Alcohol Hepatotoxicity Research Articles

Musculus senhousei peptides alleviated alcoholic liver injury via the gut-liver axis.

Alcoholic liver injury has become a leading threat to human health, with complicated pathogenesis and limited therapeutic options. Our previous study showed that Musculus senhousei peptides (MSPs) exhibit protective potential against early-stage alcoholic liver injury, although the underlying mechanism is not yet clear. In this study, histopathological analysis, mRNA abundance of injury-associated biomarkers, the gut microbiota, and faecal metabolome were evaluated using a mouse model subjected to acute alcohol exposure, aiming to identify the mechanism by which MSP can alleviate alcoholic hepatotoxicity. The results showed that MSP intervention significantly ameliorated symptoms of liver injury (suppressed serum ALT increment, hepatic lipid accumulation, and neutrophil infiltration in liver tissue), and reversed the abnormal mRNA abundance of biomarkers associated with oxidative stress (iNOS), inflammation (TNF-α, IL-1β, MCP-1, TNF-R1, and TLR4), and apoptosis (Bax and Casp. 3) in the liver. Moreover, MSP improved intestinal barrier function by increasing the expression of tight junction proteins (Claudin-1 and Claudin-3). Further analysis of faecal microbiota and metabolome revealed that MSP promoted the growth of tryptophan-metabolizing bacteria (Clostridiales, Alistipes, and Odoribacter), leading to increased production of indole derivatives (indole-3-lactic acid and N-acetyltryptophan). These results suggested that MSPs may alleviate alcohol-induced liver injury targeting the gut-liver axis, and could be an effective option for the prevention of alcoholic liver injury.

Therapeutics of L. Lanceolata and V. Doniana on Alcohol Induced Hepatic Pathology

Additive and stimulative properties of alcohol encourage large intake. Notwithstanding, chronic alcohol consumption causes severe hepatic damage, that alters normal biological function of the liver. The aim of this research was to assess the effects of Lophira lanceolata and Vitex doniana extracts on alcohol induced hepatotoxicity using rat model by examining liver serum enzymes (AST, ALT, ALP), lipid peroxidation level, antioxidant enzyme activity and haematological parameters. Thirty Wister rats weighing 70 to 120g were placed in six groups of fives per group. The negative control and treatment groups were familiarized with alcohol (42%) in drinking water before oral administration of 42% consumable alcohol (v/v, 1ml/100g body weight) for nine days. Afterward, the treatment groups were administered 600mg/kg body weight extracts of Lophira lanceolata, Vitex doniana and Vitamin C (as standard drug). Body weight and behavioural characters were monitored during the period. It was observed that, rats in the negative and treatment groups showed significant depletion in weight and negative changes in behaviour. Furthermore, biochemical assessment revealed significant elevated levels of liver serum enzymes (ALT, AST, ALP) activity, total and direct bilirubin, MDA, SOD and CAT while GSH and haematological parameters were significantly depleted at p<0.05. However, the treated groups revealed significant reduction in the liver enzymes, MDA, SOD and CAT while GSH activity and haematological parameters were significantly increased. In conclusion, both extracts have ameliorative and antioxidant properties that could mitigates chronic alcohol hepatotoxicity.

Significance of Fib4 index as an indicator of alcoholic hepatotoxicity in health examinations among Japanese male workers: a cross-sectional and retrospectively longitudinal study

BackgroundFib4 index (Fib4) is clinically used as a noninvasive marker of liver fibrosis. In this study, we aimed to preliminarily investigate whether Fib4 can be used to detect individuals who need assessment for alcoholic liver disease (ALD) in the general population by clarifying the detailed association of Fib4 with alcohol consumption and gamma-glutamyl transferase (GGT) among male workers.MethodsWe analyzed data sets on the comprehensive medical examinations of male workers as cross-sectional and retrospectively longitudinal studies. We enrolled 10 782 males (mean age: 52.2 ± 10.2 years) in FY2019 and 7845 males (mean follow-up: 12.6 ± 6.7 years) who could be consecutively followed up for 20 years from FY2000 to FY2019. Data were evaluated using logistic regression and COX proportional analysis.ResultsIn the cross-sectional setting, the rate of Fib4 ≥ 2.67 in heavy drinkers (≥ 40 g of ethanol/day) was increased dose dependently in those over 65 years old, and that of body mass index ≥ 30 kg/m2 was increased in those over 60 years old, but not in those with fatty liver. The odds ratio (OR) (95% confidence interval [CI]) for heavy drinking was 4.30 (95% CI = 1.90–9.72), and GGT ≥ 200 IU/L was considerably high (OR = 29.05 [95% CI = 17.03–49.56]). In the longitudinal setting, heavy drinkers and those with GGT ≥ 200 IU/L at 10 years after the baseline showed an increased risk for Fib4 ≥ 2.67 (hazard ratio = 2.17 [95% CI = 1.58–2.98] and 7.65 [95% CI 5.26–11.12], respectively).ConclusionsThe development of Fib4 ≥ 2.67 after 10 years was associated with heavy alcohol drinking and GGT level ≥ 200 IU/L. Therefore, Fib4 combined with GGT could indicate high risk of ALD. However, clinical examinations and course observations are essentially needed.

Effect of Porcine Placental Extract Mixture on Alcohol-Induced Hepatotoxicity in Rats.

This study was conducted to examine the effect of porcine placenta extract mixture (pPEM, enzymatic/acidic extract = 1/3) on alcoholic hepatotoxicity after pPEM dosing with alcohol in rats. The experimental groups were normal, control, silymarin, three pPEM (590, 1771, and 2511 mg/kg/day, po), and silymarin (100 mg/kg/day, po) groups (n = 10). Alcoholic hepatotoxicity was caused by a liquid ethanol diet for 4 weeks. The effect of pPEM and silymarin on alcoholic hepatotoxicity was evaluated by serology, hepatic ADH and ALDH activities, and histopathological findings. After oral dosing with alcohol for 4 weeks, ALT and AST were significantly increased to 33.7 → 115.6 and 81.37 → 235.0 in the alcohol group, respectively. These levels were decreased significantly to 83.9 and 126.7 in the silymarin group and dose-dependently to 73.6–56.9 and 139.2–122.8 in all pPEM groups. Hepatic ADH and ALDH might have been increased in the control and not in the silymarin and pPEM groups for hepatic ADH. All pPEM groups exhibited no effects on hepatic ALDH except for the high pPEM group. Mild inflammation and fatty lesions were observed in the alcohol group and were attenuated in the silymarin and pPEM groups. As a results, the pPEM showed protective activities against alcoholic hepatotoxicity on the serological markers, hepatic ADH and ALDH, and pathological findings.

Early historical report of alcohol hepatotoxicity in Minooye Kherad, a Pahlavi manuscript in Ancient Persia, 6th century CE.

Background:Historical evidence revealed that alcoholic beverages have been produced, used and abused thousands of years before the discovery of alcohol by Rhazes for medical purposes. Alcohol-induced liver disease (e.g., steatosis, steatohepatitis, fibrosis and cirrhosis) is one of the most prevalent causes of chronic liver disease all over the world. This study aims to find the early report of this complication in an ancient Persian historical text.Methods:In this study, the book of Minooye Kherad, a Zoroastrian manuscript on wisdom which was written in the late Sassanid Empire (224–637 CE) is reviewed.Results:However, the concept of alcohol hepatotoxicity as one of the most important complications of alcoholism is a new terminology, by researching historical documents it can be found that one of the oldest reports of benefits and disadvantages of drinking wine focusing on liver complications is mentioned in the book of Minooye.Conclusion:Description of the liver disease and damage caused by excessive alcohol consumption in this valuable book can be considered as the early report of hepatotoxicity of alcoholic beverages in the medical history.

Alcoholic Hepatotoxicity Inhibitory Effect Using Heat-Killed Lactic Acid Bacteria

Alcoholic Hepatotoxicity Inhibitory Effect Using Heat-Killed Lactic Acid Bacteria

NADH and NRH as potential dietary supplements or pharmacological agents for early liver injury caused by acute alcohol exposure

Alcoholism leads to many diseases, and it is also the social and economic burden of the society. Alcohol intake is the main cause of acute liver injury and chronic liver disease. Here, the ameliorative effect of NADH and dihydronicotinamide riboside (NRH) against alcohol-induced liver damage was studied and its possible mechanism was further clarified. In vitro studies showed that NADH and NRH are effective NAD+ concentration-enhancing agents. Compared with NMN, NADH and NRH can provide greater NAD+ increase at the same concentrations. Intraperitoneal injection of NADH and NRH in C57BL/6J mice also significantly increased the NAD+ content in liver, blood, brain, fat and kidney. Importantly, NADH and NRH significantly increased the liver NAD+/NADH ratio, but did not induce apoptosis markers in cells. The intragastric administration of 500 mg/kg NRH, 500 mg/kg NADH 15 min prior to acute alcohol ingestion (8 ml/kg, 40% w/v, in tap water) could dramatically enhance alcohol metabolism as revealed by the reduced concentrations of ethanol and acetaldehyde in blood as well as the decreased duration of the loss of righting reflex (LORR). Both Pretreatment and posttreatment with NADH or NRH could significantly reduce the increase of serum aspartate transaminase (AST) and alanine transaminase (ALT) after alcohol administration, indicating that they have a certain therapeutic effect on alcoholic hepatotoxicity besides preventing the adverse effects caused by alcohol. NADH and NRH could also alleviate lipid peroxidation as indicated by the repressed malondialdehyde (MDA) level and the elevated activities of superoxide dismutase (SOD) in liver tissues. Additionally, NADH or NRH can mitigate the abnormal lipid metabolism in acute alcoholic liver damage. These benefits obviously suggested that NADH or NRH could be a potential nutraceutical or pharmacological agent for promoting alcohol metabolism and preventing or treating early liver injury caused by acute alcohol exposure.

Activation of PPARα-catalase pathway reverses alcoholic liver injury via upregulating NAD synthesis and accelerating alcohol clearance

Alcohol metabolism in the liver simultaneously generates toxic metabolites and disrupts redox balance, but the regulatory mechanisms have not been fully elucidated. The study aimed to characterize the role of PPARα in alcohol detoxification. Hepatic PPARα and catalase levels were examined in patients with severe alcoholic hepatitis. Mouse studies were conducted to determine the effect of PPARα reactivation by Wy14,643 on alcoholic hepatotoxicity and how catalase is involved in mediating such effects. Cell culture study was conducted to determine the effect of hydrogen peroxide on cellular NAD levels. We found that the protein levels of PPARα and catalase were significantly reduced in the livers of patients with severe alcoholic hepatitis. PPARα reactivation by Wy14,643 effectively reversed alcohol-induced liver damage in mice. Global and targeted metabolites analysis revealed a fundamental role of PPARα in regulating the tryptophan-NAD pathway. Notably, PPARα activation completely switched alcohol metabolism from the CYP2E1 pathway to the catalase pathway along with accelerated alcohol clearance. Catalase knockout mice were incompetent in alcohol metabolism and hydrogen peroxide clearance and were more susceptible to alcohol-induced liver injury. Hydrogen peroxide-treated hepatocytes had a reduced size of cellular NAD pool. These data demonstrate a key role of PPARα in regulating hepatic alcohol detoxification. Catalase-mediated hydrogen peroxide removal represents an underlying mechanism of how PPARα preserves the NAD pool. The study provides a new angle of view about the PPARα-catalase pathway in combating alcohol toxicity.

The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology.

This review describes the history of alcoholic liver disease from the beginning of the 1950s until now. It details how the hepatotoxicity of alcohol was discovered by epidemiology and basic research primarily by using new feeding techniques in rodents and primates. The article also recognizes the pioneering work of scientists who contributed to the understanding of the pathophysiology of alcoholic liver disease. In addition, clinical aspects, such as the development of diagnostics and treatment options for alcoholic liver disease, are discussed. Up-to-date knowledge of the mechanism of the disease in 2020 is presented.

Ibuprofen Increases the Hepatotoxicity of Ethanol through Potentiating Oxidative Stress.

Over 30 million prescriptions of NSAIDs (non-steroidal anti-inflammatory drugs) are issued every year. Considering that these drugs are available without a prescription as over the counter (OTC) drugs, their use will be astronomical. With the increasing use of NSAIDs, their adverse effects are drawing attention. Especially, stomach bleeding, kidney toxicity, liver toxicity, and neurological toxicity are reported as common. Ibuprofen, one of the extensively used NSAIDs along with aspirin, can also induce liver toxicity, but few studies are addressing this point. Here we examined the liver toxicity of ibuprofen and investigated whether co-exposure to ethanol can manifest synergistic effects. We employed 2D and 3D cultured human hepatoma cells, HepG2 to examine the synergistic hepatotoxicity of ibuprofen and alcohol concerning cell viability, morphology, and histology of 3D spheroids. As a result, ibuprofen and alcohol provoked synergistic hepatotoxicity against hepatocytes, and their toxicity increased prominently in 3D culture upon extended exposure. Oxidative stress appeared to be the mechanisms underlying the synergistic toxicity of ibuprofen and alcohol as evidenced by increased production of ROS and expression of the endogenous antioxidant system. Collectively, this study has demonstrated that ibuprofen and EtOH can induce synergistic hepatotoxicity, providing a line of evidence for caution against the use of ibuprofen in combination with alcohol.

The protection of Anthrodia camphorata against acute hepatotoxicity of alcohol in rats

Antrodia camphorata is a unique mushroom of Taiwan and has been used as a folk medicine for protection against liver damage induced by alcohol intoxication. However, no report has been presented in this respect. In this rat study, we examined whether the mycelium and sporocarp of Antrodia camphorata protect against acute liver damage induced by ethanol (EtOH). Rats were orally administered with mycelium and sporocarp of Antrodia camphorata for 9 days before EtOH challenge (5.5 g/kg body wt., i.p.). Rats were divided into eight groups (A-H) and except for groups A and H, all rats were injected with alcohol. A: Control; B: EtOH control: C: Silymarin (250 mg/kg bw., p.o.); D: 0.5 g mycelium/kg; E: 1.0 g mycelium/kg; F: 0.5 g sporocarp/kg; G: 1.0 g sporocarp/kg; and H: 1.0 g mycelium/kg. The results showed that EtOH administration markedly increased the activities of glutamate-pyruvate aminotransferase (GPT) and glutamate-oxaloacetate aminotransferase (GOT). Both mycelium and sporocarp of Antrodia camphorata significantly decreased the activity of GOT and GPT, but the effects were not dose-dependent. Mycelium and sporocarp of Antrodia camphorata also significantly and dose-dependently decreased lipid peroxidation (measured as TBARS) induced by EtOH. EtOH treatment significantly increased the activities of hepatic superoxide dismutase (SOD) and catalase, but did not significantly affect the activity of glutathione peroxidase. Pre-treatment with either the mycelium or the sporocarp completely prevented the rise in the activity of SOD and catalase. The histopathological examination revealed that both mycelium and sporocarp markedly protected against lipid vacuole accumulation and hydropic degeneration of hepatocytes induced by EtOH. Thus, the present results demonstrated that both mycelium and sporocarp of Antrodia camphorata protect against acute liver damage induced by EtOH. In addition, rats fed 1.0 g mycelium without EtOH treatment produced no observable toxicity during the experimental period.

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity

BackgroundNovel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. Genetic information can improve drug discovery rates by facilitating the identification of novel biological targets and potential drugs for repurposing. MethodsThe present study utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify additional risk genes for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280). iRIGS incorporates several genomic features and closeness of these genes in network space to compute a posterior probability for protein coding genes near each SNP. We subsequently used the Target Central Resource Database to search for drug-protein interactions for these newly identified genes and previously identified risk genes for alcohol consumption. ResultsWe identified several genes that are novel contributions to the previously published alcohol consumption GWAS. Namely, ACVR2A, which is critical for liver function and linked to anxiety and cocaine self-administration, and PRKCE, which has been linked to alcohol self-administration. Notably, only a minority of the SNPs (18.4 %) were linked to genes with confidence (>0.75), underscoring the need to apply multiple methods to assign function to loci. Finally, some previously identified risk genes for alcohol consumption code for proteins that are implicated in liver function and are targeted by drugs, some of which are candidates for managing hepatotoxicity. ConclusionsThis study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight additional molecular targets and drug repurposing candidates for treating AUD and ALD.

Interaction Between Alcohol Use and Metabolic Risk Factors for Liver Disease: A Critical Review of Epidemiological Studies.

Coexistence of alcohol use and metabolic risk-the 2 commonest population risk factors for nonviral chronic liver disease-is a growing concern. Clinical evidence and mechanistic evidence point to considerable supraadditive interaction effects for the development and progression of chronic liver disease between hazardous alcohol use and metabolic abnormalities including obesity, diabetes, and the metabolic syndrome (MetS). Intermittent binge drinking once monthly or more often seems to be associated with progression of liver disease even when average alcohol intake is within the currently allowed limits for a diagnosis of nonalcoholic fatty liver disease (NAFLD), and supraadditive interaction between binge drinking and the MetS has been reported. There are contradictory findings regarding the association between low alcohol use and liver steatosis, but, clearly, the mechanisms of alcoholic hepatotoxicity extend beyond simple fat accumulation. The presence of liver steatosis seems to amplify alcoholic hepatotoxicity. Recent longitudinal studies of NAFLD subjects report low alcohol use associated with both increased fibrosis progression and an elevated risk for liver cancer and severe liver disease. There is no clear safe limit of alcohol intake in the presence of NAFLD or metabolic risk. The interaction effects between alcohol and metabolic dysfunction merit increased attention in public health policy, individual counseling, and risk stratification. Based on current evidence, a strict dichotomization of liver disease into either pure alcoholic or nonalcoholic may be inappropriate.

Aqueous extract of Baccharis trimera improves redox status and decreases the severity of alcoholic hepatotoxicity

The metabolism of ethanol occurs mainly in the liver, promoting increase of reactive oxygen species and nitrogen, leading to redox imbalance. Therefore, antioxidants can be seen as an alternative to reestablish the oxidizing/reducing equilibrium. The aim of this study was to evaluate the antioxidant and hepatoprotective effect of aqueous extract of Baccharis trimera (Less.) DC., Asteraceae, in a model of hepatotoxicity induced by ethanol. The extract was characterized and in vitro tests were conducted in HepG2 cells. It was evaluated the cells viability exposed to aqueous extract for 24h, ability to scavenging the radical DPPH, besides the production of reactive oxygen species and nitric oxide, and the influence on the transcriptional activity of transcription factor Nrf2 (12 and 24h) after exposure to 200mM ethanol. The results showed that aqueous extract was non-cytotoxic in any concentration tested; moreover, it was observed a decrease in ROS and NO production, also promoting the transcriptional activity of Nrf2. In vivo, we pretreatment male rats Fisher with 600mg/kg of aqueous extract and 1h later 5ml/kg of absolute ethanol was administrated. After two days of treatment, the animals were euthanized and lipid profile, hepatic and renal functions, antioxidant status and oxidative damage were evaluated. The treatment with extract improved liver function and lipid profile, reflecting the reduction of lipid microvesicules in the liver. It also promoted an increase of glutathione peroxidase activity, decrease of oxidative damage and MMP-2 activity. These results, analyzed together, suggest the hepatoprotective effect of B. trimera aqueous extract.

Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity.

Over the last several years, one of the major advances in the field of alcoholic liver disease research was the discovery that binge alcohol consumption induced neutrophilia and hepatic neutrophil infiltration in chronically ethanol-fed mice and human subjects with excessive alcohol use (EAU); however, the underlying mechanisms remain obscure. Here, we demonstrated that chronic EAU patients with a history of recent excessive drinking (EAU + RD) had higher serum levels of mitochondrial DNA (mtDNA)-enriched microparticles (MPs) than EAU without recent drinking (EAU - RD) and healthy controls, which correlated positively with circulating neutrophils. Similarly, mice with chronic-plus-binge (E10d + 1B) ethanol feeding also had markedly elevated serum levels of mtDNA-enriched MPs, with activation of hepatic ER stress and inflammatory responses. Inhibition of ER stress by gene KO or inhibitors attenuated ethanol-induced elevation of mtDNA-enriched MPs, neutrophilia, and liver injury. The data from the study of hepatocyte-specific deletion of the protein kinase RNA-like ER kinase (Perk) gene in mice and of cultured hepatocytes demonstrated that hepatocytes were the main source of mtDNA-enriched MPs after ethanol feeding. Finally, administration of mtDNA-enriched MPs isolated from E10d+1B-fed mice caused neutrophilia in mice. In conclusion, E10d + 1B ethanol consumption activates hepatic ER stress-dependent mtDNA-enriched MP release, leading to neutrophilia and liver injury.

Glutamate contributes to alcohol hepatotoxicity by enhancing oxidative stress in mitochondria.

Chronic alcohol intoxication is associated with increased oxidative stress. However, the mechanisms by which ethanol triggers an increase in the production of reactive oxygen species (ROS) and the role of mitochondria in the development of oxidative stress has been insufficiently studied. The biochemical and proteomic data obtained in the present work suggest that one of the main causes of an increase in ROS generation is enhanced oxidation of glutamate in response to long-term alcohol exposure. In the course of glutamate oxidation, liver mitochondria from alcoholic rats generated more superoxide anion and H2O2 than in the presence of other substrates and more than control organelles. In mitochondria from alcoholic rats, rates of H2O2 production and NAD reduction in the presence of glutamate were almost twice higher than in the control. The proteomic study revealed a higher content of glutamate dehydrogenase in liver mitochondria of rats subjected to chronic alcohol exposure. Simultaneously, the content of mitochondrial catalase decreased compared to control. Each of these factors stimulates the production of ROS in addition to ROS generated by the respiratory chain complex I. The results are consistent with the conclusion that glutamate contributes to alcohol hepatotoxicity by enhancing oxidative stress in mitochondria.

The protection of Thymus vulgaris leaves alcoholic extract against hepatotoxicity of alcohol in rats.

To investigate the protective effect of Thymus vulgaris (T. vulgaris) leaves 70% alcoholic extract against alcohol-mediate hepatotoxicity rats. The protective effect of T. vulgaris extract was investigated at dose of 500mg/kg/day (as 0.1 of LD50) orally against alcohol-mediate hepatotoxicity using adult male Wister albino rats during 21 days. Protective effect of T. vulgaris extract was evaluated comparing with silymarin standard drug at recommended dose (25mg/kg/day) orally for 21 days. Serum liver and kidney functions, serum lipid profile, liver antioxidant enzymes activities, liver glutathione concentration (GSH), liver oxidative parameters and histopathological study of liver and kidney were estimated to find out protective effect of T. vulgaris extract. Alcohol-mediate hepatotoxicity rats (alcohol-control) showed hepatocytes distortion represented as marked increment on liver biomarkers; alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) activities, as well as pronounced reduction on total protein and its fractions albumin and globulin production corresponding to normal ranges. Oxidative stress status was appeared on alcohol-control evident as significant depletion on GSH concentration, antioxidant enzymes activities; catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione- S- transferase (GST) and glutathione peroxidase (GPx) recorded significant dwindling, concurrence with significant augmentation on oxidative stress parameters; malondyaldehyde (MDA) and hydrogen peroxide (H2O2) concentrations with respect to normal values. Serum lipid profile was affected by alcohol administration, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) were significantly reduced, meanwhile high density lipoprotein cholesterol (HDL-C) was raised comparing to normal ranges. Co-administration of T. vulgaris extract with alcohol showed protective effect on hepatocytes manifested as remarkable minimizing on ALP, AST and ALT activities and marked increment on total protein, albumin and globulin production compared to alcohol-control. Amelioration was achieved on oxidative stress status on rats co-administrated T. vulgaris extract with alcohol. Accordingly, antioxidant enzymes activities; CAT, SOD, GR, GST and GPx were significantly magnified, while oxidative stress parameters; MDA and H2O2 concentration were significantly lessened corresponding to alcohol-control. Also, lipid profile was markedly improved and risk ratio was lowered by T. vulgaris extract co-administrated in comparison with alcohol-control. All these obvious results were confirmed by histopathological examination, which illustrated that extract showed normalization of degenerated and fibrotic liver tissue as of alcohol-control. T. vulgaris extract protected hepatocytes from damaging by alcohol reflecting improvement on liver performance and inhibition of oxidative stress status of liver. T. vulgaris extract appeared hepatoprotective, hypolipidemic and antioxidant activities on alcohol-mediate hepatotoxicity rats compared to silymarin.

Rg1 Attenuates alcoholic hepatic damage through regulating AMP-activated protein kinase and nuclear factor erythroid 2-related factor 2 signal pathways

Rg1 has shown multiple pharmacological activities and been considered to be evaluated for hepatic protective activity, as Rg1 could modulate different pathways in various diseases. Herein we assessed its effect and potential mechanism in a newly modified ethanol model. C57BL/6 mice were fed with Lieber-DeCarli liquid diet containing ethanol or isocaloric maltose dextrin as control diet with or without Rg1. Meanwhile, bicyclol was treated as positive drug to compare the efficacy of Rg1 against alcoholic hepatotoxicity. According to our data, Rg1 indeed improved the survival rate and lowered the abnormal high levels of serum parameters. H&E and Oil Red O staining indicated that the condition of liver damage was mitigated by Rg1 administration. Furthermore, AMPK and Nrf2 pathways were all modulated at both RNA and protein levels. In accordance with these findings, Rg1 effectively protected against alcoholic liver injury, possibly by modulating metabolism, suppressing oxidative stress, and enhancing oxidant defense systems of Nrf2 pathway. In vitro, Rg1 has no cell toxicity and promotes Nrf2 translocate into nuclear. In summary, we demonstrate that Rg1 is a potent activator of Nrf2 pathway, and could therefore be applied for prevention of hepatic damage.

Changes of the Cytoplasmic Proteome in Response to Alcoholic Hepatotoxicity in Rats.

Proteomic analyses have already been used in a number of hepatological studies and provide important information. However, few reports have focused on changes in the cytoplasmic proteome. The present study therefore aimed to evaluate changes in cytoplasmic proteome of rats in response to alcoholic hepatotoxicity. Rats were fed a Liber-DeCarli liquid diet containing ethanol for four weeks. Cytoplasmic proteins except mitochondrial proteins from the livers of these animals were investigated using two-dimensional gel electrophoresis and mass spectrometry. Alcohol induced a decrease in body weight gain and an increase in alanine transaminase (ALT), cholesterol, and phospholipid levels. Histopathological observations revealed hepatic damage characterized by necrosis and fatty change in alcohol-treated group at week 2, which continues until week 4. Our proteomic analysis revealed that 25 proteins were differentially expressed in the ethanol-fed group. Of these, 12 cytoplasmic proteins are being reported for the first time. Taken together, our results provide further insights into the disease mechanism and therapeutic information of alcoholic liver disease.

Cellular mechanisms by which alcohol promotes HIV protease inhibitor‐induced liver lipotoxicity

The development of highly‐active‐antiretroviral therapy(HAART) has allowed management of HIV and extended the lives of those infected. Alcohol abuse, which is very common in HIV‐1 infected patients, is one of the most important co‐morbid risk factors for liver injury and has been associated with the occurrence of serious metabolic syndrome and subsequent discontinuation of HAART in HIV patients. We have identified endoplasmic reticulum (ER) stress‐induced proapoptotic factor CHOP as an important factor underlying HIV PI‐induced inflammation and hepatic lipotoxicity. However, little is known about the mechanistic pathways by which alcohol promotes HIV PI‐induced hepatic lipotoxicity. The aim of this study was to determine if inhibition of CHOP expression prevents alcohol‐ and HIV PI‐induced apoptosis and dysregulation of lipid metabolism.MethodsPrimary hepatocytes from wild type or CHOP‐/‐ mice were treated with individual HIV PIs with or without alcohol. Activation of the key genes responsible for lipid metabolism was determined by real time RT‐PCR and Western Blot.ResultsCHOP‐/‐ mice prevent ethanol and HIV PI‐induced dysregulation of key genes involved in lipid metabolism in hepatocytes. CHOP‐/‐ hepatocytes treated with alcohol showed decreased biosynthesis of cholesterol, fatty acid, and bile acid.ConclusionsActivation of the ER stress‐induced proapoptotic factor CHOP is a key cellular mechanism underlying alcohol and HIV PI‐induced hepatotoxicity. CHOP expression is key for alcohol and HIV PI‐induced dysregulation of key genes involved in lipid metabolism in hepatocytes.