Visium spatial transcriptomics and proteomics identifies novel hepatic cell populations and transcriptomic signatures of alcohol-associated hepatitis.

Background: Alcohol-associated hepatitis (AH) is the clinical manifestation of alcohol-associated liver disease (ALD). AH is a complex disease encompassing the dysregulation of many cells and cell subpopulations. This study used a hepatic spatial transcriptomic and proteomic approach (10X Genomics Visium) to identify hepatic cell populations and their associated transcriptomic and proteomic alterations in human AH.

Intestine epithelial-specific hypoxia-inducible factor-1α overexpression ameliorates western diet-induced MASLD.

Background: Intestine epithelial hypoxia-inducible factor-1α (HIF-1α) plays a critical role in maintaining gut barrier function. The aim of this study was to determine whether pharmacological or genetic activation of intestinal HIF-1α ameliorates western diet-induced metabolic dysfunction-associated steatotic liver disease.

Methods: Metabolic effects of pharmacological activation of HIF-1α by dimethyloxalylglycine were evaluated in HIF-α luciferase reporter (ODD-luc) mice.

Multiomics Studies on Metabolism Changes in Alcohol-Associated Liver Disease.

Metabolic dysfunction in the liver represents a predominant feature in the early stages of alcohol-associated liver disease (ALD). However, the mechanisms underlying this are only partially understood. To investigate the metabolic characteristics of the liver in ALD, we did a relative quantification of polar metabolites and lipids in the liver of mice with experimental ALD using untargeted metabolomics and untargeted lipidomics.

Multiomics Analysis of PCB126's Effect on a Mouse Chronic-Binge Alcohol Feeding Model.

Background: Environmental pollutants, including polychlorinated biphenyls (PCBs) have been implicated in the pathogenesis of liver disease. Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in a rodent model of alcohol-associated liver disease (ALD).

Objective: To better understand how PCB126 promoted ALD in our previous model, the current study adopts multiple omics approaches to elucidate potential mechanistic hypotheses.

ALT poorly predicts Nonalcoholic Fatty Liver Disease (NAFLD) and liver fibrosis as determined by vibration-controlled transient elastography in adult National Health and Nutrition Examination Survey 2017-2018.

Background: Non-alcoholic fatty liver disease is a growing problem in the United States, contributing to a range of liver disease as well as cardiovascular disease. ALT is the most widely used liver chemistry for NAFLD evaluation. We hypothesized that the normal range many laboratories use was too high, missing many patients with clinically important steatosis and/or fibrosis.

One-month assessment of Th-cell axis related inflammatory cytokines, IL-17 and IL-22 and their role in alcohol-associated liver disease.

Introduction: Changes in the expression of cyto- and chemokines due to alcohol-associated liver disease (ALD) have been reported to be both protective and pathogenic. This study examined plasma levels of two key cytokines, Il-17 and Il-22, which construct the proinflammatory vs. anti-inflammatory axes across the spectrum of alcohol use disorder (AUD) and ALD including alcohol-associated hepatitis (AH) to determine the underlying status of the inflammation.

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.

Investigating the Acute Metabolic Effects of the N-Methyl Carbamate Insecticide, Methomyl, on Mouse Liver.

Many pesticides have been identified as endocrine and metabolism-disrupting chemicals with hepatotoxic effects. However, data are limited for insecticides in the n-methyl carbamate class, including methomyl. Here, we investigate the liver and systemic metabolic effects of methomyl in a mouse model.

Neural crest cells and fetal alcohol spectrum disorders: Mechanisms and potential targets for prevention.

Fetal alcohol spectrum disorders (FASD) are a group of preventable and nongenetic birth defects caused by prenatal alcohol exposure that can result in a range of cognitive, behavioral, emotional, and functioning deficits, as well as craniofacial dysmorphology and other congenital defects. During embryonic development, neural crest cells (NCCs) play a critical role in giving rise to many cell types in the developing embryos, including those in the peripheral nervous system and craniofacial structures. Ethanol exposure during this critical period can have detrimental effects on NCC induction, migration, differentiation, and survival, leading to a broad range of structural and functional abnormalities observed in individuals with FASD.

Altered urinary tryptophan metabolites in alcohol-associated liver disease.

Background: Alcohol-associated liver disease (ALD) leads to millions of deaths worldwide annually. A few potential biomarkers of ALD have been discovered through metabolomic or proteomic analysis. Tryptophan (Trp), one of nine essential amino acids, has been extensively studied and shown to play significant roles in many mammalian physiological processes.

Western diet unmasks transient low-level vinyl chloride-induced tumorigenesis; potential role of the (epi-)transcriptome.

Background & Aims: Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry. At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.

The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-Associated Hepatitis.

Introduction: We investigated the effect of daily oral Lactobacillus rhamnosus GG (LGG) in reducing liver injury/severity and drinking in patients with alcohol use disorder and moderately severe alcohol-associated hepatitis.

Methods: Forty-six male and female individuals with alcohol use disorder and moderate alcohol-associated hepatitis (12 ≤ model for end-stage liver disease score < 20, aged 21-67 years) received either LGG (n = 24) or placebo (n = 22). Data were collected/assessed at baseline and at 1, 3, and 6 months.

Ethanol exposure disrupted the formation of radial glial processes and impaired the generation and migration of outer radial glial cells in forebrain organoids derived from human embryonic stem cells.

Radial glial cells (RGCs) play a pivotal role in cerebral cortical development by functioning as a source of new neurons and by supporting the migration of newborn neurons. These functions are primarily dependent on the apical-basolateral structures of radial glial processes. This study aims to investigate the effects of ethanol exposure on the development of radial glial processes and the generation, migration, and transformation of outer radial glial cells (oRGCs).

Fibrosis resolution in the mouse liver: Role of Mmp12 and potential role of calpain 1/2.

Although most work has focused on resolution of collagen ECM, fibrosis resolution involves changes to several ECM proteins. The purpose of the current study was twofold: 1) to examine the role of MMP12 and elastin; and 2) to investigate the changes in degraded proteins in plasma (i.e.

The environmental pollutant, polychlorinated biphenyl 126, alters liver function in a rodent model of alcohol-associated liver disease.

Background: The prevalence of alcohol-associated liver disease (ALD), a subtype of fatty liver disease (FLD), continues to rise. ALD is a major cause of preventable death. Polychlorinated biphenyl (PCB) 126 is an environmentally relevant, dioxin-like pollutant whose negative metabolic effects have been well documented.

Different Types of Dietary Fat and Fructose Interactions Result in Distinct Metabolic Phenotypes in Male Mice.

Fat and fructose are the two major components over-represented in the Western diet. The aim of this study was to determine the combined effects of different types of dietary fat and fructose on the development of nonalcoholic fatty liver disease (NAFLD) in a murine model. Eight-week-old male C57BL/6J mice were fed with high-fat diet enriched with saturated fat (HSF), or omega-6 polyunsaturated fat (n6HUSF), or omega-3 polyunsaturated fat (n3HUSF) with 42% of calories derived from the fat.

Illustration of Gut-Thyroid Axis in Alcohol Use Disorder: Interplay of Gut Dysfunction, Pro-Inflammatory Responses, and Thyroid Function.

(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD).

Applications of Bayesian shrinkage prior models in clinical research with categorical responses.

Background: Prediction and classification algorithms are commonly used in clinical research for identifying patients susceptible to clinical conditions such as diabetes, colon cancer, and Alzheimer's disease. Developing accurate prediction and classification methods benefits personalized medicine. Building an excellent predictive model involves selecting the features that are most significantly associated with the outcome.

Positive blood phosphatidylethanol concentration is associated with unfavorable waitlist-related outcomes for patients medically appropriate for liver transplantation.

Background: Excessive alcohol use is a leading etiology of liver disease and indication for liver transplantation. Accurate measurement of alcohol use remains a challenge in the management of patients in the pre-, peri-, and post-liver transplant settings. Blood 16:0-18:1 phosphatidylethanol (PEth) concentration is a sensitive and specific biomarker of binge and moderate, chronic alcohol use.

Stochastic forecasting of COVID-19 daily new cases across countries with a novel hybrid time series model.

An unprecedented outbreak of the novel coronavirus (COVID-19) in the form of peculiar pneumonia has spread globally since its first case in Wuhan province, China, in December 2019. Soon after, the infected cases and mortality increased rapidly. The future of the pandemic's progress was uncertain, and thus, predicting it became crucial for public health researchers.

Up-regulation of microRNA-34a mediates ethanol-induced impairment of neural crest cell migration in vitro and in zebrafish embryos through modulating epithelial-mesenchymal transition by targeting Snail1.

Prenatal ethanol exposure can impair neural crest cell (NCC) development, including NCC survival, differentiation and migration, contributing to the craniofacial dysmorphology in Fetal Alcohol Spectrum Disorders (FASD). Epithelial-mesenchymal transition (EMT) plays an important role in regulating the migration of NCCs. The objective of this study is to determine whether ethanol exposure can suppress NCC migration through inhibiting EMT and whether microRNA-34a (miR-34a) is involved in the ethanol-induced impairment of EMT in NCCs.

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey.

Background: Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress.

Objectives: We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort.

Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration.

Alcohol-associated liver disease (ALD) is the leading cause of liver disease worldwide, and alcohol-associated hepatitis (AH), a severe form of ALD, is a major contributor to the mortality and morbidity due to ALD. Many factors modulate susceptibility to ALD development and progression, including nutritional factors such as dietary fatty acids. Recent work from our group and others showed that modulation of dietary or endogenous levels of n6-and n3-polyunsaturated fatty acids (PUFAs) can exacerbate or attenuate experimental ALD, respectively.