Alcohol-induced Hepatotoxicity Research Articles

The protective effects and mechanisms of modified Lvdou Gancao decoction on acute alcohol intoxication in mice

Ethnopharmacological relevanceAcute alcohol intoxication (AAI) is a ubiquitous emergency worldwide, whereas the searching for both effective and safe drugs is still a task to be completed. Modified Lvdou Gancao decoction (MLG), a traditional Chinese medicine decoction, has been confirmed to be valid to alcohol-induced symptoms and hepatotoxicity clinically, whereas its protective mechanisms have not been determined. Materials and methodsAAI mice model was established by alcohol gavage (13.25 mL/kg) and MLG (5, 10, 20 g/kg BW) was administered to mice 2 h before and 30 min after the alcohol exposure. Assay kits for alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamine transferase (GGT), total superoxide dismutase (T-SOD), malondialdehyde (MDA), nitric oxide (NO), and glutathione peroxidase (GSH-Px), as well as histopathology were used to explore the effects of MLG on acute alcohol-induced intoxication and hepatotoxicity. Mechanisms of MLG on oxidative stress and inflammatory were evaluated with RT-qPCR and Western Blot. ResultsMLG remarkably decreased the drunkenness rate, prolonged the tolerance time and shortened the sober-up time of AAI mice. After acute alcohol exposure, MLG treatment induced significant increment of ADH, ALDH, T-SOD and GSH-Px activities in liver, while serum ALT, AST, GGT and NO levels as well as hepatic MDA activity were reduced, in a dose-dependent manner. In contrast to the model group, the mRNA expression of TNFα, IL-1β and NF-κB in the MLG treated groups had a downward trend while the Nrf-2 showed an upward trend simultaneously. Furthermore, the protein levels of p65, p-p65, p-IκBα in the MLG treated groups were considerably diminished, with HO-1 and Nrf2 elevated. To sum up, our results suggested that MLG could efficaciously ameliorate AAI via accelerating the metabolism of alcohol, alleviating acute hepatotoxicity, and weakening the oxidative stress coupled with inflammation response, which might be attributed to the inhibition of the NF-κB signaling pathway and the activation of the Nrf2/HO-1 signaling pathway. ConclusionsTaken together, our present study verified the protective effect and mechanisms of MLG to AAI mice, and we further conclude that MLG may be a potent and reliable candidate for the prevention and treatment of AAI.

TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice.

Toll-Like Receptor 9 (TLR9) elicits cellular response to nucleic acids derived from pathogens or dead cells. Previous studies have shown that TLR9-driven response may lead to differential impact on the pathogenesis of liver diseases. This study aimed to determine how TLR9 may contribute to chronic alcohol exposure-induced liver pathogenesis. We observed that TLR9 KO mice were more susceptible to alcohol-induced liver injury, which was evidenced by higher serum ALT/AST levels and more lipid accumulation in alcohol-fed TLR9 KO mice than wild-type mice. Alcohol-induced oxidative stress and mitochondrial dysfunction were also exacerbated by TLR9 KO. We found that chronic alcohol exposure-induced hepatic CHOP and ATF6 activation were enhanced in TLR9 KO mice. By using primary hepatocytes and AML-12 cells, we confirmed that TLR9 activation by CpG ODN administration significantly ameliorated acetaldehyde-induced cell injury via suppressing ATF6-CHOP signaling. By using STAT3 knockdown AML12 cells, we showed that TLR9-mediated STAT3 activation inhibited ATF6-CHOP signaling cascade and thereby protecting against acetaldehyde-induced mitochondrial dysfunction and cell injury. Interestingly, we found that TLR9 KO mice ameliorate chronic alcohol exposure-induced CXCL1 induction and neutrophils infiltration in the liver. Furthermore, hepatocyte lack of STAT3 significantly ameliorated CpG ODN and LPS-increased CXCL1 levels in hepatocytes. Overall, our data demonstrate that TLR9 signaling in hepatocytes counteracts alcohol-induced hepatotoxicity but worsens proinflammatory response.

Oridonin Attenuates the Effects of Chronic Alcohol Consumption Inducing Oxidative, Glycative and Inflammatory Injury in the Mouse Liver.

Oridonin (Ori) is a diterpenoid naturally present in medicinal plants with a potential as an antioxidant agent. This study aimed to evaluate the hepatic anti-oxidative, anti-glycative and anti-inflammatory properties of Ori at 0.125 and 0.25% against chronic ethanol intake in mice. Mice were divided into five groups: i) normal diet group, ii) Ori group, iii) ethanol diet (Lieber-DeCarli liquid diet with ethanol) group, iv) ethanol diet plus 0.125% Ori and v) ethanol diet plus 0.25% Ori. After 8 weeks of Ori supplementation, blood and liver tissue were used for analyses. Ethanol increased the production of reactive oxygen species and nitric oxide, decreased glutathione content, and lowered the activity of glutathione peroxide, glutathione reductase and catalase. Ethanol suppressed the hepatic mRNA expression of nuclear factor E2-related factor 2. Ori supplements reversed these changes. Ethanol increased hepatic Ne-(carboxyethymethyl)-lysine (CML) and pentosidine levels, and enhanced aldose reductase (AR) activity and mRNA expression. Ori supplements at only 0.25% decreased CML and pentosidine levels, and lowered the AR activity as well as its mRNA expression. Ethanol increased the hepatic release of tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin (IL)-1beta and IL-6. Histological data showed that ethanol induced necrosis and inflammatory cell infiltration, while Ori supplements alleviated these inflammatory responses. Ethanol up-regulated the hepatic mRNA expression of nuclear factor kappa B, myeloperoxidase and p38. Ori supplements reversed these changes. These novel findings suggest that Ori could be used as a potent agent against alcohol-induced hepatotoxicity.

Evaluation of Antioxidant Potentials of Ocimum gratissimum and Xylopia aethiopica in Alcohol- Induced Hepatotoxic Albino Rats

Aims: This study evaluated the antioxidant potentials of Ocimum gratissimum and Xylopia aethiopica on Alcohol-induced Hepatotoxicity in Albino rats.
 Study Design: The study is an experimental case-controlled study.
 Place and Duration of Study: This study was conducted at the Department of Physiology, University of Port-Harcourt, Nigeria.
 Methodology: Fifty-five (55) healthy adult male albino rats with an average weight of about 150-200 g were used for the study. They were divided into 11 groups of 5 Rats each and subjected to different treatments of the aforementioned herbs. All the animals received humane treatments according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Institute of Health. Fresh leaves of Ocimum gratissimum and Xylopia aethiopica were bought from the Mile 3 market in Port-Harcourt. The herbs were separately extracted using maceration method. Absolute ethanol at a volume of 1 ml/kg (0.79 g/kg) was used to induce hepatotoxicity in rats. At the end of the treatment period, rats in all the groups were anaesthetized with chloroform and blood samples collected by jugular puncture. Total antioxidant capacity was analyzed using colorimetric method, whilst, malondialdehyde levels were determined using ELISA method. SPSS version 22.0 was used to analyse data generated and p values less than 0.05 were considered significant.
 Results: Results show that intraperitoneal injection of 1 ml/kg ethanol significantly raised plasma MDA levels and significantly decreased TAOC in induced rats. Treatment with 200, 400 and 600 mg/kg b.wt. of aqueous extract of Ocimum gratissimum and Xylopia aethiopica however effectively reduced ethanol induced raised activity of the MDA levels and increased the activity of TAOC in the rats, but the effects were not dose dependent and a combination of both herbs did not produce better therapeutic effect.
 Conclusion: Based on our findings, we conclude that Ocimum gratissimum and Xylopia aethiopica used separately could reduce oxidative stress in alcohol induced hepatotoxic rats.

Ozone vs Melatonin: The Therapeutic Effects In Alcoholic Liver Disease

Background: Alcoholic liver disease (ALD) is a worldwide health problem.Ozone and melatonin are agents that are widely used for their antioxidant properties in medical therapies.In this study, we aimed to evaluate the use of ozone and melatoninin ALD.Materials and Methods: Forty-eight rats were used and ethanol, melatonin, and ozone were administrated. Histopathological evaluation was performed and activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT) total antioxidant status (TAS), total oxidant status (TOS), and malondialdehyde (MDA)were determined in the blood samples, while TAS, TOS, and MDA parameters were measured in the liver tissue samples.Results: There were statistically significant differences between the studied groups concerning ALT, AST activities and TAS, TOS, and MDA levels. Vascular congestion, hepatocyte damage, periportal inflammation, and microvesicular steatosis were detected inthe alcohol-induced toxicity group.Conclusions: In the light of histopathological findings, we can claim that melatonin and ozone administrations are beneficial for alcohol-induced hepatotoxicity. However, ozone application is superior to melatonin.

Hepatoprotective Activity of Ethanolic Extract of Cissus quadrangularis linn Fruits in Alcohol-induced Liver Damage in Rats

Reactive oxygen species are one of the major reasons for liver damage. The study investigates the hepatoprotective activity of ethanolic extract of Cissus Quadrangularis (EECQ) Linn of fruits against ethanolinduced hepatotoxicity. Fruit Powder of Cissus Quadrangularis was successively extracted with ethanol. Preliminary phytochemical tests were done. The hepatoprotective activity of the AST, ALT, ALP, ALB, BIT and BID were assessed in alcohol-induced hepatotoxicity rats. The EECQ showed the presence of alkaloids, carbohydrates, steroids, saponins and triterpenes, while alkaloids, carbohydrates and saponins were present Ethanol produced significant changes in physical (increased liver weight and volume), biochemical (increase in serum alanine transaminase, aspartate transaminase, alkaline phosphatase, direct bilirubin, total bilirubin, cholesterol, triglycerides and decrease in total protein and albumin level) Pre-treatment with EECQ extract significantly prevented the physical, biochemical, histological and functional changes induced by alcohol in the liver. The present study indicates that EECQ extract possessed potential hepatoprotective activity. This activity may be attributed due to the rich phytoconstituents of the plant extract.

Hepatoprotective activity of depsidone enriched Cladonia rangiferina extract against alcohol-induced hepatotoxicity targeting cytochrome P450 2E1 induced oxidative damage

Alcoholic liver disease (ALD) is a broad-spectrum disorder, covering fatty liver, cirrhosis, alcoholic hepatitis and in extreme untreated condition hepatocellular carcinoma (HCC) may also develop. Cladonia rangiferina (CR) is a class of lichen having a broad spectrum of pharmacological activity. It is used like traditional natural sources in ancient times in India, China, Sri Lanka, etc. Folkloric record about CR has reported their use as an antimicrobial, antitumor, antioxidant, anti-inflammatory activities, etc. Hence, the present study was requested to ascertain the effect of the ethanolic extract of Cladonia rangiferina (CRE) on alcohol-induced hepatotoxicity. The animals were evaluated for the estimation of the liver in vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity. The results of this study reveal that CRE proves to be helpful in the treatment of alcohol-induced hepatotoxicity and oxidative stress. Results of different markers have shown that among all, CRE has demonstrated the best hepatoprotective activity. These observations say about the importance of the components of the extract. The ameliorative action of CRE in alcoholic liver damage may exist due to antioxidant, anti-inflammatory, and anti-apoptotic activities.

The Protective Effect of the Polysaccharide Precursor, D-Isofloridoside, from Laurencia undulata on Alcohol-Induced Hepatotoxicity in HepG2 Cells

Alcoholic liver disease (ALD) threatens human health, so it is imperative that we find ways to prevent or treat it. In recent years, the study of polysaccharides has shown that they have different kinds of bioactivities. Among them are many biological effects that have been attributed to polysaccharide precursors. D-Isofloridoside (DIF) is one of the polysaccharide precursors from the marine red alga Laurencia undulata. This study evaluated the effect of DIF on alcohol-induced oxidative stress in human hepatoma cells (HepG2). As a result, DIF attenuated alcohol-induced cytotoxicity, reduced the amount of intracellular reactive oxygen species (ROS), and effectively reduced alcohol-induced DNA damage in HepG2 cells. In addition, a western blot showed that, after DIF treatment, the expression levels of glutathione (GSH), superoxide dismutase (SOD), and B-cell lymphoma-2 (bcl-2) increased, while the expression levels of γ-glutamyl transferase (GGT), BCL2-associated X (bax), cleaved caspase-3, and mitogen-activated protein kinase (p38 and c-Jun N-terminal kinase) signal transduction proteins reduced. This showed that DIF may protect cells by reducing the amount of intracellular ROS and inhibiting intracellular oxidative stress and apoptotic processes. Finally, molecular docking demonstrated that DIF can bind to SOD, GGT, B-cell lymphoma-2, and bax proteins. These results indicated that DIF can protect HepG2 cells from alcohol-induced oxidative stress damage, making it an effective potential ingredient in functional foods.

Hepatoprotective agents as calcium channel blockers in paracetamol-induced and alcohol-induced hepatotoxicity models (curative method) in rats

Background It has been reported that accumulation of Ca++ ions in the cells causes depletion of mitochondrial respiration and ATP, synthesis leading to cell death. Furthermore, it has also been reported that paracetamol and alcohol produce hepatotoxicity by facilitating accumulation of excess Ca++ in hepatocytes. Ca++ channel blockers block the entry of Ca++ into the cells. Hence, the present study is planned to evaluate hepatoprotective activity of Ca++ channel blockers in the aforementioned models. Objective The aim was to study the hepatoprotective activity of three Ca++ channel blockers, namely, lercanidipine 1/4th TD (0.09 mg), ½ TD (0.18 mg) and 1TD (0.36 mg); felodipine 1/4 TD (0.045 mg), ½ TD (0.09 mg), and 1TD (0.18 mg); and isradipine ¼ TD (0.0225 mg), medium 1/2 TD (0.045 mg), and 1TD (0.09 mg), with three selected doses in paracetamol-induced and alcohol-induced hepatotoxicity in rats with curative aspects. Materials and methods The hepatoprotective activity of Ca++ channel blockers is evaluated in PCM- (2 g/kg) and ALC-(3.76 g/kg) induced hepatotoxic models in rats. The study recorded thiopental-induced sleeping time; physical parameters like liver weight and liver volume; and biochemical parameters, like alanine transaminase, aspartate aminotransferase, alkaline phosphatase, direct bilirubin, total bilirubin, albumin, and total protein, which were estimated by using a semiauto analyzer. Silymarin is used as a standard reference drug in both the paracetamol-induced and alcohol-induced hepatotoxic models. Standard drug silymarin produced a significant hepatoprotective activity. Results Ca++ channel blockers too at three different doses as mentioned before with curative aspect produced a significant hepatoprotective activity in paracetamol-induced and alcohol-induced hepatotoxic models. Ca++ channel blockers cured the hepatotoxic effects of both paracetamol and alcohol in rats and offered hepatoprotective activity. Conclusion Lercanidipine, felodipine, and isradipine exhibited a significant hepatoprotective activity in both paracetamol-induced and alcohol-induced hepatotoxic models in rats.

Boletus aereus protects against acute alcohol-induced liver damage in the C57BL/6 mouse via regulating the oxidative stress-mediated NF-κB pathway

Context Alcoholic liver disease, caused by abuse and consumption of alcohol, exhibits high morbidity and mortality. Boletus aereus Bull. (Boletaceae) (BA) shows antioxidant, anti-inflammatory and antimicrobial effects. Objectives To investigate the hepatoprotective effects of BA using an acute alcohol-induced hepatotoxicity mice model. Materials and methods The composition of BA fruit body was first systematically analyzed. Subsequently, a C57BL/6 mice model of acute alcohol-induced liver injury was established by intragastrically administration of alcohol, which was intragastrically received with BA powder at 200 mg/kg and 800 mg/kg for 2 weeks, 60 mg/kg silybin treatment was used as positive control group. By employing the pathological examination, ELISA, RT-PCR and western blot, the regulation of BA on oxidative stress signals was investigated. Results The LD50 of BA was much higher than 4 g/kg/p.o. In acute alcohol-damaged mice, BA reduced the levels of alanine aminotransferase (>18.3%) and aspartate aminotransferase (>27.6%) in liver, increased the activity of liver alcohol dehydrogenase (>35.0%) and serum acetaldehyde dehydrogenase (>18.9%). BA increased the activity of superoxide dismutase (>13.4%), glutathione peroxidase (>11.0%) and 800 mg/kg BA strongly reduced chemokine (C-X-C motif) ligand 13 (14.9%) and chitinase-3 like-1 protein (13.4%) in serum. BA reversed mRNA over-expression (>70%) and phosphor-stimulated expression (>45.0%) of an inhibitor of nuclear factor κ-B kinase (NF-κB, an inhibitor of nuclear factor κ-B α and nuclear factor κ-B in the liver. Conclusions BA is effective in ameliorating alcohol-induced liver injury through regulating oxidative stress-mediated NF-κB signalling, which provides a scientific basis for further research on its clinical applications.

Acorbine, a Corbicula japonica–derived tripeptide containing non-proteinogenic amino acids, suppresses ethanol-induced liver injury

Since ancient times, Corbicula extract has been believed in Japan to have hepatoprotective effects, but it remains unclear whether these claims are true, and if so, which component is responsible for hepatoprotection. In this study, we showed that Corbicula extract exerted a protective effect against liver damage. Recent work identified acorbine (β-alanyl-ornithyl-ornithine), a novel tripeptide containing non-proteinogenic amino acids, in the extract of Corbicula japonica. Synthesized acorbine cured alcohol-induced liver damage in mice. In addition, acorbine purified from Corbicula extract exerted a protective effect against alcohol-induced hepatotoxicity in a culture liver model derived from mouse ES/iPS cells. Thus, acorbine is one of the components of Corbicula extract that protects hepatocytes against ethanol-induced death.

Carvacrol inhibits cytochrome P450 and protects against binge alcohol-induced liver toxicity

Alcoholism is a serious addiction that can lead to various health complications such as liver fibrosis, steatosis, and cirrhosis. Carvacrol is present in many plant-based essential oils and used as a preservative in the food industry. In this study, we have investigated the hepatoprotective role of carvacrol against ethanol-induced liver toxicity in mice. To determine the effect of carvacrol on liver injury parameters, 5 doses of 50% ethanol (10 mL/kg body weight) were orally administered every 12 h for inducing the hepatotoxicity in experimental mice. Interestingly, carvacrol pre-treatment (50 and 100 mg/kg) reversed the ethanol-induced effects on liver function, antioxidant markers, matrix metalloproteinases activities, and histological changes. Moreover, carvacrol binds to the active pocket of cytochrome P450 (Cyt P450) and inhibits its expression. Thus, our finding suggests carvacrol can be used as an adjuvant for the amelioration of alcohol-induced hepatotoxicity.

Improved in vitro and in vivo hepatoprotective effects of liposomal silymarin in alcohol-induced hepatotoxicity in Wistar rats.

Silymarin, a known hepatoprotectant, owing to its poor oral bioavailability, has limited pharmacological effects. The present study was designed to improve its in vitro and in vivo hepatoprotection and increase its oral bioavailability against alcohol intoxication by formulating it in four different liposomal formulations namely conventional, dicetyl phosphate, stearyl amine and PEGylated liposomes. The liposomes were prepared using phosphatidylcholine, cholesterol, and silymarin in addition to dicetyl phosphate, stearyl amine and DSPE mPEG 2000 by film hydration method with 5% sucrose as a cryo-protectant. The optimized formulations were studied for their release profile at pH 1.2 and 6.8. Liposomes were studied for in vitro protection on Chang liver cells and efficacious liposomes were selected for in vivo hepatoprotection study. Further, conventional liposomes were studied for bioavailability in alcohol intoxicated Wistar rats. The conventional liposomes increased in vitro release profile at pH 1.2 and 6.8 and also showed better in vitro protection compared to silymarin alone. Conventional and PEGylated liposomes showed better improvement in liver function, better efficacy in combating inflammatory conditions, better improvement in antioxidant levels and reversal of histological changes compared to silymarin alone. Conventional also showed an almost fourfold increase in area under the curve compared to silymarin suspension. Conventional and PEGylated liposomes of silymarin were found to be more efficacious as hepatoprotective against alcohol-induced hepatotoxicity by its free radical scavenging and anti-inflammatory effects. Conventional liposomes showed enhanced bioavailability compared to silymarin alone.

Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy: A Systematic Review.

There is substantial interest in the therapeutic potential of cannabidiol (CBD), a nonpsychoactive cannabinoid found in plants of the genus Cannabis. The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a candidate pharmacotherapy for alcohol use disorder (AUD). Using a comprehensive search strategy, 303 unique potential articles were identified and 12 ultimately met criteria for inclusion (8 using rodent models, 3 using healthy adult volunteers, and 1 using cell culture). In both rodent and cell culture models, CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus. In rodent models, CBD was found to attenuate alcohol-induced hepatotoxicity, specifically, alcohol-induced steatosis. Finally, findings from preclinical rodent models also indicate that CBD attenuates cue-elicited and stress-elicited alcohol seeking, alcohol self-administration, withdrawal-induced convulsions, and impulsive discounting of delayed rewards. In human studies, CBD was well tolerated and did not interact with the subjective effects of alcohol. Collectively, given its favorable effects on alcohol-related harms and addiction phenotypes in preclinical models, CBD appears to have promise as a candidate AUD pharmacotherapy. This is further bolstered by the absence of abuse liability and its general tolerability. A clear limitation to the literature is the paucity of human investigations. Human preclinical and clinical studies are needed to determine whether these positive effects in model systems substantively translate into clinically relevant outcomes.

Optimization of Ultrasonic-Microwave Assisted Extraction and Hepatoprotective Activities of Polysaccharides from Trametes orientalis.

Ultrasonic-microwave assisted extraction (UMAE) of Trametes orientalis polysaccharides was optimized by response surface methodology. Hepatoprotective effects of a purified T. orientalis polysaccharide (TOP-2) were evaluated by alcohol-induced liver injury model mice. The optimal UMAE parameters were indicated as below: ratio of water to raw material 28 mL/g, microwave power 114 W, extraction time 11 min. The polysaccharides yield was 7.52 ± 0.12%, which was well consistent with the predicted value of 7.54%. Pre-treatment with TOP-2 effectively increased the liver index and spleen index in alcohol-treated mice. The elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of mice after alcohol exposure were inhibited by TOP-2 administration. The liver tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) levels have decreased significantly as a result of alcohol exposure, while pre-treatment with TOP-2 could mitigate these consequences. Furthermore, pre-treatment with TOP-2 could efficiently boost the superoxidase dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, and observably constrain the malondialdehyde (MDA) level. The findings suggest that TOP-2 might be useful for alleviating the alcohol-induced hepatotoxicity via its antioxidant and anti-inflammatory potential.

Dynamin-1–Like Protein Inhibition Drives Megamitochondria Formation as an Adaptive Response in Alcohol-Induced Hepatotoxicity

Despite the growing global burden of alcoholic liver diseases, therapeutic options are limited, and novel targets are urgently needed. Accumulating evidence suggests that mitochondria adapt in response to ethanol and formation of megamitochondria in the livers of patients is recognized as a hallmark of alcoholic liver diseases. The processes involved in ethanol-induced hepatic mitochondrial changes, the impact on mitochondria-shaping proteins, and the significance of megamitochondria formation remain unknown. In this study, we investigated the mitochondrial and cellular response to alcohol in hepatoma cell line VL-17A. The mitochondrial architecture rapidly changed after 3 or 14 days of ethanol exposure with double-pronged presentation of hyperfragmentation and megamitochondria, and cell growth was inhibited. Dynamin-1-like protein (Drp1) was identified as the main mediator driving these mitochondrial alterations, and its genetic inactivation was determined to foster megamitochondria development, preserving the capacity of the cells to grow despite alcohol toxicity. The role of Drp1 in mediating megamitochondria formation in mice with liver-specific inactivation of Drp1 was further confirmed. Finally, when these mice were fed with ethanol, the presentation of hepatic megamitochondria was exacerbated compared with wild type fed with the same diet. Ethanol-induced toxicity was also reduced. Our study demonstrates that megamitochondria formation is mediated by Drp1, and this phenomenon is a beneficial adaptive response during alcohol-induced hepatotoxicity.

Hepatoprotective effect of gastrodin against alcohol-induced liver injury in mice.

Alcoholic liver disease (ALD) is a common and serious threat to human health worldwide. In this study, the hepatoprotective effect of gastrodin against alcohol-induced liver injury in mice was examined. Mice with alcohol-induced hepatotoxicity were treated intragastrically with gastrodin (50, 80, or 100mg/kg). The mice treated with gastrodin experienced better outcomes than those who received only one dose of alcohol (50%, 10mL/kg b.w.). Gastrodin treatment reduced the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), decreased hepatic malondialdehyde (MDA) content, and increased hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities in a dose-dependent manner. Gastrodin also alleviated histopathological changes induced by alcohol. Gastrodin protected against alcohol-induced increases in expression levels of the cytochrome P450 2E1 (CYP2E1) and mRNA levels of chemokine (C-X-C motif) ligand 1 (CXCL-1), interferon-γ (IFN-γ), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), vascular cell adhesion molecule 1 (VCAM-1), nuclear factor-kappa B (NF-κB), Toll-like receptor 4 (TLR-4), and activator of transcription 3 (STAT-3). Moreover, gastrodin-increased nuclear transcription factor 2 (Nrf2) translocates to the nucleus and enhanced the activity of anti-oxidant enzymes, and could thereby ameliorate alcohol-induced liver injury in mice. This study demonstrated that gastrodin may be an effective therapeutic agent against alcohol-induced liver injury.

NF‐κB and AMPK/PI3K/Akt signaling pathways are involved in the protective effects of Platycodon grandiflorum saponins against acetaminophen‐induced acute hepatotoxicity in mice

Acute liver injury (ALI) induced by acetaminophen (APAP) overdose is the most common cause of drug-induced liver injury. Saponins from Platycodon grandiflorum (PGSs) ameliorate alcohol-induced hepatotoxicity and enhance human lung carcinoma cell death via AMPK signaling pathway. However, whether PGS could protect from APAP-induced ALI through AMPK activation and its downstream signals is still poorly elucidated. This work investigated the protective effect and the underlying mechanisms of PGS against APAP-induced liver toxicity in mouse. PGS was administered at 15 or 30mg/kg i.g./day for 1week before a single injection of APAP (250mg/kg, i.p.) 1hr after last treatment of PGS. Serum alanine/aspartate aminotransferases, liver tumor necrosis factor-α and interleukin-1β levels, liver malondialdehyde formation, liver glutathione depletion, cytochrome P450 E1, and 4-hydroxynonenal levels were measured to demonstrate the protective efficacy of PGS against APAP-induced ALI. Liver histological observation provided further evidence on PGS's protective effects. PGS treatment altered the phosphorylation of AMPK and PI3K/Akt, as well as the downstream signals including Bcl-2 family, caspase, and NF-κB in a dose-dependent manner. In conclusion, we demonstrate that PGS exhibits a significant liver protection against APAP-induced ALI, mainly through NF-κB and AMPK/PI3K/Akt signaling pathways.

Protective effects of Lactococcus chungangensis CAU 28 on alcohol-metabolizing enzyme activity in rats

In this study, we investigated the beneficial effects of Lactococcus chungangensis CAU 28, a bacterial strain of nondairy origin, on alcohol metabolism in rats treated with ethanol, focusing on alcohol elimination and prevention of damage and comparing the effects with those observed for Lactococcus lactis ssp. lactis ATCC 19435. Male Sprague-Dawley rats were orally administered 20% ethanol and 3 substrates (freeze-dried cells, cream cheese, and yogurt) containing Lc. chungangensis CAU 28 or Lc. lactis ssp. lactis ATCC 19435, which were provided 1 h before or 1 h after ethanol ingestion. Blood samples were collected from the tail veins of the rats at 1, 3, 6, 12, and 24 h after ingestion of ethanol, Lc. chungangensis CAU 28 substrate, or Lc. lactis ssp. lactis ATCC 19435 substrate. Alcohol and acetaldehyde concentrations in the Lc. chungangensis CAU 28 substrate-treated rats were significantly reduced in a time-dependent manner compared with those in the Lc. lactis ssp. lactis ATCC 19435 substrate-treated rats. Among the experimental groups, treatment with cream cheese before ingestion of 20% ethanol was found to be the most effective method for reducing both alcohol and acetaldehyde levels in the blood. Alanine aminotransferase and aspartate aminotransferase activities in the Lc. chungangensis CAU 28 substrate-treated rats were significantly lower than those in the positive controls. Moreover, in the Lc. chungangensis CAU 28 cream cheese-treated group, rats showed a reduction of liver enzymes by up to 60%, with good effectiveness observed for both pre- and post-ethanol ingestion. These results suggested that intake of lactic acid bacteria, particularly in Lc. chungangensis CAU 28-supplemented dairy products, may reduce blood alcohol and acetaldehyde concentrations, thereby mitigating acute alcohol-induced hepatotoxicity by altering alcohol-metabolizing enzyme activities.

Antioxidative and Anti-Inflammatory Activities of Akebia quinata Extracts in an In Vitro Model of Acute Alcohol-Induced Hepatotoxicity.

This study investigated the effects of Akebia quinata (AQ) leaf and fruit extract on acute alcohol-induced hepatotoxicity in AML12 cells. Different concentrations of AQ extracts (250 and 2500 μg/mL) were used to treat the AML12 cells with or without ethanol for 24 h for inducing acute alcohol cytotoxicity. AQ extract-treated AML12 cells showed enhanced expression of GSH-synthesizing enzymes and suppressed expression of oxidative stress makers such as NOX4, and decreased expression of tumor necrosis factor-α, inflammatory marker, in acute alcohol-induced hepatotoxicity. Furthermore, it was observed that 100 mM ethanol treatment of AML12 cells resulted in global change of mRNA expression in microarray, but AQ leaf extract treatment reversed the global change of mRNA expression pattern into normal condition. In conclusion, AQ extract or functional component from AQ can be useful therapeutic agent in acute alcohol-induced hepatotoxicity by reducing oxidative stress and inflammation responses.