Phthalates are widely used plasticizers that can leach into food products, making dietary exposure a significant food safety concern. Increasing evidence indicates that phthalates adversely affect gastrointestinal health and contribute to the development of inflammatory bowel disease (IBD), metabolic disorders, diabetes, and cardiovascular disease. Mechanistic studies demonstrate that phthalates disrupt gut microbiota composition, diversity, and metabolic activity, compromising microbial barrier function integrity and facilitating pathogen translocation. They also impair intestinal barrier function by reducing mucus secretion, altering tight junction proteins, and increasing epithelial permeability. Furthermore, phthalates promote intestinal inflammation by enhancing pro-inflammatory cytokine production, suppressing anti-inflammatory responses, and disrupting immune cell homeostasis. Emerging findings reveal detrimental effects on enteroendocrine and enteric glial cells, resulting in altered hormone secretion, impaired gut-brain signaling, and disrupted intestinal motility. This review summarizes current evidence on molecular mechanisms underlying phthalate-induced gastrointestinal toxicity and highlights potential mitigation strategies, including polyphenols, flavonoids, probiotics, prebiotics, and pharmacological interventions.
Mechlorethamine (HN2) is toxic to the skin and causes inflammation accompanied by disruption of the dermal-epidermal junction (DEJ), commonly known as vesication. HN2 is a sulfur mustard mimic used in research settings to investigate the pharmaco-toxic effects of vesicants. Effective medical countermeasures for vesicant-induced injury remain limited, underscoring the need to identify novel targets for reducing vesication. The present study used HN2 dissolved in dimethyl sulfoxide (DMSO) to induce mouse ear edema and investigate the contribution of the complement system (CS) to skin responses 24 h after exposure to HN2, with DMSO serving as the vehicle control. Tissues were homogenized and processed for proteomic analysis to examine the protein milieu in skin actively responding to HN2-mediated cutaneous injury. Comparative analysis identified 695 proteins that were differentially expressed between the vehicle- and HN2-treated groups (p < 0.05, fold change ≥1). Of these, 134 proteins were upregulated and 561 were downregulated in HN2-exposed tissues relative to DMSO-treated control tissues, with several complement proteins significantly upregulated. Protein enrichment and protein-protein interaction analyses identified the complement pathway as the most significantly enriched pathway in mouse ear skin 24 h after HN2 exposure. ELISA analysis of protein extracts confirmed increased levels of complement factor B, complement C3a, complement C5a, and complement C5b-9, also known as the membrane attack complex. Taken together, these data suggest that activation of the complement pathway may represent a novel target for vesicant countermeasure development.
Silicosis is an occupational disease caused by inhalaling free silicon dioxide (SiO2). Lipid metabolism plays an important role in silicosis. CD36 is a key factor involved in lipid transport, but its mechanism of action in silicosis remains unclear. This study aims to explore the mechanism by which the CD36 inhibitor sulfo-n-succinimide oleate (SSO) targets CD36 to regulate lipid metabolism disorders in silicosis and improve fibrosis. The results showed that SiO2 stimulation led to an increase in CD36 expression, a decrease in LXR and ABCA1 expression, and an increase in lipid dropper formation in rat alveolar macrophages NR8383. The SSO intervention can reverse these changes, resulting in the decrease in CD36 expression, the increase in LXR and ABCA1 expression, the reduction in IL-1β, IL-6 levels and TGF-β1 secretion. Subsequently, after stimulating primary fibroblasts with the supernatants of macrophages in each group, it was found that SSO stimulation reduced the increase of α-SMA and collagen-I induced by SiO2 and improved the level of fibrosis. In addition, in vivo animal experiments have found that SSO intervention alleviated the levels of inflammation, lipid metabolism and fibrosis induced by SiO2 in silicosis mice, and improved the lung function of silicosis mice. These results indicate that SSO regulates SiO2-induced lipid metabolism disorders by targeting CD36, thereby improving SiO2-induced fibrosis. Therefore, SSO targeting CD36 may be a new strategy for treating silica-induced silicosis injury.
Microplastics (MPs) are emerging environmental pollutants, and the gastrointestinal tract represents a major site of exposure following oral intake. This study investigated the effects of polystyrene MP exposure on gut microbiota composition, intestinal barrier integrity, and endotoxin-related inflammatory responses in female rats. MP exposure was associated with compositional alterations in the gut microbiota, including changes in community structure and enrichment of specific bacterial taxa. These microbial changes were accompanied by intestinal mucosal abnormalities, reduced PAS-positive mucin area, decreased expression of the tight junction proteins ZO-1, occludin, and claudin-1, and elevated serum levels of lipopolysaccharide (LPS), interleukin-6 (IL-6), and interleukin-1β (IL-1β). These findings indicate that MP exposure was associated with intestinal barrier impairment and endotoxin-related systemic inflammation. Overall, the present study supports the intestine as a major target of oral MP exposure and suggests that intestinal barrier disruption may contribute to circulating endotoxin accumulation and inflammatory responses. Further studies using direct intestinal permeability assays and targeted mechanistic interventions are needed to clarify the causal relationships among gut microbiota dysbiosis, barrier dysfunction, and systemic inflammation.
