Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin ...Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng,against alcoholic liver injury in mice.Chronic-plus-single-binge ethanol feeding caused severe liver injury,as manifested by significantly elevated serum aminotransferase levels,hepatic histological changes,increased lipid accumulation,oxidative stress,and inflammation in the liver.These deleterious effects were alleviated by the treatment with Rk2(5 and 30 mg/kg).Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inhibitor,Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver.Meanwhile,the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine.Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.展开更多
BACKGROUND Alcoholic liver disease(ALD)remains one of the major indications for liver transplantation in the United States and continues to place a burden on the national healthcare system.There is evidence of increas...BACKGROUND Alcoholic liver disease(ALD)remains one of the major indications for liver transplantation in the United States and continues to place a burden on the national healthcare system.There is evidence of increased alcohol consumption during the coronavirus disease 2019(COVID-19)pandemic,and the effect of this on the already burdened health systems remains unknown.AIM To assess the trends for ALD admissions during the COVID-19 pandemic,and compare it to a similar pre-pandemic period.METHODS This retrospective study analyzed all admissions at a tertiary health care system,which includes four regional hospitals.ALD admissions were identified by querying a multi-hospital health system’s electronic database using ICD-10 codes.ALD admissions were compared for two one-year periods;pre-COVID-19 from April 2019 to March 2020,and during-COVID-19 from April 2020 to March 2021.Data were analyzed using a Poisson regression model and admission rates were compared using the annual quarterly average for the two time periods,with stratification by age and gender.Percent increase or decrease in admissions from the Poisson regression model were reported as incident rate ratios.RESULTS One thousand three hundred and seventy-eight admissions for ALD were included.80.7%were Caucasian,and 34.3%were female.An increase in the number of admissions for ALD during the COVID-19 pandemic was detected.Among women,a sharp rise(33%)was noted in those below the age of 50 years,and an increase of 22%in those above 50 years.Among men,an increase of 24%was seen for those below 50 years,and a 24%decrease in those above 50 years.CONCLUSION The COVID-19 pandemic has had widespread implications,and an increase in ALD admissions is just one of them.However,given that women are often prone to rapid progression of ALD,this finding has important preventive health implications.展开更多
AIM:To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan (FS).METHODS...AIM:To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan (FS).METHODS:We first performed sequential LS analysis before and after normalization of serum transaminases in a learning cohort of 50 patients with ALD admitted for alcohol detoxification. LS decreased in almost all patients within a mean observation interval of 5.3 d. Six patients (12%) would have been misdiagnosed with F3and F4 fibrosis but LS decreased below critical cut-off values of 8 and 12.5 kPa after normalization of trans-aminases. RESULTS:Of the serum transaminases,the decrease in LS correlated best with the decrease in glutamic oxaloacetic transaminase (GOT). No significant chang-es in LS were observed below GOT levels of 100 U/L. After establishing the association between LS and GOT levels,we applied the rule of GOT < 100 U/L for reliable LS assessment in a second validation cohort of 101 patients with histologically confi rmed ALD. By ex-cluding those patients with GOT > 100 U/L at the time of LS assessment from this cohort,the area under the receiver operating characteristic (AUROC) for cirrhosis detection by FS improved from 0.921 to 0.945 while specificity increased from 80% to 90% at a sensitivity of 96%. A similar AUROC could be obtained for lower F3 fibrosis stage if LS measurements were restricted to patients with GOT < 50 U/L. Histological grading of inflammation did not further improve the diagnostic accuracy of LS.CONCLUSION:Coexisting steatohepatitis markedly increases LS in patients with ALD independent of fibrosis stage. Postponing cirrhosis assessment by FS during alcohol withdrawal until GOT decreases to < 100 U/mL signif icantly improves the diagnostic accuracy.展开更多
Alcoholic liver disease(ALD) is the second commonest indication for liver transplantation after viral hepatitis in the United States and Europe.Controversies surround the indications and allocation of scarce and expen...Alcoholic liver disease(ALD) is the second commonest indication for liver transplantation after viral hepatitis in the United States and Europe.Controversies surround the indications and allocation of scarce and expensive resource for this so called self inflicted disease.Controversies stem from the apprehension that alcoholic recipients are likely to relapse and cause damage to the graft.There is a need to select those candidates with lower risk for relapse with the available predictive factors and scores.Substance abuse specialist and psychiatrists are mandatory in the pre-transplant evaluation and in the post-transplant follow-up.There is conflicting evidence to support a fixed period of pretransplant abstinence,although most units do follow this.Alcoholic hepatitis(AH) continues to be a contraindication for transplantation,however there is a need for further research in this f ield as a subset of patients with AH who do not respond to medical treatment,have high early mortality and could benefit from transplantation.One year,3-year,and 5-year survival post-transplant is similar for both ALD and non-ALD recipients.The incidence of post-transplant rejection and retransplantation is also similar to other recipients.ALD with viral hepatitis especially hepatitis C virus leads to a more aggressive liver disease with early presentation for transplantation.ALD patients are more prone to develop de-novo malignancy;this is attributed to the long term effect of alcohol,tobacco combined with immunosuppression.Post-transplant surveillance is important to detect early relapse to alcoholism,presence of de-novo malignancy and treat the same adequately.展开更多
AIM To examine temporal changes in the indications for liver transplantation(LT) and characteristics of patients transplanted for alcoholic liver disease(ALD).METHODS We performed a retrospective cohort analysis of tr...AIM To examine temporal changes in the indications for liver transplantation(LT) and characteristics of patients transplanted for alcoholic liver disease(ALD).METHODS We performed a retrospective cohort analysis of trends in the indication for LT using the United Network for Organ Sharing(UNOS) database between 2002 and 2015. Patients were grouped by etiology of the liver disease and characteristics were compared using χ~2 and t-tests. Time series analysis was used identifying any year with a significant change in the number of transplants per year for ALD, and before and after eras were modeled using a general linear model. Subgroup analysis of recipients with ALD was performed by age group, gender, UNOS region and etiology(alcoholic cirrhosis, alcoholic hepatitis and hepatitis C-alcoholic cirrhosis dual listing).RESULTS Of 74216 liver transplant recipients, ALD(n = 9400, 12.7%) was the third leading indication for transplant after hepatitis C and hepatocellular carcinoma. Transplants for ALD, increased from 12.8%(553) in 2002 to 16.5%(1020) in 2015. Time series analysis indicated a significant increase in the number of transplants per year for ALD in 2013(P = 0.03). There were a stable number of transplants per year between 2002 and 2012(linear coefficient 3, 95%CI:-4.6, 11.2) an increase of 177 per year between 2013 and 2015(95%CI: 119, 234). This increase was significant for all age groups except those 71-83 years old, was observed for both genders, and was incompletely explained by a decrease in transplants for hepatitis C and ALD dual listing. All UNOS regions except region 9 saw an increase in the mean number of transplants per year when comparing eras, and this increase was significant in regions 2, 3, 4, 5, 6, 8, 10 and 11.CONCLUSION There has been a dramatic increase in the number of transplants for ALD starting in 2013.展开更多
Alcoholic liver disease(ALD)remains an important health problem worldwide.Perturbation of micronutrients has been broadly reported to be a common characteristic in patients with ALD,given the fact that micronutrients ...Alcoholic liver disease(ALD)remains an important health problem worldwide.Perturbation of micronutrients has been broadly reported to be a common characteristic in patients with ALD,given the fact that micronutrients often act as composition or coenzymes of many biochemical enzymes responsible for the inflammatory response,oxidative stress,and cell proliferation.Mapping the metabolic pattern and the function of these micronutrients is a prerequisite before targeted intervention can be delivered in clinical practice.Recent years have registered a significant improvement in our understanding of the role of micronutrients on the pathogenesis and progression of ALD.However,how and to what extent these micronutrients are involved in the pathophysiology of ALD remains largely unknown.In the current study,we provide a review of recent studies that investigated the imbalance of micronutrients in patients with ALD with a focus on zinc,iron,copper,magnesium,selenium,vitamin D and vitamin E,and determine how disturbances in micronutrients relates to the pathophysiology of ALD.Overall,zinc,selenium,vitamin D,and vitamin E uniformly exhibited a deficiency,and iron demonstrated an elevated trend.While for copper,both an elevation and deficiency were observed from existing literature.More importantly,we also highlight several challenges in terms of low sample size,study design discrepancies,sample heterogeneity across studies,and the use of machine learning approaches.展开更多
BACKGROUND Alcoholic liver disease(ALD)is a major cause of chronic liver disease worldwide.AIM To describe the epidemiological profile and mortality rates of patients with ALD admitted to public hospitals in different...BACKGROUND Alcoholic liver disease(ALD)is a major cause of chronic liver disease worldwide.AIM To describe the epidemiological profile and mortality rates of patients with ALD admitted to public hospitals in different regions of Brazil from 2006 to 2015.METHODS This is a descriptive study that evaluated aggregate data from the five Brazilian geographic regions.RESULTS A total of 160093 public hospitalizations for ALD were registered.There was a 34.07%increase in the total number of admissions over 10 years,from 12879 in 2006 to 17267 in 2015.The region with the highest proportion(49.01%)of ALD hospitalizations was Southeast(n=78463).The North region had the lowest absolute number of patients throughout the study period,corresponding to 3.9%of the total(n=6242).There was a 24.72%increase in the total number of ALD deaths between 2006 and 2015.We found that the age group between 50 and 59 years had the highest proportion of both hospitalizations and deaths:28.94%(n=46329)of total hospital admissions and 29.43%(n=28864)of all deaths.Men were more frequently hospitalized than women and had the highest proportions of deaths in all regions.Mortality coefficient rates increased over the years,and simple linear regression analysis indicated a statistically significant upward trend in this mortality(R^2=0.744).CONCLUSION Our study provides a landscape of the epidemiological profile of public hospital admissions due to ALD in Brazil.We detected an increase in the total number of admissions and deaths due to ALD over 10 years.展开更多
BACKGROUND Madelung’s disease(MD)is a rare disorder of lipid metabolism,characterized by the growth of unencapsulated masses of adipose tissue symmetrically deposited around the neck,shoulders,or other sites around t...BACKGROUND Madelung’s disease(MD)is a rare disorder of lipid metabolism,characterized by the growth of unencapsulated masses of adipose tissue symmetrically deposited around the neck,shoulders,or other sites around the body.Its pathological mechanism is not yet known.One of the most common comorbidities in MD patients is liver disease,especially chronic alcoholic liver disease(CALD);however,no reports exist of acute kidney injury(AKI)with MD.CASE SUMMARY We report a 60-year-old man who presented with complaint of edema in the lower limbs that had persisted for 3 d.Physical examination showed subcutaneous masses around the neck,and history-taking revealed the masses to have been present for 2 years and long-term heavy drinking.Considering the clinical symptoms,along with various laboratory test results and imaging characteristics,a diagnosis was made of MD with acute exacerbation of CALD and AKI.The patient was treated with liver function protection and traditional Chinese medicine,without surgical intervention.He was advised to quit drinking.After 10 d,the edema had subsided,renal function indicators returned to normal,liver function significantly improved,and size of subcutaneous masses remained stable.CONCLUSION In MD,concomitant liver or kidney complications are possible and monitoring of liver and kidney functions can be beneficial.展开更多
In recent years,the interaction between the gut microflora and liver diseases has attracted much attention.The intestinal microflora is composed of bacteria,archaea,fungi and viruses.There are few studies on the intes...In recent years,the interaction between the gut microflora and liver diseases has attracted much attention.The intestinal microflora is composed of bacteria,archaea,fungi and viruses.There are few studies on the intestinal virome,and whether it has a causal relationship with bacterial changes in the gut is still unclear.However,it is undeniable that the intestinal virome is also a very important portion of the blueprint for the development of liver diseases and the diagnosis and therapeutic modalities in the future.展开更多
Coprinus comatus polysaccharide(CCP)has significant hepatoprotective effect.To explore hepatoprotective mechanism of CCP,the study analyzed preventive effect of CCP on acute alcoholic liver injury in mice by histopath...Coprinus comatus polysaccharide(CCP)has significant hepatoprotective effect.To explore hepatoprotective mechanism of CCP,the study analyzed preventive effect of CCP on acute alcoholic liver injury in mice by histopathological examination and biochemical analysis.Simultaneously,hepatoprotective mechanism was also analyzed in conjunction with metabolomics and proliferation of gut microbiota.The results showed that CCP significantly decreased alanine aminotransferase(ALT),aspartate aminotransferase(AST)and triglyceride(TG)levels in serum of alcoholic liver disease(ALD)mice.Histopathological examination showed that CCP can significantly improve liver damage.Metabolomics results showed that there were significant differences in the level of metabolites in liver tissue of control group,ALD group and CCP group,including taurine,xanthosine,fumaric acid and arachidonic acid,among others.Metabolites pathways analysis showed that hepatoprotective effect of CCP was related to energy metabolism,biosynthesis of unsaturated fatty acids,amino acids metabolism and lipid metabolism.Additionally,CCP inhibited an increase in the number of Clostridium perfringens,Enterobacteriaceae and Enterococcus,and a decrease in the number of Lactobacillus and Bifidobacterium in the gut of ALD mice.All these findings suggested that CCP treatment reversed the phenotype of ethanol-induced liver injury and the associated metabolites pathways.展开更多
Chronic alcohol consumption causes liver steatosis,cell death,and inflammation.Melatonin(MLT)is reported to alleviate alcoholic liver disease(ALD)-induced injury.However,its direct regulating targets in hepatocytes ar...Chronic alcohol consumption causes liver steatosis,cell death,and inflammation.Melatonin(MLT)is reported to alleviate alcoholic liver disease(ALD)-induced injury.However,its direct regulating targets in hepatocytes are not fully understood.In the current study,a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT.MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models(optimal doses of 10μmol/L and 5 mg/kg,respectively),including lowered liver steatosis,cell death,and inflammation.RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase(TERT)was a key downstream effector of MLT.Biophysical assay found that epidermal growth factor receptor(EGFR)on the hepatocyte surface was a direct binding and regulating target of MLT.Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection,partly through the regulation of nuclear brahma-related gene-1(BRG1).Long-term administration(90 days)of MLT in healthy mice did not cause evident adverse effect.In conclusion,MLT is an efficacious and safe agent for ALD alleviation.Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis.MLT might be used as a complimentary agent for alcoholics.展开更多
Alcoholic liver disease(ALD)results from continuous and heavy alcohol consumption.The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention,which is a long proces...Alcoholic liver disease(ALD)results from continuous and heavy alcohol consumption.The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention,which is a long process with poor efficacy and low patient compliance.Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD,but CYP2E1 knockdown in humans was impractical,and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown.In this study,we developed a RNAi therapeutics delivered by lipid nanoparticle,and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks.This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers,and contributed to improved ALD symptoms in mice.The liver fat accumulation,hepatocyte inflammation,and fibrosis were reduced in ALD models.Therefore,this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.展开更多
Alcoholic liver disease(ALD)is a growing global health concern,and its early pathogenesis includes steatosis and steatohepatitis.Inhibiting lipid accumulation and inflammation is a crucial step in relieving ALD.Eviden...Alcoholic liver disease(ALD)is a growing global health concern,and its early pathogenesis includes steatosis and steatohepatitis.Inhibiting lipid accumulation and inflammation is a crucial step in relieving ALD.Evidence shows that puerarin(Pue),an isoflavone isolated from Pueraria lobata,exerts cardio-protective,neuroprotective,anti-inflammatory,antioxidant activities.However,the therapeutic potential of Pue on ALD remains unknown.In the study,both the NIAAA model and ethanol(EtOH)-induced AML-12 cell were used to explore the protective effect of Pue on alcoholic liver injury in vivo and in vitro and related mechanism.The results showed that Pue(100 mg·kg^(−1))attenuated EtOH-induced liver injury and inhibited the levels of SREBP-1c,TNF-α,IL-6 and IL-1β,compared with silymarin(Sil,100 mg·kg^(−1)).In vitro results were consistent with in vivo results.Mechanistically,Pue might suppress liver lipid accumulation and inflammation by regulating MMP8.In conclusion,Pue might be a promising clinical candidate for ALD treatment.展开更多
Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocell...Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocellular carcinoma.The prevalence of ALD is increasing globally,particularly among middle-aged adults.Gender-based studies have revealed that ALD affects more men;however,disease progression differs between men and women.Despite this,the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism,particularly with estrogen and estrogen receptors(ERs)in ALD,remains poor.This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs.Chronic alcohol consumption affects the immune response,and whether estrogen has any contributory effect remains inadequately studied.This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling.The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD,the development of effective therapeutic approaches,and better disease management in both men and women,as ALD remains a major public health concern.展开更多
Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol c...Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.展开更多
As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclus...As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.展开更多
Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis...Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover,ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor(FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, Fox O3a(forkhead box-containing protein class O3a) and PPARα(peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.展开更多
AIM To compare transcriptomes of non-alcoholic fatty liver disease(NAFLD) and alcoholic liver disease(ALD) in a meta-analysis of liver biopsies.METHODS Employing transcriptome data from patient liver biopsies retrieve...AIM To compare transcriptomes of non-alcoholic fatty liver disease(NAFLD) and alcoholic liver disease(ALD) in a meta-analysis of liver biopsies.METHODS Employing transcriptome data from patient liver biopsies retrieved from several public repositories we performed a meta-analysis comparing ALD and NAFLD.RESULTS We observed predominating commonalities at the transcriptome level between ALD and NAFLD,most prominently numerous down-regulated metabolic pathways and cytochrome-related pathways and a few up-regulated pathways which include ECM-receptor interaction,phagosome and lysosome.However some pathways were regulated in opposite directions in ALD and NAFLD,for example,glycolysis was down-regulated in ALD and up-regulated in NAFLD.Interestingly,we found rate-limiting genes such as HMGCR,SQLE and CYP7A1 which are associated with cholesterol processes adversely regulated between ALD(down-regulated) and NAFLD(up-regulated).We propose that similar phenotypes in both diseases may be due to a lower level of the enzyme CYP7A1 compared to the cholesterol synthesis enzymes HMGCR and SQLE.Additionally,we provide a compendium of comparative KEGG pathways regulation in ALD and NAFLD.CONCLUSION Our finding of adversely regulated cholesterol processes in ALD and NAFLD draws the focus to regulation of cholesterol secretion into bile.Thus,it will be interesting to further investigate CYP7A1-mediated cholesterol secretion into bile-also as possible drug targets.The list of potential novel biomarkers may assist differential diagnosis of ALD and NAFLD.展开更多
Alcoholic liver disease(ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine(SAMC) from aged ga...Alcoholic liver disease(ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine(SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model(the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC(300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis,insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor(INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3 b signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC(250 mmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC’s beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model.Long-term(90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3 b pathway.展开更多
基金supported by grants from the Research Committee of the University of Macao(Grant No.:MYRG2022-00020-ICMS)the Science and Technology Development Fund,Macao SAR,China(File No.:0074/2021/AFJ and 0052/2022/A1).
文摘Heavy alcohol consumption results in alcoholic liver disease(ALD)with inadequate therapeutic options.Here,we first report the potential beneficial effects of ginsenoside Rk2(Rk2),a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng,against alcoholic liver injury in mice.Chronic-plus-single-binge ethanol feeding caused severe liver injury,as manifested by significantly elevated serum aminotransferase levels,hepatic histological changes,increased lipid accumulation,oxidative stress,and inflammation in the liver.These deleterious effects were alleviated by the treatment with Rk2(5 and 30 mg/kg).Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)inhibitor,Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver.Meanwhile,the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine.Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.
文摘BACKGROUND Alcoholic liver disease(ALD)remains one of the major indications for liver transplantation in the United States and continues to place a burden on the national healthcare system.There is evidence of increased alcohol consumption during the coronavirus disease 2019(COVID-19)pandemic,and the effect of this on the already burdened health systems remains unknown.AIM To assess the trends for ALD admissions during the COVID-19 pandemic,and compare it to a similar pre-pandemic period.METHODS This retrospective study analyzed all admissions at a tertiary health care system,which includes four regional hospitals.ALD admissions were identified by querying a multi-hospital health system’s electronic database using ICD-10 codes.ALD admissions were compared for two one-year periods;pre-COVID-19 from April 2019 to March 2020,and during-COVID-19 from April 2020 to March 2021.Data were analyzed using a Poisson regression model and admission rates were compared using the annual quarterly average for the two time periods,with stratification by age and gender.Percent increase or decrease in admissions from the Poisson regression model were reported as incident rate ratios.RESULTS One thousand three hundred and seventy-eight admissions for ALD were included.80.7%were Caucasian,and 34.3%were female.An increase in the number of admissions for ALD during the COVID-19 pandemic was detected.Among women,a sharp rise(33%)was noted in those below the age of 50 years,and an increase of 22%in those above 50 years.Among men,an increase of 24%was seen for those below 50 years,and a 24%decrease in those above 50 years.CONCLUSION The COVID-19 pandemic has had widespread implications,and an increase in ALD admissions is just one of them.However,given that women are often prone to rapid progression of ALD,this finding has important preventive health implications.
基金Supported by The Dietmar Hopp Foundation and the Manfred Lautenschlger Foundation,an Olympia-Morata fellowship of the University of Heidelberg (Millonig G)
文摘AIM:To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan (FS).METHODS:We first performed sequential LS analysis before and after normalization of serum transaminases in a learning cohort of 50 patients with ALD admitted for alcohol detoxification. LS decreased in almost all patients within a mean observation interval of 5.3 d. Six patients (12%) would have been misdiagnosed with F3and F4 fibrosis but LS decreased below critical cut-off values of 8 and 12.5 kPa after normalization of trans-aminases. RESULTS:Of the serum transaminases,the decrease in LS correlated best with the decrease in glutamic oxaloacetic transaminase (GOT). No significant chang-es in LS were observed below GOT levels of 100 U/L. After establishing the association between LS and GOT levels,we applied the rule of GOT < 100 U/L for reliable LS assessment in a second validation cohort of 101 patients with histologically confi rmed ALD. By ex-cluding those patients with GOT > 100 U/L at the time of LS assessment from this cohort,the area under the receiver operating characteristic (AUROC) for cirrhosis detection by FS improved from 0.921 to 0.945 while specificity increased from 80% to 90% at a sensitivity of 96%. A similar AUROC could be obtained for lower F3 fibrosis stage if LS measurements were restricted to patients with GOT < 50 U/L. Histological grading of inflammation did not further improve the diagnostic accuracy of LS.CONCLUSION:Coexisting steatohepatitis markedly increases LS in patients with ALD independent of fibrosis stage. Postponing cirrhosis assessment by FS during alcohol withdrawal until GOT decreases to < 100 U/mL signif icantly improves the diagnostic accuracy.
文摘Alcoholic liver disease(ALD) is the second commonest indication for liver transplantation after viral hepatitis in the United States and Europe.Controversies surround the indications and allocation of scarce and expensive resource for this so called self inflicted disease.Controversies stem from the apprehension that alcoholic recipients are likely to relapse and cause damage to the graft.There is a need to select those candidates with lower risk for relapse with the available predictive factors and scores.Substance abuse specialist and psychiatrists are mandatory in the pre-transplant evaluation and in the post-transplant follow-up.There is conflicting evidence to support a fixed period of pretransplant abstinence,although most units do follow this.Alcoholic hepatitis(AH) continues to be a contraindication for transplantation,however there is a need for further research in this f ield as a subset of patients with AH who do not respond to medical treatment,have high early mortality and could benefit from transplantation.One year,3-year,and 5-year survival post-transplant is similar for both ALD and non-ALD recipients.The incidence of post-transplant rejection and retransplantation is also similar to other recipients.ALD with viral hepatitis especially hepatitis C virus leads to a more aggressive liver disease with early presentation for transplantation.ALD patients are more prone to develop de-novo malignancy;this is attributed to the long term effect of alcohol,tobacco combined with immunosuppression.Post-transplant surveillance is important to detect early relapse to alcoholism,presence of de-novo malignancy and treat the same adequately.
文摘AIM To examine temporal changes in the indications for liver transplantation(LT) and characteristics of patients transplanted for alcoholic liver disease(ALD).METHODS We performed a retrospective cohort analysis of trends in the indication for LT using the United Network for Organ Sharing(UNOS) database between 2002 and 2015. Patients were grouped by etiology of the liver disease and characteristics were compared using χ~2 and t-tests. Time series analysis was used identifying any year with a significant change in the number of transplants per year for ALD, and before and after eras were modeled using a general linear model. Subgroup analysis of recipients with ALD was performed by age group, gender, UNOS region and etiology(alcoholic cirrhosis, alcoholic hepatitis and hepatitis C-alcoholic cirrhosis dual listing).RESULTS Of 74216 liver transplant recipients, ALD(n = 9400, 12.7%) was the third leading indication for transplant after hepatitis C and hepatocellular carcinoma. Transplants for ALD, increased from 12.8%(553) in 2002 to 16.5%(1020) in 2015. Time series analysis indicated a significant increase in the number of transplants per year for ALD in 2013(P = 0.03). There were a stable number of transplants per year between 2002 and 2012(linear coefficient 3, 95%CI:-4.6, 11.2) an increase of 177 per year between 2013 and 2015(95%CI: 119, 234). This increase was significant for all age groups except those 71-83 years old, was observed for both genders, and was incompletely explained by a decrease in transplants for hepatitis C and ALD dual listing. All UNOS regions except region 9 saw an increase in the mean number of transplants per year when comparing eras, and this increase was significant in regions 2, 3, 4, 5, 6, 8, 10 and 11.CONCLUSION There has been a dramatic increase in the number of transplants for ALD starting in 2013.
基金Supported by the Municipal Natural Science Foundation of Beijing,China,No.7192085.
文摘Alcoholic liver disease(ALD)remains an important health problem worldwide.Perturbation of micronutrients has been broadly reported to be a common characteristic in patients with ALD,given the fact that micronutrients often act as composition or coenzymes of many biochemical enzymes responsible for the inflammatory response,oxidative stress,and cell proliferation.Mapping the metabolic pattern and the function of these micronutrients is a prerequisite before targeted intervention can be delivered in clinical practice.Recent years have registered a significant improvement in our understanding of the role of micronutrients on the pathogenesis and progression of ALD.However,how and to what extent these micronutrients are involved in the pathophysiology of ALD remains largely unknown.In the current study,we provide a review of recent studies that investigated the imbalance of micronutrients in patients with ALD with a focus on zinc,iron,copper,magnesium,selenium,vitamin D and vitamin E,and determine how disturbances in micronutrients relates to the pathophysiology of ALD.Overall,zinc,selenium,vitamin D,and vitamin E uniformly exhibited a deficiency,and iron demonstrated an elevated trend.While for copper,both an elevation and deficiency were observed from existing literature.More importantly,we also highlight several challenges in terms of low sample size,study design discrepancies,sample heterogeneity across studies,and the use of machine learning approaches.
文摘BACKGROUND Alcoholic liver disease(ALD)is a major cause of chronic liver disease worldwide.AIM To describe the epidemiological profile and mortality rates of patients with ALD admitted to public hospitals in different regions of Brazil from 2006 to 2015.METHODS This is a descriptive study that evaluated aggregate data from the five Brazilian geographic regions.RESULTS A total of 160093 public hospitalizations for ALD were registered.There was a 34.07%increase in the total number of admissions over 10 years,from 12879 in 2006 to 17267 in 2015.The region with the highest proportion(49.01%)of ALD hospitalizations was Southeast(n=78463).The North region had the lowest absolute number of patients throughout the study period,corresponding to 3.9%of the total(n=6242).There was a 24.72%increase in the total number of ALD deaths between 2006 and 2015.We found that the age group between 50 and 59 years had the highest proportion of both hospitalizations and deaths:28.94%(n=46329)of total hospital admissions and 29.43%(n=28864)of all deaths.Men were more frequently hospitalized than women and had the highest proportions of deaths in all regions.Mortality coefficient rates increased over the years,and simple linear regression analysis indicated a statistically significant upward trend in this mortality(R^2=0.744).CONCLUSION Our study provides a landscape of the epidemiological profile of public hospital admissions due to ALD in Brazil.We detected an increase in the total number of admissions and deaths due to ALD over 10 years.
基金Supported by the National Natural Science Foundation of China,No.81973831the Sichuan Provincial Department of Finance,Sichuan Provincial Department of Labor and Social Security(2020)No.201 Traditional Chinese Medicine Inheritance and Innovation Ten Thousands of Talents Project-Ye Chuanhui Studio.
文摘BACKGROUND Madelung’s disease(MD)is a rare disorder of lipid metabolism,characterized by the growth of unencapsulated masses of adipose tissue symmetrically deposited around the neck,shoulders,or other sites around the body.Its pathological mechanism is not yet known.One of the most common comorbidities in MD patients is liver disease,especially chronic alcoholic liver disease(CALD);however,no reports exist of acute kidney injury(AKI)with MD.CASE SUMMARY We report a 60-year-old man who presented with complaint of edema in the lower limbs that had persisted for 3 d.Physical examination showed subcutaneous masses around the neck,and history-taking revealed the masses to have been present for 2 years and long-term heavy drinking.Considering the clinical symptoms,along with various laboratory test results and imaging characteristics,a diagnosis was made of MD with acute exacerbation of CALD and AKI.The patient was treated with liver function protection and traditional Chinese medicine,without surgical intervention.He was advised to quit drinking.After 10 d,the edema had subsided,renal function indicators returned to normal,liver function significantly improved,and size of subcutaneous masses remained stable.CONCLUSION In MD,concomitant liver or kidney complications are possible and monitoring of liver and kidney functions can be beneficial.
文摘In recent years,the interaction between the gut microflora and liver diseases has attracted much attention.The intestinal microflora is composed of bacteria,archaea,fungi and viruses.There are few studies on the intestinal virome,and whether it has a causal relationship with bacterial changes in the gut is still unclear.However,it is undeniable that the intestinal virome is also a very important portion of the blueprint for the development of liver diseases and the diagnosis and therapeutic modalities in the future.
基金The current project is funded by Shandong Provincial Natural Science Foundation,China(ZR2020MH370)Major Science and Technology Innovation in Shandong Province(2017CXGC1307)Ji’nan Science and Technology Project(201303055)。
文摘Coprinus comatus polysaccharide(CCP)has significant hepatoprotective effect.To explore hepatoprotective mechanism of CCP,the study analyzed preventive effect of CCP on acute alcoholic liver injury in mice by histopathological examination and biochemical analysis.Simultaneously,hepatoprotective mechanism was also analyzed in conjunction with metabolomics and proliferation of gut microbiota.The results showed that CCP significantly decreased alanine aminotransferase(ALT),aspartate aminotransferase(AST)and triglyceride(TG)levels in serum of alcoholic liver disease(ALD)mice.Histopathological examination showed that CCP can significantly improve liver damage.Metabolomics results showed that there were significant differences in the level of metabolites in liver tissue of control group,ALD group and CCP group,including taurine,xanthosine,fumaric acid and arachidonic acid,among others.Metabolites pathways analysis showed that hepatoprotective effect of CCP was related to energy metabolism,biosynthesis of unsaturated fatty acids,amino acids metabolism and lipid metabolism.Additionally,CCP inhibited an increase in the number of Clostridium perfringens,Enterobacteriaceae and Enterococcus,and a decrease in the number of Lactobacillus and Bifidobacterium in the gut of ALD mice.All these findings suggested that CCP treatment reversed the phenotype of ethanol-induced liver injury and the associated metabolites pathways.
基金supported by grants from National Natural Science Foundation of China(82122009,82170605,81873573 and 81970515)Guangdong Natural Science Funds for Distinguished Young Scholar(2019B151502013,China)。
文摘Chronic alcohol consumption causes liver steatosis,cell death,and inflammation.Melatonin(MLT)is reported to alleviate alcoholic liver disease(ALD)-induced injury.However,its direct regulating targets in hepatocytes are not fully understood.In the current study,a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT.MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models(optimal doses of 10μmol/L and 5 mg/kg,respectively),including lowered liver steatosis,cell death,and inflammation.RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase(TERT)was a key downstream effector of MLT.Biophysical assay found that epidermal growth factor receptor(EGFR)on the hepatocyte surface was a direct binding and regulating target of MLT.Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection,partly through the regulation of nuclear brahma-related gene-1(BRG1).Long-term administration(90 days)of MLT in healthy mice did not cause evident adverse effect.In conclusion,MLT is an efficacious and safe agent for ALD alleviation.Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis.MLT might be used as a complimentary agent for alcoholics.
基金This work is kindly supported by The National Key R&D Program of China:Chinese-Australian‘Belt and Road’Joint Laboratory on Traditional Chinese Medicine for the Prevention and Treatment of Severe Infectious Diseases(2020YFE0205100,China)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(2060302,China)+7 种基金Zhenjiang social development project(SH2020036,China)National Key R&D Program of China(2019YFA0802801 and 2018YFA0801401,China)the National Natural Science Foundation of China(31871345 and 32071442,China)Medical Science Advancement Program(Basic Medical Sciences)of Wuhan University(TFJC2018004,China)the Fundamental Research Funds for the Central Universities(China)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-PT320-004,China)Applied Basic Frontier Program of Wuhan City(2020020601012216,China)Hubei Health Commission Young Investigator award(China)and startup funding from Wuhan University(China).
文摘Alcoholic liver disease(ALD)results from continuous and heavy alcohol consumption.The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention,which is a long process with poor efficacy and low patient compliance.Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD,but CYP2E1 knockdown in humans was impractical,and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown.In this study,we developed a RNAi therapeutics delivered by lipid nanoparticle,and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks.This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers,and contributed to improved ALD symptoms in mice.The liver fat accumulation,hepatocyte inflammation,and fibrosis were reduced in ALD models.Therefore,this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.
基金the National Natural Science Foundation of China(No.31900285)the Natural Science FoundationofAnhuiProvince(Nos.2108085QH309and 2208085MH203)Anhui Medical University"Three Complete Education"Comprehensive Reform Pilot Project(No.2021xsqyr05)。
文摘Alcoholic liver disease(ALD)is a growing global health concern,and its early pathogenesis includes steatosis and steatohepatitis.Inhibiting lipid accumulation and inflammation is a crucial step in relieving ALD.Evidence shows that puerarin(Pue),an isoflavone isolated from Pueraria lobata,exerts cardio-protective,neuroprotective,anti-inflammatory,antioxidant activities.However,the therapeutic potential of Pue on ALD remains unknown.In the study,both the NIAAA model and ethanol(EtOH)-induced AML-12 cell were used to explore the protective effect of Pue on alcoholic liver injury in vivo and in vitro and related mechanism.The results showed that Pue(100 mg·kg^(−1))attenuated EtOH-induced liver injury and inhibited the levels of SREBP-1c,TNF-α,IL-6 and IL-1β,compared with silymarin(Sil,100 mg·kg^(−1)).In vitro results were consistent with in vivo results.Mechanistically,Pue might suppress liver lipid accumulation and inflammation by regulating MMP8.In conclusion,Pue might be a promising clinical candidate for ALD treatment.
文摘Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocellular carcinoma.The prevalence of ALD is increasing globally,particularly among middle-aged adults.Gender-based studies have revealed that ALD affects more men;however,disease progression differs between men and women.Despite this,the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism,particularly with estrogen and estrogen receptors(ERs)in ALD,remains poor.This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs.Chronic alcohol consumption affects the immune response,and whether estrogen has any contributory effect remains inadequately studied.This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling.The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD,the development of effective therapeutic approaches,and better disease management in both men and women,as ALD remains a major public health concern.
基金supported by the National Institute of Diabetes and Digestive and Kidney(R01-DK121970)to Dr.Feng Li.
文摘Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.
文摘As a result of the obesity epidemic,Nonalcoholic fatty liver disease(NAFLD)and its complications have increased among millions of people.Consequently,a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis;metabolic-associated fatty liver disease(MAFLD).This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD.This article discusses the rationale behind the nomenclature change,the main differences,and its clinical implications.
基金supported in part by the National Institutes of Health (Nos.R01 AA020518 and R01 DK102142)National Center for Research Resources (No.5P20RR021940)+1 种基金the National Institute of General Medical Sciences (Nos.8P20 GM103549 and T32 ES007079)an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (No.P20 GM103418)
文摘Alcoholic liver disease(ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover,ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor(FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, Fox O3a(forkhead box-containing protein class O3a) and PPARα(peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.
基金Supported by The Medical Faculty of the Heinrich Heine University Düsseldorf
文摘AIM To compare transcriptomes of non-alcoholic fatty liver disease(NAFLD) and alcoholic liver disease(ALD) in a meta-analysis of liver biopsies.METHODS Employing transcriptome data from patient liver biopsies retrieved from several public repositories we performed a meta-analysis comparing ALD and NAFLD.RESULTS We observed predominating commonalities at the transcriptome level between ALD and NAFLD,most prominently numerous down-regulated metabolic pathways and cytochrome-related pathways and a few up-regulated pathways which include ECM-receptor interaction,phagosome and lysosome.However some pathways were regulated in opposite directions in ALD and NAFLD,for example,glycolysis was down-regulated in ALD and up-regulated in NAFLD.Interestingly,we found rate-limiting genes such as HMGCR,SQLE and CYP7A1 which are associated with cholesterol processes adversely regulated between ALD(down-regulated) and NAFLD(up-regulated).We propose that similar phenotypes in both diseases may be due to a lower level of the enzyme CYP7A1 compared to the cholesterol synthesis enzymes HMGCR and SQLE.Additionally,we provide a compendium of comparative KEGG pathways regulation in ALD and NAFLD.CONCLUSION Our finding of adversely regulated cholesterol processes in ALD and NAFLD draws the focus to regulation of cholesterol secretion into bile.Thus,it will be interesting to further investigate CYP7A1-mediated cholesterol secretion into bile-also as possible drug targets.The list of potential novel biomarkers may assist differential diagnosis of ALD and NAFLD.
基金supported by National Natural Science Foundation of China (81970515)Guangdong Natural Science Funds for Distinguished Young Scholar (2019B151502013, China)。
文摘Alcoholic liver disease(ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine(SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model(the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC(300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis,insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor(INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3 b signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC(250 mmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC’s beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model.Long-term(90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3 b pathway.
