Treatment Of Alcoholic Liver Disease Research Articles

Natural Compounds: A Potential Treatment for Alcoholic Liver Disease?

Excessive alcohol intake is a direct cause of alcoholic liver disease (ALD). ALD usually manifests as fatty liver in the initial stage and then develops into alcoholic hepatitis (ASH), fibrosis and cirrhosis. Severe alcoholism induces extensive hepatocyte death, liver failure, and even hepatocellular carcinoma (HCC). Currently, there are few effective clinical means to treat ALD, except for abstinence. Natural compounds are a class of compounds extracted from herbs with an explicit chemical structure. Several natural compounds, such as silymarin, quercetin, hesperidin, and berberine, have been shown to have curative effects on ALD without side effects. In this review, we pay particular attention to natural compounds and developing clinical drugs based on natural compounds for ALD, with the aim of providing a potential treatment for ALD.

Targeting the Gut Dysbiosis as a Treatment for Alcoholic Liver Disease

Alcohol Use Disorders (AUD) originates due to heavy and uncontrolled drinking of alcohol. It is one of the most prevalent mental disorders, which predominantly affects men globally. In the review article alcohol use disorders and several risk factors like gender, drinking habit, genetic differences, and obesity Hepatitis C virus has been described for the provocation of intestinal dysbiosis. Alcoholic Liver Disease (ALD) is a spectrum of diseases from steatohepatitis to Hepatocellular Carcinoma (HCC). Due to dysbiosis, there are microbial changes also taking place in the liver and it further worsens the conditions. Treatment involves treating gut dysbiosis and altered balance of the micro-organism. The treatment strategy of ALD may also involve a non-dietary approach or dietary approach or by microbiota modulation.

An iridoid glycoside from Cornus officinalis balances intestinal microbiome disorder and alleviates alcohol-induced liver injury

Abstract The intestinal microbiota plays an important role in the occurrence and development of alcoholic liver disease (ALD). The aim of this study was to investigate whether the cornel iridoid glycoside (CIG) of Cornus officinalis Sieb. et Zucc. could protect against ALD through the gut-liver axis. The results showed that, compared to an alcohol treated group, CIG could inhibit the activities of AST, ALT and MDA, promote the activities of SOD, CAT and GSH, and reduce oxidative damage to the liver. CIG could significantly alter intestinal microbial diversity, reduce the presence of serum LPS and levels of TNF-α, IL-1β and IL-6 in the liver. In addition, CIG supplementation reduced the imbalance of intestinal microbiota caused by alcohol and improved intestinal barrier function. Therefore, CIG may have a beneficial effect in alcoholic liver disease by maintaining the stability of the intestinal microbiota. We propose CIG as a potential therapeutic and prophylactic compound in clinical treatment of ALD.

ABL2 promotes alcohol‐induced steatosis through regulation of PPARg expression

Alcoholic liver disease (ALD) represents a spectrum of alcohol use-related diseases, ranging from steatosis to cirrhosis, and is one of the primary causes of chronic liver disease worldwide. Outside of alcohol abstinence, there are currently no FDA-approved treatments for advanced ALD, necessitating a greater understanding of ALD pathogenesis and potential molecular targets for therapeutic intervention. The ABL-family proteins, including ABL1 and ABL2, are non-receptor tyrosine kinases that participate in a diverse set of cellular functions including mitosis, adhesion, differentiation, and stress response. We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well liver tissues from mice subjected to an alcohol feeding regimen. To further our understanding of the role of the ABL kinases in ALD, we established strains of liver-specific ABL1 and ABL2 knockout mice. When subjected to alcohol feeding, we found that knockout of ABL2, but not ABL1, abrogated alcohol-induced steatosis. Subsequent RNA-sequencing and gene set enrichment analyses of mouse liver tissues revealed that, relative to wild-type alcohol-fed mice, ABL2 knockout alcohol-fed mice exhibited numerous pathway changes including significantly decreased PPAR signaling. Further examination revealed that PPARg, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in ABL2 knockout mice, suggesting a potential novel role for ABL2 in the regulation of PPARg. In vitro analyses conducted in HepG2, an immortalized liver cell line, revealed that PPARg protein levels increase in response to alcohol treatment leading to marked increases in lipid accumulation as determined by Oil Red O staining. shRNA-mediated knockdown of ABL2, however, abolished the alcohol-induced accumulation of PPARg as well as subsequent lipid-accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARg protein expression. Furthermore, treatment with GMB475, a recently developed, highly specific proteolysis-targeting chimera (PROTAC) directed against the ABL kinases, attenuated alcohol-induced PPARg protein accumulation as well as subsequent lipid droplet formation. Based on our current evidence, we propose that alcohol-induced ABL2 activation promotes ALD through increasing PPARg expression and ABL2 inhibition may serve as a promising target for the treatment of ALD.

Spermidine Prevents Ethanol and Lipopolysaccharide-Induced Hepatic Injury in Mice.

To date, there is no effective treatment for alcoholic liver disease, despite its prevalence world-wide. Because alcohol consumption is associated with oxidative stress-induced liver injury and pro-inflammatory responses, naturally occurring antioxidants and/or anti-inflammatories may be potential therapeutics. Spermidine is an abundant, ubiquitous polyamine that has been found to display strong antioxidant and anti-inflammatory properties. To further investigate whether spermidine is an effective intervention for alcohol-induced liver disease, we examined its hepatoprotective properties using a two-hit, chronic ethanol and acute lipopolysaccharide (LPS)-induced mouse model of liver injury. We determined that spermidine administration prevented ethanol and LPS-induced increases in liver injury using plasma ALT as a readout. Furthermore, histological analysis of tissue from control and treated animals revealed that the pathology associated with ethanol and LPS treatment was prevented in mice additionally treated with spermidine. As predicted, spermidine also prevented ethanol and LPS-induced oxidative stress by decreasing the levels of both reactive oxygen species (ROS) and lipid peroxidation. We further determined that spermidine treatment prevented the nuclear translocation of nuclear factor κB (NFκB) by blocking the phosphorylation of the inhibitory protein, IκB, thereby preventing expression of pro-inflammatory cytokines. Finally, by measuring expression of known markers of hepatic stellate cell activation and monitoring collagen deposition, we observed that spermidine also prevented alcohol and LPS-induced hepatic fibrosis. Together, our results indicate that spermidine is an antioxidant thereby conferring anti-inflammatory and anti-fibrotic effects associated with alcoholic liver injury.

Molecular factors associated with regression of liver fibrosis of alcoholic etiology

Liver fibrosis develops as a result of chronic liver damage of various etiologies, is characterized by excessive synthesis of connective tissue by activated stellate liver cells. The toxic effect of alcohol is one of the most significant and common etiological factors worldwide. Stellate cell activation results from the interaction of multiple molecular fibrogenic pathways triggered by intracellular and extracellular, hepatic and extrahepatic stimuli. Data analysis showed that knowledge about these abnormal pathways and biomolecular processes may further contribute to the improvement of approaches to assessment of disease prognosis and treatment of alcoholic liver disease.

Taxifolin, a novel food, attenuates acute alcohol-induced liver injury in mice through regulating the NF-κB-mediated inflammation and PI3K/Akt signalling pathways

Context Taxifolin (TAX) has effective anti-inflammatory, antioxidant and hepatoprotective activities, but its potential mechanism has not been revealed. Objective To evaluate the potential protective effect of TAX on acute alcohol-induced liver injury in mice. Materials and methods Alcoholic liver injury model was established by oral alcohol in mice, and randomly distributed in five groups (n = 10): Normal group (oral saline only); Alcohol group (concentration of fermented alcohol: 56%, 6 mL/kg); TAX groups, mice were orally administered with alcohol, and then TAX with doses of 20, 40, 80 mg/kg, respectively. Oral administration was conducted for 6 weeks. Results TAX treatment illustrated that the level of alanine aminotransferase (ALT) was reduced to 65.90 ± 2.26 U/L and aspartate aminotransferase (AST) to 33.28 ± 5.62 U/L compared with alcohol group (ALT 124.51 ± 4.40 U/L, AST 61.70 ± 4.09 U/L), while superoxide dismutase (SOD) was increased to 49.81 ± 2.39 U/mg and glutathione (GSH) to 8.16 ± 0.44 μmol/g, but MDA was reversed to 2.53 ± 0.24 nmol/mg. Histopathological examination showed TAX treatment alleviated alcohol-induced hepatocyte necrosis and inflammatory infiltration. Meanwhile, Western blot and rt-PCR indicated TAX reduced IL-6 to 2.49 ± 0.25 pg/mL and TNF-α to 1.79 ± 0.20 pg/mL, and inhibiting NF-κB activation in liver. Moreover, TAX reversed alcohol-induced apoptosis by regulating the expression of PI3K/Akt and its downstream apoptotic factors. Conclusions The research provides novel evidence of the hepatoprotective effect of TAX on alcohol-induced liver injury, while also providing the possibility for future treatment of alcoholic liver disease.

Effect of nicotinamide riboside on lipid metabolism and gut microflora-bile acid axis in alcohol-exposed mice.

Alcoholic liver disease (ALD) is the most common complication of alcohol abuse, while we lack safe and effective treatment for ALD. This study aimed to explore the effects of nicotinamide riboside (NR) on lipid metabolism and gut microflora‐bile acid axis in alcohol‐exposed mice. NR significantly improved liver histopathological damage and abnormal liver function. NR as a provider of nicotinamide adenine dinucleotide (NAD+) increased the NAD+/NADH ratio. Meanwhile, NR inhibited the activation of the protein phosphatase 1 signaling pathway, decreased the liver triglyceride and total bile acid levels, and reduced lipid accumulation. According to the results of gut microflora species analysis, NR intervention changed the microbial community structure at the phylum, family and genus levels, and the species abundances returned to a level similar to these of the normal control group. Besides, the results of high‐performance liquid chromatograph‐mass spectrometry showed that NR intervention resulted in fecal bile acid levels tending to be normal with decreased chenodeoxycholic acid level and increased deoxycholic acid and hyocholic acid levels. Spearman's correlation analysis showed a correlation between gut microflora and bile acids. Therefore, NR supplementation has the potential to prevent ALD, and its mechanism may be related to regulating lipid metabolism disorders and the gut microflora‐bile acid axis.

Puerariae Lobatae radix flavonoids and puerarin alleviate alcoholic liver injury in zebrafish by regulating alcohol and lipid metabolism

Exessive drinking is commonly associated with a wide spectrum of liver injuries. The term alcoholic liver disease (ALD) is generally used to refer to this spectrum of hepatic abnormalities, and the term hepatic steatosis denotes early lesions. Puerariae Lobatae Radix (PLR) is a common traditional Chinese medicine and has been widely used as an efficient treatment for alcohol-induced damage. Flavonoids are the principal components of PLR that could potentially be responsible for the activation of alcohol metabolism and lipid-lowering effects. However, little is known about the mechanisms underlying their activity against alcoholic injury. In this study, PLR flavonoids (PLF) were obtained by microwave extraction. A 2% ethanol solution was used to establish a model of alcoholic fatty liver disease by exposure of zebrafish larvae for 32 h, and then the zebrafish were administered PLF and puerarin. The results showed that PLF and puerarin significantly decreased lipid accumulation and the levels of total cholesterol and triglycerides in zebrafish larvae. Moreover, PLF and puerarin downregulated the expression of genes related to alcohol and lipid metabolism (CYP2y3, CYP3a65, ADH8a, ADH8b, HMGCRB, and FASN), endoplasmic reticulum stress, and DNA damage (CHOP, EDEM1, GADD45αa, and ATF6) and reduced levels of inflammatory factors (IL-1β, TNF-α) in zebrafish larvae. PLF and puerarin increased the phosphorylation of AMP-activated protein kinase-α (AMPKα) and decreased the total protein level of ACC1. The findings suggested that PLF and puerarin alleviated alcohol-induced hepatic steatosis in zebrafish larvae by regulating alcohol and lipid metabolism, which was closely related to the regulation of the AMPKα-ACC signaling pathway. In conclusion, the study provided a possible therapeutic drug for ALD treatment.

New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism.

BACKGROUNDIntestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism.AIMTo evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice.METHODSA new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography–mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing.RESULTSThe P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation.CONCLUSIONBased on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.

Dihydromyricetin improves mitochondrial outcomes in the liver of alcohol-fed mice via the AMPK/Sirt-1/PGC-1α signaling axis.

Alcoholic liver disease (ALD), due to the multifactorial damage associated with alcohol (ethanol) consumption and metabolism, is one of the most prevalent liver diseases in the United States. The liver is the primary site of ethanol metabolism and is subsequently injured due to the production of reactive oxygen species (ROS), acetaldehyde, and metabolic stress. Building evidence suggests that dihydromyricetin (DHM), a bioactive flavonoid isolated from Hovenia dulcis, provides hepatoprotection by enhancing ethanol metabolism in the liver by maintaining hepatocellular bioenergetics, reductions of oxidative stress, and activating lipid oxidation pathways. The present study investigates the utility of DHM on hepatic mitochondrial biogenesis via activation of the AMP-activated protein kinase (AMPK)/Sirtuin (Sirt)-1/PPARG coactivator 1 (PGC)-1α signaling pathway. We utilized a forced drinking ad libitum study that chronically fed 30% ethanol to male C57BL/6J mice over 8 weeks and induced ALD pathology. We found that chronic ethanol feeding resulted in the suppression of AMPK activation and cytoplasmic Sirt-1 and mitochondrial Sirt-3 expression, effects that were reversed with daily DHM administration (5mg/kg; intraperitoneally [i.p.]). Chronic ethanol feeding also resulted in hepatic hyperacetylation of PGC-1α, which was improved with DHM administration and its mediated increase of Sirt-1 activity. Furthermore, ethanol-fed mice were found to have increased expression of mitochondrial transcription factor A (TFAM), reduced mitochondrial content as assessed by mitochondrial DNA to nuclear DNA ratios, and significantly lower levels of hepatic ATP. In contrast, DHM administration significantly increased TFAM expression, hepatic ATP concentrations, and induced mitochondrial expression of respiratory complex III and V. In total, this work demonstrates a novel mechanism of DHM that improves hepatic bioenergetics, metabolic signaling, and mitochondrial viability, thus adding to the evidence supporting the use of DHM for treatment of ALD and other metabolic disorders.

Ursolic acid reduces hepatocellular apoptosis and alleviates alcohol-induced liver injury via irreversible inhibition of CASP3 in vivo.

Alcoholic liver disease (ALD) is one of the pathogenic factors of chronic liver disease with the highest clinical morbidity worldwide. Ursolic acid (UA), a pentacyclicterpenoid carboxylic acid, has shown many health benefits including antioxidative, anti-inflammatory, anticancer, and hepatoprotective activities. We previously found that UA was metabolized in vivo into epoxy-modified UA containing an epoxy electrophilic group and had the potential to react with nucleophilic groups. In this study we prepared an alkynyl-modified UA (AM-UA) probe for tracing and capturing the target protein of UA from liver in mice, then investigated the mode by which UA bound to its target in vivo. By conducting proteome identification and bioinformatics analysis, we identified caspase-3 (CASP3) as the primary target protein of UA associated with liver protection. Molecule docking analysis showed that the epoxy group of the UA metabolite reacted with Cys-163 of CASP3, forming a covalent bond with CASP3. The binding mode of the UA metabolites (UA, CM-UA, and EM-UA) was verified by biochemical evaluation, demonstrating that the epoxy group produced by metabolism played an important role in the inhibition of CASP3. In alcohol-treated HepG2 cells, pretreatment with the UA metabolite (10 μM) irreversibly inhibited CASP3 activities, and subsequently decreased the cleavage of PARP and cell apoptosis. Finally, pre-administration of UA (20-80 mg· kg-1 per day, ig, for 1 week) dose-dependently alleviated alcohol-induced liver injury in mice mainly via the inhibition of CASP3. In conclusion, this study demonstrates that UA is a valuable lead compound for the treatment of ALD.

The effects of Gentiana dahurica Fisch on alcoholic liver disease revealed by RNA sequencing

Ethnopharmacological relevanceThe root of Gentiana dahurica Fisch (called Qin-Jiao in China), a traditional Chinese medicine, is used in China to treat alcoholic liver disease (ALD), but there has been no scientific report on the treatment of ALD. Aim of the studyTo investigate the therapeutic effects of Gentiana dahurica Fisch ethanol extract (GDEE) on ALD and to reveal its possible mechanism of action using RNA sequencing. Materials and methodsThe model of ALD was established by continuous gavage with alcohol in mice, and GDEE was used to treat ALD. Pathological observation (HE staining, oil red O staining) and biochemical indicators were performed to evaluate liver tissue lesions and efficacy of GDEE. RNA sequencing analysis of liver tissues was carried out to elucidate the pathogenesis of ALD and the mechanism of hepatoprotective effect by GDEE. The RNA sequencing results were verified by detecting mRNA and protein expressions of acetyl coenzyme A carboxylase α (Acacα), fatty acid synthase (Fasn) and carnitine palmitoyltransferase 1A (Cpt1a) by quantitative real-time polymerase chain reaction (PCR) and Western blot. ResultsMeasurements of biochemical parameters showed that GDEE could inhibit the increased transaminase activities in the serum and lipid levels in the liver caused by alcohol. It was observed that GDEE could alleviate fatty degeneration, edema and cell necrosis caused by alcohol in the liver tissue. RNA sequencing analysis of liver tissues found that 719 genes and 1137 genes were significantly changed by alcohol and GDEE, respectively. GDEE reversed most of the changes in triglycerides synthesis-related genes up-regulated by alcohol. GDEE up-regulated most of the genes involved in the fatty acid degradation in ALD mice, while alcohol had little effect on them. In addition, GDEE suppressed most of the genes involved in cholesterol synthesis that were up-regulated by alcohol. GDEE up-regulated genes related to bile acid synthesis in ALD mice, and down-regulated genes related to bile acid reabsorption, while alcohol had no significant effect on genes related to bile acid metabolism. In the validation experiments, the Acacα, Fasn and Cpt1a expressions quantified by real-time PCR and Western blot were consistent with the RNA sequencing results. ConclusionsGDEE can alleviate liver damage and steatosis in ALD mice, and its mechanism of action may be related to the process of regulating triglycerides and cholesterol.

The lymphatic system in alcohol-associated liver disease.

The lymphatic system plays vital roles in interstitial fluid balance and immune cell surveillance. The effect of alcohol on the lymphatic system is poorly understood. This review article explores the role of the lymphatic system in the pathogenesis of alcohol-related disease including alcoholic liver disease (ALD) and the therapeutic potential of targeting hepatic lymphatics for the treatment of ALD.

Medical Treatment of Alcoholic Liver Disease

Alcoholic liver disease is a major cause of liver disease that results in significant morbidity and mortality in Korea. Abstinence is the most important strategy to prevent disease progression. Corticosteroids improve the one-month survival in patients with severe alcoholic hepatitis, but it was not effective on long-term survival. An N-acetylcysteine treatment combined with corticosteroids may provide a short-term survival benefit than corticosteroids alone. Pentoxifylline is unlikely to affect short-term survival. Hence, studies on new therapies, such as granulocyte colony-stimulating factor and fecal microbiota transplantation, are ongoing. This paper briefly reviews the current knowledge of the medical treatment of alcoholic liver disease.

Alcoholic liver disease. Clinical example

Alcoholic liver disease (ALD) is one of the major liver diseases associated with high mortality rates. There are about 3 million alcohol-related deaths worldwide every year. ALD covers the spectrum of liver damage ranging from asymptomatic steatosis, alcoholic steatohepatitis and fibrosis to cirrhosis. In addition, patients may suffer from acute and chronic liver failure, alcoholic hepatitis (AH), bleeding from esophageal or gastric varices, ascites, coagulopathy, hepatic encephalopathy and liver cancer. In most patients, AH is diagnosed at advanced stages of the disease with higher complication and mortality rates. Patients abusing alcohol may simultaneously have viral hepatitis B or C, genetic diseases such as alpha-1 antitrypsin deficiency or hemochromatosis. The clinical manifestations of the disease are very diverse. There is no special laboratory test to detect the alcoholic cause of liver damage. A liver biopsy in the context of alcohol abuse in the history is a diagnostic test, but is not indicated for all patients. The main focus of therapy for ALD patients regardless of the stage of the disease is prolonged alcoholic abstinence. Abstinence is also the main key to preventing alcoholic liver diseases. Corticosteroids provide short-term survival improvement in about half of the patients with severe AH, and long-term survival is related to the severity of the underlying liver disease and depends on alcohol abstinence. General therapeutic measures in patients hospitalized with ALD include inpatient treatment of complications, treatment of alcohol withdrawal syndrome, monitoring of concomitant infectious diseases and their early effective antibiotic therapy, addition of hepatoprotectors to therapy regimens, and treatment of the underlying alcohol-related disorder. Liver transplantation (LT) is the final treatment option in patients with decompensated alcoholic liver cirrhosis. LT may also be considered in individual patients with AH who do not respond to drug therapy. Existing AH treatment regimens have insufficient efficacy, therefore, development of new methods and regimens of ALD targeted therapy is required. In this article we will consider the pathogenesis and treatment of ALD, paying more attention to AH, its topical and promising methods of treatment.

Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease

BackgroundIt is well acknowledged that alcoholic liver disease (ALD) is widely prevalent all over the world, characterized by aberrant lipid deposition and excessive oxidative stress in hepatocytes. Recently, pyroptosis, a new type of programmed cell death, has been found in ALD, which provides new ideas for the treatment of ALD. MethodsMale ICR mice were treated with the Lieber-De-Carli diet (Dyets) or isocaloric liquid diet for 8 weeks, and binge alcohol model was also used for ALD. Blood and livers were taken to evaluate the efficacy of oroxylin A. The levels of factors related to hepatocyte pyroptosis were measured via western blot analyses, immunofluorescence analyses and quantitative reverse transcriptase in vitro. ResultOur study found that oroxylin A suppressed hepatocyte pyroptosis through a NLRP3 inflammasome dependent-canonical caspase-1 pathway. Results illuminated that oroxylin A inhibited NLRP3 inflammasome activation by reducing ROS accumulation. Furthermore, oroxylin A upregulated mitofusin 2 (Mfn2) to resist lipid deposition and mitochondria-derived ROS overproduction. As an upstream mediator of Mfn2, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a major regulator of mitochondria, was found to promote transcription of Mfn2 under oroxylin A treatment. ConclusionOur research revealed that oroxylin A could alleviate ALD via PGC-1α/Mfn2 signaling mediated canonical pyroptosis pathway resistance.

Liver regeneration and alcoholic liver disease.

Alcoholic liver diseases (ALD) are a wide spectrum of liver diseases caused by excessive alcohol consumption, from steatosis to cirrhosis. The pathogenesis of ALD is insufficiently understood, but mainly involves oxidative stress, inflammation, bacterial translocation, cell death, and impaired regeneration. Despite numerous attempts to improve patient prognosis, the treatment of advanced ALD is still based on abstinence, brief exposure to corticosteroids, or liver transplantation. However, poor response to corticosteroids and the shortage of liver donors leaves patients helpless towards the end stages. Advances in basic research have contributed to a better understanding of ALD pathophysiology, which offers new options for treatment. In recent years, several therapies related to liver regeneration have been tested with promising prospects, including molecule-induced liver regeneration, stem cell transplantation, and full-function 3D artificial liver assembly. This review discusses mechanisms underlying ALD that can be considered therapeutic targets for regeneration-based treatments.

Alcoholic liver diseases: Disease spectrum, pathophysiology, oxidative stress and role of flavonoids in alcoholic liver injury

An Alcoholic Liver Disease (ALD) has emerged as the serious health problem globally, with high morbidity and mortality rate. Heavy alcohol consumption resulted in broad spectrum of liver diseases ranging from steatosis (alcoholic fatty liver), alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In this review the detailed patho-physiology of the ALD, role of oxidative stress ALD, the mechanism of action of flavonoids with different models used have been explained. Heavy alcohol consumption leads to severe liver diseases, which is demonstrated by increased blood levels of ALT, AST, and/or lactate dehydrogenase (LDH) and accumulation of lipid in the hepatocytes causing steatosis. There are three mechanisms involved in causing of ALD, those are: (a) acetaldehyde toxicity; (b) oxidative stress or generation of ROS; and lastly (c) provocation of the immune response of hepatocytes causing oxidative stress. This shows that oxidative stress is a major cause for ALD, therefore, defence activities against this stress are most vital in the prevention of ALD. Application of antioxidants especially flavonoids signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Flavonoids inhibit ROS formation by regulating glutathione S-transferase, mitochondrial succinoxidase etc. Since lipid peroxidation is a result of oxidative stress, lipids are protected from oxidative damage using flavonoids. Various flavonoids and their mechanism of action have been discussed in this review, formulation of these flavonoids will be highly beneficial for treatment of ALD.

Bile Acid Membrane Receptor TGR5 Inhibits Alcohol‐Induced Liver Steatosis

Alcoholic liver disease (ALD) is one of the leading causes of liver failure in the world. It progresses from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized with hepatic inflammation. Chronic ASH will result in fibrosis, cirrhosis and hepatocellular cancer (HCC) eventually. However, very few treatment options for ALD are available currently. Therefore, there is an urgent unmet medical need to better understand the molecular mechanisms underneath the development of ALD and develop effective treatment approaches. Bile acid signaling in the liver‐gastrointestinal tract axis is important for the integrated regulation of lipid, glucose, and energy metabolism. Dysregulated bile acid signaling is associated with ALD due to the fact that alcohol significantly alters bile acids pool and composition in humans and rodents. G‐protein‐coupled bile acid receptor, Gpbar1 (TGR5), is a membrane bound bile acid receptor. It is more broadly expressed, but its hepatic expression is limited to Kupffer cells, macrophages and sinusoidal endothelial cells. Little information regarding the effects of TGR5 in the pathological development of ALD has been reported before. In this study, we use C57BL/6(WT) and TGR5 knockout (TGR5−/−) mice to study the potential role of TGR5 in alcohol‐induced liver disease. Mice were challenged with chronic 5% ethanol feeding (10 days) plus a binge dose of alcohol by oral gavage (5 g/kg body weight) or with acute high dose alcohol gavage. The results showed that the liver/body weight ratio was increased in both WT and TGR5−/− ethanol fed mice, while it was significant higher in ethanol fed TGR5−/− mice than WT mice. The liver injury marker serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were both increased. Alcohol feeding altered gene expression in bile acid homeostasis. The hepatic triglycerides were upregulated almost 30% higher in TGR5−/− mice than WT group. The haematoxylin Eosin (H&E) and Oil Red O staining showed more fat vacuoles in the liver of ethanol fed TGR5−/− mice than that in WT mice. We also treat the mice with a novel potent TGR5 agonist ligand and found protective effects on ALD in WT but not TGR5−/− mice. Collectively, these results suggest that TGR5 may prevent the development of ALD and represent a novel target for ALD treatment.Support or Funding InformationCity of Hope Departmental Internal funding