Biology subjects

Melgar, S.

Publications and source records attributed to Melgar, S..

3 recordsLinked to original sources

bioRxiv2025

The dietary emulsifier polysorbate-80 induces lipid accumulation and cell death in intestinal epithelial cells via ferroptosis

Chronic inflammatory and metabolic diseases are major global health issues increasingly linked to dietary factors. Consumption of dietary emulsifiers like polysorbate-80 (p80), common in ultra-processed foods and pharmaceuticals, has raised concerns about gut health. RNA sequencing on intestinal epithelial cells (IECs) exposed to p80 revealed increased expression of ferroptosis-associated genes and disruption of lipid metabolism pathways further demonstrated by mitochondrial dysfunction, including altered membrane potential and architecture, and accumulation of reactive oxygen species, iron, lipid peroxidation, and lipid droplet formation. Lipidomic profiling identified significant alterations in triglyceride species and elevated pro-ferroptotic polyunsaturated fatty acids. These data indicate that p80 disrupts lipid homeostasis in IECs and triggers ferroptotic cell death, mechanisms potentially contributing to the increased incidence of chronic conditions like inflammatory bowel disease and metabolic syndrome. The study highlights critical implications for public health, emphasizing the need for reassessment of emulsifier safety standards while balancing needs with consumer safety.

cell biology↗

bioRxiv2025

IL-32 drives inflammatory responses in IFN-γ primed human macrophages via a Myddosome-dependent pathway and is elevated in COVID-19

IFN-{gamma} is secreted by multiple lymphoid subsets in response to antigen stimulation and can reprogram and prime macrophages epigenetically and transcriptionally to increase responses to inflammatory stimuli such as LPS, IL-1{beta} or TNF-. IFN-{gamma}-driven M1-like inflammatory macrophage states are shared across human immune-mediated inflammatory diseases (IMIDs) and while IFN-{gamma} is nonredundant for defense to intracellular pathogens it is unclear if this is also the case in IMIDs. To identify additional secreted ligands which could prime and induce M1-like macrophages we screened >600 human proteins in human primary macrophages. Using complementary functional genomics approaches, we discovered that IL-32{beta} induced an M1-like inflammatory state in non-primed and IFN-{gamma}-primed macrophages. IL-32{beta} induced signaling, transcriptional, tolerance, cross-tolerance, and inflammatory responses in macrophages which were MyD88, IRAK1 and Myddosome-dependent. These responses to host IL-32{beta} were similar to yet distinct from, those induced by microbial LPS. IL-32 protein was elevated in serum from patients with severe COVID-19 and IL-32{beta} together with IFN-{gamma} were expressed by T cells and induced a macrophage transcriptional response which was shared by monocytes and macrophages in mild and severe COVID-19.

immunology↗

bioRxiv2022

An IBD-associated pathobiont synergises with NSAID to promote colitis which is blocked by NLRP3 inflammasome and Caspase-8 inhibitors

Conflicting evidence exists on the association between consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and symptomatic worsening of inflammatory bowel disease (IBD). We hypothesise that the heterogeneous prevalence of pathobionts [e.g., adherent-invasive Escherichia coli (AIEC)], might explain this inconsistent NSAIDs/IBD correlation. Using IL10 -/- mice, we show aggravation of colitis in AIEC-colonised animals fed NSAID. This is accompanied by activation of the NLRP3 inflammasome, Caspase-8, apoptosis and pyroptosis; features not seen in mice exposed to AIEC or NSAID alone, revealing an AIEC/NSAID synergistic effect. Inhibition of NLRP3 or Caspase-8 activity ameliorated colitis, with reduction in NLRP3 inflammasome activation, cell death markers and activated T-cells and macrophages, improved histology and increased abundance of Clostridium cluster XIVa species. Our findings provide mechanistic insights into how NSAID and an opportunistic gut-pathobiont can synergise to worsen IBD symptoms. Thus, targeting the NLRP3 inflammasome and Caspase-8 could be a potential therapeutic strategy in patients with NSAID-worsened inflammation.

immunology↗