores when docking with COX-2, ALOX5, CYP2E1, CYP2C9, CYP2C19, EGFR SRC, Nrf2, MAPK14 and MAPK8. The study demonstrated that Schisandrol A could play critical roles in DILI by APAP via regulating TNF signaling pathway, inhibiting oxidative stress, inflammation and inhibiting the activities of cytochrome P450 enzymes, which contributed to searching for leading compounds and the development of new drugs for DILI by APAP.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dose-Response Relationship, Drug; Lignans; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

Drug-induced liver injury (DILI) occurs frequently worldwide. Acetaminophen (APAP) is a common drug causing DILI. Current treatment methods are difficult to achieve satisfactory results. Therefore, there is an urgent need to provide safe and effective treatment for patients. Schizandrin B (Sch B), the main component of Schisandra, has a protective effect on liver. However, the potential mechanism of Sch B in the treatment of APAP induced liver injury has not been elucidated to date. In our research, we studied the effect of Sch B on protecting damaged liver cells and explored the potential mechanism underlying its ability to reduce APAP liver injury. We found that Sch B could reduce hepatocyte apoptosis, oxidative stress injury and inflammatory response. These effects were positively correlated with the dose of Sch B. Sch B regulated glucose 6-phosphate dehydrogenase expression by upregulating the expression of p21-activated kinase 4 and polo-like kinase 1. Sch B could inhibit the mitogen-activated protein kinase (MAPK)-c-Jun N-terminal kinase (JNK)-extracellular signal-regulated kinase (ERK) signaling pathway and regulate the expression of apoptosis-related proteins to reduce the incidence of cell apoptosis. In addition, Sch B reduced the expression levels of reactive oxygen species and inflammatory cytokines in hepatocyte. Consequently, we described for the first time that Sch B could not only activate the pentose phosphate pathway but also inhibit the MAPK-JNK-ERK signaling pathway, thereby achieving antioxidative and anti-inflammatory effects and inhibiting hepatocyte apoptosis. These findings indicated the potential use of Sch B in curing liver damage induced by APAP.

Topics: Acetaminophen; Apoptosis Regulatory Proteins; Chemical and Drug Induced Liver Injury; Cyclooctanes; Hepatocytes; Humans; Lignans; Mitogen-Activated Protein Kinase Kinases; Polycyclic Compounds

Pirarubicin (THP) is one of anthracycline anticancer drugs. It is widely used in the treatment of various cancers, but its hepatotoxicity cannot be ignored. Schisandrin B (SchB) is a traditional liver-protecting drug, which has the ability to promote mitochondrial function and upregulate cellular antioxidant defense mechanism. However, whether it can resist THP-induced hepatotoxicity has not been reported. The purpose of this study was to observe and explore the effect of SchB on THP-induced hepatotoxicity and its potential mechanism by adding SchB to the diet of rats with THP-induced hepatotoxicity.. The rat model of THP-induced hepatotoxicity was established and partly treated with SchB diet. The changes of serum liver function indexes ALT and AST were observed. The histomorphological changes of liver were observed by HE staining. The biomarker levels of oxidative stress in rat serum and liver were measured to observe oxidative stress state. The expressions of ferroptosis-related protein GPX4 and oxidative stress-related protein were detected by Western blot. Primary hepatocytes were prepared and cocultured with THP, SchB, and Fer-1 to detect the production of reactive oxygen species (ROS) and verify the above signal pathways.. THP rats showed a series of THP-induced hepatotoxicity changes, such as liver function damage, oxidative stress, and ferroptosis. SchB diet effectively alleviated these adverse reactions. Further studies showed that SchB had strong antioxidant and antiferroptosis abilities in THP-induced hepatotoxicity.. SchB has obvious protective effect on THP-induced hepatotoxicity. The mechanism may be closely related to inhibiting oxidative stress and ferroptosis in the liver.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Cyclooctanes; Diet; Doxorubicin; Ferroptosis; Lignans; Lipid Peroxidation; Oxidative Stress; Polycyclic Compounds; Rats

Schisandrol B (SolB) is one of the bioactive components from a traditional Chinese medicine Schisandra chinensis or Schisandra sphenanthera. It has been demonstrated that SolB exerts hepatoprotective effects against drug-induced liver injury and promotes liver regeneration. It was found that SolB can induce hepatomegaly but the involved mechanisms remain unknown.. This study aimed to explore the mechanisms involved in SolB-induced hepatomegaly.. Male C57BL/6 mice were injected intraperitoneally with SolB (100 mg/kg) for 5 days. Serum and liver samples were collected for biochemical and histological analyses. The mechanisms of SolB were investigated by qRT-PCR and western blot analyses, luciferase reporter gene assays and immunofluorescence.. SolB significantly increased hepatocyte size and proliferation, and then promoted liver enlargement without liver injury and inflammation. SolB transactivated human PXR, activated PXR in mice and upregulated hepatic expression of its downstream proteins, such as CYP3A11, CYP2B10 and UGT1A1. SolB also significantly enhanced nuclear translocation of PXR and YAP in human cell lines. YAP signal pathway was activated by SolB in mice.. These findings demonstrated that SolB can significantly induce liver enlargement, which is associated with the activation of PXR and YAP pathways.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Proliferation; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Gene Expression Regulation; Hep G2 Cells; Hepatocytes; Hepatomegaly; Humans; Lignans; Liver; Male; Mice, Inbred C57BL; Organ Size; Pregnane X Receptor; Schisandra; Signal Transduction; Transcription Factors; YAP-Signaling Proteins

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

The action principles of traditional Chinese medicines (TCMs) feature multiactive components, multitarget sites, and weak combination with action targets. In the present study, we performed an integrated analysis of metabonomics, proteomics, and lipidomics to establish a scientific research system on the underlying mechanism of TCMs, and

Topics: Acetaminophen; Administration, Oral; Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Diglycerides; Disease Models, Animal; Drugs, Chinese Herbal; Hepatocytes; Humans; Lignans; Lipid Metabolism; Lipidomics; Liver; Male; Mice; Primary Cell Culture; Protective Agents; Protein Kinase C; Proteomics; Schisandra; Triglycerides

This study aimed to explore the pharmacological properties of pinoresinol-4-O-β-D-glucopyranoside (PG), isolated from prunes.. In-vitro antioxidant activity was assessed using ferric reducing antioxidant power (FRAP) and 2,2'-azino-bis [3-ethylbenzothiazoline-6-sulfonic acid]-diammonium salt (ABTS) assays. In-vivo hepatoprotective activity was evaluated using CCl. Pinoresinol-4-O-β-D-glucopyranoside is a natural entity combating oxidative stress, hepatic damage and diabetes.

Topics: alpha-Amylases; alpha-Glucosidases; Animals; Antioxidants; Blood Glucose; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Fruit; Glucosides; Glycoside Hydrolase Inhibitors; Insulin; Lignans; Liver; Male; Mice; Molecular Docking Simulation; Oxidative Stress; Plant Extracts; Prunus domestica; Streptozocin

Sesamin is the main lignan in sesame and is reported to have many benefits and medicinal properties. However, its protective effects against fluoride-induced damage in the liver of zebrafish have not been elucidated. Our previous studies found that fluoride exposure caused damage to the liver of zebrafish. In the study, the effects of sesamin on oxidative stress and immune damage in liver of zebrafish exposed to fluoride were measured. The results indicated that fluoride exposure damaged the microstructures of liver, increased significantly the oxidative stress, decreased remarkably the activities of ACP, AKP, and LZM, and affected obviously the expressions of immune-related genes. Treatment with sesamin remarkably attenuated fluoride-induced liver damage in a dose-dependent manner, indicated by the histopathological observation. Furthermore, sesamin treatment also significantly inhibited the production of ROS and oxidative stress, such as the decrease of lipid peroxidation level and the increase of CAT and SOD activities in liver. Sesamin treatment reversed the activities of immune-related enzymes and the expressions of immune-related genes in liver exposed to fluoride. These findings suggested that sesamin could protect the liver from fluoride-induced immune damage by oxidative stress downstream-mediated changes in reversing the activities of immune-related enzymes and the expressions of immune-related genes. Taken together, sesamin plays an important role in maintaining hepatic health and preventing liver from toxic damage caused by fluoride.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytokines; Dioxoles; Fluorides; Gene Expression Regulation; Lignans; Liver; Male; Oxidative Stress; Protective Agents; Water Pollutants, Chemical; Zebrafish

Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel mechanism that contributes to acetaminophen-induced hepatotoxicity through the induction of ferroptosis, a distinctive form of programmed cell death. We subsequently identified therapies protective against acetaminophen-induced liver damage and found that (+)-clausenamide ((+)-CLA), an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, inhibited acetaminophen-induced hepatocyte ferroptosis both in vivo and in vitro. Consistently, (+)-CLA significantly alleviated acetaminophen-induced or erastin-induced hepatic pathological damages, hepatic dysfunctions and excessive production of lipid peroxidation both in cultured hepatic cell lines and mouse liver. Furthermore, treatment with (+)-CLA reduced the mRNA level of prostaglandin endoperoxide synthase 2 while it increased the protein level of glutathione peroxidase 4 in hepatocytes and mouse liver, confirming that the inhibition of ferroptosis contributes to the protective effect of (+)-CLA on drug-induced liver damage. We further revealed that (+)-CLA specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability, thereby leading to the activation of the Keap1-Nrf2 pathway to prevent drug-induced hepatocyte ferroptosis. Our studies illustrate the innovative mechanisms of acetaminophen-induced liver damage and present a novel intervention strategy to treat drug overdose by using (+)-CLA.

Topics: Animals; Chemical and Drug Induced Liver Injury; Ferroptosis; Hepatocytes; Lactams; Lignans; Liver; Liver Failure, Acute; Male; Mice, Inbred C57BL; Oxidative Stress; Protective Agents; Reactive Oxygen Species

Herbal medicines (HMs) have been proven to be productive sources of leads for the development of drugs. To date approximately 150 lignans have been identified from Schisandra sphenanthera. Hepatoprotective activity is a well-known characteristic of schisandra lignans, yet the authentic types of active lignans are still not well known.. The present study aimed to develop a reliable and efficient strategy for identifying the hepatoprotective ingredients of schisandra lignan extract (SLE).. SLEs were prepared by extracting Schisandra sphenanthera powder using 10%, 50% and 90% ethanol (w/w 1:10) combining 5-fold volume of ethyl acetate. The schisandra lignans in SLEs were qualitatively analyzed based on liquid chromatography hybrid ion trap time-of-flight mass spectrometry (LCMS-IT-TOF). Preparative liquid chromatography (PLC) was used to collect ingredient fractions. The hepatoprotective activity of schisandra lignans was systematically investigated on in vivo and in vitro models.. The SLE extracted by 50% ethanol and 5-fold volume of ethyl acetate (50%SLE) had the highest lignan content and exhibited significantly stronger hepatoprotective activity than other SLEs (P <  0.01). The hepatoprotective effect of 50%SLE mainly attributed to the SLE segment which collected from 12 to 22 min by PLC. Schisantherin A (Sth A) was confirmed as the most promising hepatoprotective drug in Schisandra sphenanthera due to high content in crude materials, high exposure level in vivo and high efficiency on APAP-induced hepatotoxicity.. The hepatoprotective ingredients of SLEs were systematically investigated based on the presently developed approach, and Sth A was identified as the optimum hepatoprotective candidate in Schisandra sphenanthera.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Cyclooctanes; Dioxoles; Drug Evaluation, Preclinical; Lignans; Liver; Male; Mass Spectrometry; Mice, Inbred BALB C; Plant Extracts; Protective Agents; Rats, Sprague-Dawley; Schisandra

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver damage. Magnolia officinalis is a traditional hepatoprotective Chinese medicine and Honokiol (HO) is the major active constituent. The present study was to investigate the effect of HO on APAP-induced hepatotoxicity and related mechanisms.. Four groups of mice were subjected to treatment as vehicle, APAP, APAP + HO and APAP + HO + NRF2 inhibitor. The morphological and biochemical assessments were used to evaluate the hepatoprotective effects. The extent of APAP-protein adducts was determined through evaluate the hepatic content 3‑(cystein‑S‑yl)acetaminophen (APAP-Cys), the hydrolysis products of APAP-protein adducts. The activities of CYP2E1, CYP1A2 and CYP3A4 were evaluated by cocktail incubation, and the protein expression levels of NRF2, GCLC, GCLM, GS and GST were evaluated by western blot analysis.. Morphological and biochemical assessments clearly demonstrated that HO could alleviate APAP-induced liver damage. The hepatoprotective effect of HO was positively associated with the reduction of APAP-protein adducts. Further investigation suggested that HO induced inhibition of CYP 2E1 and CYP2A1 as well as upregulation of GSH co-contributed to the reduction of APAP-protein adducts. Furthermore, HO induced activations of NRF2 and its target enzymes, such as GCLC, GCLM and GST, gave rise to the upregulation of GSH.. Our results suggested that HO could alleviate APAP-induced liver damage through reducing the generation of APAP-protein adducts, which might be mediated by inhibiting the activity of CYP 2E1 and CYP2A1 as well as enhancing the generation of GSH via NRF2 pathway.

Topics: Acetaminophen; Animals; Biphenyl Compounds; Chemical and Drug Induced Liver Injury; Glutathione; Lignans; Liver; Male; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Signal Transduction

Cholestasis is a clinical syndrome caused by toxic bile acid retention that will lead to serious liver diseases. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for its treatment. Thus, there is a clear need to develop new therapeutic approaches for cholestasis. Here, anti-cholestasis effects of the lignans from a traditional Chinese herbal medicine, Schisandra sphenanthera, were investigated as well as the involved mechanisms.. Adult male C57BL/6J mice were randomly divided into 9 groups including the control group, LCA group, LCA with specific lignan treatment of Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), Schisantherin A (StnA) and Schisantherin B (StnB), respectively. Mice were treated with each drug (qd) for 7 days, while the administration of lithocholic acid (LCA) (bid) was launched from the 4th day. Twelve hours after the last LCA injection, mice were sacrificed and samples were collected. Serum biochemical measurement and histological analysis were conducted. Metabolomics analysis of serum, liver, intestine and feces were performed to study the metabolic profile of bile acids. RT-qPCR and Western blot analysis were conducted to determine the hepatic expression of genes and proteins related to bile acid homeostasis. Dual-luciferase reporter gene assay was performed to investigate the transactivation effect of lignans on human pregnane X receptor (hPXR). RT-qPCR analysis was used to detect induction effects of lignans on hPXR-targeted genes in HepG2 cells.. Lignans including SinA, SinB, SinC, SolA, SolB, StnA, StnB were found to significantly protect against LCA-induced intrahepatic cholestasis, as evidenced by significant decrease in liver necrosis, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity. More importantly, serum total bile acids (TBA) and total bilirubin (Tbili) were also significantly reduced. Metabolomics analysis revealed these lignans accelerated the metabolism of bile acids and increased the bile acid efflux from liver into the intestine or feces. Gene analysis revealed these lignans induced the hepatic expressions of PXR-target genes such as Cyp3a11 and Ugt1a1. Luciferase reporter gene assays illustrated that these bioactive lignans can activate hPXR. Additionally, they can all upregulate hPXR-regulate genes such as CYP3A4, UGT1A1 and OATP2.. These results clearly demonstrated the lignans from Schisandra sphenanthera exert hepatoprotective effects against LCA-induced cholestasis by activation of PXR. These lignans may provide an effective approach for the prevention and treatment of cholestatic liver injury.

Topics: Animals; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Cholestasis; Feces; HEK293 Cells; Hep G2 Cells; Humans; Intestinal Mucosa; Lignans; Lithocholic Acid; Liver; Male; Mice, Inbred C57BL; Pregnane X Receptor; Protective Agents; Schisandra

Radix Wikstroemia indica (RWI), named "Liao Ge Wang" in Chinese, is a kind of toxic Chinese herbal medicine (CHM) commonly used in Miao nationality of South China. "Sweat soaking method" processed RWI could effectively decrease its toxicity and preserve therapeutic effect. However, the underlying mechanism of processing is still not clear, and the Q-markers database for processed RWI has not been established.. Our study is to investigate and establish the quality evaluation system and potential Q-markers based on "effect-toxicity-chemicals" relationship of RWI for quality/safety assessment of "sweat soaking method" processing.. The variation of RWI in efficacy and toxicity before and after processing was investigated by pharmacological and toxicological studies. Cytotoxicity test was used to screen the cytotoxicity of components in RWI. The material basis in ethanol extract of raw and processed RWI was studied by UPLC-Q-TOF/MS. And the potential Q-markers were analyzed and predicted according to "effect-toxicity-chemical" relationship.. RWI was processed by "sweat soaking method", which could preserve efficacy and reduce toxicity. Raw RWI and processed RWI did not show significant difference on the antinociceptive and anti-inflammatory effect, however, the injury of liver and kidney by processed RWI was much weaker than that by raw RWI. The 20 compounds were identified from the ethanol extract of raw product and processed product of RWI using UPLC-Q-TOF/MS, including daphnoretin, emodin, triumbelletin, dibutyl phthalate, Methyl Paraben, YH-10 + OH and matairesinol, arctigenin, kaempferol and physcion. Furthermore, 3 diterpenoids (YH-10, YH-12 and YH-15) were proved to possess the high toxicity and decreased by 48%, 44% and 65%, respectively, which could be regarded as the potential Q-markers for quality/safety assessment of "sweat soaking method" processed RWI.. A Q-marker database of processed RWI by "sweat soaking method" was established according to the results and relationship of "effect-toxicity-chemicals", which provided a scientific evidence for processing methods, mechanism and the clinical application of RWI, also provided experimental results to explore the application of Q-marker in CHM.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; China; Chromatography, Liquid; Coumarins; Drugs, Chinese Herbal; Emodin; Furans; Humans; Lignans; Mass Spectrometry; Mice; Plant Extracts; Wikstroemia

Schisandrin B (Sch B) a main active component of. The present study determined and identifed the carbene reactive metabolite of Sch B in human and mice liver microsomes. Its roles in activating Nrf2 pathway and modifying macromolecules were further explored in human liver microsomes. Moreover the potential cytotoxicity and hepatoxicity of carbene on HepG-2 and mice were also investigated.. The present study revealed that CYP450s mediate the conversion of Sch B to carbene, which subsequently binds to Keap1 and elicits Nrf2 pathway, which could further increase the elimination of carbene and thus exhibit a less harmful effect on mice liver.

Topics: Activation, Metabolic; Animals; Cell Survival; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cytochrome P-450 Enzyme System; Hep G2 Cells; Humans; Kelch-Like ECH-Associated Protein 1; Lignans; Liver; Male; Methane; Mice; Microsomes, Liver; NF-E2-Related Factor 2; Polycyclic Compounds; 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

This study was conducted to test the effects of schizandrin B (Sch B) on clozapine (CLZ) induced\ chronic liver injury in mice and the mechanism of action, and this may provide a new approach for clinical\ prevention of CLZ-induced side effects. The CLZ was given to mice for three weeks alone or co-administration\ with Sch B. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase\ (ALP) and antioxidation indexes superoxide dismutase (SOD), malonic dialdehyde (MDA), glutathione (GSH)\ and liver histological evaluation were determined. Expression of Nrf2 was assayed in hepatic cells by immunohistochemical\ staining and Western blotting. The changes of relative gene expression of NAD(P)H: quinone\ oxidoreductase l (NQO1) and heme oxygenase 1 (HO-1) were assayed by real-time Q-PCR. The results showed\ that pretreatment with a lower dosage of Sch B (25, 50 mg·kg−1) prevented CLZ-induced liver injury as indicated\ by the reduced levels of ALT, AST and ALP, and the preserved activities of SOD, GSH and inhibiting MDA. It\ was shown that Sch B could up-regulate Nrf2 expression leading to nuclear accumulation of Nrf2 to induce\ oxidative response genes such as NQO1 and HO-1. These results suggest that Sch B could protect against liver\ injury induced by CLZ via the activation of the Nrf2/ARE signal pathway in a dose-dependent manner.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clozapine; Cyclooctanes; Glutathione; Heme Oxygenase-1; Lignans; Liver; Malondialdehyde; Membrane Proteins; Mice; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Polycyclic Compounds; Protective Agents; Signal Transduction; Superoxide Dismutase

Hepatic fibrosis is an important outcome of chronic liver injury and results in excess synthesis and accumulation of extracellular matrix (ECM) components. Phyllanthin (PLN) isolated from Phyllanthus amarus exhibits strong antioxidative property and protects HepG2 cells from carbon tetrachloride (CCl4)-induced experimental toxicity. The present study reports the antifibrotic potential of PLN. The in vivo inhibitory effect of PLN on CCl4-mediated lipid peroxidation and important profibrotic mediator transforming growth factor β1 and on predominant ECM components collagen and fibronectin were also studied. The results show that PLN acts by suppressing the expression of inflammatory cytokine tumor necrosis factor-α and prevents activation of nuclear factor-κB in hepatic tissue. Our study highlights the molecular mechanism responsible for the antifibrotic efficacy of PLN.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Down-Regulation; Female; Hep G2 Cells; Humans; Lignans; Lipid Peroxidation; Liver; Liver Cirrhosis; Mice; NF-kappa B; Oxidative Stress; Phyllanthus; Plant Extracts; Protective Agents; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

We previously reported that the ethanol extract of Schisandra sphenanthera [Wuzhi (WZ) tablet] significantly protects against acetaminophen-induced hepatoxicity. However, whether WZ exerts a protective effect against cholestasis remains unclear. In this study, the protective effect of WZ on lithocholic acid (LCA)-induced intrahepatic cholestasis in mice was characterized and the involved mechanisms were investigated. WZ pretreatment (350 mg/kg) with LCA significantly reversed liver necrosis and decreased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activity. More importantly, serum total bile acids and total bilirubin were also remarkably reduced. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis showed that hepatic expression of pregnane X receptor (PXR) target genes such as CYP3A11 and UDP-glucuronosyltransferase (UGT) 1A1 were significantly increased by WZ treatment. Luciferase assays performed in LS174T cells illustrated that WZ extract and its six bioactive lignans could all activate human PXR. In addition, WZ treatment significantly promoted liver regeneration via inhibition of p53/p21 to induce cell proliferation-associated proteins such as cyclin D1 and proliferating cell nuclear antigen. In conclusion, WZ has a protective effect against LCA-induced intrahepatic cholestasis, partially owing to activation of the PXR pathway and promotion of liver regeneration.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cholestasis; Cytochrome P-450 CYP3A; Drugs, Chinese Herbal; Glucuronosyltransferase; Lignans; Lithocholic Acid; Liver; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Pregnane X Receptor; Protective Agents; Receptors, Steroid; Schisandra; Signal Transduction

Schisandrin B is a hepatoprotective component isolated from a traditional Chinese herb, Schisandra chinensis (Turcz.) Baill. This study determined the effect of Schisandrin B on d-galactosamine -induced liver injury and the role of heat shock proteins 27 and 70 against liver injury in mice. Acute liver injury was induced by intraperitoneal injection of d-galactosamine to mice, and Schisandrin B was given orally. The protein and gene expression of heat shock proteins 27 and 70 were detected by western blot and real-time quantitative polymerase chain reaction, respectively. Liver tissues were subjected to histological evaluation, and the activities of alanine aminotransferase and aspartate aminotransferase in the serum were measured. Pretreatment of Schisandrin B significantly attenuated d-galactosamine-induced liver injury in mice. This result was evidenced by improved alteration of histopathological hepatic necrosis and reduced alanine aminotransferase and aspartate aminotransferase activities in the serum. The hepatoprotective effect was accompanied with overexpression of heat shock proteins 27 and 70 both at the protein and mRNA levels. However, the aforementioned actions of Schisandrin B were all markedly suppressed by the heat shock protein inhibitor quercetin. Heat shock proteins 27 and 70 were involved in the protective effect of Schisandrin B against d-galactosamine-induced liver injury in mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cyclooctanes; Galactosamine; Gene Expression; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Lignans; Liver; Male; Mice; Mice, Inbred ICR; Polycyclic Compounds; Protective Agents; Quercetin; Schisandra

The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect.. Male C57BL/6 mice were treated with SolB (200 mg · kg(-1) · d(-1), ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay.. SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5-20 μmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells.. SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Antioxidant Response Elements; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Gene Expression Regulation; Hep G2 Cells; Humans; Lignans; Liver; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Protective Agents; RNA, Messenger; Schisandra; Signal Transduction

The ethanol extract of Cynara cornigera L. was fractionated and the fractions were subjected to hepatoprotective assays using Wistar albino rats at a dose of 500 and 250mg/kg. The liver injury was induced in rats using carbon tetrachloride. Biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin were estimated as reflections of the liver condition, with silymarin as a positive control. Phytochemical investigation and chromatographic separation of the hepatoprotective fractions led to the isolation of a new sesqui-lignan namely cornigerin (1), along with eight known compounds: apigenin (2), luteolin (3), β-sitosterol glycoside (4), apigenin 7-O-β-D-glucopyranoside (5), luteolin-7-O-β-D-glucopyranoside (6), apigenin-7-O-rutinoside (7), cynarin 1,5-di-O-caffeoylquinic acid (8), and apigenin-7-O-β-D-glucuronide (9). This is the first report for the isolation of 8 and 9 from this plant.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chemical Fractionation; Cynara; Lignans; Male; Plant Extracts; Rats, Wistar

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose-dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI-GSH. A molecular docking model also predicted that SolB had potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and antiapoptotic-related proteins such as cyclin D1 (CCND1), PCNA, and BCL-2. This study demonstrated that SolB exhibited a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA, and BCL-2 to promote liver regeneration.

Topics: Acetaminophen; Activation, Metabolic; Animals; Apoptosis Regulatory Proteins; Benzoquinones; Binding Sites; Biomarkers; Catalytic Domain; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Cytoprotection; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glutathione; Imines; Lignans; Liver; Liver Regeneration; Male; Membrane Proteins; Mice, Inbred C57BL; Mitochondria, Liver; Molecular Docking Simulation; Protein Binding; Protein Conformation; Signal Transduction

Background. Liver diseases still represent a major health burden worldwide. Moreover, medicinal plants have gained popularity in the treatment of several diseases including liver. Thus, the present study was to evaluate the effectiveness of Piper cubeba fruits in the amelioration of CCl4-induced liver injuries and oxidative damage in the rodent model. Methods. Hepatoprotective activity was assessed using various biochemical parameters like SGOT, SGPT, γ-GGT, ALP, total bilirubin, LDH, and total protein. Meanwhile, in vivo antioxidant activities as LPO, NP-SH, and CAT were measured in rat liver as well as mRNA expression of cytokines such as TNFα, IL-6, and IL-10 and stress related genes iNOS and HO-1 were determined by RT-PCR. The extent of liver damage was also analyzed through histopathological observations. Results. Treatment with PCEE significantly and dose dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, PCEE significantly reduced the lipid peroxidation in the liver tissue and restored activities of defense antioxidant enzymes NP-SH and CAT towards normal levels. The administration of PCEE significantly downregulated the CCl4-induced proinflammatory cytokines TNFα and IL-6 mRNA expression in dose dependent manner, while it upregulated the IL-10 and induced hepatoprotective effect by downregulating mRNA expression of iNOS and HO-1 gene.

Topics: Animals; Antioxidants; Biphenyl Compounds; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Cytokines; Disease Models, Animal; Ethanol; Free Radical Scavengers; Lignans; Liver; Male; Malondialdehyde; Oxidative Stress; Phytochemicals; Picrates; Piper; Plant Extracts; Protective Agents; Rats, Wistar; RNA, Messenger; Sulfhydryl Compounds

Herpetospermum caudigerum (HCD) is traditionally used for the treatment of liver diseases, cholic diseases, and dyspepsia as a well-known Tibetan medicine in China. The present study was designed to investigate the hepatoprotective effect of HCD and ascertain its active ingredients and possible mechanism.. Mice were orally administrated with different parts (seeds, testa and kernel) and fractions of HCD. The hepatoprotective activities of different parts (seeds, testa and kernel) and three fractions (petroleum ether fraction, ethyl acetate fraction and aqueous fraction) with different polarities of HCD and herpetrione (HPE) isolated from HCD were determined using a mouse model of CCl4-induced liver injury based on the analysis of serum ALT and AST activities and the changes of antioxidant parameters like malondialdehyde (MDA) content, glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the liver. Moreover, the chemical analysis of different parts and fractions of HCD was later analyzed by HPLC.. Our results showed that the ethyl acetate fraction and HPE significantly alleviated liver injury as indicated by the decreased levels of serum ALT and AST and reduce the pathological tissue damage induced by CCl4. Moreover, they decreased the MDA content and increased the levels of SOD, GSH and GSH-Px. Chemical analysis indicated that the ethyl acetate fraction were rich in HPE.. The lignans extract of Herpetospermum caudigerum is effective for the prevention of CCl4-induced hepatic damage in mice and HPE may be partially responsible for the pharmacological effect of hepatoprotection. The hepatoprotective effect may be related to its free radical scavenging effect, inhibiting lipid peroxidation and increasing antioxidant activity.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cucurbitaceae; Furans; Glutathione; Glutathione Peroxidase; Lignans; Liver; Malondialdehyde; Mice; Phytotherapy; Plant Extracts; Protective Agents; Seeds; Superoxide Dismutase

Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra fructus is widely-used traditional Chinese medicine which possesses hepato-protective potential. Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), and Schisantherin A (SthA) are the major bioactive lignans. Most recently, we found SolB exerts significant hepato-protection against APAP-induced liver injury. In this study, the protective effects of the other five schisandra lignans against APAP-induced acute hepatotoxicity in mice were investigated and compared with that of SolB. The results of morphological and biochemical assessment clearly demonstrated significant protective effects of SinA, SinB, SinC, SolA, SolB, and SthA against APAP-induced liver injury. Among these schisandra lignans, SinC and SolB exerted the strongest hepato-protective effects against APAP-induced hepatotoxicity. Six lignans pretreatment before APAP dosing could prevent the depletions of total liver glutathione (GSH) and mitochondrial GSH caused by APAP. Additionally, the lignans treatment inhibited the enzymatic activities of three CYP450 isoforms (CYP2E1, CYP1A2, and CYP3A11) related to APAP bioactivation, and further decreased the formation of APAP toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) in mouse microsomal incubation system. This study demonstrated that SinA, SinB, SinC, SolA, SolB and SthA exhibited significant protective actions toward APAP-induced liver injury, which was partially associated with the inhibition of CYP-mediated APAP bioactivation.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Dioxoles; Lignans; Liver; Male; Membrane Proteins; Mice, Inbred C57BL; Polycyclic Compounds; Protective Agents; Schisandra

A number of drugs and herbal compounds have been documented to cause hepatoxicity. Schisandrin B (Sch B) is an active dibenzocyclooctadiene isolated from Schisandrae fructus, with a wide array of pharmacological activities. However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated. In the present study, we aimed to investigate the liver toxic effects and the molecular mechanisms of Sch B in mouse liver and macrophage cells. The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells. Sch B markedly arrested cells in G1 phase in both cell lines, accompanied by the down-regulation of cyclin dependent kinase 2 (CDK2) and cyclin D1 and up-regulation of p27 Kip1 and checkpoint kinase 1. Furthermore, Sch B markedly increased the apoptosis of AML-12 and RAW 264.7 cells with a decrease in the expression of B-cell lymphoma-extra-large and (Bcl-xl) B-cell lymphoma 2 (Bcl-2), but an increase in the expression of B-cell lymphoma 2-associated X protein (Bax). Sch B promoted the cleavage of caspase 3 and poly-adenosine diphosphate-ribose polymerase (PARP) in both cell lines. Additionally, Sch B significantly induced autophagy of AML-12 and RAW 264.7 cells. Sch B inhibited the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as indicated by their altered phosphorylation, contributing to the proautophagic effect of Sch B. Taken together, our findings show that the inducing effects of Sch B on cell cycle arrest, apoptosis, and autophagy may contribute to its liver toxic effects, which might provide a clue for the investigation of the molecular toxic targets and underlying mechanisms for Sch B-induced hepatotoxicity in herbal consumers. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.

Topics: Animals; Apoptosis; Autophagy; Cell Cycle; Cell Division; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Cyclooctanes; G1 Phase; Hepatocytes; Lignans; Macrophages; Mice; Mitochondria, Liver; Polycyclic Compounds; S Phase; Signal Transduction

Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (P<0.0001). Reduction of TBARS (P<0.01 and P<0.001) followed by enhancement of GSH., SOD and catalase (P<0.0001) in liver homogenate in sesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Dioxoles; Disease Models, Animal; Lignans; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar

Phyllanthin, a sparingly water-soluble hepatoprotective lignin obtained from Phyllanthus amarus Schum. et Thonn. (Euphorbiaceae) possesses low bioavailability. Phyllanthin along with piperine (a nutraceutical bioenhancer) was formulated as a mixed micellar lipid formulation (MMLF) in the present study and investigated to resolve the low bioavailability and enhance hepatoprotective effects on oral administration. Hepatoprotective, antioxidant and bioavailability studies of MMLF, a complex phosphatidylcholine formulation of phyllanthin (CP-PC), phyllanthin + piperine (CP-P-PC) and its corresponding non-formulated phyllanthin have been carried out. Phyllanthin (30 mg kg(-1) p.o.), CP-PC (30 mg kg(-1) p.o.), CP-P-PC (30 mg kg(-1) p.o.) and the reference drug silymarin (100 mg kg(-1), p.o.) were administered daily to rats for 10 days, followed by liver damage by administering a 1 : 1 (v/v) mixture of CCl4 and olive oil (1 ml kg(-1), i.p.) for 7 days from day 4 to day 10. The degree of protection was evaluated by determining the level of marker enzymes (SGOT and SGPT), bilirubin (TB) and total proteins (TP). Further, the effects of MMLF on lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) were estimated in liver homogenates to evaluate the antioxidant activity. Finally the concentration of phyllanthin was evaluated in plasma. EC50 values for the in vitro antioxidant assay with DPPH were found to be 19.99, 15.94 and 13.5 for phyllanthin, CP-PC and CP-P-PC, respectively. CP-P-PC (30 mg kg(-1) p.o.) showed significant (p < 0.05) hepatoprotective effect by reducing the levels of serum marker enzymes (SGOT, SGPT, and TB), whereas, elevated the levels of depleted total protein (TP), lipid peroxidation and antioxidant marker enzyme activities such as, GSH, SOD, CAT, GPX, and GR. The complex MMLF normalized adverse conditions of rat livers more efficiently than the non-formulated phyllanthin. The present findings indicate that the MMLF is helpful in solving the problem of low bioavailability of phyllanthin.

Topics: Administration, Oral; Alkaloids; Animals; Antioxidants; Benzodioxoles; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chemistry, Pharmaceutical; Cytochrome P-450 Enzyme Inhibitors; Glutathione; Glutathione Peroxidase; Lignans; Lipid Peroxidation; Lipids; Liver; Male; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Protective Agents; Rats; Rats, Wistar; Silymarin

Chronic injury to liver triggers synthesis of extracellular matrix components resulting in progressive fibrosis and eventually cirrhosis. Transforming growth factor-β1 (TGF-β1) transduces its signal by binding to TGF-β type 1 receptor kinase or activin like kinase (ALK5) receptor and mediates hepatic fibrosis by increasing the transcription of downstream entities such as collagen via Smad2 and Smad3. The present study was carried out to investigate the mechanism by which phyllanthin, a hepatoprotective lignin isolated from the plant Phyllanthus amarus (P. amarus) exerts its anti-fibrotic effect. The inhibitory role of phyllanthin on ALK5 was first analyzed using molecular docking experiments. Phyllanthin was found to effectively bind to serine (Ser) 280 at the active site of ALK5 by forming hydrogen bonds. The in vivo protective effect of phyllanthin against carbon tetrachloride (CCl4)-induced hepatic fibrosis was established by studying the protein expressions of TGF-β1, ALK5 and Smad2 and 3 and by determining various biochemical and histopathological parameters. Phyllanthin was found to exert its anti-fibrotic effect by down-regulating TGF signaling pathway via ALK5 and Smad2 and 3 inhibition.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Collagen; Female; Lignans; Liver Cirrhosis; Liver Function Tests; Mice; Molecular Docking Simulation; Phyllanthus; Protective Agents; Protein Binding; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1

Schisandrin B is an active component isolated from Schisandra chinensis (TurcZ.) Baill. that is widely used as an antihepatotoxic agent. Schisandrin B has significant hepatoprotective effect against chemical and immunological liver injury. This study aimed to investigate the effect of Schisandrin B on the expression of 27- and 70-kDa heat-shock protein (HSP) and its role in protection against acetaminophen-induced liver injury in mice.. After the mice were pretreated, Western blot and real-time quantitative polymerase chain reaction were used to detect the protein and gene expression of HSP27 and HSP70, respectively; the liver tissues were subjected to histological evaluation, and alanine aminotransferase and aspartate aminotransferase activities in the serum were measured.. Oral administration of Schisandrin B increased the expression of HSP27 and HSP70 in a time- and dose-dependent manner. The inducing effect of Schisandrin B on HSP27 and HSP70 was also confirmed by real-time quantitative polymerase chain reaction. In the acetaminophen-induced liver injury mouse model, the prior oral administration of Schisandrin B (200 mg/kg) three times in 24 h markedly alleviated liver injury as indicated by the amelioration of histopathological hepatic necrosis and the reduction of alanine aminotransferase and aspartate aminotransferase activities in the serum. However, the earlier actions of Schisandrin B were all suppressed significantly by Quercetin, a known HSP inhibitor.. The hepatic cytoprotective action of Schisandrin B against acetaminophen-induced liver injury is mediated, at least in part, by the induction of HSP27 and HSP70 in mice.

Topics: Acetaminophen; Administration, Oral; Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Lignans; Liver; Male; Mice; Phytotherapy; Polycyclic Compounds; Schisandra; Time Factors

Sesamin (Ses), one of the major lignan derived from sesame seeds, has been reported to have many benefits and medicinal properties. However, its protective effects against carbon tetrachloride (CCl4) induced injury in liver have not been clarified. The aim of the present study was to investigate the hepatoprotective effects of sesamin on oxidative stress and apoptosis in mice exposed to CCl4. Our data showed that sesamin significantly prevented CCl4-induced hepatotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of liver damage (serum aminotransferase activities) and histopathological analysis. Moreover, CCl4-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of the total antioxidant capacity (TAC) in liver, were suppressed by treatment with sesamin. Furthermore, TUNEL assay showed that CCl4-induced apoptosis in mouse liver was significantly inhibited by sesamin. In exploring the underlying mechanisms of sesamin action, we found that activities of caspase-3 were markedly inhibited by the treatment of sesamin in the liver of CCl4 treated mice. Sesamin increased expression levels of phosphorylated Jun N-terminal kinases (JNK) in liver, which in turn inactivated pro-apoptotic signaling events restoring the balance between mitochondrial pro- and anti-apoptotic Bcl-2 proteins and decreasing the release of mitochondrial cytochrome c in liver of CCl4 treated mice. JNK was also involved in the mitochondrial extrinsic apoptotic pathways of sesamin effects against CCl4 induced liver injury by regulating the expression levels of phosphorylated c-Jun proteins, necrosis factor-alpha (TNF-α) and Bak. In conclusion, these results suggested that the inhibition of CCl4-induced apoptosis by sesamin is due at least in part to its anti-oxidant activity and its ability to modulate the JNK signaling pathway.

Topics: Animals; Apoptosis; Carbon Tetrachloride; Caspase 3; Chemical and Drug Induced Liver Injury; Dioxoles; Enzyme Activation; Lignans; Liver; Male; MAP Kinase Kinase 4; Mice; Mice, Inbred ICR; Oxidative Stress; Phosphorylation; Reactive Oxygen Species

Phyllanthus amarus is a medicinal herb used in traditional Indian medicine for liver disorders. Several researches also show that it acts primarily in the liver, but the molecules were unidentified for liver protective activity. This study was to determine whether the lignans isolated from P. amarus attenuates the D-galactosamine (GalN) / Lipopolysaccharide (LPS)- induced acute hepatitis in mice. Standardize mixture of lignans (slPA) isolated from leaves of P. amarus using automated chromatographic technique was used for experiments. Experimental mice were orally pre-treated with slPA (10, 30 and 100 mg/kg) for 7 days before intra-peritoneal injection of GalN/LPS. Acute hepatitis in mice was confirmed by significant increase of pro-inflammatory cytokines, and hepatotoxic markers. Pre-treatment of slPA exhibit significant liver protection in dose dependant mannaer. In-silico molecular docking studies also suggests that lignans are preferentially more active due to strong binding affinity against pro-inflammatory cytokines; IL-1β, IL-6, and TNF-α. The electronic parameters of lignans for bioavailability, drug likeness and toxicity were within the acceptable limit. In-vivo and in-silico results suggest that pretreatment of slPA exhibit potent hepatoprotection against GalN/LPS-induced hepatitis in mice and the liver protective effects may be due to the inhibition of inflammatory mediators.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Computer Simulation; Cytokines; Galactosamine; Lignans; Lipid Peroxidation; Lipopolysaccharides; Mice; Models, Chemical; Molecular Structure; Phyllanthus

Topics: Chemical and Drug Induced Liver Injury; Dioxoles; Humans; Lignans

In this study, we investigated the potential anti-inflammatory and antioxidative effects of sesamin on acute liver injury. Lead (Pb) causes oxidative damage and enhances the effects of low-dose lipopolysaccharide (LPS), inducing acute hepatic injury in rats.. Male Sprague-Dawley rats were given intraperitoneal injections of Pb acetate (5 mg/kg) and LPS (50 μg/kg) to induce liver injury, and we tested the effects of oral administration of sesamin (10 mg/kg) on liver damage. To assess the extent of acute hepatic injury in the rats, we measured the anti-inflammatory and antioxidant markers and relevant signaling pathways: serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP), reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, nitric oxide (NO), and cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS) levels, mitogen-activated protein kinases (MAPKs), c-Fos, and GADD45β.. Sesamin significantly decreased the serum AST, ALT, and CRP levels in the rat model. In the Pb and LPS-stressed rats, sesamin administration reduced the serum levels of TNF-α, IL-1, IL-6, NO, and ROS generation, and liver tissue expressions of c-Jun N-terminal kinase (JNK), p38 MAPK, GADD45β, COX-2, and iNOS.. Collectively, these results demonstrate that sesamin is associated with antioxidant and anti-inflammatory activity. The observed effect of scavenging of ROS and NO and inhibiting the production of proinflammatory cytokines may be achieved through the suppression of COX-2, iNOS, and MAPK pathways in the acute hepatic injury rats.

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Dioxoles; Lignans; Lipopolysaccharides; Male; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

The principal bioactive lignan of Schisandra chinensis fructus, commonly used for traditional Chinese medicine, is schisandrin A. Schisandrin A has been widely reported as being very effective for the treatment of liver disease. However, the mechanisms of its protective effects in liver remain unclear.. To explore the hepatoprotective mechanisms of schisandrin A.. d-Galactosamine (d-GalN)-induced liver injury in mice was used as a model. Schisandrin A was examined for its protective mechanisms using hematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), western blotting and real-time PCR (RT-PCR).. Aspartate amino-transferase (AST) and alanine transaminase (ALT) levels in the schisandrin A group were significantly decreased (p < 0.01) compared with those in the d-GalN-treated group. HE results showed that the pathological changes in hepatic tissue seen in the d-GalN-treated were reduced in the schisandrin A/d-GalN-treated group, with the morphological characteristics being close to those of the control (untreated) group. Western blotting results showed that schisandrin A can activate autophagy flux and inhibit progression of apoptosis. The immune function of the schisandrin A-pretreated group was assayed by flow cytometry. It was found that the mechanism may involve activated autophagy flux, inhibited apoptosis, and improved immunity in response to liver damage.. Our results show that the hepatoprotective mechanisms of schisandrin A may include activation of autophagy flux and inhibition of apoptosis. These results provide pharmacological evidence supporting its future clinical application.

Topics: Animals; Autophagy; Chemical and Drug Induced Liver Injury; Cyclooctanes; Galactosamine; Lignans; Male; Mice; Mice, Inbred ICR; Polycyclic Compounds; Random Allocation; Schisandra

Twelve novel 7'-hydroxy lignan glucosides (1-12), including two benzofuran-type neolignans, two 8-O-4' neolignans, two dibenzylbutyrolactone lignans, and six tetrahydrofuranoid lignans, together with six known lignan glucosides (13-18), were isolated from the fruit of Arctium lappa L. (Asteraceae), commonly known as Arctii Fructus. Their structures were elucidated using spectroscopy (1D and 2D NMR, MS, IR, ORD, and UV) and on the basis of chemical evidence. The absolute configurations of compounds 1-12 were confirmed using rotating frame nuclear overhauser effect spectroscopy (ROESY), the circular dichroic (CD) exciton chirality method, and Rh2(OCOCF3)4-induced CD spectrum analysis. All of the isolated compounds were tested for hepatoprotective effects against D-galactosamine-induced cytotoxicity in HL-7702 hepatic cells. Compounds 1, 2, 7-12, and 17 showed significantly stronger hepatoprotective activity than the positive control bicyclol at a concentration of 1 × 10(-5) M.

Topics: Apoptosis; Arctium; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Chemical and Drug Induced Liver Injury; Circular Dichroism; Drugs, Chinese Herbal; Fruit; Glucosides; Humans; Lignans; Liver Neoplasms; Magnetic Resonance Spectroscopy; Molecular Structure

In the present review, the literature data on the chemical constituents and biological investigations of the genus Pedicularis are summarized. Some species of Pedicularis have been widely applied in traditional Chinese medicine. A wide range of chemical components including iridoid glycosides, phenylpropanoid glycosides (PhGs), lignans glycosides, flavonoids, alkaloids and other compounds have been isolated and identified from the genus Pedicularis. In vitro and in vivo studies indicated some monomer compounds and extracts from the genus Pedicularis have been found to possess antitumor, hepatoprotective, anti-oxidative, antihaemolysis, antibacterial activity, fatigue relief of skeletal muscle, nootropic effect and other activities.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Antioxidants; Chemical and Drug Induced Liver Injury; Fatigue; Flavonoids; Glycosides; Humans; In Vitro Techniques; Iridoid Glycosides; Lignans; Medicine, Chinese Traditional; Mice; Molecular Conformation; Nootropic Agents; Pedicularis; Phytotherapy; Plant Extracts; Propanols

Schisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice.. Institute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125-2 g/kg) or SFO (0.3-5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6-120 hours postdosing.. Serum ALT activity was elevated by 60%, with maximum effect (E(max)) = 45.77 U/L and affinity (K(D)) = 1.25 g/kg at 48-96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (E(max) =2.30 nmol/mg protein and K(D) =0.41 g/kg) and 22% (E(max) = 1.42 nmol/mg protein and K D = 2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%-60% (E max = 11.01, K(D) = 0.68 g/kg) and 8%-32% (E(max) = 9.88, K D = 4.47 g/kg) at 12-120 hours and 24-120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%-158% and 35%-85%, respectively, at 12-96 hours and 6-48 hours after Sch B and SFO treatment, respectively. The values of E max and K D for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 μmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of E(max) = 5.50/4.60 mmol/L and K D = 0.43/2.84 g/kg, respectively.. The findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time-dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The E max and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO.

Topics: Administration, Oral; Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dose-Response Relationship, Drug; Lignans; Liver; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Molecular Structure; Plant Oils; Polycyclic Compounds; Schisandra; Time Factors; Triglycerides

In the present study, we investigated the hepatoprotective effects of schisandrin B (Sch B) and green tea polyphenols (GrTP), two natural antioxidants, against Hg hepatotoxicity. Fifty-six rats were randomly divided into four groups of fourteen animals in each group: control group, Hg-treated group, Sch B pretreated group, and GrTP pretreated group. HgCl2 injection increased Hg accumulation, pathological and ultrastructural injury, lactate dehydrogenase (LDH) level, alanine transaminase (ALT) level, apoptosis, reactive oxygen species (ROS) level, glutathione (GSH) level, and malondialdehyde (MDA) level. HgCl2 injection decreased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Sch B and GrTP protected against Hg-induced dysfunction and liver injury by enhancing the antioxidant defense system. Our results indicate that Sch B and GrTP exert antioxidative effects against Hg-induced hepatotoxicity in rats.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Cyclooctanes; Lignans; Liver; Mercuric Chloride; Oxidative Stress; Polycyclic Compounds; Polyphenols; Random Allocation; Rats; Rats, Wistar; Tea

It is valuable to establish a chemical-pharmacokinetic (PK)-pharmacodynamics (PD) fingerprint of traditional Chinese medicine (TCM) for comprehensively understanding the TCM integrated conception and revealing the material foundation. The chemical, metabolic in vitro, and PK/PD in vivo fingerprints of Schisandra chinensis (SC) alcoholic extract were established and comparatively analyzed using HPLC-UV-MS method, rat liver microsomes in vitro and CCl4 intoxicated rats in vivo. Four known effective lignans, schisandrin, schisantherin A, deoxyschizandrin and gamma-schisandrin, were detected as the standard references in SC alcoholic extract with high concentration. SC alcoholic extract and four lignans when incubated with rat liver microsomes produced several metabolites in NAPDH-dependent manner. Chemical fingerprint of some components with bioactivities were also identified in PK and PD fingerprints in normal and ALI rats that explained the material foundation of SC alcoholic extract for multiple pharmacological effects. Schisandrin, schisantherin A, deoxyschizandrin and gamma-schisandrin could be considered as the "PK marker" of SC alcoholic extract or its relevant preparations, while two metabolites of the four lignans, 7, 8-dihydroxy-schizandrin and another one (M(W) 432), could be recognized as drug-metabolism (DM) Marker. This work provides experimental data for the further studies of metabolism or material foundation of SC components.

Topics: Alanine Transaminase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Cyclooctanes; Drugs, Chinese Herbal; Lignans; Male; Microsomes, Liver; Plants, Medicinal; Polycyclic Compounds; Random Allocation; Rats; Rats, Sprague-Dawley; Schisandra; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet

Hyperlipidemia is referred to as hypercholesterolemia, hypertriglyceridemia, or both in combined hyperlipidemia. Here, a novel mouse model of combined hyperlipidemia is described. Mice were orally given a single dose of a modeling agent (MA) made of a mixture of schisandrin B/cholesterol/bile salts (1/2/0.5 g/kg) suspended in olive oil. MA treatment increased serum triglycerides (TG) and total cholesterol (TC) (up to 422% and 100% at 12 - 96 h post-treatment, respectively) and hepatic TG and TC (up to 220% and 26%, respectively) in a time- and dose-dependent manner, associated with elevation of high-density lipoprotein and low-density lipoprotein levels. Serum alanine/aspartate aminotransferase activities, indicators of liver cell damage, were also elevated (up to 198%) at 48 and 72 h post-MA treatment. Fenofibrate blocks MA-induced hyperlipidemia, lipid accumulation in the liver, as well as liver injury. Oral administration of a mixture of schisandrin B, cholesterol, and bile salt could generate an interesting mouse model of combined hyperlipidemia associated with hepatic steatosis and steatohepatitis.

Topics: Administration, Oral; Animals; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Cholesterol; Cyclooctanes; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Liver; Fenofibrate; Hyperlipidemias; Lignans; Lipoproteins; Male; Mice; Mice, Inbred ICR; Polycyclic Compounds; Time Factors; Triglycerides

The aim of the present study was to investigate the protective effects of gomisin A, a lignan compound isolated from Schisandra chinensis, against liver and kidney damage induced by CCl(4) exposure. We assessed alterations in organ weights, levels of serum biochemical indicators, and activation of the caspase-3 and MAPK signaling pathways and carried out histological analysis of liver and kidney tissue in rats pretreated with gomisin A for four days. In the gomisin A/CCl(4)-treated group, only the liver experienced a significant increase in weight, whereas the other organs did not undergo any changes. Five biochemical indicators in serum indicated that liver and kidney toxicity dramatically decreased upon gomisin A pretreatment, although the decrease in ratios varied. Upon histological analysis, the gomisin A/CCl(4)-treated group showed less hepatocellular necrosis, a poorly dilated central vein in the liver section, decreased diameter of the glomerulus, a lower number of capillaries, and a convoluted tubule in the kidney section. Furthermore, the formation of active caspase-3 was inhibited by gomisin A pretreatment in the gomisin A/CCl(4)-treated group, whereas the expression level of Bax protein was slightly increased. Western blot analysis revealed that there were differences between the liver and kidney in terms of activation of the MAPK signaling pathway. In the liver, gomisin A pretreatment increased phosphorylation of three members of the MAPK pathway when compared to that in the vehicle pretreatment group. However, in the kidney, only the phosphorylation level of p38 was elevated upon gomisin A pretreatment, whereas levels of the other two members were decreased. These results suggest that gomisin A induces marked protective effects against hepatic and renal injury induced by CCl(4) exposure through differential regulation of the MAPK signal transduction pathway.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Apoptosis; Body Weight; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Kidney; Lignans; Liver; MAP Kinase Signaling System; Organ Size; Phosphorylation; Protective Agents; Rats; Rats, Sprague-Dawley; Schisandra

Oxidative damage and inflammation are implicated in the pathogenesis of liver injury and fibrosis. In the present study, we investigated the molecular mechanism by which gomisin A conferred a hepatoprotective effect, focusing on its antioxidant and anti-inflammatory effects using rats with carbon tetrachloride (CCl(4))-induced acute liver injury. Pretreatment with gomisin A prior to the administration of CCl(4) markedly prevented an increase in alanine aminotransferase, aspartate aminotransferase, and histological hepatic lesions. Gomisin A was also associated with a decrease in hepatic lipid peroxidation, and increased superoxide dismutase activity, suggesting that gomisin A has an antioxidant effect. In addition gomisin A treatment ameliorated mRNA levels of CCl(4)-induced inflammatory mediators, including tumor necrosis factor-α, interleukin-1β and inducible nitric oxide (NO) synthase, and the protein levels of transcriptional upregulator nuclear factor kappa B (NF-κB) and phospho-inhibitor of NF-κB (IκB). Furthermore, α-smooth muscle actin (α-SMA), a myofibroblast marker, was also inhibited by gomisin A treatment. These results suggest that gomisin A inhibits the oxidative stress and activation of NF-κB, leading to down-regulation of pro-inflammatory mediators and amelioration of fibrogenesis.

Topics: Actins; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Interleukin-1beta; Lignans; Lipid Peroxidation; Male; Malondialdehyde; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; RNA, Messenger; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

To identify key proteins involved in the hepatoprotection afforded by schisandrin B (Sch B), we used a proteomic approach to screen proteins that were specifically regulated by Sch B in mouse livers and to investigate the role of the proteins in hepatoprotection. Thirteen proteins were specifically activated or suppressed by Sch B treatment. Among the 13 proteins, Raf kinase inhibitor protein (RKIP) was postulated to be the key regulator involved in the development of hepatotoxin-induced cellular damage. The results indicated that the downregulation of RKIP by antisense RKIP vector transfection led to the activation of the Raf-1/MEK/ERK signaling pathway, as evidenced by increases in the level of MEK/ERK phosphorylation and the level of nuclear factor erythroid 2-related factor 2 in the nucleus. The signaling effect produced by RKIP downregulation resembled that triggered by Sch B, wherein both treatments resulted in a decrease in the extent of carbon tetrachloride-induced apoptotic cell death in AML12 hepatocytes. Overexpression of RKIP by the sense RKIP transfection vector or the inhibition of MEK kinase by PD98059 was able to abrogate the cytoprotective effect of Sch B in the hepatocytes. The results indicate that Sch B triggers the Raf/MEK/ERK signaling pathway, presumably by downregulating RKIP, thereby protecting against carbon tetrachloride-induced cytotoxicity.

Topics: Animals; Apoptosis; Blotting, Western; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Electrophoresis, Gel, Two-Dimensional; Extracellular Signal-Regulated MAP Kinases; Lignans; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred BALB C; Phosphatidylethanolamine Binding Protein; Polycyclic Compounds; Protective Agents; Proteins; Proteome; Proteomics; Proto-Oncogene Proteins c-raf; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Statistics, Nonparametric

Although magnolol is cytoprotective against warm ischemia/reperfusion injury, its effect on cold preservation has not been fully investigated. This study aimed at examining whether magnolol maintains the liver graft integrity after cold preservation and elucidating the underlying mechanisms in terms of apoptotic signaling under both normothermic and hypothermic conditions. After being preserved in Ringer's lactate (RL) at 4 degrees C for 6h ex vivo, the magnolol-treated grafts demonstrated significantly higher AST, ALT, and LDH levels in perfusates than those from negative controls. TUNEL staining showed no difference in the number of apoptotic nuclei in both groups, whereas a more intense apoptotic signal in magnolol-treated grafts was shown as compared with the controls. In vitro data showed no significant difference in viability of RL-preserved clone-9 hepatocytes between the magnolol-treated and control groups, while magnolol pretreatment at 30min before cold preservation prominently induced hepatocyte cell death. RT-PCR and Western blotting analyses revealed a suppression in Bcl-2, but an up-regulation in Bax expression in clone-9 cells after magnolol treatment. Magnolol suppressed the ratios of NF-kappaB to I-kappaBalpha protein contents and I-kappaBalpha phosphorylation induced by TNF-alpha, and potentiated mitochondrial cytochrome c release and subsequent caspase-3 cleavage. Conversely, caspase-3 inhibitor attenuated magnolol-induced hepatotoxicity. We concluded that magnolol could not protect liver grafts from cold ischemia/reperfusion injury. High concentration of magnolol under serum-reduced conditions attenuates NF-kappaB-mediated signaling and induces intrinsic apoptotic pathway, thereby inducing in vitro hepatotoxicity.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Biphenyl Compounds; Blotting, Western; Caspase 3; Chemical and Drug Induced Liver Injury; Cold Temperature; Cryopreservation; Cytochromes c; I-kappa B Proteins; In Situ Nick-End Labeling; Lignans; Liver; Liver Transplantation; Magnolia; Male; Mitochondria; NF-kappa B; Plant Bark; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Serum; Signal Transduction; Tumor Necrosis Factor-alpha

Although pharmacokinetic alternations by hepatic injury have been extensively studied, little is known about the potential influence of hepatoprotective agent's treatment. This study was aimed to investigate the holistic pharmacokinetics of multiple lignans, CYP3A regulations, and their correlations with hepatic injury biomarkers, in hepatic injured rats pretreated with or without schisandra lignan extract (SLE) and dimethyl-diphenyl-bicarboxylate (DDB). Integral pharmacokinetics of multiple lignans based on an AUC-weighting approach was determined in normal, CCl4 induced hepatic injury rats pretreated with or without SLE and DDB. Protein expression and activities of CYP3A were determined. Pharmacokinetic parameters and CYP3A activities were correlated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. CCl4 induced acute hepatic injury resulted in a nearly 8-fold enhancement of integral plasma exposures of multiple lignans, which was caused by the significant down-regulation of CYP3A. SLE and DDB pretreatment exhibited potent hepatoprotective effects, accompanied with the restored expression and activity of CYP3A, and the recovery of the respective and integral pharmacokinetics of lignans components. The integral AUC(0-tn) and CYP3A activities correlated well with ALT and AST. This study suggested that the pharmacokinetic regulating effects of hepatoprotective agent's on themselves and co-prescribed drugs should be of concern, and hepatic injury biomarkers may serve as good predictors.

Topics: Alanine Transaminase; Animals; Area Under Curve; Aspartate Aminotransferases; Biomarkers; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Dioxoles; Disease Models, Animal; Down-Regulation; Female; Fruit; Herb-Drug Interactions; Lignans; Male; Phytotherapy; Plant Extracts; Protective Agents; Rats; Rats, Sprague-Dawley; Reference Values; Schisandra

To study the effects of schisandrin B and sesamin mixture on carbon tetrachloride (CCl(4))-induced hepatic oxidative stress in male Sprague-Dawley rats. The rats were randomly assigned to five groups: control group (olive oil injection), CCl(4) group (CCl(4) injection), silymarin group (CCl(4) injection combined with supplementation of silymarin, 7.5 mg/kg/day), low dose group (CCl(4) injection combined with supplementation of schisandrin B and sesamin mixture at a low dose, 43 mg/kg/day) and high dose group (CCl(4) injection combined with the supplementation of schisandrin B and sesamin mixture at a high dose, 215 mg/kg/day). The hepatic superoxide dismutase and glutathione peroxidase activities of rats in the low dose and high dose groups were increased significantly compared with those in the CCl(4) group. The hepatic reduced glutathione concentration in the silymarin, low dose and high dose groups were increased significantly (48%, 45% and 53%, respectively) when compared with those of the CCl(4) group. In addition, the concentration of glutathione in the erythrocytes of the low dose group was significantly higher than the CCl(4) group by 25%. These results suggest that the schisandrin B-sesamin mixture exerted a hepatoprotective effect by improving the antioxidative capacity in rats under CCl(4)-induced hepatic oxidative stress.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Drug Combinations; Drugs, Chinese Herbal; Glutathione; Glutathione Peroxidase; Lignans; Liver; Liver Diseases; Male; Oxidative Stress; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Silymarin; Superoxide Dismutase

The aim of this study was to investigate the synergistic hepatoprotective effect of lignans from Fructus Schisandrae chinensis (LFS) with Astragalus polysaccharides (APS) on chronic liver injury in male Sprague-Dawley rats. Subcutaneous injection of 10% CCl(4) twice a week for 3 months resulted in significantly (p<0.001) elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the liver, significantly elevated levels (p<0.001) of malondialdehyde (MDA), lowered levels of reduced glutathione (GSH) (p<0.05) and catalase (CAT) (p<0.001), superoxide dismutase (SOD) (p<0.01)were observed following CCl(4) administration. 'LFS+ASP' treatment of rats at doses of 'LFS (45mg/kg)+APS (150mg/kg)' and 'LFS (135mg/kg)+APS (450mg/kg)' displayed hepatoprotective and antioxidative effects than the administration of either LFS or APS, as evident by lower (p<0.005 or 0.001) levels of serum ALT, AST, ALP and hepatic MDA (p<0.001) concentration, as well as higher SOD (p<0.05 or 0.005), CAT activities(p<0.01 or 0.005), GSH concentration (p<0.05 or 0.005) compared to the toxin treated group. Histopathological examinations revealed severe fatty degeneration in the toxin group, and mild damage in groups treated with 'LFS+APS' were observed. The coefficients drug interaction (CDI) between each individual drug and their combination (at the same dose of their single treatment) of these foregoing parameters were all less than 1, indicating that LFS and APS display hepatoprotective and antioxidant properties and act in a synergistic manner in CCl(4) induced liver injury in rats.

Topics: Animals; Astragalus propinquus; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chronic Disease; Drug Synergism; Drug Therapy, Combination; Enzymes; Fatty Liver; Fruit; Lignans; Liver; Male; Malondialdehyde; Phytotherapy; Plant Extracts; Plant Roots; Polysaccharides; Protective Agents; Rats; Rats, Sprague-Dawley; Schisandra

The present study was an attempt to investigate the hepatoprotective and antioxidative property of Phyllanthus amarus (P. amarus) extract and phyllanthin. Phyllanthin, one of the active lignin present in this plant species was isolated from the aerial parts, by silica gel column chromatography employing gradient elution with hexane-ethyl acetate solvent mixture. It was obtained in high yields (1.23%), compared to reported procedures and the purity was ascertained by HPTLC and reversed-phase HPLC analysis. Characterization of phyllanthin was done by mp, UV-Visible spectrophotometry, elemental analysis, FT-IR, 1H NMR, 13C NMR and mass spectral analysis. Free radical scavenging activity of P. amarus extract and phyllanthin was also examined using DPPH assay. The protective effect of P. amarus extract and phyllanthin was studied on CCl4-induced toxicity in human hepatoma HepG2 cell line. The results indicated that CCl4 treatment caused a significant decrease in cell viability. In addition, the toxin treatment initiated lipid peroxidation (LPO), caused leakage of enzymes like alanine transaminase (ALT) and lactate dehydrogenase (LDH) with a significant decrease in glutathione (GSH) levels. It was observed that phyllanthin effectively alleviated the changes induced by CCl4 in a concentration-dependent manner, with much smaller strengths as compared to P. amarus extract.

Topics: Antioxidants; Carbon Tetrachloride Poisoning; Cell Line; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Humans; Lignans; Lipid Peroxidation; Magnetic Resonance Spectroscopy; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared

Mercury represents an ubiquitous environmental toxic metal. Heat shock proteins (HSP) and metallothioneins (MTs) help to protect cells against metal toxicity. Schisandrin B (Sch B), a lignoid from Schisandra chinensis, has been successfully used to treat hepatitis, but its effect against mercury hepatotoxicity remains unknown. We analyzed whether Sch B could protect rat liver against mercuric chloride (HgCl2) intake by analyzing stress proteins and histopathological changes. Wistar rats were administered Sch B (10mg/kg/day by gavage) or vehicle (olive oil) for 10 days. A subset of each group also received low-dose HgCl2 (0.1mg/kg/day) for 3 days on days 8-10. Another group received Sch B for 10 days with a single high dose of HgCl2 (1mg/kg intraperitoneally) on day 10. In rats treated with Sch B and HgCl2, HSP72, HSP25 and MTs were overexpressed in liver zones 1 and 3 irrespective of HgCl2 dosing schedules. Furthermore Sch B alone induced perinuclear rough endoplasmic reticulum alignment and if associated to HgCl2, increased mitochondrial density and dense bodies, all signs of intense detoxification machinery. Taking together these data suggest that dietary Sch B counteracts HgCl2 hepatotoxicity in the rat by stimulating chaperones responsible for anabolic activity.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cytoprotection; Heat-Shock Proteins; Lignans; Male; Mercuric Chloride; Polycyclic Compounds; Rats; Rats, Wistar

Cisplatin is one of the most effective antineoplastic drugs, but it has undesirable side effects such as hepatotoxicity at high doses. This study investigated the protective effect of macelignan, isolated from Myristica fragrans HOUTT. (nutmeg), against cisplatin-induced hepatotoxicity and the possible mechanisms involved in these effects in mice. Pretreatment with macelignan for 4 d significantly prevented the increased serum enzymatic activities of alanine and aspartate aminotransferase in a dose-dependent manner. The results also showed that the protective effects of macelignan on cisplatin-induced hepatotoxicity may be associated with the mitogen activated protein kinase (MAPK) signaling pathway. Cisplatin-induced phosphorylation of c-Jun N-terminal kinase1/2 (JNK1/2) and extracellular signal-regulated kinase1/2 (ERK1/2) was abrogated by pretreatment with macelignan, however, that of p38 was not significantly affected. It was also found that macelignan attenuated the expression of phosphorylated c-Jun in cisplatin-treated mice. Accordingly, it is suggested that the hepatoprotective effects of macelignan could be related to activation of the MAPK signaling pathway, especially JNK and c-Jun, its substrate. The present findings suggest that co-treatment of cisplatin with macelignan may provide more advantage than cisplatin treatment alone in cancer therapy.

Topics: Alanine Transaminase; Animals; Antineoplastic Agents; Aspartate Aminotransferases; Blotting, Western; Chemical and Drug Induced Liver Injury; Cisplatin; Dose-Response Relationship, Drug; Enzyme Activation; JNK Mitogen-Activated Protein Kinases; Lignans; Liver Function Tests; Male; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Myristica; Signal Transduction; Transcription Factors

Effects of schisandrin B enantiomer ((+)Sch B and (-)Sch B) treatment on the reduced cellular glutathione (GSH) level and susceptibility to menadione-induced toxicity were investigated and compared in AML12 hepatocytes. (+)Sch B or (-)Sch B treatment at 6.25 micromol/l produced a time-dependent change in cellular GSH level, with the maximal stimulation occurring 16 h after dosing. (+)Sch B/(-)Sch B pretreatment for 16 h dose-dependently protected against menadione toxicity, with the maximum degree of protection observable at 6.25 micromol/l and the extent of protection afforded by (-)Sch B being larger than that of (+)Sch B. The cytoprotection was associated with a parallel enhancement in cellular GSH level in both non-menadione (control) and menadione-intoxicated cells. While the GSH depletion produced by buthionine sulfoximine/phorone treatment largely abrogated the cytoprotective action of (+)Sch B/(-)Sch B, it almost completely abolished the GSH-enhancing effect of (+)Sch B and (-)Sch B in both control and menadione-treated cells. Both (+)Sch B and (-)Sch B treatments increased the GSH reductase activity in control and menadione-treated cells, with the stimulatory action of (-)Sch B being more potent than that of (+)Sch B in the control condition. (+)Sch B and (-)Sch B also enhanced the gamma-glutamate cysteine ligase activity in menadione-intoxicated cells. The results indicate that (-)Sch B is more effective than (+)Sch B in enhancing cellular GSH and protecting against oxidant injury in hepatocytes.

Topics: Animals; Cell Line; Chemical and Drug Induced Liver Injury; Cyclooctanes; Glutamate-Cysteine Ligase; Glutathione; Glutathione Reductase; Hepatocytes; L-Lactate Dehydrogenase; Lignans; Mice; Polycyclic Compounds; Vitamin K 3

The hepatoprotective effect of taxiresinol ( 1) and (7' R)-7'-hydroxylariciresinol ( 2), two tetrahydrofuran-type lignans isolated from the wood of Taxus yunnanensis, were investigated on D-galactosamine ( D-GalN)/lipopolysaccharide (LPS)-induced hepatic liver injury in mice. Pre-administration of 1 or 2 at doses of 50 and 10 mg/kg ( i. p.) at 12 and 1 h before D-GalN/LPS injection significantly inhibited hepatocyte DNA fragmentation and apoptotic body formation. Pre-treatment of these two lignans further suppressed hepatic necrosis which occur at later stage of D-GalN/LPS intoxication as demonstrated by the significant and dose-dependent reduction in serum glutamic pyruvic transaminase (sGPT) and serum glutamic oxaloacetic transaminase (sGOT) at 8 h after intoxication. The elevation of serum tumor necrosis factor-alpha (TNF- alpha) level by D-GalN/LPS toxication was significantly inhibited by 1 or 2 at doses of 50 and 10 mg/kg. Moreover, both of these lignans significantly protected hepatocytes from D-GalN/TNF- alpha-induced cell death in primary cultured mouse hepatocytes. These results suggested that 1 and 2 had protected the hepatocytes from apoptosis via an inhibition of TNF- alpha production by activated macrophages and a direct inhibition of apoptosis induced by TNF- alpha in D-GalN/LPS-treated mice.

Topics: Animals; Chemical and Drug Induced Liver Injury; Furans; Galactosamine; Lignans; Lipopolysaccharides; Male; Mice; Phytotherapy; Plant Extracts; Plants, Medicinal; Protective Agents; Trees

The effects of secoisolariciresinol (1) and isotaxiresinol (2), two major lignans isolated from the wood of Taxus yunnanensis, on tumor necrosis factor-alpha (TNF-alpha)-dependent hepatic apoptosis induced by D-galactosamine (d-GalN)/lipopolysaccharide (LPS) were investigated in mice. Co-administration of d-GalN (700 mg/kg) and LPS (10 microg/kg) resulted in a typical hepatic apoptosis characterized by DNA fragmentation and the formation of apoptotic bodies. Serum glutamic pyruvic transaminase (sGPT) and glutamic oxaloacetic transaminase (sGOT) levels were also raised at 8 h after d-GalN/LPS intoxication due to a severe necrosis of hepatocytes. Pre-administration of 1 or 2 (50, 10 mg/kg, i.p.) 12 and 1 h before d-GalN/LPS significantly reduced DNA fragmentation and prevented chromatin condensation, apoptotic body formation and hepatitis. Pro-inflammatory cytokines such as TNF-alpha and interferon-gamma (IFN-gamma) secreted from LPS-activated macrophages are important mediators of hepatocyte apoptosis in this model. Pre-treatment with 1 or 2 significantly inhibited the elevation of serum TNF-alpha and IFN-gamma levels. In a separate experiment, both lignans had a significant dose-dependent protective effect on d-GalN/TNF-alpha-induced cell death in primary cultured mouse hepatocytes and TNF-alpha-mediated cell death in murine L929 fibrosarcoma cells. These results indicated that 1 and 2 prevent d-GalN/LPS-induced hepatic injury by inhibiting hepatocyte apoptosis through the blocking of TNF-alpha and IFN-gamma production by activated macrophages and direct inhibition of the apoptosis induced by TNF-alpha.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Butylene Glycols; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Therapy, Combination; Furans; Galactosamine; Injections, Intraperitoneal; Interferon-gamma; Lignans; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred Strains; Phytotherapy; Plant Extracts; Plants, Medicinal; Taxus; Tumor Necrosis Factor-alpha

Carbon tetrachloride (CCl(4)) -induced hepatotoxicity is a commonly used model for investigating lipid peroxidation-related tissue injury. In the present study, the effect of flaxseed extract was observed on histological sections, glutathione-content and DNA strand breaks. Lignan-containing flaxseed extract (1.6 g/kg body weight/day) was daily administered with intragastric injection to rats for three days, on the fourth day, CCl(4) (2 g/kg) was intraperitoneally injected. Liver tissue was sampled at 24 hr after administering CCl(4). Liver-necrosis was observed in CCl(4)-injected rats without pretreatment of flaxseed extract. Pretreatment of flaxseed extract reduced extent of the necrosis found 24 hr after the intraperitoneal administration of CCl(4). Pretreatment of flaxseed extract protect against CCl(4)-induced decrease of reduced glutathione-content measured from reactions with 5,5'-dithiobis-(2-nitrobenzoic acid) and also protect against the elevation of DNA strand breaks in the liver cells measured by comet assay. Flaxseed-extract appears to protect liver cells against CCl(4)-induced necrosis.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; DNA Damage; Drug Administration Schedule; Flax; Glutathione; Lignans; Liver; Liver Diseases; Necrosis; Plant Extracts; Rats; Rats, Inbred Strains

The in vivo antioxidant action of a lignan-enriched extract of the fruit of Schisandra chinensis (FS) and an anthraquinone-containing extract of the root of Polygonum multiflorum (PME) was compared with their respective active constituents schisandrin B (Sch B) and emodin by examining their effect on hepatic mitochondrial glutathione antioxidant status in control and carbon tetrachloride (CCl 4 )-intoxicated mice. FS and PME pretreatments produced a dose-dependent protection against CCl 4 hepatotoxicity, with the effect of FS being more potent. Pretreatment with Sch B, emodin or alpha-tocopherol (alpha-Toc) also protected against CCl 4 hepatotoxicity, with the effect of Sch B being more potent. The extent of hepatoprotection afforded by FS/Sch B and PME/emodin pretreatment against CCl 4 toxicity was found to correlate well with the degree of enhancement in hepatic mitochondrial glutathione antioxidant status, as evidenced by increases in reduced glutathione level and activities of glutathione reductase, glutathione peroxidase as well as glutathione S-transferases, in both control and CCl 4 -intoxicated mice. alpha-Toc, which did not enhance mitochondrial glutathione antioxidant status, seemed to be less potent in protecting against CCl 4 hepatotoxicity. The ensemble of results indicates that FS/PME produced a more potent in vivo antioxidant action than alpha-Toc by virtue of their ability to enhance hepatic mitochondrial glutathione antioxidant status and that the differential potency of FS and PME can be attributed to the difference in in vivo antioxidant potential between Sch B and emodin. Abbreviations. ALT:alanine aminotransferases CCl 4 :carbon tetrachloride FS:lignan-enriched extract of Schisandra fruit GRD:glutathione reductase GSH:reduced glutathione GSH-Px: Se-glutathione peroxidase GST:glutathione S-transferases mt:mitochondrial MDA:malondialdehyde PME:anthraquinone-containing fraction of Polygonum root Sch B:schisandrin B SDH:sorbitol dehydrogenase alpha-Toc:alpha-tocopherol

Topics: Alanine Transaminase; alpha-Tocopherol; Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Emodin; Female; Fruit; Glutathione; L-Iditol 2-Dehydrogenase; Lignans; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Phytotherapy; Plant Extracts; Plant Roots; Polycyclic Compounds; Polygonum; Random Allocation; Schisandra

Larrea tridentata (Moc & Sess) Cov. (Zygophyllaceae) is an ethnobotanically important plant found in the American Southwest and northern Mexico. Although numerous beneficial effects have been attributed to this plant, several case reports have demonstrated high doses of Larrea-containing herbals induce hepatotoxicity and nephrotoxicity in humans. Nordihydriguaiaretic acid (NDGA) is a lignan found in high amounts (up to 10% by dry weight) in the leaves and twigs of L. tridentata. Previously, NDGA has been shown to induce cystic nephropathy in the rat, however, no reports have been made concerning this compound's hepatotoxic potential. Here, we report that intraperitoneal administration of NDGA is lethal in the mouse (LD(50)=75 mg/kg). Administration is associated with a time and dose-dependent increase in serum alanine aminotransferase levels, which suggest liver damage. Indeed, freshly isolated mouse hepatocytes are more sensitive to NDGA than human melanoma cells. Furthermore, we have identified glucuronidation as a potential detoxification mechanism for NDGA. Both mono and diglucuronide conjugates of NDGA are formed after intravenous dosing. The monoglucuronide is also formed after incubation of NDGA with human hepatic microsomes; suggesting that glucuronide conjugation is important in the metabolism of NDGA by humans. In summary, this report indicates that NDGA may contribute to the hepatotoxicity of L. tridentata and provides preliminary information on NDGA metabolism.

Topics: Alanine Transaminase; Animals; Antioxidants; Cell Survival; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Hepatocytes; Humans; Inactivation, Metabolic; Injections, Intraperitoneal; Larrea; Lignans; Masoprocol; Melanoma; Mice; Mice, Inbred BALB C; Microsomes, Liver; Plant Components, Aerial; Plant Extracts; Time Factors; Tumor Cells, Cultured

The effects of schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, and dimethyl diphenyl bicarboxylate (DDB), a synthetic intermediate of schisandrin C (also a dibenzocyclooctadiene derivative), on hepatic mitochondrial glutathione redox status in control and carbon tetrachloride (CCl4)-intoxicated mice were examined. Treating mice with Sch B or DDB at a daily oral dose of 1 mmol/kg for 3 d did not produce any significant alterations in plasma alanine aminotransferase (ALT) and sorbital dehydrogenase (SDH) activities. CCl4 treatment caused drastic increases in both plasma ALT and SDH activities in mice. Pretreating mice with Sch B or DDB at the same dosage regimen significantly suppressed the CCl4-induced increase in plasma ALT activity, with the inhibitory effect of Sch B being much more potent. Sch B, but not DDB, pretreatment could also decrease the plasma SDH activity in CCl4-intoxicated mice. The lowering of plasma SDH activity, indicative of hepatoprotection against CCl4 toxicity, by Sch B pretreatment was associated with an enhancement in hepatic mitochondrial glutathione redox status as well as an increase in mitochondrial glutathione reductase (mtGRD) activity in both non-CCl4 and CCl4-treated mice. DDB pretreatment, though enhancing both hepatic mitochondrial glutathione redox status and mtGRD activity in control animals, did not produce any beneficial effect in CCl4-treated mice. The difference in hepatoprotective action against CCl4 toxicity between Sch B and DDB may therefore be related to their ability to maintain hepatic mitochondrial glutathione redox status under oxidative stress condition.

Topics: Alanine Transaminase; Animals; Antioxidants; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Female; Glutathione; Glutathione Reductase; Hydrocarbons, Chlorinated; Insecticides; L-Iditol 2-Dehydrogenase; Lignans; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Oxidation-Reduction; Oxidative Stress; Polycyclic Compounds

To evaluate the potential activity of Schisandra chinensis in restoring hepatic drug metabolism in CCl4 damaged liver, antipyrine was employed as a probe for the possible effects of the herb on Phase I oxidative metabolism in rats. Schisandra lignan fraction (160 mg/kg) was given orally to male Sprague-Dawley rats (220-240 g) 30 min or 6 h before CCl4 intoxication (4 ml/kg, s.c.). Following a single oral dose of antipyrine (80 mg/kg) to the rats with damaged liver, the pharmacokinetics of antipyrine in whole blood were determined and levels of liver enzymes, e.g. SGPT, SGOT, and cytochrome P450 were measured. Pharmacokinetic parameters for antipyrine were estimated using noncompartmental analysis. Results indicated that CCl4 significantly increased the elimination half-life (t(1/2)) of antipyrine from 2.59 +/- 1.04 to 11.25 +/- 3.91 h (P < 0.001) and decreased its clearance (CL) from 65.94 to 10.84 ml/h as compared to control. Pretreatment with the Schisandra lignan fraction 30 min or 6 h before intoxication significantly (P < 0.001) improved antipyrine elimination by reducing its t(1/2) to 3.30 +/- 0.52 and 3.58 +/- 1.05 h, respectively. The corresponding improvements observed for CL, i.e. 49.06 +/- 21.75 ml/h (P < 0.01); 21.10 +/- 10.42 ml/h (P < 0.05), were also substantial. Moreover, normalization of SGPT, SGOT and P450 levels was observed with the two Schisandra pretreatment schedules. In conclusion, Schisandra lignans exhibited strong protective effect on Phase I oxidative metabolism in the liver damaged by CCl4. Furthermore, pretreatment of Schisandra 30 min before intoxication showed a more pronounced effect than that of the 6 h pretreatment. The current pharmacokinetic approach allowed the protective effects of Schisandra on oxidative drug metabolism in damaged liver to be systemically examined and will certainly help in the evaluation of hepato-protectants obtained from natural sources.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antipyrine; Area Under Curve; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Fruit; Hong Kong; Lignans; Liver; Liver Diseases; Male; Medicine, Chinese Traditional; Molecular Probes; Oxidation-Reduction; Plant Extracts; Plants, Medicinal; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Seeds

To explore whether the methylenedioxy group and cyclooctadiene ring of the dibenzocyclooctadiene skeleton of schisandrins (Sch) play a role in the liver mitochondrial glutathione status enhancing activity.. The effects of three dibenzocyclooctadiene derivatives, Sch A, Sch B, Sch C, and a synthetic intermediate of Sch C, (dimethyl biphenyl dicarboxylate, DBD) on carbon tetrachloride (CCl4)-hepatotoxicity and liver mitochondrial glutathione status were examined in mice.. Pretreating mice with intragastric Sch B, Sch C, or DBD 1.mmol.kg-1.d-1 for 3 d protected against CCl4-hepatotoxicity. The hepatoprotection afforded by Sch B or Sch C pretreatment was associated with increases in liver mitochondrial reduced glutathione (mtGSH) level and glutathione reductase (mtGRD) activity, an indication of enhanced mitochondrial glutathione status. In contrast, the hepatoprotective action of DBD was not accompanied by any detectable changes in mtGSH level and mtGRD activity.. Both the methylenedioxy group and the cyclooctadiene ring of the dibenzocyclooctadiene molecule are important structural determinants in the enhancement of liver mitochondrial glutathione status.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Female; Glutathione; Glutathione Reductase; Lignans; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Polycyclic Compounds; Structure-Activity Relationship

As a preliminary approach to exploring whether the methylenedioxy group of the dibenzocyclooctadiene skeleton of schisandrins plays an important role in hepatic mitochondrial-reduced glutathione (GSH) stimulatory activity, we examined the effects of three schisandrins, namely schisandrin A (Sch A), schisandrin B (Sch B), and schisandrin C (Sch C), on carbon tetrachloride (CCl4) hepatotoxicity and hepatic mitochondrial GSH status in mice. Pretreating mice with Sch A at a daily oral dose of 1 mmol/kg for 3 days did not protect against CCl4 hepatotoxicity, whereas pretreatment with Sch B or Sch C at the same dosage regimen produced almost complete protection. The hepatoprotection afforded by Sch B or Sch C pretreatment was associated with significant increases in the hepatic mitochondrial GSH level and glutathione reductase (EC 1.6.4.2) activity. Our results indicate that the methylenedioxy group of the dibenzocyclooctadiene skeleton of schisandrin is an important structural determinant in the stimulation of hepatic mitochondrial GSH, particularly under conditions of CCl4 intoxication.

Topics: Alanine Transaminase; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Drugs, Chinese Herbal; Female; Glutathione; Lignans; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Polycyclic Compounds; Structure-Activity Relationship

The streptozotocin-induced short-term (2 week) diabetic rats showed an increase in susceptibility to carbon tetrachloride (CCl4)-induced hepatocellular damage. This diabetes-induced change was associated with a marked impairment in the hepatic glutathione antioxidant/detoxification response to CCl4 challenge, as indicated by the abrogation of the increases in hepatic reduced glutathione (GSH) level, glucose-6-phosphate dehydrogenase and microsomal glutathione S-transferases (GST) activities upon challenge with increasing doses of CCl4. While the hepatic GSH level was increased in diabetic rats, the hepatic mitochondrial GSH level and Se-glutathione peroxidase activity were significantly reduced. Insulin treatment could reverse most of the biochemical alterations induced by diabetes. Both insulin and schisandrin B (Sch B) pretreatments protected against the CCl4 hepatotoxicity in diabetic rats. The hepatoprotection was associated with improvement in hepatic glutathione redox status in both cytosolic and mitochondrial compartments, as well as the increases in hepatic ascorbic acid level and microsomal GST activity. The ensemble of results suggests that the diabetes-induced impairment in hepatic mitochondrial glutathione redox status may at least in part be attributed to the enhanced susceptibility to CCl4 hepatotoxicity. Sch B may be a useful hepatoprotective agent against xenobiotics-induced toxicity under the diabetic conditions.

Topics: Alanine Transaminase; Animals; Antioxidants; Blood Glucose; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclooctanes; Diabetes Mellitus, Experimental; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Insulin; Lignans; Liver; Liver Diseases; Male; Microsomes; Mitochondria, Liver; Oxidation-Reduction; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Streptozocin

The effects of sesamin, a potent inhibitor of delta 5-desaturase in polyunsaturated fatty acid biosynthesis, on the fatty acid compositions of tissue lipids and liver functions were examined in rodents. When a mixture of sesamin and episesamin (51.1:48.2, w/w) was given to rats at a dietary level of 0.5% for 13 days, the proportions of dihomo-gamma-linolenic acid significantly increased not only in the liver but also in plasma and hemocytes, suggesting an interference with delta 5-desaturation by these lignans. The sesamin preparation at the dietary level of 1% improved changes in various blood parameters of the mouse, such as aspartate aminotransferase and alanine aminotransferase activities, and the concentrations of total cholesterol, triglyceride and total bilirubin, caused by continuous inhalation of ethanol. In addition, sesamin showed a significant protective effect against the accumulation of fat droplets and vacuolar degeneration in the mouse liver, as confirmed on histological examination. Sesamin, at the level of 100 mg/kg body weight, also tended to prevent liver lipid accumulation by carbon tetrachloride in mice. These results indicate that sesamin and a related lignan compound have an ability to improve liver function.

Topics: Administration, Inhalation; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Dioxoles; Ethanol; Fatty Acid Desaturases; Fatty Acids; Lignans; Lipid Metabolism; Liver Diseases; Male; Mice; Microsomes, Liver; Rats; Rats, Wistar

The preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats was examined by histological and biochemical analysis. Acetaminophen at a dose of 750 mg/kg was administered to male Wistar rats with or without pretreatment with 50 mg/kg of gomisin A. Gomisin A inhibited not only the elevation of serum aminotransferase activity and hepatic lipoperoxides content, characteristic of acetaminophen administration, but also the appearance of histological changes such as degeneration and necrosis of hepatocytes. However, gomisin A did not affect the decrease in liver glutathione content. These results suggest that gomisin A protects the liver from injury after administration of acetaminophen through the suppression of lipid peroxidation.

Topics: Acetaminophen; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Glutathione; Lignans; Lipid Peroxides; Liver; Liver Diseases; Male; Organ Size; Rats; Rats, Wistar; Time Factors

It has been reported that leukotrienes (LTs) may play a role in inflammatory liver diseases, and several inhibitors of LTs show an inhibitory effect on experimental liver injuries. In this study, the effect of Gomisin A (TJN-101), which is a lignan component of schisandra fruits, on the arachidonic acid cascade in macrophages was examined to explain the mechanisms of the inhibitory effect of TJN-101 on liver injuries. The production of leukotriene B4 was suppressed by treatment with TJN-101, while the activity of 5-lipoxygenase was not affected. The release of arachidonic acid from macrophages stimulated with fMet-Leu-Phe or the Ca++ ionophore A23187 was suppressed by treatment with TJN-101. The activity of phospholipase A2 was not affected by treatment with TJN-101. These results suggested that TJN-101 produces an inhibitory effect on the biosynthesis of LTs by preventing the release of arachidonic acid, and it was thought that the preventive effect on the arachidonic acid cascade may be partially associated with the inhibitory effect of TJN-101 on liver injuries.

Topics: Animals; Arachidonic Acids; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Exudates and Transudates; Leukotriene B4; Lignans; Lipoxygenase; Macrophages; Male; Phospholipases A; Phospholipases A2; Polycyclic Compounds; Rats; Rats, Inbred Strains

Fructus Schizandrae (FS) is a well-known Chinese herb which has been widely used in ancient China. During recent decades, it has been found to be effective in viral and chemical induced hepatitis. In this paper, we report the studies on the chemical constituents and pharmacological actions of FS on mice liver. The results indicated that FS and its several components can mainly protect liver from injury induced by toxic substances such as CCl4; they have anti-oxidant activities against oxygen free radicals; FS and four components have inducing action on liver cytochrome P-450; they also promote certain anabolic metabolism such as serum protein biosynthesis and glycogenesis. All these activities would be of importance in the protection and repair of the injured liver cells. The clinical use of FS is also presented.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cytochrome P-450 Enzyme System; Dioxoles; Drugs, Chinese Herbal; Hepatitis B; Humans; Lignans; Lipid Peroxidation; Mice; Microsomes, Liver; Polycyclic Compounds; Rats

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Glutathione; Lignans; Liver; Male; Mice; Microsomes, Liver; Polycyclic Compounds

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Guinea Pigs; Lignans; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Inbred BALB C; Polycyclic Compounds; Rats

Topics: Animals; Carboxymethylcellulose Sodium; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Lignans; Liver; Male; Plant Extracts; Plants, Medicinal; Polycyclic Compounds; Polysorbates; Rats; Rats, Inbred Strains; Solvents; Transaminases

Effects of oral administration of gomisin A, one of the components isolated from Schizandra fruits, on liver injuries induced by CCl4, d-galactosamine and dl-ethionine and on liver microsomal drug-metabolizing enzyme activities were investigated. Gomisin A suppressed the increase of serum transaminase activities and the appearances of histological changes such as degeneration and necrosis of hepatocyte, inflammatory cell infiltration and fatty deposition in each type of liver injury. The repeated administration of gomisin A (30 or 100 mg/kg, p.o., daily for 4 days) induced an apparent increase of liver weight in liver-injured and normal rats. Gomisin A decreased serum triglyceride and lipid contents of the liver in biochemical studies. Increases of microsomal cytochrome b5 and P-450, elevations of NADPH cytochrome C reductase, aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities and decrease of 3,4-benzo(a)pyrene hydroxylase activity per cytochrome P-450 were observed after the administration of gomisin A. In addition, gomisin A was found to enhance the incorporation of 14C-phenylalanine into liver protein and to shorten the hexobarbital-induced sleeping time. These changes caused by gomisin A were similar to those by phenobarbital. However, gomisin A is distinctly different from phenobarbital in the finding that phenobarbital lessened the survival ratio of CCl4-intoxicated mice, but gomisin A did not. Our observation suggest that gomisin A shows an antihepatotoxic action by oral application and also has hypolipidemic (mainly triglyceridemic) and liver protein synthesis-facilitating actions and that the enlargement of the liver seen with gomisin A is the adaptive hypertrophy which is due to the induction of drug-metabolizing enzymes.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Ethionine; Galactosamine; Lignans; Liver Diseases; Male; Microsomes, Liver; Mixed Function Oxygenases; Protein Biosynthesis; Rats; Rats, Inbred Strains; Sleep

The effects of wuweizisu C, a lignan component of schizandra fruits, on liver injuries induced by carbon tetrachloride (CCl4), d-galactosamine and dl-ethionine were investigated by means of serum-biochemical and histopathological examinations in rats. Pretreatment or combined administration of wuweizisu C dose-dependently reduced the elevation of serum transaminase activity and histological changes such as fatty degeneration, cell necrosis, inflammatory cell infiltration, etc., which were caused by the single administration of 1 ml/kg, p.o., or the repeated administration of 0.2 ml/kg, s.c., daily for 4 days of CCl4, respectively. The effects of wuweizisu C on the liver injuries induced by a low dose (200 mg/kg, i.p.) and a high dose (400 mg/kg, i.p.) of d-galactosamine were compared with those of uridine. Wuweizisu C significantly lowered the rise of serum transaminase activity after the administration of a low dose of d-galactosamine in the serum-biochemical analysis. A tendency was also shown to inhibit cell necrosis and inflammatory cell infiltration caused by both doses of d-galactosamine in the histopathological examination. On the other hand, uridine markedly repaired the serum-biochemical and histopathological changes after the administrations of both doses of d-galactosamine. Also wuweizisu C cured the liver injury by the repeated administration of 150 mg/kg, i.p., daily for 4 days of d-galactosamine. After the repeated administration of 250 mg/kg, s.c., daily for 4 days of ethionine, liver cell atrophy, diffuse fatty degeneration and decrease of serum triglyceride were observed, but not cell necrosis. Wuweizisu C dose-dependently inhibited fatty degeneration and decrease of serum triglyceride. These findings suggest that wuweizisu C can be protective and/or therapeutic on hepatocellular phenomena such as cell necrosis, fatty degeneration, inflammatory cell infiltration, etc., in human hepatitis.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Ethionine; Fatty Liver; Galactosamine; Hepatitis; Lignans; Liver Diseases; Male; Plant Extracts; Plants, Medicinal; Polycyclic Compounds; Rats; Rats, Inbred Strains

The effects of gomisin A, which is a lignan component of schizandra fruits, on liver functions in various experimental liver injuries and on bile secretion in CCl4-induced liver injury were studied. Gomisin A weakly accelerated the disappearance of plasma ICG by itself at a high dose (100 mg/kg, i.p.). All of the hepatotoxic chemicals used in this study inhibited the excretion of ICG from plasma. Gomisin A showed a tendency to prevent the delays of the disappearance of plasma ICG induced by CCl4, d-galactosamine and orotic acid, but not that by ANIT. Bile flow and biliary outputs of total bile acids and electrolytes (Na+, K+, Cl- and HCO3-) were decreased in CCl4-treated rats. Gomisin A maintained bile flow and biliary output of each electrolyte nearly to the level of the vehicle-treated group, but did not affect biliary output of total bile acids. These findings suggest that gomisin A possesses a liver function-facilitating property in normal and liver injured rats and that its preventive action on CCl4-induced cholestasis is due to maintaining the function of the bile acids-independent fraction.

Topics: 1-Naphthylisothiocyanate; Animals; Bile; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Galactosamine; Indocyanine Green; Lignans; Liver; Liver Function Tests; Male; Orotic Acid; Polycyclic Compounds; Rats; Rats, Inbred Strains

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Lignans; Male; Microsomes, Liver; Polycyclic Compounds; Rats; Rats, Inbred Strains

Among phyllanthin, hypophyllanthin, triacontanal and tricontanol isolated from a hexane extract of Phyllanthus niruri, phyllanthin and hypophyllanthin protected against carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes, while triacontanal was protective only against galactosamine-induced toxicity.

Topics: Animals; Carbon Tetrachloride Poisoning; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Galactosamine; Lignans; Plant Extracts; Plants, Medicinal; Rats

Topics: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Lignans; Plant Extracts; Rats; Structure-Activity Relationship

Topics: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Lignans; Plant Extracts; Plants; Rats; Structure-Activity Relationship

Topics: Animals; Chemical and Drug Induced Liver Injury; Lignans; Mice; Plant Extracts; Plants, Medicinal

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cycloparaffins; Drug Evaluation, Preclinical; Lignans; Liver Diseases; Male; Plant Extracts; Plants, Medicinal; Polycyclic Compounds; Rats; Rats, Inbred Strains