Unveiling the effect of estrogen receptors in alcoholic liver disease:A novel outlook

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.

Prolonged existence of SARS-CoV-2 RNAs in the extracellular vesicles of respiratory specimens from patients with negative reverse transcription-polymerase chain reaction

Background and aim:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is primarily in the respiratory tract,particularly in patients with underlying comorbidities.This study aimed to investigate the presence of the virus inside the extracellular vesicles(EVs)in patients with and without chronic liver disease(CLD).Methods:Eighty patients with positive SARS-CoV-2,including twenty-four patients with CLD and fiftysix patients without CLD,and five healthy controls with negative SARS-CoV-2 were enrolled.Nasal swab specimens were tested for the detection of SARS-CoV-2 using reverse transcription-polymerase chain reaction(RT-PCR).Patients with coronavirus disease 2019(COVID-19)were followed up on days 7 and 14.Nasal swab,collected in viral transport media(VTM),and plasma samples were investigated at each time point.EVs were isolated from the nasal swabs(collected in VTM)and plasma using differential ultracentrifugation and estimated at each time point.The transmission or replication by the EVs was assessed in Vero E6 cells.Results:In patients with baseline RT-PCR positive,SARS-CoV-2 RNAs inside the EVs were found in 68/80(85%)patients with higher viral load in the nasal swabs than in the EVs(cycle threshold(Ct)value,23.4±5.7 vs.30.3±5.0,P<0.001).On follow-up at day 7,of the 32 patients negative for COVID-19,15(46.9%)had virus persistence in the EVs(Ct value,30.7±2.7),and on day 14,of the 56 patients with negative SARS-CoV-2,16 patients(28.6%)had positive SARS-CoV-2 RNAs in the EVs(Ct value,31.4±3.0).The mean viral load decreased on days 7 and 14 compared to baseline in the nasal swabs(P<0.001)but not in the EVs.Additionally,SARS-CoV-2 RNAs were undetectable in the plasma,but 12.5% of patients were positive in the plasma EVs.Significantly prolonged and high viral load was found in the EVs on day 14 in COVID-19 patients combined with CLD compared with COVID-19 patients(P?0.0004).We found significant higher levels of EV-associated with endothelial cells and hepatocytes in the COVID-19 t CLD group than COVID-19 group(P?0.032 and P?0.002,respectively),suggesting more endothelial cells and hepatocytes cellular injury in liver disease patients with COVID-19.Interestingly,we also found EVs could transmit SARS-CoV-2 RNAs into Vero E6 cells at 24 h post-infection.Conclusions:The identification of SARS-CoV-2 RNAs in the EVs in patients with negative RT-PCR indicates the persistence of infection and likely recurrence of the infection.It is suggestive of another route of transmission as EVs harbor SARS-CoV-2 RNAs.EV-associated RNAs may determine the ongoing inflammation and clinical course of subjects with undetectable SARS-CoV-2 virus and this may have relevance to better management of patients with CLD.

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

Background and Aims:Cirrhosis patients exhibit cyto-penia,and,at times refractory neutropenia to granulocyte colony-stimulating factor(G-CSF),which acts through the CSF3-receptor(CSF3R),and changes in CSF3R can affect the response.We conducted this study to assess the CSF3R status and its relevance in cirrhotic patients.Methods:Cirrhotic patients(n=127)and controls(n=26)with clini-cally indicated bone marrow(BM)examination were stud-ied.BM assessment was done by qRT-PCR and immunohis-tochemistry(IHC)for CSF3R.Circulating G-CSF,CSF3R,and carcinoembryonic antigen cell adhesion molecule-1(CEACAM1)were measured.BM hematopoietic precursor cells and their alterations were examined by flow cytom-etry.The findings were validated in liver cirrhosis patients who received G-CSF for severe neutropenia.Results:The mean age was 48.6±13.4 years,and 80.3%were men.Circulatory CSF3R reduction was noted with the advance-ment of cirrhosis,and confirmed by qRT-PCR and IHC in BM.CSF3R decline was related to decreased hematopoietic stem cells(HSCs)and downregulation of CSF3R in the re-maining HSCs.Cocultures confirmed that CEACAM1 led to CSF3R downregulation in BM cells by possible lysosomal degradation.Baseline low peripheral blood-(PB)-CSF3R also predisposed development of infections on follow-up.Decreased CSF3R was also associated with nonresponse to exogenous G-CSF treatment of neutropenia.Conclu-sions:Advanced liver cirrhosis was associated with low CSF3R and high CEACAM1 levels in the BM and circula-tion,making patients prone to infection and inadequate response to exogenous G-CSF.