Impact of chronic ethanol consumption and SARS-COV-2 on the liver and intestine: A pilot dose-response study in mice.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD).

Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice.

Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer's disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD.

Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes.

Background: Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM.

Experimentally Induced Reductions in Alcohol Consumption and Brain, Cognitive, and Clinical Outcomes in Older Persons With and Those Without HIV Infection (30-Day Challenge Study): Protocol for a Nonrandomized Clinical Trial.

Background: Both alcohol consumption and HIV infection are associated with worse brain, cognitive, and clinical outcomes in older adults. However, the extent to which brain and cognitive dysfunction is reversible with reduction or cessation of drinking is unknown.

Objective: The 30-Day Challenge study was designed to determine whether reduction or cessation of drinking would be associated with improvements in cognition, reduction of systemic and brain inflammation, and improvement in HIV-related outcomes in adults with heavy drinking.

Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury.

Background: It is well established that females are more susceptible to the toxic effects of alcohol, although the exact mechanisms are still poorly understood. Previous studies noted that alcohol reduces the expression of mitogen-activated protein kinase phosphatase 1 (MKP1), a negative regulator of mitogen-activated protein kinases (MAPK) in the liver. However, the role of hepatocyte- specific MKP1 in the pathogenesis of alcohol-associated liver disease (ALD) remains uncharacterized.

A conceptual analysis of SBIRT implementation alongside the continuum of PrEP awareness: domains of fit and feasibility.

Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a supplementary intervention that can be incorporated into the Pre-Exposure Prophylaxis (PrEP) Care Continuum, complementing initiatives and endeavors focused on Human Immunodeficiency Virus (HIV) prevention in clinical care and community-based work. Referencing the Transtheoretical Model of Change and the PrEP Awareness Continuum, this conceptual analysis highlights how SBIRT amplifies ongoing HIV prevention initiatives and presents a distinct chance to address identified gaps. SBIRT's mechanisms show promise of fit and feasibility through (a) implementing universal Screening (S), (b) administering a Brief Intervention (BI) grounded in motivational interviewing aimed at assisting individuals in recognizing the significance of PrEP in their lives, (c) providing an affirming and supportive Referral to Treatment (RT) to access clinical PrEP care, and (d) employing client-centered and destigmatized approaches.

Tributyrin Mitigates Ethanol-Induced Lysine Acetylation of Histone-H3 and p65-NFκB Downregulating CCL2 Expression and Consequent Liver Inflammation and Injury.

Purpose: Chemokine-driven leukocyte infiltration and sustained inflammation contribute to alcohol-associated liver disease (ALD). Elevated hepatic CCL2 expression, seen in ALD, is associated with disease severity. However, mechanisms of CCL2 regulation are not completely elucidated.

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies.

Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol.

Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.

Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho-specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho-associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization.

Osteopontin Is Associated with Dementia in the Presence of Cerebral Small Vessel Disease.

Background: Osteopontin (OPN) is a proinflammatory cytokine that has been recently implicated in neuroinflammation and neurodegeneration. We hypothesized that an increase in plasma OPN is a deleterious neuroinflammatory marker in people with dementia and cerebral small vessel disease (CSVD).

Methods: A pilot study was conducted on participants in the Northern Manhattan Study (NOMAS).

SmartPill™ Administration to Assess Gastrointestinal Function after Spinal Cord Injury in a Porcine Model-A Preliminary Study.

Gastrointestinal (GI) complications, including motility disorders, metabolic deficiencies, and changes in gut microbiota following spinal cord injury (SCI), are associated with poor outcomes. After SCI, the autonomic nervous system becomes unbalanced below the level of injury and can lead to severe GI dysfunction. The SmartPill™ is a non-invasive capsule that, when ingested, transmits pH, temperature, and pressure readings that can be used to assess effects in GI function post-injury.

Probiotic-derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation.

Background And Aims: Intestinal farnesoid X receptor (FXR) plays a critical role in alcohol-associated liver disease (ALD). We aimed to investigate whether alcohol-induced dysbiosis increased intestinal microRNA194 (miR194) that suppressed Fxr transcription and whether Lactobacillus rhamnosus GG-derived exosome-like nanoparticles (LDNPs) protected against ALD through regulation of intestinal miR194-FXR signaling in mice.

Approach And Results: Binge-on-chronic alcohol exposure mouse model was utilized.

Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis.

Introduction: The phosphodiesterase 4 (PDE4) inhibitor, rolipram, has beneficial effects on tissue inflammation, injury and fibrosis, including in the liver. Since rolipram elicits significant CNS side-effects in humans (ie, nausea and emesis), our group developed a fusogenic lipid vesicle (FLV) drug delivery system that targets the liver to avoid adverse events. We evaluated whether this novel liposomal rolipram formulation reduces emesis.

Age-Associated Gut Dysbiosis, Marked by Loss of Butyrogenic Potential, Correlates With Altered Plasma Tryptophan Metabolites in Older People Living With HIV.

Background: Imbalance in tryptophan (TRP) metabolism and its neuroactive metabolites, serotonin and kynurenine (KYN), is a known pathogenic mechanism underlying neurocognitive impairment. Gut microbiota plays an important role in TRP metabolism, and the production of these neuroactive molecules affects neurocognitive function. Although both HIV infection and normal aging independently induce gut dysbiosis and influence TRP metabolism, their interactive effects on compositional/functional changes in gut microbiota and consequent alterations in TRP metabolites remain largely undetermined.

Serological assessment of SARS-CoV-2 infection during the first wave of the pandemic in Louisville Kentucky.

Serological assays intended for diagnosis, sero-epidemiologic assessment, and measurement of protective antibody titers upon infection or vaccination are essential for managing the SARS-CoV-2 pandemic. Serological assays measuring the antibody responses against SARS-CoV-2 antigens are readily available. However, some lack appropriate characteristics to accurately measure SARS-CoV-2 antibodies titers and neutralization.

Decrease in acetyl-CoA pathway utilizing butyrate-producing bacteria is a key pathogenic feature of alcohol-induced functional gut microbial dysbiosis and development of liver disease in mice.

Emerging research evidence has established the critical role of the gut-liver axis in the development of alcohol-associated liver disease (ALD). The present study employed 16S rRNA gene and whole genome shotgun (WGS) metagenomic analysis in combination with a revised microbial dataset to comprehensively detail the butyrate-producing microbial communities and the associated butyrate metabolic pathways affected by chronic ethanol feeding. Specifically, the data demonstrated that a decrease in several butyrate-producing bacterial genera belonging to distinct families within the Firmicutes phyla was a significant component of ethanol-induced dysbiosis.

Association of Syndemic Unhealthy Alcohol Use, Smoking, and Depressive Symptoms on Incident Cardiovascular Disease among Veterans With and Without HIV-Infection.

Unhealthy alcohol use, smoking, and depressive symptoms are risk factors for cardiovascular disease (CVD). Little is known about their co-occurrence - termed a syndemic, defined as the synergistic effect of two or more conditions-on CVD risk in people with HIV (PWH). We used data from 5621 CVD-free participants (51% PWH) in the Veteran's Aging Cohort Study-8, a prospective, observational study of veterans followed from 2002 to 2014 to assess the association between this syndemic and incident CVD by HIV status.

Exosome-Like Nanoparticles From GG Protect Against Alcohol-Associated Liver Disease Through Intestinal Aryl Hydrocarbon Receptor in Mice.

Alcohol-associated liver disease (ALD) is a major cause of mortality. Gut barrier dysfunction-induced bacterial translocation and endotoxin release contribute to the pathogenesis of ALD. Probiotic GG (LGG) is known to be beneficial on experimental ALD by reinforcing the intestinal barrier function.

Cathelicidin-related antimicrobial peptide alleviates alcoholic liver disease through inhibiting inflammasome activation.

Alcoholic liver disease (ALD) is associated with gut dysbiosis and hepatic inflammasome activation. While it is known that antimicrobial peptides (AMPs) play a critical role in the regulation of bacterial homeostasis in ALD, the functional role of AMPs in the alcohol-induced inflammasome activation is unclear. The aim of this study was to determine the effects of cathelicidin-related antimicrobial peptide (CRAMP) on inflammasome activation in ALD.

Epigenetic Mechanisms Underlying HIV-Infection Induced Susceptibility of CD4+ T Cells to Enhanced Activation-Induced FasL Expression and Cell Death.

Background: Chronic immune activation and CD4 T cell depletion are significant pathogenic features of HIV infection. Expression of Fas ligand (FasL), a key mediator of activation-induced cell death in T cells, is elevated in people living with HIV-1 infection (PLWH). However, the epigenetic mechanisms underlying the enhanced induction of FasL expression in CD4 T lymphocytes in PLWH are not completely elucidated.

Acetylator Genotype-Dependent Dyslipidemia in Rats Congenic for -Acetyltransferase 2.

Recent reports suggest that arylamine -acetyltransferases (NAT1 and/or NAT2) serve important roles in regulation of energy utility and insulin sensitivity. We investigated the interaction between diet (control vs. high-fat diet) and acetylator phenotype (rapid vs.

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease.

The importance of cyclic adenosine monophosphate (cAMP) in cellular responses to extracellular signals is well established. Many years after discovery, our understanding of the intricacy of cAMP signaling has improved dramatically. Multiple layers of regulation exist to ensure the specificity of cellular cAMP signaling.

Elevated Fructose and Uric Acid Through Aldose Reductase Contribute to Experimental and Human Alcoholic Liver Disease.

Background And Aims: Alcohol-associated liver disease (ALD) is a common chronic liver disease worldwide with high morbidity and mortality, and no Food and Drug Administration-approved therapies. Fructose (dietary or endogenous), its metabolite uric acid, and aldose reductase (AR, the only endogenous enzyme that produces fructose) are strongly associated with the development of nonalcoholic fatty liver disease. However, the role of AR or its metabolites in ALD remains understudied and was examined using human specimens, cultured cells, and mouse model systems.