Aging exaggerates acute-on-chronic alcohol-induced liver injury in mice and humans by inhibiting neutrophilic sirtuin 1-C/EBPα-miRNA-223 axis.

BACKGROUND AND AIMS: Aging exacerbates liver neutrophil infiltration and alcohol-associated liver disease (ALD) in mice and humans, but the underlying mechanisms remain obscure. This study aimed to examine the effect of aging and alcohol consumption on neutrophilic Sirtuin 1 (SIRT1) and microRNA-223 (miR-223), and their contribution to ALD pathogeneses. APPROACH AND RESULTS: Young and aged myeloid-specific Sirt1 knockout mice were subjected to chronic-plus-binge ethanol feeding. Blood samples from healthy controls and patients with chronic alcohol drinking who presented with acute intoxication were analyzed. Neutrophilic Sirt1 and miR-223 expression were down-regulated in aged mice compared with young mice. Deletion of the Sirt1 gene in myeloid cells including neutrophils exacerbated chronic-plus-binge ethanol-induced liver injury and inflammation and down-regulated neutrophilic miR-223 expression. Immunoprecipitation experiments revealed that SIRT1 promoted C/EBPα deacetylation by directly interacting with C/EBPα, a key transcription factor that controls miR-223 biogenesis, and subsequently elevated miR-223 expression in neutrophils. Importantly, down-regulation of SIRT1 and miR-223 expression was also observed in circulating neutrophils from middle-aged and elderly subjects compared with those from young individuals. Chronic alcohol users with acute intoxication had a reduction in neutrophilic SIRT1 expression in young and middle-aged patients, with a greater reduction in the latter group. The neutrophilic SIRT1 expression correlated with neutrophilic miR-223 and serum alanine transaminase levels in those patients. CONCLUSIONS: Aging increases the susceptibility of alcohol-induced liver injury in mice and humans through the down-regulation of the neutrophilic SIRT1-C/EBPα-miR-223 axis, which could be a therapeutic target for the prevention and/or treatment of ALD.

The Prevalence and Genotype Distribution of Hepatitis C Virus in Kenya: A Systematic Review and Meta-Analysis.

BACKGROUND: Hepatitis C (HCV) is a virus that causes chronic liver disease, end-stage cirrhosis, and liver cancer, yet most infected individuals remain undiagnosed or untreated. Kenya is a country located in Sub-Saharan Africa (SSA) where the prevalence of HCV remains high but with uncertain disease burden due to little population-based evidence of the epidemic. We aimed to highlight the HCV disease burden in Kenya with a summary of the available data. METHODS: The study was performed as per the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We searched publications reporting HCV prevalence and genotypes in Kenya between January 2000 to December 2022. The effect size, i.e., the HCV prevalence, was defined as the proportion of samples testing positive for HCV antibody. Study quality was assessed by the Joanna Briggs Institute (JBI) critical appraisal checklist. Due to high study heterogeneity, the studies were categorized into low-, intermediate-, and high-risk for HCV infection. The pooled estimate prevalence per category was determined by the random effects model. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42023401892). RESULTS: A total of 29 studies with a sample size of 90,668 met our inclusion criteria, a third of which were from the capital city Nairobi (34.5%). Half of the studies included HIV-infected individuals (31%) or injection drug users (20.7%). HCV genotype 1 was the most common, with genotype 4 only slightly less common, and together they accounted for 94% of cases. The pooled prevalence for the low-, intermediate- and high-risk groups were 2.0%, 3.4%, and 15.5%, respectively. Over 80% of the studies had a score of > 6 on the JBI scale, indicating a low risk of bias in terms of study design, conduct and analysis. CONCLUSION: Our findings demonstrate that there is a higher prevalence of HCV in key populations such as HIV-infected individuals and drug users than in the general population in Kenya. We found that HCV genotypes 1 and 4 were the most common genotypes. More data from the general population is required in order to establish baseline data on the prevalence and genotypes of HCV in Kenya.

Neutrophils inhibit CD8+ T cells immune response by arginase-1 signaling in patients with sepsis.

BACKGROUND: Patients with sepsis often exhibit an acute inflammatory response, followed by an immunosuppressive phase with a poor immune response. However, the underlying mechanisms have not been fully elucidated. METHODS: We sought to comprehensively characterize the transcriptional changes in neutrophils of patients with sepsis by transcriptome sequencing. Additionally, we conducted a series of experiments, including real-time quantitative polymerase chain reaction (RT-qPCR) and flow cytometry to investigate the role of arginase-1 signaling in sepsis. RESULTS: Through the analysis of gene expression profiles, we identified that the negative regulation of T cell activation signaling was enriched, and the expression of arginase-1 was high in neutrophils from patients with sepsis. Furthermore, we conducted flow cytometry and found that the function of CD8+ T cells in septic patients was impaired. Moreover, neutrophils from septic patients inhibited the percentage of polyfunctional effector CD8+ T cells through arginase-1. Additionally, the proportions of granzyme B+IFN-γ+CD8+ T and TNF-α+IFN-γ+CD8+ T cells increased after inhibition of arginase-1 signaling. CONCLUSION: The impaired effector function of CD8+ T cells could be restored by blocking arginase-1 signaling in patients with sepsis.

Persistent deficiency of mucosa-associated invariant T (MAIT) cells during alcohol-related liver disease.

BACKGROUND: Alcohol-related liver disease (ALD) is a major cause of chronic liver diseases. Inflammatory response is a basic pathological feature of ALD. Mucosal-associated invariant T(MAIT) cells are a novel population of innate immune cells, which may be depleted in various inflammatory diseases. However, the changes of MAIT cell in ALD remains unclear. RESULTS: In this study, the levels of MAIT cell were significantly decreased in patients with alcoholic fatty liver disease, alcoholic cirrhosis, and mixed cirrhosis (alcoholic + viral). Furthermore, the reduction of circulating MAIT cells was correlated with liver function in patients with cirrhosis. Functional changes among circulating MAIT cells in patients with alcoholic cirrhosis, including increased production of IL-17A and perforin, and reduced production of TNF-α. Plasma cytokine and chemokine levels were quantified using multiple immunoassays and ELISA. Serum levels of chemokine IL-8 were correlated with MAIT cell frequency in patients with alcoholic cirrhosis. Moreover, no differences were observed in the expression of CCR6, CXCR6, and PD-1 in circulating MAIT cells of patients with alcoholic cirrhosis. The MAIT cells in patients with alcoholic cirrhosis were prone to apoptosis, which was promoted by IL-12, IL-18, and IL-8. CONCLUSIONS: Our findings indicate persistent MAIT cell loss during alcohol-related liver disease and suggest that MAIT cells can be promising indicator and therapeutic targets in ALD.

Diagnostic Value of Neutrophil-Lymphocyte Ratio for Predicting the Severity of Acute Pancreatitis: A Meta-Analysis.

BACKGROUND: Acute pancreatitis (AP) is a life-threatening disease caused by a variety of factors, and once it progresses to severe acute pancreatitis, the prognosis is poor. The purpose of this study was to investigate the diagnostic value of the neutrophil-lymphocyte ratio (NLR) for predicting the severity of acute pancreatitis. MATERIALS AND METHODS: We searched the databases of PubMed, EMBASE, Web of Science, and Cochrane Library to identify eligible studies using the NLR to predict the severity of AP. The sensitivity (SEN), specificity (SPE), negative likelihood ratio (NLR), positive likelihood ratio (PLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) were combined using a bivariate mixed model. RESULTS: A total of 10 articles containing 394 cases and 1319 controls were included in the study. The combined SEN, SPE, NLR, PLR, DOR, and AUC are 79% (73%-84%), 71% (59%-80%), 0.30 (0.21-0.41), 2.7 (1.8-4.0), 9 (5-18), and 0.82 (0.78-0.85), respectively. CONCLUSIONS: NLR has a moderately high diagnostic value in predicting the severity of acute pancreatitis.