N-palmitoyl-D-glucosamine limits mucosal damage and VEGFmediated angiogenesis by PPARα-dependent suppression of pAkt/mTOR/HIF1α pathway and increase in PEA levels in AOM/DSS colorectal carcinoma in mice

Chronic intestinal inflammation and neo-angiogenesis are interconnected in colorectal carcinoma (CRC) pathogenesis. Molecules reducing inflammation and angiogenesis hold promise for CRC prevention and treatment. N-Palmitoyl-D-glucosamine (PGA), a natural glycolipid analog with anti-inflammatory properties, has shown efficacy against acute colitis. Micronized PGA (mPGA) formulations exhibit superior antiinflammatory activity. This study investigates the in vivo anti-angiogenic and protective effects of mPGA in a mouse model of colitis-associated CRC induced by azoxymethane/ dextran sodium sulfate (AOM/DSS). CRC was induced in C57BL/6J mice using intraperitoneal azoxymethane followed by three cycles of 2.5% dextran sodium sulfate (DSS) in drinking water. Mice were treated with mPGA (30–150 mg/kg) with or without the PPARα inhibitor MK886 (10 mg/kg). At Day 70 post-azoxymethane injection, mice underwent anesthetized endoscopic colon evaluation. Post-mortem analysis of tumorigenesis and angiogenesis was performed using histological, immunohistochemical, and immunoblotting techniques. mPGA improved disease progression and survival rates in a dose- and PPARα-dependent manner in AOM/DSSexposed mice. It reduced polyp formation, decreased pro-angiogenic CD31, proproliferative Ki67, and pro-inflammatory TLR4 expression levels, and inhibited VEGF and MMP-9 secretion by disrupting the pAkt/mTOR/HIF1α pathway. mPGA increased colon PEA levels, restoring anti-tumoral PPARα and wtp53 protein expression. Given its lack of toxicity, mPGA shows potential as a nutritional intervention to counteract inflammation-related angiogenesis in CRC.