Chronic Alcoholic Liver Disease Research Articles

Mechanism of Shenling Baizhu Powder on treatment of alcoholic liver disease by regulating TLR4/NLRP3 pathway

This study aims to investigate the regulatory effects of Shenling Baizhu Powder(SBP) on cellular autophagy in alcoholic liver disease(ALD) and its intervention effect through the TLR4/NLRP3 pathway. A rat model of chronic ALD was established by gavage of spirits. An ALD cell model was established by stimulating BRL3A cells with alcohol. High-performance liquid chromatography(HPLC) was utilized for the compositional analysis of SBP. Liver tissue from ALD rats underwent hematoxylin-eosin(HE) and oil red O staining for pathological evaluation. Enzyme-linked immunosorbent assay(ELISA) was applied to quantify lipopolysaccharides(LPS), tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1β), and interleukin-18(IL-18) levels. Quantitative reverse transcription polymerase chain reaction(qRT-PCR) was conducted to evaluate the mRNA expression of myeloid differentiation factor 88(MyD88) and Toll-like receptor 4(TLR4). The effect of different drugs on BRL3A cell proliferation activity was assessed through CCK-8 analysis. Western blot analysis was performed to examine the protein expression of NOD-like receptor pyrin domain-containing 3(NLRP3), nuclear factor-kappa B P65(NF-κB P65), phosphorylated nuclear factor-kappa B P65(p-P65), caspase-1, P62, Beclin1, and microtubule-associated protein 1 light chain 3(LC3Ⅱ). The results showed that SBP effectively ameliorated hepatic lipid accumulation, reduced liver function, mitigated hepatic tissue inflammation, and reduced levels of LPS, TNF-α, IL-1β, and IL-18. Moreover, SBP exhibited the capacity to modulate hepatic autophagy induced by prolonged alcohol intake through the TLR4/NLRP3 signaling pathway. This modulation resulted in decreased expression of LC3Ⅱ and Beclin1, an elevation in P62 expression, and the promotion of autolysosome formation. These research findings imply that SBP can substantially enhance liver function and mitigate lipid irregularities in the context of chronic ALD. It achieves this by regulating excessive autophagic responses caused by prolonged spirit consumption, primarily through the inhibition of the TLR4/NLRP3 pathway.

The Preventative Effect of Chitooligosaccharides against Chronic Alcoholic Liver Disease by Regulating Alcohol Metabolism, Fatty Acid Metabolism, and Intestinal Barrier Damage

Since chronic alcoholic liver disease (ALD) is a significant global health concern, several studies have shown that chitooligosaccharides (COS) exhibit hepatoprotective effects. This paper examined the COS protective effect on chronic ALD mice. Results showed that COS improved the lipid accumulation, liver injury, and oxidative stress levels in the mice while inhibiting cytochrome P450 protein 2E1 (CYP2E1) expression in the liver and promoting alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH1) expression, indicating that COS could ameliorate alcohol metabolism. Moreover, COS intervention also enhanced the antioxidant capacity of the liver and upregulated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1), silent information regulator 1 (SIRT1), HO-1, and nuclear factor-erythroid 2-related factor 2 (NRF2) protein levels. In addition, COS increased peroxisome proliferator-activated receptor α (PPARα), acyl-CoA oxidase (ACOX), acyl-CoA synthetase long-chain family member (ACSL), carnitine palmitoyltransferase 1A (CPT-1A), and carnitine palmitoyltransferase 2 (CPT2) protein levels by upregulating the fatty acid β oxidation pathway and restoring mitochondrial genesis. From a liver-gut axis perspective, COS enhanced intestinal barrier function by increasing the adhesion junction (AJ) and intestinal tight junction (TJ) protein expression. Therefore, COS displayed a protective ability against chronic ALD. The results provide a theoretical basis for utilizing supplemental dietary COS as a functional food alternative for treating chronic ALD.

Insights of mitochondrial involvement in alcoholic fatty liver disease.

Alcoholic liver disease (ALD) is a global concern affecting most of the population and leading to the development of end-stage liver disease. Metabolic alterations due to increased alcohol consumption surge the hepatic accumulation of lipids and develop into a severe form of alcoholic steatohepatitis (ASH), depending on age and the consumption rate. The mitochondria in the hepatocyte actively regulate metabolic homeostasis and are disrupted in ALD pathogenesis. The increased NADH upon ethanol metabolism inhibits the mitochondrial oxidation of fatty acids, alters oxidative phosphorylation, and favors de novo lipogenesis. The higher mitochondrial respiration in early ALD increases free radical generation, whereas mitochondrial respiration is uncoupled in chronic ALD, affecting the cellular energy status. The defective glutathione importer due to excessive cholesterol loading and low adenosine triphosphate accounts for additional oxidative stress leading to hepatocyte apoptosis. The defective mitochondrial transcription machinery and sirtuins function in ALD affect mitochondrial function and biogenesis. The metabolites of ethanol metabolism epigenetically alter the gene expression profile of hepatic cell populations by modulating the promoters and sirtuins, aiding hepatic fibrosis and inflammation. The defect in mitophagy increases the accumulation of megamitochondria in hepatocytes and attracts immune cells by releasing mitochondrial damage-associated molecular patterns to initiate hepatic inflammation and ASH progression. Thus, maintaining mitochondrial lipid homeostasis and antioxidant capacity pharmacologically could provide a better outcome for ALD management.

Establishment and bioinformatics evaluation of the ethanol combined with palmitic acid-induced mouse hepatocyte AFLD model (the Hu-Qiu Model)

Chronic alcoholic liver disease has brought great harm to human health. Alcoholic fatty liver disease is the first stage in the progression of all chronic alcoholic liver diseases. At present, there is no cell model that fully matches the etiology (high-fat diet + alcohol) of human alcoholic fatty liver disease. We used 100 mM ethanol +6.25 μM PA to establish the ethanol combined with PA-induced mouse hepatocyte AFLD model (EP-AFLD hepatocyte model) and performed the RNA-seq transcriptome sequencing. Through bioinformatics analysis and comparison, we discovered that the EP-AFLD hepatocyte model was more suitable for studying the pathological mechanism of AFLD than the mouse AFLD hepatocyte model induced by ethanol alone. And through bioinformatics analysis, we further discovered that 77 genes from the differential expression gene set of EP-AFLD hepatocyte model were engaged in the pathological process of mouse AFLD and 40 genes were involved in the pathogenesis of both mouse AFLD and human AFLD. In this study, a novel mouse hepatocyte AFLD model was successfully established by combining ethanol and PA, which can be used to study the molecular mechanism of the pathogenesis of AFLD in mice or humans. This study will provide a brand-new in vitro experimental platform for the in-depth study of AFLD pathogenesis and the screening of AFLD therapeutic drugs.

Protection of Inonotus hispidus (Bull.) P. Karst. against Chronic Alcohol-Induced Liver Injury in Mice via Its Relieving Inflammation Response.

Alcoholic liver disease (ALD) can be induced by excessive alcohol consumption, and has a worldwide age-standardized incidence rate (ASIR) of approximately 5.243%. Inonotus hispidus (Bull.) P. Karst. (IH) is a mushroom with pharmacological effects. In ALD mice, the hepatoprotective effects of IH were investigated. IH strongly ameliorated alcohol-induced pathological changes in the liver, including liver structures and its function-related indices. Intestinal microbiota and serum metabolomics analysis showed that IH altered the associated anti-inflammatory microbiota and metabolites. According to results obtained from Western blot, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA), IH downregulated the levels of pro-inflammation factors interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α), enhanced the expressions of peroxisome proliferator-activated receptor alpha (PPARα) and 15-hydroxprostaglandin dehydrogenase (15-PGDH), and inhibited the phosphorylated activation of Janus kinase (JAK) 1 and signal transducer and activator of transcription (STAT) 3, confirming the hepatoprotection of IH against alcohol damage via anti-inflammation. This study provides the experimental evidence for the hepatoprotective effects of IH in chronic ALD.

A Screening Model for Probiotics Against Specific Metabolic Diseases Based on Caco-2 Monolayer Membrane

Recent studies have revealed the potency of probiotics in alleviating metabolic diseases associated with intestinal barrier dysfunction. However, an efficient model for screening probiotic strains against specific metabolic diseases has not been well developed. In the present study, a Caco-2 cell monolayer membrane model treated with tumor necrosis factor (TNF-α) or alcohol was used to evaluate the effect of 139 Lactobacillus strains on intestinal barrier function in vitro . We then selected 11 Lactobacillus strains with different regulatory abilities on the gut barrier to determine their effect against ovariectomy-induced osteoporosis or chronic alcoholic liver injury in vivo . Our results showed that the Pearson coefficient between the data of cell and animal models were 0.82 and −0.97 for the protection of probiotics against osteoporosis and alcoholic liver disease, respectively, suggesting the reliability of the cell model to simulate the in vivo protective effects of probiotics. This study established a potential in vitro approach based on a Caco-2 cell monolayer membrane model for the efficient screening of potential probiotics against specific metabolic diseases such as osteoporosis and chronic alcoholic liver disease.

Rhabdomyolysis caused by interaction between rosuvastatin and vadadustat: a case report

BackgroundRhabdomyolysis is a potentially life-threatening disease caused by melting or necrosis of skeletal muscle cells and leakage of muscle components into the bloodstream. It has been reported that the interaction of the HMG-CoA reductase inhibitor rosuvastatin with the renal anemia drug vadadustat increases the blood concentration of rosuvastatin in vitro. In this study, we report a case of suspected rhabdomyolysis caused by the drug interaction of rosuvastatin and vadadustat in clinical practice.Case presentationA 62-year-old male with medical records of hypertension, myocardial infarction, chronic renal failure, renal anemia, dyslipidemia, and alcoholic liver disease. The patient had been diagnosed with chronic kidney disease (CKD) at the Department of Nephrology, and treated by outpatient care with renal support therapy for the past two years. On X-63 day, his prescription was rosuvastatin (10 mg/day) and a continuous erythrocyte-stimulating agent, epoetin beta pegol (genetical recombination, 100 μg). X-Day 0, blood tests revealed creatine phosphokinase (CPK) 298 U/L, serum creatinine (SCr) 5.26 mg/dL, and hemoglobin (Hb) 9.5 g/dL; thus, the prescription was changed from epoetin beta pegol 100 μg to vadadustat 300 mg/day. On X + day 80, a prescription for a diuretic (azosemide 15 mg/day) was added for swelling of the lower extremities. On X + day 105, we found CPK 16,509 U/L, SCr 6.51 mg/dL, and Hb 9.5 g/dL. The patient was diagnosed as rhabdomyolysis and hospitalized. After hospitalization, rosuvastatin and vadadustat were discontinued and we administered intravenous fluids. Thereafter, CPK and SCr values of the patient improved. On X + day 122, CPK improved to 29 U/L, SCr to 2.6 mg/dL, and Hb to 9.6 g/dL, and he was discharged on X + day 124. At discharge, rosuvastatin 2.5 mg/day was resumed. A blood test on X + day 133 showed CPK 144 U/L and SCr 4.2 mg/dL.ConclusionWe experienced a case of rhabdomyolysis caused by drug interactions between rosuvastatin and vadadustat.

Nonheavy Alcohol Use Associates With Liver Fibrosis and Nonalcoholic Steatohepatitis in the Framingham Heart Study

Background and AimsWhile heavy alcohol use consistently associates with liver disease, the effects of nonheavy alcohol consumption are less understood. We aimed to investigate the relationship between nonheavy alcohol use and chronic liver disease. MethodsThis cross-sectional study included 2629 current drinkers in the Framingham Heart Study who completed alcohol use questionnaires and transient elastography. We defined fibrosis as liver stiffness measurement (LSM) ≥8.2 kPa. We defined at-risk nonalcoholic steatohepatitis (NASH) as FibroScan-aspartate aminotransferase (FAST) score >0.35 (90% sensitivity) or ≥0.67 (90% specificity). We performed logistic regression to investigate associations of alcohol use measures with fibrosis and NASH, adjusting for sociodemographic and metabolic factors. Subgroup analysis excluded heavy drinkers (>14 drinks per week for women or >21 for men). ResultsIn this sample (mean age 54.4 ± 8.9 years, 53.3% women), mean LSM was 5.6 ± 3.4 kPa, 8.2% had fibrosis, 1.9% had NASH by FAST ≥0.67, and 12.4% had NASH by FAST >0.35. Participants drank 6.2 ± 7.4 drinks per week. Total drinks per week and frequency of drinking associated with increased odds of fibrosis (adjusted odds ratio [aOR], 1.18; 95% confidence interval [CI], 1.04–1.33; and aOR, 1.08; 95% CI, 1.01–1.16, respectively). Risky weekly drinking, present in 17.4%, also associated with fibrosis (aOR, 1.49; 95% CI, 1.03–2.14). After excluding 158 heavy drinkers, total drinks per week remained associated with fibrosis (aOR, 1.16; 95% CI, 1.001–1.35). Multiple alcohol use measures positively associated with FAST >0.35. ConclusionsIn this community cohort, we demonstrate that nonheavy alcohol use associates with fibrosis and NASH, after adjustment for metabolic factors. Longitudinal studies are needed to determine the benefits of moderating alcohol use to reduce liver-related morbidity and mortality.

Acute-on-chronic liver failure or Alcoholic Hepatitis? In patients with chronic alcoholic liver disease

Acute-on-chronic liver failure or Alcoholic Hepatitis? In patients with chronic alcoholic liver disease

Diagnostic Performance of Noninvasive Tests for Advanced Hepatic Fibrosis in Young Age Population

Most noninvasive tests (NITs) for hepatic fibrosis are designed for middle-aged patients with chronic liver disease. We compared the diagnostic performance of major NITs (aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score) for a community-based cohort. This cross-sectional study analyzed 8775 participants who underwent magnetic resonance elastography at community health check-up centers. Advanced hepatic fibrosis (≥F3)was defined by magnetic resonance elastography thresholds of 3.6 kPa. Thediagnostic performance of 3 NITs was evaluated according to the etiology of liver disease, sex,metabolic syndrome, obesity, and increased aminotransferase levels in 4 age groups. The APRI generally showed the best area under the receiver operating characteristic curve in patients aged 45 years or younger, and it was statistically significant in patients with chronic viral hepatitis and alcoholic fatty liver disease (P < .043). The best APRI cut-off value for detecting advanced hepatic fibrosis was 0.4, with a sensitivity and specificity of 75.8% and 73.5%, respectively, in the community-based cohort. The APRI showed balanced sensitivity and specificity across all age groups, whereas the other metrics showed low sensitivity in those aged <45 and low specificity in those >65 years. The APRI showed better sensitivity and negative predictive value than the Fibrosis-4 index and the nonalcoholic fatty liver disease fibrosis score in community-based populations with mixed etiology, and, thus, can be performed as the primary test in young adults (age, ≤45 y).

P-016 SMALL BOWEL PERFORATION WITHIN A GIANT INGUINOSCROTAL HERNIA DUE TO AN INGESTED FOREIGN BODY

Abstract Introduction Bowel perforation due to an ingested foreign body is a rare event. Its presentation within an inguinoscrotal hernia, is even more uncommon. Case Description We report the case of a 69-year-old indigent man with a chronic alcoholic liver disease history, who presented in the emergency department due to sepsis. He was complaining of nausea, vomiting and mild abdominal pain. Clinical examination revealed a painful, giant right inguinoscrotal hernia, with cutaneous trophic changes and subcutaneous emphysema. Blood test showed leukocytosis and lactic acidosis. CT scan revealed small bowel perforation with peritonitis inside the hernia sac. The patient underwent emergency surgery. Two 5-centimeters long fishbones were found. Ileocecal resection with ileocolic side-to-side anastomosis and Lichtenstein hernioplasty open repair were performed. A polypropylene mesh was placed. Discussion Accidental foreign body ingestion followed by gastrointestinal tract perforation is a rare cause of peritonitis. There are few case reports about this event happening inside a hernia. Perforation is more common at points of physiological angulation or narrowing of the passage within the digestive tract, such as lower esophageal sphincter, pylorus or ileocecal valve. Inguinoscrotal hernias present as a pathologic stenotic area where foreign bodies can produce an obstruction or perforation. In these cases, the hernia repair is challenging due to the contaminated scenario. Conclusion The diagnosis of perforation within an inguinal hernia should be suspected in cases of acute abdomen and incarcerated hernia, in order to choose the best surgical treatment option.

Elevated gamma-glutamyl transpeptidase level is associated with an increased risk of hip fracture in postmenopausal women

The aim of this study was to evaluate the association between gamma-glutamyl transferase (GGT) levels and the risk of hip fracture among middle-aged women by using the Korean National Health Insurance Service claims database from 2002 to 2015. After exclusion of those with any chronic liver disease, heavy alcohol consumption, any missing values required for our analysis, or GGT levels less than 1 or greater than 99 percentile, we classified subjects into three groups according to baseline GGT levels. A total of 127,141 women aged 50 years or older were included for analysis (GGT range: 8–106 U/L). During an average 12.1 years of follow-up, 2758 patients sustained hip fractures (2.17%). Compared with the group in the lowest tertile, the group in the highest tertile had the highest cumulative incidence of hip fracture. One log-unit increase in GGT was associated with a 17% increased risk of hip fracture. Subgroup analysis by BMI (≥ 25 vs. < 25 kg/m2), presence of diabetes, levels of other liver enzymes, and alcohol consumption level did not show significant effect modification. In summary, elevated baseline GGT level was associated with an increased risk of hip fracture in postmenopausal women, independent of alcohol consumption and chronic liver disease.

A STUDY OF HAEMATOLOGICAL ABNORMALITIES IN CHRONIC LIVER DISEASE IN AJMER REGION

Chronic liver disease refers to a disease of the liver, which had lasted more than six months. The disease process involves progressive destruction and regeneration of liver parenchyma leading to brosis and cirrhosis. This study evaluates the various hematological indices as these parameters are part of an inexpensive, easily accessible, and routinely performed test for almost all patients admitted to health facilities to nd out a correlation between variation in hematological parameters and the illness under study. This study is conducted in the department of Pathology J.L.N Medical College and Associated group of hospitals, Ajmer (Rajasthan) prospectively from July 2019 to June 2020 (one year). In our study, the mean age for chronic liver disease was 44.48±11.84 years and the highest incidence was seen between the age group of 41-50 years (4th decade). M: F ratio was 6:1. Alcohol has been implicated as the most common cause. In the case of non- alcoholic hepatitis B has been implicated as the most common cause. The most common anemia is normocytic normochromic anemia. Microcytic anemia is most common among women. Macrocytosis is almost common with alcoholics. The mean MCV, MCH and MCHC were signicantly higher in alcoholic chronic liver disease patients. Thrombocytopenia is present in more than 30% of patients. In chronic liver failure patients, most of them had abnormalities in hematological parameters. Hence with this study, all the chronic liver disease patients must be evaluated for hematological and should be monitored for any complications. Early treatment to correct these comorbidities can decrease mortality.

Caveolin-1 Alleviates Acetaminophen-Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis.

Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.

Coral Hydrate, a Novel Antioxidant, Improves Alcohol Intoxication in Mice.

Alcohol-drinking culture may cause individuals to periodically experience unpleasant hangovers. In addition, ethanol catabolism stimulates the production of free radicals that may cause liver injury and further lead to the development of chronic alcoholic fatty liver disease. Although a number of studies have suggested that hydrogenated water may be consumed to act as free radical scavenger, its instability limits its application. In this study, we used coral hydrate (i.e., hydrogenated coral materials) as a more stable hydrogen source and evaluated its effects in a murine model of alcohol intoxication. In solution, coral hydrate exhibited much more stable redox potential than did hydrogenated water. Furthermore, administration of coral hydrate by oral gavage significantly prolonged the time to fall asleep and decreased the total sleep time in mice that received intraperitoneal injection of ethanol. The mice receiving coral hydrate also had lower plasma ethanol and acetaldehyde levels than controls. In line with this observation, hepatic expression of alcohol dehydrogenase, acetaldehyde dehydrogenase, catalase and glutathione peroxidase were all significantly increased by the treatment. Meanwhile, alcohol-induced upregulation of pro-inflammatory factors was attenuated by the administration of coral hydrate. Taken together, our data suggest that coral hydrate might be an effective novel treatment for alcohol intoxication.

Prevalence of underlying cirrhosis etiologies in hepatocellular carcinoma patients of Hispanic versus non-Hispanic ethnicity.

e16163 Background: While the incidence and rates of mortality are in decline for the vast majority of cancers, those of hepatocellular carcinoma (HCC) continue to increase. Forecasts from the Surveillance, Epidemiology, and End Results (SEER) database suggest that the Hispanic population will have the highest incidence rate of HCC in the United States by the end of this decade. As a result, further studies are needed to identify specific risk factors for the development of HCC in this ethnic group. Methods: This was a retrospective, single center study conducted in Southern California to identify the prevalence of underlying cirrhosis etiologies in HCC patients of Hispanic versus non-Hispanic ethnicity. Causes of cirrhosis included nonalcoholic fatty liver disease (NAFLD), viral hepatitis, alcohol, and other chronic liver disease. The designation of NAFLD cirrhosis was assigned to patients in whom there was an exclusion of viral hepatitis B, viral hepatitis C, significant alcohol consumption, other etiology of chronic liver disease, and who had the presence of fatty liver on imaging or were diagnosed with cirrhosis with a concomitant metabolic risk factor (diabetes mellitus, hypertension, hyperlipidemia, or obesity). Results: A total of 165 patients were included in this study. There were 57 patients of Hispanic ethnicity and 108 patients of non-Hispanic ethnicity. No significant differences in age or gender were found between the two groups. When analyzing the prevalence of cirrhosis etiologies, 17 patients (29.8%) of Hispanic background were found to have underlying NAFLD cirrhosis compared to 10 patients (9.3%) of non-Hispanic background (p = 0.001). In contrast, 67 patients (62%) in the non-Hispanic group had diagnoses of cirrhosis associated with viral hepatitis B or C compared to 22 patients (38.6%) in the Hispanic group (p = 0.005). There was no significant difference in the prevalence of alcoholic cirrhosis (24.6% vs 13%, p = 0.08), cirrhosis due to other chronic liver disease (1.8% vs 2.8%, p = 1), or HCC without cirrhosis (5.3% vs 13%, p = 0.178) between Hispanic and non-Hispanic patients, respectively (Table). Conclusions: There were significantly higher rates of NAFLD cirrhosis identified in HCC patients of Hispanic ethnicity compared to those of non-Hispanic ethnicity. With the continually rising incidence rate of HCC in this patient group, it is important for providers to be aware of this association so that appropriate surveillance and prevention strategies may be pursued.[Table: see text]

Spider nevi secondary to alcoholic chronic liver disease.

Spider nevi secondary to alcoholic chronic liver disease.

Non-Alcoholic Components in Huangjiu as Potential Factors Regulating the Intestinal Barrier and Gut Microbiota in Mouse Model of Alcoholic Liver Injury.

Different alcoholic beverages and drinking patterns might exert divergent impacts on alcoholic liver disease (ALD) progression. Whether the abundant non-alcoholic components (NAC) in fermented wine could alleviate ethanol (EtOH)-induced adverse influences on the liver remains unknown. Hence, the chronic ALD mouse model was established to compare the effects of Huangjiu (a typical fermented wine) and EtOH feeding on the liver, intestinal barrier, gut microbiota, and intestinal short-chain fatty acids (SCFAs) content. Although Huangjiu intake led to slight hepatic steatosis, it mitigated oxidative stress, inflammation, and intestinal damage relative to EtOH intake. In comparison with EtOH feeding, Huangjiu significantly improved the intestinal barrier integrity and reduced hepatic lipopolysaccharide levels by up-regulating the expression of intestinal tight junction proteins (ZO-1 and occludin) and antimicrobial activity peptides (Reg3β and Reg3γ). The administration of Huangjiu NAC partially restored alcohol-induced gut microbiota dysbiosis via recovering the abundance of Lactobacillus, Faecalibaculum, and Akkermansia. Moreover, mice receiving Huangjiu showed higher SCFAs levels (such as acetic acid and butyric acid) than those receiving EtOH. Huangjiu consumption resulted in lower hepatotoxicity than pure EtOH, at the same alcohol dose. The NAC in Huangjiu might attenuate the progression of ALD by regulating intestinal barrier function and microbiota-meditated gut ecology.

Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a worldwide healthcare problem featured by inflammation, reactive oxygen species (ROS), and lipid dysregulation. Roxadustat is used for chronic kidney disease anemia treatment. As a specific inhibitor of prolyl hydroxylase, it can maintain high levels of hypoxia-inducible factor 1α (HIF-1α), through which it can further influence many important pathways, including the three featured in ALD. However, its effects on ALD remain to be elucidated. In this study, we used chronic and acute ALD mouse models to investigate the protective effects of roxadustat in vivo. Our results showed that long- and short-term alcohol exposure caused rising activities of serum transaminases, liver lipid accumulation, and morphology changes, which were reversed by roxadustat. Roxadustat-reduced fatty liver was mainly contributed by the reducing sterol-responsive element-binding protein 1c (SREBP1c) pathway, and enhancing β-oxidation through inducing peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) expression. Long-term alcohol treatment induced the infiltration of monocytes/macrophages to hepatocytes, as well as inflammatory cytokine expression, which were also blocked by roxadustat. Moreover, roxadustat attenuated alcohol caused ROS generation in the liver of those two mouse models mainly by reducing cytochrome P450 2E1 (CYP2E1) and enhancing superoxidase dismutase 1 (SOD1) expression. In vitro, we found roxadustat reduced inflammation and lipid accumulation mainly via HIF-1α regulation. Taken together, our study demonstrates that activation of HIF-1α can ameliorate ALD, which is contributed by reduced hepatic lipid synthesis, inflammation, and oxidative stress. This study suggested that roxadustat could be a potential drug for ALD treatment.

The amelioration of alcohol-induced liver and intestinal barrier injury by Lactobacillus rhamnosus Gorbach-Goldin (LGG) is dependent on Interleukin 22 (IL-22) expression

ABSTRACT Alcoholic liver disease (ALD) is a common clinical liver injury disease. Lactobacillus rhamnosus Gorbach-Goldin (LGG) has been revealed to alleviate alcohol-induced intestinal barrier and liver injury. However, the underlying mechanism of LGG treatment for ALD remains unclear. To clarify this aspect, a chronic plus binge ALD model was constructed using C57BL/6 mice in line with a chronic alcohol binge feeding protocol. Interleukin 22 (IL-22) level was determined by quantitative real-time polymerase-chain reaction and enzyme-linked immunosorbent assays. Effects of LGG in model or IL-22 knockdown in LGG-treated model on the liver injury and steatosis status, as well as intestinal barrier function were assessed by hematoxylin eosin (HE) staining. Levels of alanine aminotransferase (ALT), triglyceride (TG), and aspartate aminotransferase (AST) in serum were measured by the corresponding kit. Western blot analysis was conducted to detect protein expressions of intestinal tight junction protein 1 (ZO-1) and Claudin-1. Concretely, LGG elevated IL-22 level in liver tissues and serum, while inhibiting ALT, TG, and AST levels in alcohol-exposed mice. Moreover, LGG alleviated liver injury, steatosis, and intestinal barrier injury caused by alcohol, and enhanced ZO-1 and Claudin-1 expressions. Furthermore, IL-22 knockdown increased ALT, TG, and AST levels in serum, and aggravated liver injury, steatosis, and intestinal barrier injury. ZO-1 and Claudin-1 levels were downregulated by IL-22 silencing. Importantly, downregulation of IL-22 reversed the effect of LGG on the liver and intestinal barrier injury. To conclude, LGG protects against chronic alcohol-induced intestinal and liver injury via regulating the intestinal IL-22 signaling pathway.