Exploration of BAY 11-7082 as a Potential Antibiotic.

Exposure of the Gram-negative pathogen to subinhibitory concentrations of antibiotics increases the formation of biofilms. We exploited this phenotype to identify molecules with potential antimicrobial activity in a biofilm-based high-throughput screen. The anti-inflammatory compound BAY 11-7082 induced dose-dependent biofilm stimulation, indicative of antibacterial activity.

Metabolic endotoxemia is dictated by the type of lipopolysaccharide.

Lipopolysaccharides (LPSs) can promote metabolic endotoxemia, which is considered inflammatory and metabolically detrimental based on Toll-like receptor (TLR)4 agonists, such as Escherichia coli-derived LPS. LPSs from certain bacteria antagonize TLR4 yet contribute to endotoxemia measured by endotoxin units (EUs). We found that E.

Inflammation promotes adipocyte lipolysis via IRE1 kinase.

Obesity associates with inflammation, insulin resistance, and higher blood lipids. It is unclear if immune responses facilitate lipid breakdown and release from adipocytes via lipolysis in a separate way from hormones or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis from adrenergic or hormonal stimuli.

Gut microbiota impairs insulin clearance in obese mice.

Objective: Hyperinsulinemia can be both a cause and consequence of obesity and insulin resistance. Hyperinsulinemia can result from increased insulin secretion and/or reduced insulin clearance. While many studies have focused on mechanisms triggering insulin secretion during obesity, the triggers for changes in insulin clearance during obesity are less defined.

NOD2 in hepatocytes engages a liver-gut axis to protect against steatosis, fibrosis, and gut dysbiosis during fatty liver disease in mice.

Obesity promotes nonalcoholic fatty liver disease (NAFLD). The intestinal microbiota contributes to NAFLD progression through a gut-to-liver pathway that promotes inflammation and fibrosis. Gut microbiota-derived factors can travel to the liver and activate immune responses in liver resident cells to promote inflammation and NAFLD.

Statins activate the NLRP3 inflammasome and impair insulin signaling via p38 and mTOR.

Statins lower cholesterol and risk of cardiovascular disease. Statins can increase blood glucose and risk of new-onset diabetes. It is unclear why statins can have opposing effects on lipids versus glucose.

The NLRP3 inflammasome regulates adipose tissue metabolism.

Adipose tissue regulates metabolic homeostasis by participating in endocrine and immune responses in addition to storing and releasing lipids from adipocytes. Obesity skews adipose tissue adipokine responses and degrades the coordination of adipocyte lipogenesis and lipolysis. These defects in adipose tissue metabolism can promote ectopic lipid deposition and inflammation in insulin-sensitive tissues such as skeletal muscle and liver.

Postbiotics for NOD2 require nonhematopoietic RIPK2 to improve blood glucose and metabolic inflammation in mice.

Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2.

Statins Promote Interleukin-1β-Dependent Adipocyte Insulin Resistance Through Lower Prenylation, Not Cholesterol.

Statins lower cholesterol and adverse cardiovascular outcomes, but this drug class increases diabetes risk. Statins are generally anti-inflammatory. However, statins can promote inflammasome-mediated adipose tissue inflammation and insulin resistance through an unidentified immune effector.

Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice.

Those with diabetes invariably develop complications including cardiovascular disease (CVD). To reduce their CVD risk, diabetics are generally prescribed cholesterol-lowering 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (i.e.

Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia.

Inflammation underpins aspects of insulin resistance and dysglycemia. Microbiota-derived cell wall components such as muropeptides or endotoxin can trigger changes in host immunity and metabolism. Specific peptidoglycan motifs promote metabolic tissue inflammation, lipolysis and insulin resistance via Nucleotide-binding oligomerization domain-containing protein 1 (Nod1).

Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4.

Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. We found that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires NOD2.

Is immunity a mechanism contributing to statin-induced diabetes?

Statins lower cholesterol and are commonly prescribed for prevention and treatment of cardiovascular disease risk. Statins have pleotropic actions beyond cholesterol lowering, including decreased protein prenylation, which can alter immune function. The general anti-inflammatory effect of statins may be a key pleiotropic effect that improves cardiovascular disease risk.

Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance.

Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes.

Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1.

Obesity is associated with inflammation that can drive metabolic defects such as hyperlipidemia and insulin resistance. Specific metabolites can contribute to inflammation, but nutrient intake and obesity are also associated with altered bacterial load in metabolic tissues (i.e.