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Celecoxib alleviates zinc deficiency-promoted colon tumorigenesis through suppressing inflammation.

ABSTRACT: Accumulating evidence has shown that dietary zinc deficiency (ZD) increases the risk of various cancers including esophageal and gastric cancer. However, the role of ZD in colon tumorigenesis is unknown and the related mechanisms need to be investigated. Apc^min/+ mice, widely used to mimic the spontaneous process of human intestinal tumor, were used to construct a ZD mice model in this study. Inflammatory mediators such as COX-2, TNF-α, CCL, CXCL, and IL chemokines families were evaluated using real-time PCR and Enzyme-linked immunosorbent assay (ELISA). Besides, the immunoreactivities of cyclin D1, PCNA, and COX-2 in the colon were detected by immunohistochemistry. We found that zinc deficiency could promote colon tumorigenesis in Apc^min/+ mice. The mechanisms are involved in the upregulation of inflammatory mediators: COX-2, TNF-α, CCL, CXCL, and IL chemokines families. Administration of celecoxib, a selective COX-2 inhibitor, decreased colon tumorigenesis in Apc^min/+ mice via inhibiting the inflammatory mediators. ZD plays an important role in the process of colon cancers of Apc^min/+ mice. Celecoxib attenuates ZD-induced colon tumorigenesis in Apc^min/+ mice by inhibiting the inflammatory mediators. Our novel finding would provide potential prevention of colorectal tumor-induced by ZD.

SUBMITTER: Yin X

PROVIDER: S-EPMC8034938 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose:To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE). Methods:The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine. Results:In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1?, IL-6, IL-8, and TNF-?. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells. Conclusions:Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.

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Celecoxib alleviates zinc deficiency-promoted colon tumorigenesis through suppressing inflammation.

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