Key regulators of hepatic stellate cell activation in alcohol liver Disease: A comprehensive review.

Alcoholic liver disease (ALD) is a broad category of disorders that begin with liver injury, lead to liver fibrosis, and ultimately conclude in alcohol-induced liver cirrhosis, the most chronic and irreversible liver damage. Liver fibrosis (LF) is a common pathological characteristic observed in most chronic liver inflammatory conditions that involve prolonged inflammation. In this review, we have summarized ethanol-mediated hepatic stellate cell (HSCs) activation and its role in liver fibrosis progression. We highlight important molecular mechanisms that are modulated by ethanol, play a role in the activation of HSCs and the progression of liver fibrosis and identifying potential targets to ameliorate liver fibrosis.

Safety and Effectiveness of Liv.52 DS in Patients With Varied Hepatic Disorders: An Open-Label, Multi-centre, Phase IV Study.

Background The hepatoprotective function of polyherbal formulation Liv.52 in chronic liver diseases is well recognized in published literature. The objective of this open-label, phase IV study was to further strengthen and validate its safety and effectiveness using a large patient pool in a real-world scenario and provide scientific data on symptomatic improvement and supportive treatment in liver function with improvement in quality of life. Methods Adult patients of either sex with one or more clinical symptoms like fatigue, nausea, anorexia, abdominal pain or discomfort, muscle cramps, jaundice, or any other signs and symptoms with a history suggestive of mild-to-moderate hepatic disorders like alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), drug-induced hepatotoxicity, or hepatitis were treated with two Liv.52 DS tablets (oral) twice daily for 12 weeks. Results Out of the 1000 enrolled patients, 962 (96%) completed the study with the following subgroups ALD: 375 (38.9%), NAFLD: 379 (39.3%), drug-induced hepatotoxicity: 78 (8.1%), hepatitis: 130 (13.5%). The mean age of enrolled patients was 37.7 years, and the majority of them, 785 (78.5%) were men. The common adverse events observed (with >1.5% incidence) in the study were abdominal pain: 26 (2.6%) and headache: 17 (1.7%). Liv.52 showed statistically significant improvement (P<0.0001) in various clinical signs and symptoms in the majority of patients namely, fatigue: 357/723 (49%), anorexia: 485/620 (78.2%), jaundice: 48/52 (92%). Majority of the patients showed significant improvements from baseline to end of 12 weeks in the liver function test parameters namely, aspartate aminotransferase: 633/840 (75.36%), alanine aminotransferase: 592/729 (81.21%), serum bilirubin: 244/347 (70.32%), alkaline phosphatase: 279/355 (78.59%) with P<0.0001 for all parameters. Statistically significant improvement (P<0.005) was also seen in all the components of the chronic liver disease questionnaire (CLDQ) scores from baseline to 12 weeks. Conclusions The study demonstrated that Liv.52 was hepatoprotective and well tolerated in the study population after treatment for 12 weeks. Significant improvements were seen in clinical signs and symptoms, laboratory parameters of liver function, and CLDQ scores from baseline to 12 weeks. No significant or new safety signals emerged from this study.

Butyrate alleviates alcoholic liver disease-associated inflammation through macrophage regulation and polarization via the HDAC1/miR-155 axis.

BACKGROUND: We recently found that butyrate could ameliorate inflammation of alcoholic liver disease (ALD) in mice. However, the exact mechanism remains incompletely comprehended. Here, we examined the role of butyrate on ALD-associated inflammation through macrophage (Mψ) regulation and polarization using in vivo and in vitro experiments. METHODS: For in vivo experiments, C57BL/6J mice were fed modified Lieber-DeCarli liquid diets supplemented with or without ethanol and sodium butyrate (NaB). After 6 weeks of treatment, mice were euthanized and associated indicators were analyzed. For in vitro experiments, lipopolysaccharide (LPS)-induced inflammatory murine RAW264.7 cells were treated with NaB or miR-155 inhibitor/mimic to verify the anti-inflammatory effect and underlying mechanism. RESULTS: The administration of NaB alleviated pathological damage and associated inflammation, including LPS, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß levels in ALD mice. NaB intervention restored the imbalance of macrophage polarization by inhibiting inducible nitric oxide synthase (iNOS) and elevating arginase-1 (Arg-1). Moreover, NaB reduced histone deacetylase-1 (HDAC1), nuclear factor kappa-B (NF-κB), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and miR-155 expression in ALD mice, but also increased peroxisome proliferator-activated receptor-γ (PPAR-γ). Thus, MiR-155 was identified as a strong regulator of ALD. To further penetrate the role of miR-155, LPS-stimulated RAW264.7 cells co-cultured with NaB were treated with the specific inhibitor or mimic. Intriguingly, miR-155 was capable of negatively regulated inflammation with NaB intervention by targeting SOCS1, SHIP1, and IRAK-M genes. CONCLUSION: Butyrate suppresses the inflammation in mice with ALD by regulating macrophage polarization via the HDAC1/miR-155 axis, which may potentially contribute to the novel therapeutic treatment for the disease.

Glucosamine attenuates alcohol-induced acute liver injury via inhibiting oxidative stress and inflammation.

Alcohol liver disease (ALD) is a liver disease caused by long-term heavy drinking. Glucosamine (GLC) is an amino monosaccharide that plays a very important role in the synthesis of human and animal cartilage. GLC is commonly used in the treatment of mild to moderate osteoarthritis and has good anti-inflammatory and antioxidant properties. In this study, alcoholic injury models were constructed in mice and human normal hepatocyte L02 cells to explore the protective effect and mechanism of GLC on ALD. Mice were given GLC by gavage for 30 days. Liver injury models of both mice and L02 cells were produced by ethanol. Detecting the levels of liver injury biomarkers, lipid metabolism, oxidative stress biomarkers, and inflammatory factors through different reagent kits. Exploring oxidative and inflammatory pathways in mouse liver tissue through Western blot and RT-PCR. The results showed that GLC can significantly inhibit the abnormal increase of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), triglycerides (TG), total cholesterol (TC), very low density lipoprotein (VLDL), low-density lipoprotein cholesterol (LDL-C), and can significantly improve the level of high-density lipoprotein cholesterol (HDL-C). In addition, GLC intervention significantly improved alcohol induced hepatic oxidative stress by reducing the levels of malondialdehyde (MDA) and, increasing the levels of glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) in the liver. Further mechanisms suggest that GLC can inhibit the expression of ethanol metabolism enzyme cytochrome P4502E1 (CYP2E1), activate the antioxidant pathway Keap1/Nrf2/HO-1, down-regulate the phosphorylation of MAPK and NF-κB signaling pathways, and thus reduce the expression of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). Therefore, GLC may be a significant candidate functional food for attenuating alcohol induced acute liver injury.

FXR overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in alcoholic liver disease.

BACKGROUND AND PURPOSE: Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. METHODS: The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber-DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH-DA staining was adopted to visualize reactive oxidative species (ROS). RESULTS: FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite. CONCLUSIONS: FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation.

Impacts of gut microbiota alteration on age-related chronic liver diseases.

The gut microbiome and its metabolites are involved in developing and progressing liver disease. Various liver illnesses, such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis C, and hepatocellular carcinoma, are made worse and have worse prognoses with aging. Dysbiosis, which occurs when the symbiosis between the microbiota and the host is disrupted, can significantly negatively impact health. Liver disease is linked to qualitative changes, such as an increase in hazardous bacteria and a decrease in good bacteria, as well as quantitative changes in the overall amount of bacteria (overgrowth). Intestinal gut microbiota and their metabolites may lead to chronic liver disease development through various mechanisms, such as increasing gut permeability, persistent systemic inflammation, production of SCFA, bile acids, and alteration in metabolism. Age-related gut dysbiosis can disrupt the communication between gut microbiota and the host, impacting the host's health and lifespan. With aging, a gradual loss of the ability to maintain homeostasis because of structural alteration and gut dysbiosis leads to the disease progression in end-stage liver disease. Recently chronic liver disease has been identified as a global problem. A large number of patients are receiving liver transplants yearly. Thereby gut microbiome ecology is changing in the patients of the gut due to the changes in pathophysiology during the preoperative stage. The present review summarises the age-associated dysbiosis of gut microbial composition and its contribution to chronic liver disease. This review also provides information about the impact of liver transplant on the gut microbiome and possible disadvantageous effects of alteration in gut microbiota.

Zebrafish as a Useful Model System for Human Liver Disease.

Liver diseases represent a significant global health challenge, thereby necessitating extensive research to understand their intricate complexities and to develop effective treatments. In this context, zebrafish (Danio rerio) have emerged as a valuable model organism for studying various aspects of liver disease. The zebrafish liver has striking similarities to the human liver in terms of structure, function, and regenerative capacity. Researchers have successfully induced liver damage in zebrafish using chemical toxins, genetic manipulation, and other methods, thereby allowing the study of disease mechanisms and the progression of liver disease. Zebrafish embryos or larvae, with their transparency and rapid development, provide a unique opportunity for high-throughput drug screening and the identification of potential therapeutics. This review highlights how research on zebrafish has provided valuable insights into the pathological mechanisms of human liver disease.

Omega-3 intake is associated with liver disease protection.

Background: Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease are among the most common liver diseases worldwide, and there are currently no Food and Drug Administration (FDA)-approved treatments. Recent studies have focused on lifestyle changes to prevent and treat NAFLD. Omega-3 supplementation is associated with improved outcomes in patients with chronic liver disease. However, it is unclear whether Omega-3 supplementation can prevent the development of liver disease, particularly in individuals at an increased (genetic) risk. Methods: In this UK Biobank cohort study, we established a multivariate cox proportional hazards model for the risk of incident liver disease during an 11 year follow up time. We adjusted the model for diabetes, prevalent cardiovascular disorders, socioeconomic status, diet, alcohol consumption, physical activity, medication intake (insulin, biguanides, statins and aspirin), and baseline characteristics. Results: Omega-3 supplementation reduced the risk of incident liver disease (HR = 0.716; 95% CI: 0.639, 0.802; p = 7.6 × 10-9). This protective association was particularly evident for alcoholic liver disease (HR = 0.559; 95% CI: 0.347, 0.833; p = 4.3 × 10-3), liver failure (HR = 0.548; 95% CI: 0.343, 0.875; p = 1.2 × 10-2), and non-alcoholic liver disease (HR = 0.784; 95% CI: 0.650, 0.944; p = 1.0 × 10-2). Interestingly, we were able to replicate the association with reduced risk of NAFLD in a subset with liver MRIs (HR = 0.846; 95% CI: 0.777, 0.921; p = 1.1 × 10-4). In particular, women benefited from Omega-3 supplementation as well as heterozygous allele carriers of the liver-damaging variant PNPLA3 rs738409. Conclusions: Omega-3 supplementation may reduce the incidence of liver disease. Our study highlights the potential of personalized treatment strategies for individuals at risk of metabolic liver disease. Further evaluation in clinical trials is warranted before Omega-3 can be recommended for the prevention of liver disease.

Protective effects of isoflavones on alcoholic liver diseases: Computational approaches to investigate the inhibition of ALDH2 with isoflavone analogues.

Excessive and chronic alcohol intake can lead to the progression of alcoholic liver disease (ALD), which is a major cause of morbidity and mortality worldwide. ALD encompasses a pathophysiological spectrum such as simple steatosis, alcoholic steatohepatitis (ASH), fibrosis, alcoholic cirrhosis, and hepatocellular carcinoma (HCC). Aldehyde dehydrogenase (ALDH2) is the most vital enzyme that produces acetate from acetaldehyde and is expressed at high levels in the liver, kidneys, muscles, and heart. The ALDH2*2 allele is found in up to 40% of East Asian populations, and has a significant impact on alcohol metabolism. Interestingly, several studies have shown that individuals with ALDH2 deficiency are more susceptible to liver inflammation after drinking alcohol. Furthermore, there is growing evidence of an association between ALDH2 deficiency and the development of cancers in the liver, stomach, colon, and lung. Isoflavone analogues are low molecular-weight compounds derived from plants, similar in structure and activity to estrogen in mammals, known as phytoestrogens. Recent studies have reported that isoflavone analogues have beneficial effects on the progression of ALD. This mini-review summarizes the current knowledge about the roles of isoflavone analogues in ALD and discusses the therapeutic potential of isoflavone analogues in liver pathophysiology. In particular, we highlight the significance of computational approaches in this field.

Noninvasive Positron Emission Tomography Imaging of SIRT1 in a Model of Early-Stage Alcoholic Liver Disease.

Accrued evidence has indicated that epigenetic mechanisms altered by alcohol have been implicated in the progression and development of alcoholic liver disease (ALD). SIRT1 plays an important role in ALD progression and has emerged as a promising therapeutic target for treating ALD. The purpose of this study is to investigate the efficacy of [11C]WL-1 for quantitative imaging of SIRT1 in mouse models of early-stage ALD. Positron emission tomography/computerized tomography (PET/CT) imaging was carried out 60 min following the injection of [11C]WL-1 in mouse models of early-stage ALD and normal control mice. The time-activity curves for ALD mouse livers showed remarkably decreased total uptake of [11C]WL-1 relative to that for control mouse livers. Moreover, compared with the normal control mice, decreased uptake in the cortex, hippocampus, and cerebellum was also observed in early-stage ALD mice, while the uptake of [11C]WL-1 in amygdala showed no significant changes. Western blot analysis confirmed that the protein levels of SIRT1 in the brains of early-stage ALD mice were decreased significantly when compared to the normal control mouse brains. Collectively, PET imaging with [11C]WL-1 would facilitate future clinical studies, aiming to demonstrate the roles of SIRT1 in ALD.

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

BACKGROUND: Fib4 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. METHODS: We 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. RESULTS: In 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). CONCLUSIONS: The 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.

Genome Editing and Fatty Liver.

Fatty liver disease is characterized as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Fatty liver disease is one of the most common causes of chronic liver disease worldwide among adults and children. It is characterized by excessive fat accumulation in the liver cells. It has a genetically heterogenous background with complex pathogenesis and progressions and is accompanied by significant morbidity, mortality, and healthcare costs. NAFLD's risk factors include metabolic syndrome, abdominal obesity, type 2 diabetes, and atherogenic dyslipidemia. ALD is associated with the excessive consumption of alcohol. Here, we describe the functions of various proteins encoded by gene variants contributing to the pathogenesis of nonalcoholic fatty liver disease and alcoholic fatty liver disease. Advancements in genome engineering technology have generated various in vivo and in vitro fatty liver disease models reflecting the genetic abnormalities contributing toward fatty liver disease. We will discuss currently developed different ALD and NAFLD models using the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) genome editing tool.Furthermore, we will also discuss the salient features of CRISPR/Cas9 editing technology and Cas9 variants such as prime and base editors to replicate genetic topographies linked specifically to ALD and NAFLD. The advantages and limitations of currently available genome delivery methods necessary for optimal gene editing will also be discussed in this review. This review will provide the essential guidance for appropriate genome editing tool selection and proper gene delivery approaches for the effective development of ALD and NAFLD models, leading to the development of clinical therapeutics for fatty liver disease.

Phosphodiesterase 4 mRNA Level Suppression is Important for Extract of Black Carrot to Protect Against Hepatic Injury Induced by Ethanol.

Excessive alcohol use often results in alcoholic liver disease (ALD). An early change in the liver due to excessive drinking is hepatic steatosis, which may ultimately progress to hepatitis, liver fibrosis, cirrhosis, and liver cancer. Among these debilitating processes, hepatic steatosis is reversible with the appropriate treatment. Therefore, it is important to find treatments and foods that reverse hepatic steatosis. Black carrot has antioxidant and anti-inflammatory effects. In this study, we examined the effectiveness of black carrot extract (BCE) on hepatic steatosis in in vivo and in vitro ethanol-induced liver injury models. For the in vivo experiments, serum aminotransferase activities enhanced by ethanol- and carbon tetrachloride were significantly suppressed by the BCE diet. Furthermore, morphological changes in the liver hepatic steatosis and fibrosis were observed in the in vivo ethanol-induced liver injury model, however, BCE feeding resulted in the recovery to an almost normal liver morphology. In the in vitro experiments, ethanol treatment induced reactive oxygen species (ROS) levels in hepatocytes at 9 h. Conversely, ROS production was suppressed to control levels and hepatic steatosis was suppressed when hepatocyte culture with ethanol were treated with BCE. Furthermore, we investigated enzyme activities, enzyme protein levels, and messenger RNA levels of alcohol dehydrogenase (ADH), cytochrome p450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) using enzyme assays, western blot, and quantitative reverse transcription-polymerase chain reaction analyses. We found that the activities of ADH, CYP2E1, and ALDH were regulated through the cAMP-PKA pathway at different levels, namely, translational, posttranslational, and transcriptional levels, respectively. The most interesting finding of this study is that BCE increases cAMP levels by suppressing the Pde4b mRNA and PDE4b protein levels in ethanol-treated hepatocytes, suggesting that BCE may prevent ALD.

Galacto-Oligosaccharide Alleviates Alcohol-Induced Liver Injury by Inhibiting Oxidative Stress and Inflammation.

Alcoholic liver disease (ALD) is a primary cause of mortality and morbidity worldwide. Oxidative stress and inflammation are important pathogenic factors contributing to ALD. We investigated the protective mechanism of galacto-oligosaccharide (GOS) against ALD through their antioxidant and anti-inflammatory activities by performing in vivo and in vitro experiments. Western blot and RT‒PCR results indicated that the expression of cytochrome P450 protein 2E1 (CYP2E1) in liver tissues and L02 cells was reduced in the GOS-treated mice compared with the model group. In addition, GOS prominently reduced the expression of Kelch-like ECH-associated protein 1 (Keap1), increased the expression of the nuclear factor erythroid-2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1) proteins, and enhanced the antioxidant capacity. In addition, GOS decreased inflammation by reducing inflammatory factor levels and inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. Based on these results, GOS may be a prospective functional food for the prevention and treatment of ALD.

Fine-tuning of regulatory T cells is indispensable for the metabolic steatosis-related hepatocellular carcinoma: A review.

The majority of chronic hepatic diseases are caused by nutritional imbalance. These nutritional inequities include excessive intake of alcohol and fat, which causes alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), respectively. The pathogenesis of hepatic diseases is mainly dependent on oxidative stress, autophagy, DNA damage, and gut microbiota and their metabolites. These factors influence the normal physiology of the liver and impact the hepatic microenvironment. The hepatic microenvironment contains several immune cells and inflammatory cytokines which interact with each other and contribute to the progression of chronic hepatic diseases. Among these immune cells, Foxp3+ CD4+ regulatory T cells (Tregs) are the crucial subset of CD4+ T cells that create an immunosuppressive environment. This review emphasizes the function of Tregs in the pathogenesis of ALD and NAFLD and their role in the progression of NAFLD-associated hepatocellular carcinoma (HCC). Briefly, Tregs establish an immunosuppressive landscape in the liver by interacting with the innate immune cells and gut microbiota and their metabolites. Meanwhile, with the advancement of steatosis, these Tregs inhibit the proliferation, activation and functions of other cytotoxic T cells and support the progression of simple steatosis to HCC. Briefly, it can be suggested that targeting Tregs can act as a favourable prognostic indicator by modulating steatosis and insulin resistance during the pathogenesis of hepatic steatosis and NAFLD-associated HCC.

Identification of Gut Microbiome Metabolites via Network Pharmacology Analysis in Treating Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is linked to a broad spectrum of diseases, including diabetes, hypertension, atherosclerosis, and even liver carcinoma. The ALD spectrum includes alcoholic fatty liver disease (AFLD), alcoholic hepatitis, and cirrhosis. Most recently, some reports demonstrated that the pathogenesis of ALD is strongly associated with metabolites of human microbiota. AFLD was the onset of disease among ALDs, the initial cause of which is alcohol consumption. Thus, we analyzed the significant metabolites of microbiota against AFLD via the network pharmacology concept. The metabolites from microbiota were retrieved by the gutMGene database; sequentially, AFLD targets were identified by public databases (DisGeNET, OMIM). The final targets were utilized for protein-protein interaction (PPI) networks and signaling pathway analyses. Then, we performed a molecular docking test (MDT) to verify the affinity between metabolite(s) and target(s) utilizing the Autodock 1.5.6 tool. From a holistic viewpoint, we integrated the relationships of microbiota-signaling pathways-targets-metabolites (MSTM) using the R Package. We identified the uppermost six key targets (TLR4, RELA, IL6, PPARG, COX-2, and CYP1A2) against AFLD. The PPI network analysis revealed that TLR4, RELA, IL6, PPARG, and COX-2 had equivalent degrees of value (4); however, CYP1A2 had no associations with the other targets. The bubble chart showed that the PI3K-Akt signaling pathway in nine signaling pathways might be the most significant mechanism with antagonistic functions in the treatment of AFLD. The MDT confirmed that Icaritin is a promising agent to bind stably to RELA (known as NF-Κb). In parallel, Bacterium MRG-PMF-1, the PI3K-Akt signaling pathway, RELA, and Icaritin were the most significant components against AFLD in MSTM networks. In conclusion, we showed that the Icaritin-RELA complex on the PI3K-Akt signaling pathway by bacterial MRG-PMF-1 might have promising therapeutic effects against AFLD, providing crucial evidence for further research.

Exercise Affects the Formation and Recovery of Alcoholic Liver Disease through the IL-6-p47phox Oxidative-Stress Axis.

(1) Background: To explore the effect of exercise on the formation and recovery of alcoholic liver disease (ALD) and whether the IL-6−p47phox oxidative−stress axis is involved in that process. (2) Methods: Firstly, 23 six-week-old male C57BL/6J mice were randomly divided into the Con group, ALD group, ALD + NOXI group, ALD + Ex group, and ALD + Ex + NOXI group. The Liber−DeCarli alcoholic liquid diet was used for 6 weeks to establish the ALD mice model, and the Con group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet, and exercise intervention was started after the ALD model establishment and lasted for another 6 weeks, with or without administration of the NOX inhibitor apocynin by intraperitoneal injection on every exercise training day. Secondly, 28 mice were randomly divided into the Sed group, Eth group, Eth + Ex group and Eth + Ex + NOXI group. The Sed group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet and exercise intervention was started synchronously combined with or without administration of intraperitoneal apocynin injections on every exercise training day for 5 weeks. After each individual experiment was accomplished, physiological assessment and biochemical analysis of blood and tissue samples were examined. (3) Results: The levels of TG in serum and IL-6 protein content in liver tissue in the ALD group were significantly increased compared to the Con group (p < 0.05); compared with ALD, p47phox expression in muscle was increased significantly in the ALD + NOXI group (p < 0.05), and TG in serum decreased in the ALD + Ex group (p < 0.05). TG in serum, AST/ALT ratio, and IL-6 content in both liver and muscle decreased (p < 0.05) in the ALD + Ex + NOXI group with MDA in muscle significantly increased (p < 0.01). The AST/ALT ratio, TG in serum, SOD in liver, and p47phox in both liver and muscle in the ALD + Ex + NOXI group were significantly decreased compared with the ALD + NOXI group (p < 0.01). Compared with the ALD + Ex group, the liver index and HDL-C levels in serum were decreased (p < 0.05) in the ALD + Ex + NOXI group. The degree of hepatocyte steatosis and inflammatory infiltration were ameliorated after exercise intervention. In the Eth group, the relative epididymal fat content, HDL-C level, and AST/ALT ratio were significantly decreased, and TG and gp91phox in liver were significantly higher than in the Sed group (p < 0.05, p < 0.01). Compared with the Eth group, the AST/ALT ratio, MDA in the liver, and NOX4 and p47phox protein expression in the liver were significantly increased, and body weight decreased significantly in the Eth + Ex group (p < 0.05, p < 0.01), as did TG in the liver and MDA in muscle. In the th + Ex + NOXI group, gp91phox expression in the liver and body weight were significantly decreased (p < 0.05, p < 0.01). In the Eth + Ex + NOXI group, the ratio of AST/ALT and MDA in muscle were increased when compared with the Eth + Ex group, and the protein expression of gp91phox and p47phox were much lower (p < 0.01). (4) Conclusions: 6 weeks of exercise intervention during the recovery phase of ALD ameliorates hepatocyte damage and dyslipidemia through the IL-6−p47phox oxidative−stress axis, and applying a NOX inhibitor in combination could optimize this. However, drinking alcohol during exercise exacerbates dyslipidemia and oxidative stress, with hepatocyte IL-6−p47phox downregulated.

The Translational Bridge between Inflammation and Hepatocarcinogenesis.

Viral infections or persistent alcohol or drug abuse, together with intrinsic factors, lead to hepatitis, which often ends in the development of liver cirrhosis or hepatocellular carcinoma (HCC). With this review, we describe inflammatory liver diseases, such as acute liver failure, virus-induced hepatitis, alcoholic- and non-alcoholic steatohepatitis, and autoimmune hepatitis, and highlight their driving mechanisms. These include external factors such as alcohol misuse, viral infection and supernutrition, as well as intrinsic parameters such as genetic disposition and failure, in immune tolerance. Additionally, we describe what is known about the translational machinery within all these diseases. Distinct eukaryotic translation initiation factors (eIFs) with specific functional roles and aberrant expression in HCC are reported. Many alterations to the translational machinery are already triggered in the precancerous lesions described in this review, highlighting mTOR pathway proteins and eIFs to emphasize their putative clinical relevance. Here, we identified a lack of knowledge regarding the roles of single eIF proteins. A closer investigation will help to understand and treat HCC as well as the antecedent diseases.

Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI) and GSK3ß in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1-Nrf2 PPI and inhibits GSK3ß to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD.