35kDa SPECIFIC-SIZED HYALURONAN AMELIORATES HIGH-FAT DIET-INDUCED LIVER INJURY IN MURINE MODEL OF MODERATE OBESITY.

Obesity is a growing concern in the US and world-wide, associated with an increased risk for several cardiometabolic diseases, including metabolic associated steatotic liver disease (MASLD). Currently, therapeutic interventions to prevent and/or treat MASLD are limited, and research is needed to identify new therapeutic targets. The specific-sized 35kDa fragment of hyaluronan (HA35), has gut protective and anti-inflammatory properties and a previous pilot clinical study reported it is well tolerated in healthy individuals.

Hyperglycemic environments directly compromise intestinal epithelial barrier function in an organoid model and hyaluronan (∼35 kDa) protects via a layilin dependent mechanism.

Background: Metabolic syndrome and diabetes in obese individuals are strong risk factors for development of inflammatory bowel disease (IBD) and colorectal cancer. The pathogenic mechanisms of low-grade metabolic inflammation, including chronic hyperglycemic stress, in disrupting gut homeostasis are poorly understood. In this study, we sought to understand the impact of a hyperglycemic environment on intestinal barrier integrity and the protective effects of small molecular weight (35 kDa) hyaluronan on epithelial barrier function.

The protein kinase R modifies gut physiology to limit colitis.

Here we investigate the function of the innate immune molecule protein kinase R (PKR) in intestinal inflammation. To model a colitogenic role of PKR, we determine the physiological response to dextran sulfate sodium (DSS) of wild-type and two transgenic mice strains mutated to express either a kinase-dead PKR or to ablate expression of the kinase. These experiments recognize kinase-dependent and -independent protection from DSS-induced weight loss and inflammation, against a kinase-dependent increase in the susceptibility to DSS-induced injury.

35kDa hyaluronan ameliorates ethanol driven loss of anti-microbial defense and intestinal barrier integrity in a TLR4-dependent manner.

Acute and chronic alcohol exposure compromise intestinal epithelial integrity, due to reduced expression of anti-microbial peptides (AMP) and loss of tight junction integrity. Ameliorating gut damage is beneficial in preventing associated distant organ pathologies. Orally administered purified hyaluronan (HA) polymers with an average size of 35 kDa have multiple protective effects in the gut and are well-tolerated in humans.

M1 Macrophages Induce Protumor Inflammation in Melanoma Cells through TNFR-NF-κB Signaling.

The tumor microenvironment, with distinctive cell types and a complex extracellular matrix has a tremendous impact on cancer progression. In this study, we investigated the effects of proinflammatory (M1) and immunosuppressive (M2) macrophages on hyaluronan (HA) matrix formation and inflammatory response in melanoma cells. Proinflammatory factors secreted from M1 macrophages stimulated the formation of a thick pericellular HA matrix in melanoma cells due to upregulation of HA synthase 2 (HAS2).