stilbenes and Chemical-and-Drug-Induced-Liver-Injury

Traditional Chinese medicine Heshouwu, named Polygoni Multiflori Radix in Pharmacopoeia of the People's Republic of China (PPRC, 2020), is derived from the root tuber of Polygonum multiflorum Thunb., Heshouwu or processed Heshouwu is well known for its function in reducing lipids and nourishing the liver. However, increasing cases of Heshouwu-induced hepatotoxicity were reported in recent years. Researchers have begun to study the paradoxical effects of Heshouwu on the liver. 2,3,5,4'-tetrahydroxystilbene-2-

Topics: Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Medicine, Chinese Traditional; Rats; Stilbenes

Use of natural products is increasingly popular. In fact, many patients with liver diseases self-medicate with herbal supplements. Resveratrol (RSV), in particular, is a common natural product that can reduce injury in experimental models of liver disease. Xenobiotic hepatotoxicity is a particularly important area-of-need for therapeutics. Drug-induced liver injury, for example, is the most common cause of acute liver failure (ALF) and ALF-induced deaths in many countries. Importantly, RSV protects against hepatotoxicity in animal models in vivo caused by several drugs and chemicals and may be an effective intervention. Although many mechanisms have been proposed to explain the protection, not all are consistent with other data. Furthermore, RSV suffers from other issues, including limited bioavailability due to extensive hepatic metabolism. The purpose of this article is to summarize recent findings on the protective effects of RSV in xenobiotic-induced liver injury and other forms of liver injury and to provide a critical review of the underlying mechanisms. New mechanisms that are more consistent with data emerging from the toxicology field are suggested. Efforts to move RSV into clinical use are also considered. Overall, RSV is a promising candidate for therapeutic use, but additional studies are needed to better understand its effects.

Topics: Antioxidants; Chemical and Drug Induced Liver Injury; Humans; Liver Failure, Acute; Resveratrol; Stilbenes; Xenobiotics

Topics: Animals; Antineoplastic Agents; Apoptosis; Arachidonic Acid; Cell Degranulation; Chemical and Drug Induced Liver Injury; Glucosides; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipid Peroxidation; Neoplasm Metastasis; Neutrophils; Phytotherapy; Polygonum; Resveratrol; Stilbenes

This study investigated the potential of resveratrol (RSV) and its derivative pterostilbene (PT) to prevent diquat (DQ)-induced hepatic oxidative damage and mitochondrial dysfunction in piglets. Seventy-two weanling piglets were randomly divided into the following treatment groups: non-challenged control group, DQ-challenged control group, and DQ-challenged groups supplemented with either 300 mg RSV per kg of diet or an equivalent amount of PT. Each treatment group consisted of six replicates with three piglets per replicate (n = 6). After a two-week feeding trial, piglets were intraperitoneally injected with either 10 mg DQ per kg of body weight or sterile saline. At 24 hours post-injection, one piglet from each replicate (six piglets per treatment) was randomly selected for sample collection and biochemical analysis. Compared with the DQ-challenged control group, PT attenuated the growth loss of piglets after the DQ challenge (P < 0.05). Administration of PT was more effective than its parent compound in inhibiting the DQ-induced hepatic apoptosis and the increased generation of total cholesterol, superoxide anion, and lipid peroxidation products (P < 0.05). Specifically, PT facilitated nuclear factor erythroid 2-related factor 2 signals and the expression and activity of manganese superoxide dismutase, while it also prevented mitochondrial swelling, membrane potential collapse, and adenosine triphosphate depletion, possibly through the activation of sirtuin 1 (P < 0.05). These results indicate that PT may be superior to RSV as an antioxidant to protect the liver of young piglets from oxidative insults.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Diquat; Energy Metabolism; Gene Expression Regulation; Glutathione; Herbicides; Liver; Male; Mitochondrial Diseases; NF-E2-Related Factor 2; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes; Superoxides; Swine

The unregulated use of acetaminophen (APAP), an antipyretic and analgesic drug, harms hepatocytes and kidney cells, leading to liver failure and acute kidney injury. Herein, we investigate whether APAP damages macrophages in the immune system by observing its effects on macrophage proliferation and apoptosis. Using proteomics, we analyzed the effects of APAP on macrophage protein expression profiles and evaluated whether polydatin, the active ingredient in grapes and wine, can repair the damaged cells. The results showed that APAP alters the morphology and physiological processes of macrophages, inhibits macrophage proliferation, and promotes apoptosis. We observed 528 differentially expressed proteins when 500 µg/mL APAP was administered to the cells. These proteins are involved in biological processes including cell division, apoptosis, and acute phase response. Overall, our findings demonstrate that APAP harms the immune system by damaging macrophages and that polydatin can repair this damage.

Topics: Acetaminophen; Chemical and Drug Induced Liver Injury; Glucosides; Macrophages; Reynoutria; Stilbenes; Vitis

Herb-induced liver injury results from the interplay between the herb and host with the herbal components serving as the major origin for hepatotoxicity. Although Polygoni Multiflori Radix (PMR) has been frequently reported to induce liver injury, contributions of its major components such as emodin, emodin-8-O-β-D-glucopyranoside, physcion and 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside (TSG) towards its hepatotoxicity have not been clearly identified. Our initial cytotoxicity screenings of the major PMR components using rat hepatocytes identified emodin as the most toxic. Subsequently, the bile acid homeostasis-related mechanisms of emodin and its combination treatment with TSG in PMR-associated liver injury were explored in sandwich-cultured rat hepatocytes (SCRH) and verified in rats. In SCRH, emodin was found to be able to induce total bile acid accumulation in a dose-dependent manner. In both SCRH and rats, the presence of TSG significantly enhanced the hepatotoxicity of emodin via i) increasing its hepatic exposure by inhibiting its glucuronidation mediated metabolism; ii) enhancing its disruption on bile acid homeostasis through amplifying its inhibition on bile acid efflux transporters and its up-regulation on bile acids synthesis enzymes; iii) enhancing its apoptosis. Our study for the first time demonstrated the critical role of the combination treatment with emodin and TSG in PMR-induced liver injury.

Topics: Animals; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Drug-Related Side Effects and Adverse Reactions; Emodin; Glucosides; Rats; Stilbenes

2,3,5,4'-Tetrahydroxy stilbene-2-Ο-β-D-glucoside (TSG) and emodin (EMD) are two main components of Polygonum multiflorum Thunb. (PMT). Its root is widely used as herbal medicine and supplement. However, PMT-induced liver injury has drawn increasing attention. The purpose of this study was to investigate the interaction of TSG with EMD in the aspects of enzymology, pharmacokinetics, and hepatotoxicity. Co-administration with TSG increased internal exposure of EMD, EMD-derived hepatic protein adduction, and EMD-induced liver injury in mice. Mouse and human liver microsomal incubation study demonstrated that co-incubation with TSG decreased the formation of hydroxylation metabolites of EMD. Human recombinant cytochrome P450 enzyme incubation study showed that TSG induced time-, concentration-, NADPH-dependent and irreversible inhibition of CYP2C19 and CYP3A4. An epoxide metabolite derived from TSG was responsible for the observed enzyme inactivations. The findings allow us to better understand the mechanisms by which herbal processing detoxifies raw PMT.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Emodin; Glucosides; Humans; Mice; Stilbenes

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Interactions; Drugs, Chinese Herbal; Emodin; Fallopia multiflora; Humans; Medicine, Chinese Traditional; Rats; Stilbenes

In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Bibenzyls; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Complement Membrane Attack Complex; Guaiacol; Hepatocytes; Humans; Inflammation; Lipid Peroxidation; Lithocholic Acid; Liver; Male; Mice, Inbred ICR; Oxidative Stress; Phenanthrenes; Proteome; Rats, Sprague-Dawley; Stilbenes

This study investigated the effects of pterostilbene (PT) supplementation on growth performance, hepatic injury, and antioxidant variables in a broiler chicken model with diquat (DQ)-induced oxidative stress. There were 192 one-day-old male Ross 308 broiler chicks randomly allocated to one of two treatment groups: 1) broilers fed a basal diet and 2) broilers fed a diet supplemented with 400 mg/kg PT. At 20 D of age, half of the broilers in each group were intraperitoneally injected with DQ (20 mg per kg BW), whereas the other half were injected with an equivalent amount of sterile saline. Diquat induced a rapid loss of BW (P < 0.001) 24 h post-injection, but dietary PT supplementation improved the BW change of broilers (P = 0.014). Compared with unchallenged controls, the livers of DQ-treated broilers were in severe cellular damage and oxidative stress, with the presence of higher plasma transaminase activities (P < 0.05), a greater number of apoptotic hepatocytes (P < 0.001), and an increased malondialdehyde content (P = 0.007). Pterostilbene supplementation prevented the increases in plasma aspartate aminotransferase activity (P = 0.001), the percentage of hepatocyte apoptosis (P < 0.001), and the hepatic malondialdehyde accumulation (P = 0.011) of the DQ-treated broilers. Regarding the hepatic antioxidant function, PT significantly increased total antioxidant capacity (P = 0.007), superoxide dismutase activity (P = 0.016), reduced glutathione content (P = 0.011), and the ratio of reduced glutathione to oxidized glutathione (P = 0.003), whereas it reduced the concentration of oxidized glutathione (P = 0.017). Pterostilbene also boosted the expression levels of nuclear factor erythroid 2-related factor 2 (P = 0.010), heme oxygenase 1 (P = 0.037), superoxide dismutase 1 (P = 0.014), and the glutamate-cysteine ligase catalytic subunit (P = 0.001), irrespective of DQ challenge. In addition, PT alleviated DQ-induced adenosine triphosphate depletion (P = 0.010). In conclusion, PT attenuates DQ-induced hepatic injury and oxidative stress of broilers presumably by restoring hepatic antioxidant function.

Topics: Animal Feed; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Chickens; Diet; Dietary Supplements; Diquat; Dose-Response Relationship, Drug; Herbicides; Male; Oxidative Stress; Poultry Diseases; Protective Agents; Random Allocation; Stilbenes

Topics: Animals; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dyslipidemias; Glycemic Load; Male; Protective Agents; Rats; Rats, Sprague-Dawley; Specific Pathogen-Free Organisms; Stilbenes

The potential hepatotoxicity of. This study investigated the specific mechanism by which 2,3,5,4'-tetrahydroxy-stilbene-2-. The toxic effects of TSG (10, 100, 1000 μg/mL) on WRL-68 cells were examined using MTT, flow cytometry, and LDH assay after 24 h of incubation. Untreated cells served as the control. Gene and protein expression levels were determined by quantitative real-time PCR and Western blot, respectively. Immunofluorescence analysis was conducted to investigate the expression of light chain 3 (LC3). Luciferase activity assay was used to assess the targeted regulation of RUNX1 by miR-122.. The half maximal inhibitory concentration (IC50) of TSG in WRL-68 cells was calculated as 1198.62 μg/mL. TSG (1000 μg/mL) inhibited cell viability and LDH activity and promoted WRL-68 cell apoptosis by inducing autophagy. Subsequent findings showed that TSG induced autophagy and promoted apoptosis in WRL-68 cells by downregulating the levels of p-PI3K, p-Akt, and p-mTOR proteins, while RUNX1 overexpression rescued this inhibition. Additionally, the effect of TSG on hepatocyte apoptosis was reversed by miR-122 knockdown. Furthermore, bioinformatics and dual luciferase reporter assay results indicated that miR-122 targeted RUNX1.. Our data demonstrate for the first time that TSG regulates hepatotoxicity, possibly by upregulating miR-122 and inhibiting the RUNX1-mediated PI3K/Akt/mTOR pathway to promote autophagy and induce hepatocyte apoptosis. Further

Topics: Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Core Binding Factor Alpha 2 Subunit; Glucosides; Hepatocytes; Humans; MicroRNAs; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stilbenes; TOR Serine-Threonine Kinases

Topics: Animals; Cell Line; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Fibrin; Gene Expression Regulation; Humans; Inflammation; Macrolides; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Specific Pathogen-Free Organisms; Stilbenes; Thromboplastin

Polygoni Multiflori Radix (PMR) has been a reputable tonifying traditional Chinese medicine for a long history. However, clinical side effects regarding its idiosyncratic hepatotoxicity are occasionally reported. The containing anthraquinones, particularly emodin, could cause liver injury in both in vitro and in vivo experiments. It is well-known that some compounds could influence other compounds' pharmacokinetic parameters significantly. In this work, the influence of trans-2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucopyranoside (TSG) on the pharmacokinetic behavior of emodin in rats was evaluated by an ultra-high performance liquid chromatography/triple quadrupole mass spectrometry (UHPLC/MS-MS) approach. Pharmacokinetic parameters of emodin, PMR extract, and TSG-free PMR extract (prepared by a component "knock-out" strategy with TSG eliminated), in rats after one-day and seven-day administration were determined and compared. We found that, after seven-day administration of the whole PMR extract (rather than TSG-free extract), emodin in rats was accumulated. And accordingly, the exposure of emodin in rats pre-treated with single TSG for seven days could be significantly enhanced. The results indicate that TSG was able to accelerate the exposure and metabolism of emodin. The effect of TSG on the metabolic activities of cytochrome P450 enzymes was further assessed by an LC-MS cocktail method. The accelerated exposure and metabolism of emodin could result from the up-regulation activity of CYP450s, in particular CYP1A2 isozyme. The findings obtained in this work firstly unveiled DDI between TSG and emodin in the administration of PMR, thus may provide a basis for unveiling the underlying mechanism of PMR-induced liver injury.

Topics: Administration, Oral; Animals; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A2; Disease Models, Animal; Drug Interactions; Drugs, Chinese Herbal; Emodin; Glucosides; Humans; Male; Plant Roots; Polygonum; Rats; Rats, Sprague-Dawley; Stilbenes; Tandem Mass Spectrometry

Sulfur mustard (SM) is a chemical warfare agent that was applied in a series of military conflicts and still poses a severe threat to civilians and military personnel. Although the cellular and molecular mechanisms of SM toxicity are still not fully understood, oxidative stress has been considered as the initial vital process for damage. Polydatin, the product of resveratrol and glucose, is a promising candidate for the treatment of oxidative stress-related diseases. However, its effects on SM-induced hepatic injury remain unknown. Thus, we investigated the protective effects of polydatin against SM-induced hepatic injury and its possible mechanism. We found that treatment with polydatin remarkably improved the survival rate of mice bear subcutaneously injected with SM. Polydatin decreased the SM-induced increase of serum aminotransferase levels and ameliorated hepatic pathological damage. We also found that indexes of oxidative stress were improved in mouse liver samples and L02 cells. Meanwhile, changes in the Sirtuin family after treatment with SM were explored in mice and cells since polydatin is a potent activator of Sirt1 and Sirt3. Polydatin significantly increased the expression of Sirt1, HO-1, and NQO1; and the nuclear translocation of Nrf2 in mouse liver and L02 cells. Furthermore, we also observed that either Sirt1 or Nrf2 knockdown abolished the protective effect of polydatin. Our data indicated that polydatin could provide protection against SM-induced hepatic injury through the Sirt1/Nrf2 pathway, suggesting that polydatin is a novel potential antidote for sulfur mustard.

Topics: Animals; Antioxidants; Cell Line; Chemical and Drug Induced Liver Injury; Chemical Warfare Agents; Glucosides; Hepatocytes; Humans; Liver; Male; Mice, Inbred ICR; Mustard Gas; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Sirtuin 1; Stilbenes

The purpose of this study was to compare the hepatoprotective effects of Oxy (oxyresveratrol), Res (resveratrol), and MulA (mulberroside A) (80 mg/kg body weight/d, i.g.) on acute liver injury (ALI) induced by lipopolysaccharide (LPS)/d-galactosamine (d-GalN) in mice. After 7 h of LPS (50 μg/kg body weight, i.p.) and d-GalN (500 mg/kg body weight, i.p.) exposure, the activities of serum transaminases and antioxidant enzymes were determined. The expressions of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signal pathway, the nuclear factor-kappa B (NF-κB) signal pathway, and the mitogen-activated protein kinase (MAPK) signal pathway related proteins were evaluated by Western blot assays. Histopathological analysis was performed by hematoxylin-eosin (H&E) staining on the separated livers of mice. The results showed that treatment with Oxy, Res, and MulA could significantly decreases the levels of alanine transaminase (ALT) and aspartate transaminase (AST) ( P < 0.01). MulA was the most effective ingredient among the three, and the ALT and AST levels were reduced at 90.3 ± 1.3% and 93.9 ± 1.1% compared with the LPS/D-GalN treated group ( P < 0.01). Meanwhile, the stilbenes curbed the expression of inflammatory factors, NF-κB pathway activation, and MAPKs phosphorylation and upregulated antioxidant enzymes, Nrf2, NAD (P) H:quinone oxidoreductase (NQO1), and heme oxygenase-1 (HO-1) expression levels. Stilbenes might protect the ALI caused by LPS/d-GalN through inhibiting the negative effectiveness of oxidation stress and inflammation. The protective performance of MulA was better than those of Oxy and Res, and we hypothesize that it might be due to the mediation of the specific metabolic pathway of the MulA in vivo. All of these results implied that stilbenes in mulberry twigs might be promising as natural additives.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Humans; Kelch-Like ECH-Associated Protein 1; Liver; Male; Mice; Morus; NF-E2-Related Factor 2; NF-kappa B; Plant Extracts; Plant Stems; Protective Agents; Stilbenes

Cholestasis is defined as a functional impairment of bile secretion which results in the accumulation of bile acids (BAs) and other toxic molecules in the blood and liver, however, there are very few effective therapies for cholestasis. The farnesoid X receptor (FXR), as a nuclear receptor for BAs, is important in the regulation of BA levels in enterohepatic circulation. It has previously been demonstrated that activation of the FXR pathway may be a useful strategy with which to treat cholestasis. Resveratrol, one of the important ingredients from grape skins and Chinese medicine Polygonum cuspidatum, resulted in FXR‑activated effects in vitro and exhibited a protective effect against α‑naphthylisothiocyanate (ANIT)‑induced cholestasis through FXR regulation in vivo. The underlying mechanisms of resveratrol against ANIT‑induced cholestasis may be due to the regulation of BA homeostasis, improvement of liver injury and attenuation of the inflammatory response, which were regulated in a FXR‑dependent manner and in turn contributed to overall cholestasis alleviation. Overall, resveratrol as a FXR agonist may act as a potential compound for the treatment of drug‑induced cholestasis.

Topics: 1-Naphthylisothiocyanate; Animals; Chemical and Drug Induced Liver Injury; Cholestasis; HEK293 Cells; Hep G2 Cells; Hepatocytes; Humans; Lipopolysaccharides; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Receptors, Cytoplasmic and Nuclear; Resveratrol; Signal Transduction; Stilbenes

Amanita phalloides species mushrooms containing alpha-amanitin (α-AMA) are responsible for the majority of fatal mushroom intoxications and can lead to severe poisonings resulting in hepatotoxicity and acute hepatic failure. Existing antidotes, such as silibinin, are not sufficiently effective in the prevention and/or resolution of α-AMA-induced hepatotoxicity. We investigated the effects of resveratrol on α-AMA-induced hepatotoxicity and compared with silibinin, a known antidote using in vivo and in vitro toxicity models. In the in vivo protocol, resveratrol (30 mg/kg) was given simultaneously with α-AMA (α-AMA + SR) or 12 (α-AMA + 12R) or 24 (α-AMA + 24R) hr after α-AMA administration. Silibinin (5 mg/kg) (α-AMA + Sil) and normal saline (α-AMA + NS) were given simultaneously with α-AMA. We found that liver transaminase levels in α-AMA + SR and α-AMA + 12R groups and histomorphologic injury score in the α-AMA + SR, α-AMA + 12R, α-AMA + 24R and α-AMA + Sil groups were significantly lower than that of the α-AMA + NS group. Resveratrol decreased mononuclear cell infiltration, necrosis and active caspase-3 immunopositivity in the liver. In the in vitro protocol, the effects of resveratrol and silibinin were evaluated in a reduction in cell viability induced by α-AMA in THLE-2 and THLE-3 hepatocytes. Neither resveratrol nor silibinin was found to be effective in increasing cell viability decreased by α-AMA + NS. As a conclusion, resveratrol was found to be effective in α-AMA-induced hepatotoxicity with its anti-inflammatory properties in in vivo conditions. It is a promising compound with the potential for use in the treatment of hepatotoxicity associated with Amanita phalloides type mushroom poisonings.

Topics: Alanine Transaminase; Alpha-Amanitin; Antioxidants; Aspartate Aminotransferases; Caspase 3; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Humans; Liver; Mushroom Poisoning; Nucleic Acid Synthesis Inhibitors; Protective Agents; Resveratrol; Silybin; Silymarin; Stilbenes

Oxyresveratrol (Oxy) is a natural polyhydroxystilbene abundant in mulberry that has anti-inflammation and anti-oxidant activities. We evaluated the protective effect of Oxy in the context of the lipopolysaccharide and d-galactosamine (LPS/d-GalN) induced acute liver injury. Oxy restricted the development of histopathological changes, markedly reduced the activity of alanine transaminase (ALT) and aspartate transaminase (AST), which are indicators of impaired liver function. Oxy significantly regulated the contents of oxidative stress related enzymes and products, and inhibited expressions of inflammatory mediators and cytokines. Oxy treatment diminished the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway in liver, activated the Kelch-like ECH-associated protein 1(Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, and increased expressions of heme oxygenase 1 (HO-1) and quinine oxidoreductase 1(NQO1). Pretreatment with Oxy decreased LPS/d-GalN stimulated hepatocyte apoptosis by efficaciously raising the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X (Bax) ratio, inhibiting the expression and activation of caspases, and activating the phosphoinoside-3-kinase (PI3K)-Akt pathway. Our results demonstrate the hepatoprotective efficacy of Oxy. The protection is mainly due to the prevention of TLR4/NF-κB pathway activation, induced activation of Keap1-Nrf2 signaling pathway, and decreased hepatocyte apoptosis. Oxy warrants further study as a potential therapeutic agent candidate for the management of acute liver injury.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cells, Cultured; Chemical and Drug Induced Liver Injury; Galactosamine; Heme Oxygenase-1; Hepatocytes; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; Liver; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Morus; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; NF-kappa B; Plant Extracts; Signal Transduction; Stilbenes; Toll-Like Receptor 4

Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo.. C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay.. In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H2O2) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H2O2-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice.. Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.

Topics: Acetaminophen; AMP-Activated Protein Kinases; Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Hep G2 Cells; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Stilbenes; Superoxide Dismutase

Acetaminophen (APAP) is commonly used to relieve pain and fever in a clinical setting, but its excessive use can lead to serious hepatotoxicity. Our previous study demonstrated that polydatin (PD) can effectively attenuate d-galactose- and alcohol-induced hepatotoxicity, however, its effect on APAP-induced hepatotoxicity is still unknown. In this study, we explore the protective effect and potential mechanism of PD against APAP-induced hepatotoxicity in mice. The results indicate that PD effectively improves the survival of mice with APAP-induced hepatotoxicity, significantly alleviating histopathologic alterations in the liver, and decreasing the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). PD significantly and dose-dependently reduces oxidative stress by lowering the content of oxidized glutathione (GSSG), reactive oxygen species (ROS), nitric oxide (NO) and malonaldehyde (MDA), while enhancing the hepatic activities of glutathione (GSH), glutathione peroxidase (GSH-Px) and the GSH/GSSG ratio. Meanwhile, PD also substantially inhibits the levels and mRNA expressions of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (NOX2). Additionally, PD markedly arrests apoptosis by assuaging TUNEL-positive hepatocytes and the apoptotic index, decreasing the levels and expression of cytochrome c (CytC), cleaved-caspase-9, apoptotic protease activating factor 1 (Apaf-1), cleaved-caspase-3, and Bax and increasing the level and expression of Bcl-2. Overall, PD pretreatment shows a potent protective effect against APAP-induced hepatotoxicity by relieving oxidative stress and inhibiting apoptosis.

Topics: Acetaminophen; Alanine Transaminase; Animals; Antioxidants; Apoptosis; Apoptotic Protease-Activating Factor 1; Aspartate Aminotransferases; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Chemical and Drug Induced Liver Injury; Glucosides; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Hepatocytes; Liver; Male; Malondialdehyde; Mice; Mice, Inbred ICR; NADPH Oxidase 2; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents; Reactive Oxygen Species; Stilbenes

The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent "knock-out" and "knock-in" strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Fallopia multiflora; Lipopolysaccharides; Liver; Male; Medicine, Chinese Traditional; Metabolomics; Plant Extracts; Rats; Rats, Sprague-Dawley; Stilbenes

Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. However, PMR-associated hepatotoxicity is becoming a safety issue. In our previous in vivo study, an interaction between stilbenes and anthraquinones has been discovered and a hypothesis is proposed that the interaction between stilbene glucoside-enriching fraction and emodin may contribute to the side effects of PMR. To further support our previous in vivo results in rats, the present in vitro study was designed to evaluate the effects of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside (TSG) on the cellular absorption and human liver microsome metabolism of emodin. The obtained results indicated that the absorption of emodin in Caco-2 cells was enhanced and the metabolism of emodin in human liver microsomes was inhibited after TSG treatment. The effects of the transport inhibitors on the cellular emodin accumulation were also examined. Western blot assay suggested that the depressed metabolism of emodin could be attributed to the down-regulation of UDP-glucuronosyltransferases (UGTs) 1A8, 1A10, and 2B7. These findings definitively demonstrated the existence of interaction between TSG and emodin, which provide a basis for a better understanding of the underlying mechanism for PMR-induced liver injury.

Topics: Caco-2 Cells; Chemical and Drug Induced Liver Injury; Emodin; Fallopia multiflora; Glucosides; Glucuronosyltransferase; Humans; Plant Roots; Stilbenes

The root of Polygonum multiflorum Thunb (PM) has been used in China to treat a variety of diseases, such as constipation, early graying of the hair and hyperlipemia. Recent evidence shows that PM causes idiosyncratic drug-induced liver injury (IDILI) in humans. In this study, we investigated the molecular basis of PM-induced liver injury in a rat model of IDILI based on a non-hepatotoxic dose of LPS. SD rats were orally administered 3 potentially hepatotoxic compounds of PM: cis-stilbene glucoside (cis-SG, 50 mg/kg), trans-SG (50 mg/kg) or emodin (5 mg/kg), followed by injection of LPS (2.8 mg/kg, iv). Serum and liver histology were evaluated 7 h after LPS injection. Among the 3 compounds tested, cis-SG, but not emodin or trans-SG, induced severe liver injury in rats when combined with LPS. The levels of AST and ALT in plasma and inflammatory cytokines in both plasma and liver tissues were markedly elevated. The liver tissues showed increased injury, hepatocyte apoptosis, and macrophage infiltration, and decreased cell proliferation. Microarray analysis revealed a negative correlation between peroxisome proliferator-activated receptor-γ (PPAR-γ) and LPS/cis-SG-induced liver injury. Immunohistochemical staining and RT-PCR results further confirmed that cis-SG significantly inhibited activation of the PPAR-γ pathway in the liver tissues of LPS/cis-SG-treated rats. Pre-treatment with a PPAR-γ agonist pioglitazone (500 g/kg, ig) reversed LPS/cis-SG-induced liver injury, which was associated with inhibiting the nuclear factor kappa B (NF-κB) pathway. These data demonstrate that cis-stilbene glucoside induces immunological idiosyncratic hepatotoxicity through suppressing PPAR-γ in a rat model of IDILI.

Topics: Animals; Chemical and Drug Induced Liver Injury; Emodin; Fallopia multiflora; Glucosides; Lipopolysaccharides; Male; Microarray Analysis; NF-kappa B; Pioglitazone; Plant Roots; PPAR gamma; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Stereoisomerism; Stilbenes; Thiazolidinediones

Oxyresveratrol is a polyphenolic phytoalexin produced by plants as an antioxidant. This study investigated the hepatoprotective effects of oxyresveratrol as well as its underlying mechanism of action. Here, we evaluated the protective effects of oxyresveratrol against tert-butyl hydroperoxide (tBHP)-induced severe oxidative stress in HepG2 cells as well as acute liver injury caused by carbon tetrachloride (CCl4) in mice. tBHP-induced reactive oxygen species production and cell death in hepatocytes were blocked by oxyresveratrol, as indicated by MTT, TUNEL, and FACS analyses. Moreover, pretreatment with oxyresveratrol increased nuclear translocation and transactivation of NF-E2-related factor 2 (Nrf2), as assessed by antioxidant response element reporter gene expression and immunofluorescence staining, and transactivated expression of both hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit. More importantly, oxyresveratrol induced phosphorylation of Nrf2 mediated through activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Further, ERK inhibitors such as PD98059 and U0126 blocked phosphorylation of Nrf2 as well as the protective effect of oxyresveratrol in mitochondria. In mice, oral administration of oxyresveratrol significantly prevented hepatocyte degeneration, inflammatory cell infiltration, as well as elevation of plasma markers such as ALT and AST induced by CCl4 injection. In conclusion, this study confirmed that oxyresveratrol protected hepatocytes against oxidative stress and mitochondrial dysfunction, which might be associated with activation of Nrf2.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Hep G2 Cells; Hepatocytes; Humans; Liver; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Phosphorylation; Plant Extracts; Stilbenes; tert-Butylhydroperoxide

We investigated whether Notch signaling was increased in an experimental liver fibrosis model and examined the effects of resveratrol on Notch expression. Rats were divided into four groups: the control group, injected with physiological saline; the CCl₄ group; the CCl₄ plus resveratrol group; and the resveratrol group. After treatment, immunostaining was performed to detect Notch1, Notch3, Notch4, transforming growth factor (TGF)-beta, alpha-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and proliferating cell nuclear antigen (PCNA), and TUNEL assays were performed to evaluate apoptosis. Sirius red staining was used to detect fibrosis. Samples were also biochemically evaluated for glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), lipid peroxidation, and protein oxidation. GSH, GPx, and catalase activities were significantly decreased (p⟨0.001) in the CCl₄ group. Distinct collagen accumulation was detected around the central vein and portal areas, and numbers of Notch1-, Notch3-, and Notch4-positive cells were significantly increased (p⟨0.001) in fibrotic areas in the CCl₄ group. Increased expression of Notch proteins in fibrotic areas may support the role of Notch in mediating signaling associated with liver fibrosis through activation of hepatic stellate and progenitor cells. In contrast, resveratrol prevented liver fibrosis by decreasing lipid peroxidation and may be effective for inhibiting Notch signaling.

Topics: Animals; Antioxidants; Apoptosis; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; Immunohistochemistry; In Situ Nick-End Labeling; Rats; Rats, Wistar; Receptors, Notch; Resveratrol; Signal Transduction; Stilbenes

Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model.. CBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study.. Combination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance.. Combination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cadherins; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Diphosphates; Epithelial-Mesenchymal Transition; Humans; Indoles; Liver Neoplasms; Male; Mice; Mice, Inbred CBA; Protein Kinase Inhibitors; Pyrroles; Stilbenes; Sunitinib; Vimentin; Xenograft Model Antitumor Assays; Zinc Finger E-box-Binding Homeobox 1

Topics: Aging; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Brain Diseases; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Galactose; Glucosides; Liver; Malondialdehyde; Mice; Molecular Structure; Oxidative Stress; Stilbenes

The present study was undertaken to evaluate the protective effect of pterostilbene against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard hepatoprotective agent. A single dose of acetaminophen (800 mg/kg i.p.), injected to male rats, caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, total cholesterol, triglycerides, tumor necrosis factor alpha, and hepatic contents of malondialdehyde, nitric oxide, caspase-3, hydroxyproline, with significant decreases in serum HDL-cholesterol, total proteins, albumin, and hepatic activities of reduced glutathione, superoxide dismutase and catalase as compared with the control group. On the other hand, administration of each of pterostilbene (50 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) for 15 days before acetaminophen ameliorated liver function and oxidative stress parameters. Histopathological evidence confirmed the protection offered by pterostilbene from the tissue damage caused by acetaminophen. In conclusion, pterostilbene possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Antioxidants; Biomarkers; Chemical and Drug Induced Liver Injury; Liver; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Silymarin; Stilbenes

The increased consumption of high-fructose corn syrup (HFCS) may contribute to the worldwide epidemic of fatty liver. In this study, we have investigated whether HFCS intake (20% beverages) influences lipid synthesis and accumulation in conjunction with insulin receptor substrate-1/2 (IRS-1; IRS-2), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and inducible NOS (iNOS) expressions in liver of rats. Resveratrol was tested for its potential efficacy on changes induced by HFCS.. Animals were randomly divided into four groups as control, resveratrol, HFCS and resveratrol plus HFCS (resveratrol + HFCS). HFCS was given as 20% solutions in drinking water. Feeding of all rats was maintained by a standard diet that enriched with or without resveratrol for 12 weeks.. Dietary HFCS increased triglyceride content and caused mild microvesicular steatosis in association with up-regulation of fatty acid synthase and sterol regulatory element binding protein (SREBP)-1c in liver of rats. Moreover, HFCS feeding impaired hepatic expression levels of IRS-1, eNOS and SIRT1 mRNA/proteins, but did not change iNOS level. Resveratrol promoted IRS, eNOS and SIRT1, whereas suppressed SREBP-1c expression in rats fed with HFCS.. Resveratrol supplementation considerably restored hepatic changes induced by HFCS. The improvement of hepatic insulin signaling and activation of SIRT1 by resveratrol may be associated with decreased triglyceride content and expression levels of the lipogenic genes of the liver.

Topics: Animals; Body Weight; Chemical and Drug Induced Liver Injury; Enzyme Activation; Fatty Acid Synthase, Type I; Gene Expression; High Fructose Corn Syrup; Insulin; Insulin Receptor Substrate Proteins; Liver; Male; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Resveratrol; RNA, Messenger; Signal Transduction; Sirtuin 1; Sterol Regulatory Element Binding Protein 1; Stilbenes; Triglycerides

Polygoni Multiflori Radix (PMR) has been traditionally used as a tonic and an anti-aging remedy for centuries; however, hepatic lesions linked to PMR have been frequently reported.. This work attempted to investigate the hepatotoxic potential of PMR extract and the toxicokinetics of stilbene glucoside and anthraquinones in PMR extract following repeated administration.. Histopathological and biochemical tests were performed to assess the hepatotoxicity of PMR extract. A rapid and sensitive liquid chromatography-mass spectrometry (LC-MS) assay was developed for toxicokinetic analysis of the main constituents of PMR extract, including 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin-8-O-β-D-glucoside and emodin.. The histopathological and biochemical tests indicated that repeated administration of high-dose PMR extract (20 g/kg) for 3 weeks could cause hepatic lesions, while the low-dose treatment (1 g/kg) was safe. Necrosis and steatosis of hepatic cells, inflammatory cell infiltration and mild fibrosis were the main toxicity symptoms caused by high-dose PMR extract in rat liver. The aspartate aminotransferase (AST) levels increased by approximately 17%, from 110.80±0.84 to 129.75±10.83 IU/L, in the high-dose group compared with the control group. The proposed LC-MS method was proven to be suitable for the simultaneous quantification of these three constituents by affording desirable linearity (r(2)>0.998) and satisfactory precision (error less than 10%). The toxicokinetic study showed that emodin could not be detected in the low-dose group, but the AUC and Cmax of emodin displayed a gradual increase with repeated treatments in the high-dose group. The toxicokinetics of TSG in the low- and high-dose groups exhibited similar trends after repeated administration.. Consideration needs to be given to the rational application of PMR in the clinic to balance its benefits and risks. The increased emodin exposure in vivo provided a putative explanation for the observed hepatic lesions induced by PMR extract, although further studies to confirm the potentially causal link between emodin exposure and hepatic lesions are still necessary.

Topics: Animals; Chemical and Drug Induced Liver Injury; Emodin; Glucosides; Liver; Male; Plant Extracts; Plant Roots; Polygonum; Rats, Sprague-Dawley; Stilbenes; Toxicokinetics

Overdose of acetaminophen (APAP) is a common cause of acute liver injury and liver failure. The mechanism involves formation of a reactive metabolite, protein binding, oxidative stress and activation of c-Jun N-terminal kinase (JNK), mitochondrial dysfunction, and nuclear DNA fragmentation caused by endonucleases released from damaged mitochondria. Previous work has shown that the natural product resveratrol (RSV) can protect against APAP hepatotoxicity in mice through prevention of lipid peroxidation and anti-inflammatory effects. However, these earlier studies did not take into consideration several fundamental aspects of the pathophysiology. To address this, we treated C57Bl/6 mice with 300 mg/kg APAP followed by 50 mg/kg RSV 1.5 h later. Our results confirmed that RSV reduced liver injury after APAP overdose in mice. Importantly, RSV did not inhibit reactive metabolite formation and protein bindings, nor did it reduce activation of JNK. However, RSV decreased protein nitration after APAP treatment, possibly through direct scavenging of peroxynitrite. Interestingly, RSV also inhibited release of apoptosis-inducing factor and endonuclease G from mitochondria independent of Bax pore formation and prevented the downstream nuclear DNA fragmentation. Our data show that RSV protects against APAP hepatotoxicity both through antioxidant effects and by preventing mitochondrial release of endonucleases and nuclear DNA damage.

Topics: Acetaminophen; Animals; Apoptosis Inducing Factor; Chemical and Drug Induced Liver Injury; DNA Fragmentation; Drug Overdose; Endonucleases; Hepatocytes; JNK Mitogen-Activated Protein Kinases; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Oxidative Stress; Peroxynitrous Acid; Protein Binding; Resveratrol; Stilbenes; Tyrosine

Resveratrol (RES) has been shown to possess many pharmacological activities including protective effect against liver damage induced by hepatotoxins. In the present study, the hepato-protective effect of RES against acetaminophen (APAP)-induced liver injury in mice and the involved mechanisms was investigated. This study clearly demonstrated that administration of RES three days before APAP treatment significantly alleviated APAP-induced hepatotoxicity, as evidenced by morphological, histopathological, and biochemical assessments such as GSH content and serum ALT/AST activity. Treatment with RES resulted in significant inhibition of CYP2E1, CYP3A11, and CYP1A2 activities, and then caused significant inhibition of the bioactivation of APAP into toxic metabolite NAPQI. Pretreatment with RES significantly reduced APAP-induced JNK activation to protect against mitochondrial injury. Additionally, RES treatment significantly induced SIRT1 and then negatively regulated p53 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, and PCNA to promote hepatocyte proliferation. This study demonstrated that RES prevents APAP-induced hepatotoxicity by inhibition of CYP-mediated APAP bioactivation and regulation of SIRT1, p53, cyclin D1 and PCNA to facilitate liver regeneration following APAP-induced liver injury.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Gene Expression Regulation; Liver; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Random Allocation; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Tumor Suppressor Protein p53

Herbal medicines have recently been recognized as the second most common cause of drug-induced liver injury (DILI) in the United States. However, reliable methods to identify the DILI causality of some herbs, such as Heshouwu (dried root of Polygonum multiflorum), remain lacking. In this study, a total of 12 307 inpatients with liver dysfunction and 147 literature-reported cases of Heshouwu DILI were screened. A general algorithm indicated that only 22.5% (9/40) and 30.6% (45/147) of all hospitalization and literature case reports, respectively, demonstrate the high probability of DILI causality of Heshouwu. By contrast, 95% (19/20) of all cases prospectively investigated by pharmacognosy, phytochemistry, and metabolomic tests exhibited highly probable causality, including a patient who was previously incorrectly attributed and a case that was excluded from Heshouwu causality by pharmacognostic evidence. Toxin (heavy metals, pesticides, and mycotoxins) contamination was also excluded from Heshouwu DILI causality. The objectivity of these screening methods for Heshouwu DILI diagnosis addresses safety concerns regarding stilbene-containing herbal medicines and dietary supplements.

Topics: Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Fallopia multiflora; Humans; Liver Function Tests; Medicine, Chinese Traditional; Metabolome; Risk Assessment; Stilbenes

Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.

Topics: Acetaminophen; Animals; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Hepatocytes; Male; Rats; Rats, Wistar; Resveratrol; Sirtuin 1; Stilbenes

Acute liver injury is manifested by different degree of hepatocyte necrosis and may recover via the process of hepatocyte regeneration once the injury is discontinued. Most of the liver injury is associating with inflammatory cytokines. Resveratrol (RSV) is a natural phytoalexin with powerful anti-inflammatory effects.. The effects of RSV on cellular factors mediating liver damage and regeneration in acute carbon tetrachloride (CCl4 ) liver injury were investigated.. RSV decreased alanine aminotransferase, aspartate aminotransferase, necrosis, and 4-hydroxynonenal in the CCl4 -injured liver. RSV decreased hepatocyte apoptosis by reducing caspase 8 and caspase 3 but not Bax and Bcl-xL. RSV reduced Kupffer cells recruitment, the expressions of tumor necrosis factor-α and interleukin-6, but not interleukin-10. RSV lowered the numbers of anti-5-bromon-2'-deoxyuridine and anti-Ki67-positive hepatocytes. Hepatic hepatocyte growth factor, c-Met and transforming growth factor-α expressions were reduced by RSV, while transforming growth factor-β1 and hepatic stellate cells activation were not changed. RSV reduced the injury-induced CXCL10 elevations in serum and liver in vivo. Besides, RSV inhibited CXCL10 release from CCl4 -injured hepatocytes in vitro. In contrast, recombinant CXCL10 improved the viability of CCl4 -injured hepatocytes.. RSV therapy can be beneficial for acute toxic liver injury. RSV reduced hepatocyte apoptosis but limited hepatocyte regeneration possibly through reducing the hepatomitogenic signaling and the release of CXCL10.

Topics: Alanine Transaminase; Aldehydes; Animals; Anti-Inflammatory Agents; Apoptosis; Aspartate Aminotransferases; Carbon Tetrachloride; Caspase 3; Caspase 8; Chemical and Drug Induced Liver Injury; Chemokine CXCL10; Cytokines; Hepatocytes; Inflammation Mediators; Liver; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Necrosis; Phytoalexins; Phytotherapy; Resveratrol; Sesquiterpenes; Stilbenes

Protective effect of resveratrol on sodium fluoride-induced oxidative stress, hepatotoxicity and neurotoxicity were studied in rats. A total of 28 Wistar albino male rats were used. Four study groups were randomly formed with seven animals in each. The groups were treated for 21days with distilled water (control group), with water containing 100ppm fluoride (fluoride group), with resveratrol (12.5mg/kg i.p., resveratrol group), or with 100ppm fluoride+12.5mg/kg resveratrol i.p. (fluoride+resveratrol group). At the end of the trial, blood samples were collected by cardiac puncture and tissue samples were taken simultaneously. The total antioxidant and oxidant status in plasma and tissues as well as plasma 8-hydroxydeoxyguanosine levels were measured. Histopathological analyses of rat liver and brain tissues were performed in all groups to identify any changes. In the fluoride group, the total oxidant levels increased in plasma, liver and brain and total antioxidant levels decreased, as did the plasma 8-hydroxy-deoxyguanosine levels. These changes were prevented by co-administration of resveratrol. In addition, fluoride-associated severe histopathological changes in brain and liver tissues were not observed in the fluoride+resveratrol group. Consequently, these data suggested that resveratrol had beneficial effects in alleviating fluoride-induced oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Brain; Chemical and Drug Induced Liver Injury; Deoxyguanosine; Heart; Liver; Male; Neurotoxicity Syndromes; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Sodium Fluoride; Stilbenes

D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

Topics: Animals; Antioxidants; Carbazoles; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Galactosamine; Lipid Peroxidation; Lipopolysaccharides; Liver; Male; Rats, Wistar; Resveratrol; Sirtuin 1; Stilbenes

Acute liver injury was induced in male BALB/c mice by coadministering isoniazid and rifampicin. In this work, the effects of resveratrol (1) were investigated in the hepatotoxicity caused by isoniazid-rifampicin in mice. Compound 1 was administered 30 min prior to isoniazid-rifampicin. Serum biochemical tests, liver histopathological examination, oxidative stress, myeloperoxidase activity, cytokine production (TNF-α, IL-12p70, and IL-10), and mRNA expression of SIRT1-7 and PPAR-γ/PGC1-α were evaluated. The administration of 1 significantly decreased aspartate transaminase and alanine aminotransferase levels, myeloperoxidase activity, and cytokine levels. Furthermore, 1 reverted the decrease of catalase and glutathione activities and ameliorated the histopathological alterations associated with antituberculosis drugs. Modulation of SIRT1 and PPAR-γ/PGC1-α expression is likely involved in the protective effects of 1. The results presented herein show that 1 was able to largely prevent the hepatotoxicity induced by isoniazid and rifampicin in mice, mainly by modulating SIRT1 mRNA expression.

Topics: Alanine Transaminase; Animals; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Glutathione; Interleukin-10; Isoniazid; Liver; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Oxidation-Reduction; Oxidative Stress; Peroxidase; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Resveratrol; Rifampin; Sirtuin 1; Stilbenes; Transcription Factors; Tumor Necrosis Factor-alpha

α-Naphthylisothiocyanate (ANIT) is a well-characterized cholestatic agent for rats. The aim of this study was to examine whether resveratrol could attenuate ANIT-induced acute cholestasis and liver injury in rats.. SD rats were treated with resveratrol (15 or 30 mg/kg, ip) or a positive control drug ursodeoxycholic acid (100 mg/kg, po) for 5 consecutive days followed by a single dose of ANIT (60 mg/kg, po). Bile flow, and serum biochemical markers and bile constituents were measured 48 h after ANIT administration. Hepatic levels of oxidative repair enzymes (glutathione peroxidase, catalase and MnSOD), myeloperoxidase activity, TNF-α, IL-6 and ATP content, as well as the expression of liver transporter genes and proteins were assayed.. ANIT exposure resulted in serious cholestasis and liver injury, as shown by marked neutrophil infiltration in liver, dramatically increased serum levels of ALT, AST, GGT, ALP, TBA, TBIL, IBIL and DBIL, and significantly decreased bile excretion and biliary output of GSH and HCO3(-). ANIT significantly increased TNF-α and IL-6 release and myeloperoxidase activity, decreased mitochondrial biogenesis in liver, but had little effect on hepatic oxidative repair enzymes and ATP content. Furthermore, ANIT significantly decreased the expression of Mrp2, FXR and Cyp7a1, markedly increased Mrp3 expression in liver. Pretreatment with resveratrol attenuated ANIT-induced acute cholestasis and liver injury, and other pathological changes. Pretreatment with ursodeoxycholic acid was less effective.. Resveratrol effectively attenuates ANIT-induced acute cholestasis and liver injury in rats, possibly through suppression of neutrophil infiltration, as well as upregulation of expression of hepatic transporters and enzymes, thus decreasing accumulation of bile acids.

Topics: 1-Naphthylisothiocyanate; Adenosine Triphosphate; Animals; Anti-Inflammatory Agents; Bile; Biomarkers; Chemical and Drug Induced Liver Injury; Cholagogues and Choleretics; Cholestasis; Cytoprotection; Disease Models, Animal; DNA, Mitochondrial; Inflammation Mediators; Liver; Male; Membrane Transport Proteins; Neutrophil Infiltration; Oxidative Stress; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Hepatotoxicity is one of the major complications of methotrexate (MTX) therapy. This study was carried out to evaluate the possible protective effect of resveratrol (trans-3,5,4'-trihydroxystilbene, RVT) against MTX-induced hepatotoxicity. Rats were randomly divided into four groups as control, MTX treated (7 mg/kg/day, intraperitoneally (i.p.), once daily for 3 consecutive days), MTX + RVT treated (20 mg/kg/day, i.p.), and RVT treated. First dose of RVT was administrated 3 days before the MTX injection and continued for 3 days. Histopathology of liver was evaluated by light microscopy. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. The levels of thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and activities of hepatic antioxidant enzymes such as catalase (CAT) and glutathione-S-transferase (GST) were used to analyze the oxidative stress-mediated lipid peroxidation in liver sections. Our results showed that MTX administration significantly increased ALT, ASP, and ALP levels. TBARS, CAT, and GST levels were also markedly increased in liver after MTX administration. RVT treatment significantly prevented MTX-induced hepatotoxicity, as indicated by AST, ALT, and ALP levels and liver histopathology. Moreover, administration of RVT significantly decreased the elevated levels of TBARS and activities of CAT and GST in the liver compared to MTX-treated group. These results revealed that RVT may have a protective effect against MTX-induced hepatotoxicity by inhibiting oxidative stress-mediated lipid peroxidation. Consequently, RVT treatment might be a promising strategy against MTX-induced hepatotoxicity.

Topics: Animals; Catalase; Chemical and Drug Induced Liver Injury; Enzyme Inhibitors; Glutathione Transferase; Lipid Peroxidation; Male; Methotrexate; Rats; Rats, Wistar; Resveratrol; Stilbenes; Thiobarbituric Acid Reactive Substances

Danning tablet, as a composite prescription of traditional Chinese medicine, has been used clinically to relieve liver and gallbladder diseases in China. However, the mechanisms involved are still unclear.. The present investigation was designed to assess the effects and possible mechanisms of Danning tablet on α-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis.. Danning tablet (3, 1.5 or 0.75g/kg body weight/day) was intragastrically (i.g.) given to experimental rats for seven days before they were treated with ANIT (60mg/kg daily via i.g.) which caused liver injury. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltranspeptidase (γ-GTP), total bilirubin (T-Bil), direct bilirubin (D-Bil), total bile acid (TBA) and bile flow were measured to evaluate the protective effect of Danning tablet at 48h after ANIT treatment. Furthermore, protective mechanisms of Danning tablet against ANIT-induced liver injury were elucidated by assays of liver enzyme activities and component contents including myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (Gpx), catalase (CAT) and glutathione S-transferase (GST), as well as liver lipid peroxide (LPO) and glutathione (GSH). The biochemical observations were supplemented by histopathological examination. Phytochemical analysis of Danning tablet was performed by UPLC-MASS.. Obtained results demonstrated that high dose (3g/kg) of Danning tablet significantly prevented ANIT-induced changes in bile flow (P<0.01), and serum levels of ALT, AST, ALP, γ-GTP, T-Bil, D-Bil (P<0.01) and TBA (P<0.05). In addition, ANIT-induced increases in hepatic MPO, GST activities and GSH, LPO contents were significantly (P<0.01) reduced, while SOD, Gpx, CAT activities in the liver tissue which were suppressed by ANIT were significantly (P<0.01) elevated in the groups pretreated with Danning tablet at the dose of 3g/kg B.W. Histopathology of the liver tissue showed that pathological injuries were relieved after Danning tablet (3g/kg) pretreatment. The results also showed that medium dose (1.5g/kg) of Danning tablet exhibited partially protective effect on ANIT-induced liver injury with cholestasis by reversing part of biochemical parameters and histopathological changes. Low dose (0.75g/kg) of Danning tablet did not show any protective effect on ANIT-induced liver injury with cholestasis. Phytochemical analyses revealed the presence of anthraquinones, flavonoids and stilbene in the Danning tablet.. These findings indicate that Danning tablet exerts a dose-dependently protective effect on ANIT-induced liver injury with cholestasis in rats, and the possible mechanism of this activity is likely due to its attenuation of oxidative stress in the liver tissue and neutrophil infiltration.

Topics: 1-Naphthylisothiocyanate; Acute Disease; Animals; Anthraquinones; Antioxidants; Bile; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Flavonoids; Liver; Magnoliopsida; Male; Neutrophil Infiltration; Phytotherapy; Rats, Wistar; Stilbenes; Transaminases

Polydatin is one of main compounds in Polygonum cuspidatum, a plant with both medicinal and nutritional value. The possible hepatoprotective effects of polydatin on acute liver injury mice induced by carbon tetrachloride (CCl(4)) and the mechanisms involved were investigated. Intraperitoneal injection of CCl(4) (50 µl/kg) resulted in a significant increase in the levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and hepatic malondialdehyde (MDA), also a marked enhancement in the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclearfactor-kappa B (NF-κB). On the other hand, decreased glutathione (GSH) content and activities of glutathione transferase (GST), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were observed following CCl(4) exposure. Nevertheless, all of these phenotypes were evidently reversed by preadministration of polydatin for 5 continuous days. The mRNA and protein expression levels of hepatic growth factor-beta1 (TGF-β(1)) were enhanced further by polydatin. These results suggest that polydatin protects mice against CCl(4)-induced liver injury through antioxidant stress and antiinflammatory effects. Polydatin may be an effective hepatoprotective agent and a promising candidate for the treatment of oxidative stress- and inflammation-related diseases.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Fallopia japonica; Gene Expression; Glucosides; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Inflammation Mediators; Liver; Male; Mice; Mice, Inbred ICR; NF-kappa B; Oxidative Stress; Stilbenes; Superoxide Dismutase; Transforming Growth Factor beta1; Up-Regulation

Radix Polygoni Multiflori (RPM) and Radix Polygoni Multiflori Praeparata (RPMP) were traditionally widely used as Chinese herbal medicine. However, liver adverse reactions caused by RPM or RPMP were frequently reported all around the world recent years. The aim of this study was to study the cytotoxicities of RPM, RPMP and their major constituents on human liver cell L-02 simultaneously.. Multi-assays, including MTT assay, neutral red uptake (NRU) assay, LDH leakage percentage and liver enzyme secretion (AST, ALT and ALP) were used. Cytotoxicities of major chemical constituents of RPM, 2, 3, 5, 4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG), physcion and emodin, were tested. The cytotoxicities of water, 50% ethanol and 95% ethanol extractions of RPM and RPMP were tested. HPLC-DAD analysis was carried to reveal the content change of TSG, physcion and emodin after the processing procedure.. The TD(50) of TSG, physcion and emodin in MTT assay were >10,000 μM, 2853.61 μM and 520.37 μM. In the NRU assay, the TD(50) of TSG, physcion and emodin were much smaller (1401.53 μM, 1140.00 μM, and 3.80 μM). Emodin induced much severe liver enzyme secretion than TSG and physcion. Cell proliferation and LDH leakage rate showed no difference between RPM and RPMP extractions, but ALP, AST and ALT secretions in RPMP extractions were significant lower than that of PMR groups. Water extractions of RPM and RPMP were less toxic than any other solvent in most of the assays. Positive correlation was found between the TSG/emodin ratio and MTT survival rate. The emodin/physcion ratio also showed positive correlation with the LDH leakage percentage.. In conclusion, Radix Polygonum multiflorum and Radix Polygonum multiflorum Praeparata were not liver injure inducing in our in vitro assays. However, the processing produce of RPM could reduce its effect on both cell proliferation and enzyme secretion of liver cell. Judging from cell proliferation, integrity of cell membrane and enzyme secretion, three major chemical constituents of RPM: TSG, physcion and emodin showed no, moderate and severe cytotoxicity against human liver cell line L-02 respectively. Chemical constituents-cytotoxicity relationship investigation revealed that TSG and physcion probably had attenuating effect to emodin. The attenuating mechanisms were still under investigation.

Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Cell Line; Cell Proliferation; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Emodin; Glucosides; Humans; L-Lactate Dehydrogenase; Liver; Plant Roots; Plants, Medicinal; Polygonaceae; Solvents; Stilbenes

There has been a recently increase in the development of novel stilbene-based compounds with in vitro anti-inflamatory properties. For this study, we synthesized and evaluated the anti-inflammatory properties of 2 fluorinated stilbenes on carbon tetrachloride (CCl₄)-induced acute liver damage. To achieve this, CCl₄ (4 g·kg(-1), per os) was administered to male Wistar rats, followed by either 2-fluoro-4'-methoxystilbene (FME) or 2,3-difluoro-4'-methoxystilbene (DFME) (10 mg·kg(-1), per os). We found that although both of the latter compounds prevented cholestatic damage (γ-glutamyl transpeptidase activity), only DFME showed partial but consistent results in the prevention of necrosis, as assessed by both alanine aminotransferase activity and histological analysis. Since inflammatory responses are mediated by cytokines, mainly tumour necrosis factor α (TNF-α), we used the Western blot technique to determine the action of FME and DFME on the expression level of this cytokine. The observed increase in the level of TNF-α caused by CCl₄ administration was only prevented by treatment with DFME, in agreement with our biochemical findings. This result was confirmed by measuring interleukin-6 (IL-6) levels, since the expression of this protein depends on the level of TNF-α. In this case, DFME completely blocked the CCl₄-induced increase of IL-6. Our results suggest that DFME possesses greater anti-inflammatory properties in vivo than FME. DFME constitutes a possible therapeutic agent for liver disease and could serve as a template for structure optimization.

Topics: Animals; Anti-Inflammatory Agents; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cholestasis; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hydrocarbons, Fluorinated; Interleukin-6; Male; Necrosis; Rats; Rats, Wistar; Stilbenes; Tumor Necrosis Factor-alpha

Recent studies indicate the chemopreventive role of resveratrol in many animal models like ischemia, rheumatoid arthritis, human cancer, and diabetes. The present study was designed to investigate the chemopreventive potential of resveratrol in rat hepatic injury model by carbon tetrachloride. Male Wistar rats were treated with carbon tetrachloride (0.4 g/kg body weight) intraperitoneally daily for 8 weeks. Resveratrol (100 mg/kg, 200 mg/kg body weight) was given orally from first day until the last day of experiment. The investigation assesses the effect of resveratrol on morphological, oxidative status, histopathological, immunohistochemical, and apoptotic analysis in carbon tetrachloride-challenged liver tissue. The study indicated that the inflammatory cytokines TNF-α and IL-6 were profoundly expressed in experimental rats, whereas resveratrol decreases the immunopositivity of TNF-α and IL-6 and restored the altered architectural structure of challenged hepatic tissue. Resveratrol also protects liver cells by suppressing oxidative stress and apoptosis.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Gene Expression Regulation; Immunohistochemistry; Interleukin-6; Lipid Peroxidation; Male; Rats; Rats, Wistar; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Hepatocellular carcinoma (HCC), one of the most frequent and deadliest cancers, has been increasing considerably in the United States. In the absence of a proven effective therapy for HCC, novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality of HCC. Recently, we have reported that resveratrol, a compound present in grapes and red wine, significantly prevents diethylnitrosamine (DENA)-induced liver tumorigenesis in rats, although the mechanism of action is not completely understood. In the present study, we have examined the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by investigating the effects of resveratrol on oxidative damage and inflammatory markers during DENA-initiated rat liver carcinogenesis. There was a significant increase in hepatic lipid peroxidation and protein oxidation in carcinogen control animals compared with their normal counterparts at the end of the study (20 weeks). Elevated expressions of inducible nitric oxide synthase and 3-nitrotyrosine were noticed in the livers of the same animals. Dietary resveratrol (50-300 mg/kg) administered throughout the study reversed all the aforementioned markers in a dose-responsive fashion in rats challenged with DENA. Resveratrol also elevated the protein and mRNA expression of hepatic nuclear factor E2-related factor 2 (Nrf2). Results of the present investigation provide evidence that attenuation of oxidative stress and suppression of inflammatory response mediated by Nrf2 could be implicated, at least in part, in the chemopreventive effects of this dietary agent against chemically induced hepatic tumorigenesis in rats. The outcome of this study may benefit the development of resveratrol in the prevention and intervention of human HCC.

Topics: Animals; Antioxidants; Carcinogens; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Induction; Female; Hyperplasia; Inflammation; Lipid Peroxidation; Liver; Liver Neoplasms, Experimental; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Oxidative Stress; Phenobarbital; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Stilbenes; Tyrosine

The aim of this study to investigate the possible protective effect of resveratrol on some liver and serum/plasma parameters in methotrexate induced toxicity in rats. Methotrexate is used widely to treat various neoplastic diseases such as acute lymphoblastic leukemia, lymphoma, solid cancers, and autoimmune diseases. We hypothesized that resveratrol has a potential to decrease the oxidant damage in MTX-induced hepatic injury.. Following a single dose of methotrexate (20 mg/kg, i.p.), either saline or resveratrol (10 mg/kg, orally) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the liver was removed to measure malondialdehyde and glutathione levels, myeloperoxidase and thromboplastic activities and collagen content. Aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase activity were measured in the serum samples, while TNF-alpha and total antioxidant capacity were assayed in plasma samples.. Our results showed that MTX administration increased the hepatic malondialdehyde levels, myeloperoxidase and thromboplastic activities and collagen contents and decreased glutathione, while these alterations were reversed in resveratrol-treated group. Elevated aspartate aminotransferase and alanine aminotransferase activities and TNF-alpha level observed following MTX treatment was depressed with resveratrol.. The present study showed that resveratrol protects against methotrexate-induced hepatic injury and may be of therapeutic potential in alleviating the systemic side effects of chemotherapeutics.

Topics: Alanine Transaminase; Animals; Antimetabolites, Antineoplastic; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Female; Liver; Male; Methotrexate; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Several in vitro studies have demonstrated the ability of pure trans-resveratrol (t-Res) to act as an anti-oxidant, but the scientific literature is lacking in in vivo studies dealing with dietary t-Res bioavailability in oxidative stress models. Our aim was to investigate the bioavailability of t-Res from dietary sources and its effect on an animal model of carbon tetrachloride (CCl4)-induced liver lipid peroxidation.. Ten rats were intragastrically administered for 14 days with a grape-stalk extract determining a daily t-Res dosage of 3 mg/kg. The control group (10 rats) was daily injected with the vehicle solvent without the t-Res extract. After 1 week, the induction of liver lipid peroxidation by CCl4 injection was carried out. Serum and liver samples, at different time intervals, were collected to evaluate t-Res content, by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectometry-mass spectometry (LC-MS-MS). Liver malondialdehyde (MDA) as marker of oxidative stress was measured.. t-Res accumulates in the liver reaching 49.8 +/- 10.2 ng/g after 7 days and 191.8 +/- 15.3 ng/g after 14 days. No t-Res was detected in serum. The increase of MDA liver concentration due to CCl4 injection after 24 h and 1 week was reduced by 38% and a 63%, respectively, by the treatment with the t-Res extract.. A moderate consumption of t-Res from a dietary source resulted in a time-dose-dependent liver accumulation. It was able to counteract in vivo CCl4-induced liver lipid peroxidation thus demonstrating the hepatoprotective property of t-Res.

Topics: Animals; Antioxidants; Biological Availability; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytoprotection; Diet; Disease Models, Animal; Intubation, Gastrointestinal; Lipid Peroxidation; Liver; Liver Diseases; Male; Malondialdehyde; Plant Stems; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Vitis

The hepatoprotective effects and pharmacokinetics of trans-resveratrol and hydroxystilbenes of the garden rhubarb (Rheum rhaponticum L., R. rhaponticum) root ethanol extract were studied. Ethanol was administered to male BALB/c mice for 35 days in an inhalation chamber. During this time vehicle, trans-resveratrol (20 mg/kg per day) or R. rhaponticum extract was intraperitoneally (i.p.) administered and mice were sacrificed for the collection of liver and blood. In an additional experiment, the level of parent compounds and metabolites was estimated in the blood after acute i.p. administration of trans-resveratrol or R. rhaponticum extract. The levels of hydroxystilbenes, their metabolites and fatty acid oxy-metabolites (oxylipins) were studied by LC-tandem DAD-MS/MS. Ethanol induced hepatotoxicity, as evidenced by histological changes and accumulation of oxylipins in the blood. Both trans-resveratrol and R. rhaponticum extract reduced the extent of these changes. The pharmacokinetics of trans-resveratrol was characterized by a rapid removal from the blood and metabolism to sulfates and glucuronides. After the administration of R. rhaponticum extract, in addition to trans-resveratrol glucoside and its metabolites, several other hydroxystilbenes were found. Inhibition of oxidation of polyunsaturated fatty acids is proposed as a basis of the hepatoprotective effect of both trans-resveratrol and R. rhaponticum extract.

Topics: Animals; Chemical and Drug Induced Liver Injury; Ethanol; Fatty Acids, Unsaturated; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred BALB C; Oxidation-Reduction; Plant Extracts; Plant Roots; Resveratrol; Rheum; Stilbenes

Oxidative damage to biomolecules occurs by the accumulation of molecular damage due to free radicals and/or a diminution of antioxidant protection. The aim of this study was to evaluate the protection of organic and conventional purple grape juices in brain, liver, and plasma from adult Wistar rats (7 months old) against the oxidative damage provoked by carbon tetrachloride (CCl(4)). Adult rats were divided into three groups (control, conventional purple grape juice, and organic purple grape juice). Half of the rats received CCl(4), and the other half received the vehicle (vegetable oil). The chemical analytical determination showed that the highest levels of total phenolic, resveratrol, and catechins were seen in organic purple grape juices. Considering the treatment groups, it was observed that in all tissues (brain structures and liver) and plasma, CCl(4) treatment increased the lipid peroxidation (LP) levels. Both grape juices were capable to reduce LP levels in cerebral cortex and hippocampus; however, in the striatum and substantia nigra only the organic grape juice reduced LP level. CCl(4) caused an increase in catalase activity in cerebral cortex, hippocampus, and substantia nigra and in superoxide dismutase activity in substantia nigra. This increase was reduced by both juices in substantia nigra and hippocampus structures (P < .05). In the alkaline version of the comet assay performed on whole blood, it was observed that CCl(4) was capable of inducing mainly DNA damage class 4 and 3 frequencies, which was significantly reduced in groups that received both purple grape juices. This implies that both grape juices have an important antigenotoxic activity.

Topics: Animals; Antimutagenic Agents; Antioxidants; Beverages; Brain; Carbon Tetrachloride; Catalase; Catechin; Chemical and Drug Induced Liver Injury; DNA Damage; Food, Organic; Fruit; Lipid Peroxidation; Liver; Phenols; Phytotherapy; Plant Preparations; Random Allocation; Rats; Rats, Wistar; Resveratrol; Stilbenes; Vitis

Previously, we reported that pyrogallol, an anti-psoriatic agent, causes hepatotoxicity in experimental animals and silymarin, an herbal antioxidant, reduces pyrogallol-induced changes [Upadhyay, G., Kumar, A., Singh, M.P., 2007. Effect of silymarin on pyrogallol- and rifampicin-induced hepatotoxicity in mouse. Eur. J. Pharmacol. 565, 190-201.]. The present study was undertaken to assess the effect of resveratrol against pyrogallol-induced changes in hepatic damage markers, xenobiotic metabolizing enzymes and oxidative stress. Swiss albino mice were treated intraperitoneally, daily with pyrogallol (40 mg/kg), for one to four weeks, along with respective controls. In some set of experiments, animals were pre-treated with resveratrol (10 mg/kg), 2 h prior to pyrogallol treatment, along with respective controls. Alanine aminotransaminase, aspartate aminotransaminase and bilirubin were measured in blood plasma and mRNA expression of cytochrome P-450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione-S-transferase (GST)-ya and GST-yc, catalytic activity of CYP1A1, CYP1A2, CYP2E1, GST, glutathione reductase and glutathione peroxidase, lipid peroxidation and reduced glutathione (GSH) level were measured in liver. Resveratrol reduced pyrogallol-mediated increase in alanine aminotransaminase, aspartate aminotransaminase, bilirubin, lipid peroxidation and mRNA expression and catalytic activity of CYP2E1 and CYP1A2. Pyrogallol-mediated decrease in GST-ya and GST-yc expressions, GST, glutathione peroxidase and glutathione reductase activities and GSH content was significantly attenuated in resveratrol co-treated animals. CYP1A1 expression and catalytic activity were not altered significantly in any treated groups. The results demonstrate that resveratrol modulates pyrogallol-induced changes in hepatic toxicity markers, xenobiotic metabolizing enzymes and oxidative stress.

Topics: Animals; Antioxidants; Aryl Hydrocarbon Hydroxylases; Bilirubin; Biomarkers; Catalysis; Chemical and Drug Induced Liver Injury; Dermatologic Agents; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Lipid Peroxidation; Liver; Male; Mice; Oxidative Stress; Pyrogallol; Resveratrol; Stilbenes; Transaminases; Xenobiotics

2,5-Dihydroxy-4,3'-di(beta-d-glucopyranosyloxy)-trans-stilbene was identified from Morus bombycis Koidzumi roots. The 2,5-dihydroxy-4,3'-di(beta-D-glucopyranosyloxy)-trans-stilbene at a dose of 400-600 mg/kg had hepatoprotective activity comparable to the standard agent, silymarin. The biochemical assays were confirmed by histological observations showing that the 2,5-dihydroxy-4,3'-di(beta-d-glucopyranosyloxy)-trans-stilbene from Morus bombycis Koidzumi roots decreased cell ballooning in response to CCl4 treatment. These results demonstrate that the 2,5-dihydroxy-4,3'-di(beta-d-glucopyranosyloxy)-trans-stilbene component has a liver protective action against CCl4-induced hepatotoxicity.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Lipid Peroxidation; Male; Morus; Phytotherapy; Plant Extracts; Plant Roots; Protective Agents; Rats; Rats, Wistar; Reactive Oxygen Species; Stilbenes

Topics: Alcoholic Intoxication; Animals; Chemical and Drug Induced Liver Injury; Ethics, Professional; Liver Diseases; Mice; Parenteral Nutrition, Total; Periodicals as Topic; Professional Misconduct; Publishing; Research Support as Topic; Resveratrol; Stilbenes

We investigated hepatoprotective activity and antioxidant effect of the 2,5-dihydroxy-4,3'-di(beta-D-glucopyranosyloxy)-trans-stilbene that purified from Morus bombycis Koidzumi roots against CCl4-induced liver damage in rats. The 2,5-dihydroxy-4,3'-di(beta-D-glucopyranosyloxy)-trans-stilbene displayed dose-dependent superoxide radical scavenging activity (IC50 = 430.2 microg/ml), as assayed by the electron spin resonance (ESR) spin-trapping technique. The increase in aspartate aminotransferase (AST) activities in serum associated with carbon tetrachloride (CCl4)-induced liver injury was inhibited by 2,5-dihydroxy-4,3'-di(beta-D-glucopyranosyloxy)-trans-stilbene and at a dose of 400 - 600 mg/kg samples had hepatoprotective activity comparable to the standard agent, silymarin. The biochemical assays were confirmed by histological observations showing that the 2,5-dihydroxy-4,3'-di(beta-d-glucopyranosyloxy)-trans-stilbene decreased cell ballooning in response to CCl4 treatment. These results demonstrate that the 2,5-dihydroxy-4,3'-di(beta-D-glucopyranosyloxy)-trans-stilbene is a potent antioxidant with a liver protective action against CCl4-induced hepatotoxicity.

Topics: Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Dose-Response Relationship, Drug; Free Radical Scavengers; Liver; Male; Morus; Plant Extracts; Plant Roots; Plants, Medicinal; Rats; Rats, Wistar; Silymarin; Stilbenes; Structure-Activity Relationship; Superoxides; Tumor Necrosis Factor-alpha; Wound Healing

Resveratrol is a polyphenol with important antiinflammatory and antioxidant properties. We investigated the effect of resveratrol on alcohol-induced mortality and liver lesions in mice.. Mice were randomly distributed into four groups (control, resveratrol-treated control, alcohol and resveratrol-treated alcohol). Chronic alcohol intoxication was induced by progressively administering alcohol in drinking water up to 40% v/v. The mice administered resveratrol received 10 mg/ml in drinking water. The animals had free access to standard diet. Blood levels were determined for transaminases, IL-1 and TNF-alpha. A histological evaluation was made of liver damage, and survival among the animals was recorded.. Transaminase concentration was significantly higher in the alcohol group than in the rest of the groups (p < 0.05). IL-1 levels were significantly reduced in the alcohol plus resveratrol group compared with the alcohol group (p < 0.05). TNF-alpha was not detected in any group. Histologically, the liver lesions were more severe in the alcohol group, though no significant differences between groups were observed. Mortality in the alcohol group was 78% in the seventh week, versus 22% in the alcohol plus resveratrol group (p < 0.001). All mice in the alcohol group died before the ninth week.. The results obtained suggest that resveratrol reduces mortality and liver damage in mice.

Topics: Alanine Transaminase; Alcoholism; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drinking; Eating; Interleukin-1; Liver; Liver Diseases; Male; Mice; Mice, Inbred BALB C; Resveratrol; Stilbenes; Transaminases; Tumor Necrosis Factor-alpha

Chemical investigation of the EtOH extract of Morus alba L. (Moraceae), as guided by free radical scavenging activity, furnished 5,7-dihydroxycoumarin 7-methyl ether (1), two prenylflavones, cudraflavone B (2) and cudraflavone C (3), and oxyresveratrol (4). Compounds 1 and 4 showed superoxide scavenging effects with the IC(50) values of 19.1 +/- 3.6 and 3.81 +/- 0.5 microM, respectively. Compound 4 exhibited a DPPH free radical scavenging effect (IC(50) = 23.4 +/- 1.5 microM). Compounds 2 and 4 showed hepatoprotective effects with EC(50) values of 10.3 +/- 0.42 and 32.3 +/- 2.62 micro, respectively, on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells.

Topics: Biphenyl Compounds; Cell Line; Chemical and Drug Induced Liver Injury; Coumarins; Flavonoids; Free Radical Scavengers; Humans; Inhibitory Concentration 50; Morus; Phytotherapy; Picrates; Plant Extracts; Plant Structures; Stilbenes

To study the protective effect of Gn-3 (a stilbene polymer isolated from Gnetum parvifolium) against liver injury induced by CCl4, N-acetyl-p-aminophenol (APAP) and Bacillus Calmette-Guerin (BCG) plus bacterial lipopolysaccharide (LPS) in mice.. The experimental model of liver injury were induced by 0.1% CCl4 i.p. (10 mL.kg-1.d-1 for 3d), APAP i.p. (150 mg.kg-1) or BCG (5 mg) plus LPS (7.5 micrograms) in mice. The levels of ALT in serum, MDA and GSH in liver tissues were detected. The histopathologic changes were observed by light microscope.. Gn-3 was shown to markedly reduce the elevated serum ALT levels, liver tissue MDA and improve the histopathological changes in all the three experimental liver injury models. No effect of Gn-3 was observed on the liver GSH level in liver injury mice.. Gn-3 was found to inhibit the development of liver injury caused by CCl4, APAP, or BCG plus LPS. This means that Gn-3 has liver protective effects.

Topics: Acetaminophen; Alanine Transaminase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Gnetum; Lipopolysaccharides; Liver; Male; Malondialdehyde; Mice; Mycobacterium bovis; Plants, Medicinal; Protective Agents; Random Allocation; Stilbenes

The methanol extract of the Oriental medicinal plant Vitis coignetiae (Vitaceae) showed hepatoprotective activity in the in vitro assay method using primary cultured rat hepatocytes. Activity-guided fractionation of the extract afforded epsilon-viniferin as an active principle. The protective effect of epsilon-viniferin against mice carbon tetrachloride-induced hepatic injury in mice was shown by serum enzyme assay as well as by pathological examination. In addition to epsilon-viniferin, plant oligostilbenes, ampelopsins A, C, F and the mixture of vitisin A and cis-vitisin A were also present in the extract. Among them, ampelopsin C and the mixture of vitisin A and cis-vitisin A were found to be powerful hepatotoxins.

Topics: Animals; Benzofurans; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Liver Diseases; Male; Mice; Molecular Structure; Plants, Medicinal; Stilbenes

Topics: Animals; Chemical and Drug Induced Liver Injury; Lipid Peroxides; Male; Plants, Medicinal; Rats; Rats, Inbred Strains; Stilbenes

Topics: Animals; Biphenyl Compounds; Chemical and Drug Induced Liver Injury; Mice; Plant Extracts; Stilbenes