Mitoquinol improves phagocytosis and glycolysis in ethanol-exposed macrophages via HIF-1α-PFKP axis.

Alcohol use disorder increases sepsis mortality. Acute ethanol exposure impairs pathogen clearance in the macrophages via dampened glycolysis and phagocytosis, exaggerates oxidative stress, and regulates the function of the hypoxia-regulating factor 1α (HIF-1α), a master regulator of glycolysis. Decreased expression of the platelet isoform of phosphofructokinase (PFKP), a key glycolytic enzyme, in ethanol-exposed macrophages, is reported.

TRPV4 Regulates the Macrophage Metabolic Response to Limit Sepsis-induced Lung Injury.

Sepsis is a systemic inflammatory response that requires effective macrophage metabolic functions to resolve ongoing inflammation. Previous work showed that the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), mediates macrophage phagocytosis and cytokine production in response to lung infection. Here, we show that TRPV4 regulates glycolysis in a stiffness-dependent manner by augmenting macrophage glucose uptake by GLUT1.

Effect of ethanol exposure on innate immune response in sepsis.

Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis.

Hemoglobin resident in the lung epithelium is protective for smooth muscle soluble guanylate cyclase function.

Hemoglobin (Hb) present in the lung epithelium is of unknown significance. However Hb being an nitric oxide (NO) scavenger can bind to NO and reduce its deleterious effects. Hence we postulated an NO scavenging role for this lung Hb.

Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation.

Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia.

SIRT2-PFKP interaction dysregulates phagocytosis in macrophages with acute ethanol-exposure.

Alcohol abuse, reported by 1/8 critically ill patients, is an independent risk factor for death in sepsis. Sepsis kills over 270,000 patients/year in the US. We reported that the ethanol-exposure suppresses innate-immune response, pathogen clearance, and decreases survival in sepsis-mice sirtuin 2 (SIRT2).

Hepatic kinome atlas: An in-depth identification of kinase pathways in liver fibrosis of humans and rodents.

Background And Aims: Resolution of pathways that converge to induce deleterious effects in hepatic diseases, such as in the later stages, have potential antifibrotic effects that may improve outcomes. We aimed to explore whether humans and rodents display similar fibrotic signaling networks.

Approach And Results: We assiduously mapped kinase pathways using 340 substrate targets, upstream bioinformatic analysis of kinase pathways, and over 2000 random sampling iterations using the PamGene PamStation kinome microarray chip technology.

Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways.

Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation.

Sirtuin 2 Dysregulates Autophagy in High-Fat-Exposed Immune-Tolerant Macrophages.

Obesity increases morbidity and resource utilization in sepsis patients. The immune response in sepsis transitions from an endotoxin-responsive hyper- to an endotoxin-tolerant hypo-inflammatory phase. The majority of sepsis mortality occurs during hypo-inflammation.

Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans.

Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH.

Ethanol Exposure Attenuates Immune Response in Sepsis via Sirtuin 2 Expression.

Background: Sepsis and septic shock kill over 270,000 patients per year in the United States. Sepsis transitions from a hyper-inflammatory to a hypo-inflammatory phase. Alcohol dependence is a risk factor for mortality from sepsis.

MLKL-dependent signaling regulates autophagic flux in a murine model of non-alcohol-associated fatty liver and steatohepatitis.

Background & Aims: Autophagy maintains cellular homeostasis and plays a critical role in the development of non-alcoholic fatty liver and steatohepatitis. The pseudokinase mixed lineage kinase domain-like (MLKL) is a key downstream effector of receptor interacting protein kinase 3 (RIP3) in the necroptotic pathway of programmed cell death. However, recent data reveal that MLKL also regulates autophagy.

Dietary Synbiotic Supplementation Protects Barrier Integrity of Hepatocytes and Liver Sinusoidal Endothelium in a Mouse Model of Chronic-Binge Ethanol Exposure.

Alcohol overconsumption disrupts the gut microbiota and intestinal barrier, which decreases the production of beneficial microbial metabolic byproducts and allows for translocation of pathogenic bacterial-derived byproducts into the portal-hepatic circulation. As ethanol is known to damage liver sinusoidal endothelial cells (LSEC), here we evaluated dietary supplementation with a previously studied synbiotic on gut microbial composition, and hepatocyte and LSEC integrity in mice exposed to ethanol. We tested a chronic-binge ethanol feeding mouse model in which C57BL/6 female mice were fed ethanol (5% vol/vol) for 10 days and provided a single ethanol gavage (5 g/kg body weight) on day 11, 6 h before euthanasia.

Nontranscriptional Activity of Interferon Regulatory Factor 3 Protects Mice From High-Fat Diet-Induced Liver Injury.

Interferon regulatory factor 3 (IRF3) has both transcriptional and nontranscriptional functions. Transcriptional activity is dependent on serine phosphorylation of IRF3, while transcription-independent IRF3-mediated apoptosis requires ubiquitination. IRF3 also binds to inhibitor of nuclear factor kappa B kinase (IKKβ) in the cytosol, restricting nuclear translocation of p65.

A Designer Synbiotic Attenuates Chronic-Binge Ethanol-Induced Gut-Liver Injury in Mice.

Gut dysbiosis and altered short-chain fatty acids are associated with ethanol-induced liver injury. SCFA are fermentation byproducts of the gut microbiota known to have many beneficial biological effects. We tested if a designer synbiotic could protect against ethanol-induced gut-liver injury.

The Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with prevalence increasing in parallel with the rising incidence in obesity. Believed to be a "multiple-hit" disease, several factors contribute to NAFLD initiation and progression. Of these, the gut microbiome is gaining interest as a significant factor in NAFLD prevalence.

Complement Factor D protects mice from ethanol-induced inflammation and liver injury.

Complement plays a crucial role in microbial defense and clearance of apoptotic cells. Emerging evidence suggests complement is an important contributor to alcoholic liver disease. While complement component 1, Q subcomponent (C1q)-dependent complement activation contributes to ethanol-induced liver injury, the role of the alternative pathway in ethanol-induced injury is unknown.

Faecalibacterium prausnitzii and a Prebiotic Protect Intestinal Health in a Mouse Model of Antibiotic and Clostridium difficile Exposure.

Background: Clostridium difficile (CD) infection (CDI) increases patient morbidity, mortality and healthcare costs. Antibiotic treatment induces gut dysbiosis and is both a major risk factor for CD colonization and treatment of CDI. Probiotics have been trialed to support commensal gut microbiota and reduce CDI.

Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip.

TLR4 signaling in hepatic macrophages is increased after chronic ethanol feeding. Treatment of hepatic macrophages after chronic ethanol feeding with small-specific sized hyaluronic acid 35 (HA35) normalizes TLR4 signaling; however, the mechanisms for HA35 action are not completely understood. Here we used Next Generation Sequencing of microRNAs to identify negative regulators of TLR4 signaling reciprocally modulated by ethanol and HA35 in hepatic macrophages.

Myeloid-MyD88 Contributes to Ethanol-Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation.

Background: Toll-like receptor 4 (TLR4) is critical for ethanol (EtOH)-induced liver injury. TLR4 signaling is mediated by 2 proximal adaptor molecules: myeloid differentiation primary response protein (MyD88) and TLR-domain-containing adaptor-inducing interferon-β (TRIF). Studies utilizing global knockouts of MyD88 and TRIF identified a predominant role for TRIF signaling in the progression of EtOH-induced liver injury.

Limited Excessive Voluntary Alcohol Drinking Leads to Liver Dysfunction in Mice.

Background: Liver damage is a serious and sometimes fatal consequence of long-term alcohol intake, which progresses from early-stage fatty liver (steatosis) to later-stage steatohepatitis with inflammation and fibrosis/necrosis. However, very little is known about earlier stages of liver disruption that may occur in problem drinkers, those who drink excessively but are not dependent on alcohol.

Methods: We examined how repeated binge-like alcohol drinking in C57BL/6 mice altered liver function, as compared with a single binge-intake session and with repeated moderate alcohol consumption.