Background Pyroptosis is a form of proinflammatory gasdermin-mediated programmed cell death. Abnormal mucosal inflammation in the intestine is a critical risk factor for colitis-associated colorectal cancer (CAC). However, it is unknown whether pyroptosis participates in the development of CAC. Methods To investigate the role of gasdermin E (GSDME)-mediated pyroptosis in the development of CAC, Gsdme−/− mice and their wild-type (WT) littermate controls were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce a CAC model. Neutralizing antibodies against high-mobility group box protein 1 (HMGB1) were used to determine the role of HMGB1 in CAC. To identify the role of ERK1/2 in HMGB1-induced colon cancer cell proliferation, we performed western blotting and CCK8 assays using the ERK1/2-specific inhibitor U0126 in CT26 colon cancer cells. Results In the CAC model, Gsdme−/− mice exhibited reduced weight loss and colon shortening, attenuated rectal prolapse, and reduced tumor numbers and sizes compared to WT littermates. Furthermore, treatment with neutralizing anti-HMGB1 antibodies decreased the numbers and sizes of tumors, ERK1/2 activation and proliferating cell nuclear antigen (PCNA) expression in AOM/DSS-challenged WT mice. In addition, our in vitro experiments demonstrated that HMGB1 induced proliferation and PCNA expression in CT26 colon cancer cells through the ERK1/2 pathway. Conclusion GSDME-mediated pyroptosis promotes the development of CAC by releasing HMGB1, which induces tumor cell proliferation and PCNA expression through the ERK1/2 pathway. This finding reveals a previously unrecognized link between pyroptosis and CAC tumorigenesis and offers new insight into CAC pathogenesis.
Mequindox is used as a veterinary antibiotic drug. As part of systematic investigations into mequindox as a veterinary medicine and its subsequent applications in food safety, we conducted the investigation to assess the metabolic response of mice to mequindox using metabonomics, which combines NMR metabolic profiles of biofluids or tissues and pattern recognition data analysis. In this study, we delivered a single dose of mequindox to mice with dosage levels of 15, 75, and 350 mg/kg body weight and collected urine samples over a 7 day period, as well as plasma and liver tissues at 7 days postdose. Principal components analysis (PCA) and orthogonal projection to latent structure discriminant analysis (O-PLS-DA) were performed on (1)H NMR spectra of biofluids and liver, showing that low dose levels of mequindox exposure had no adverse effects, consistent with histological observations of the liver. High and moderate levels of mequindox exposure caused suppression of glycolysis and stimulation of fatty acid oxidation accompanied with increased levels of oxidative stress. Our metabonomic analyses also showed disruption of amino acid metabolism, consistent with liver damage observed from histopathological examinations. Furthermore, mequindox perturbed gut microbial activity manifested in the altered excretion of urinary trimethylamine (TMA), trimethylamine-N-oxide (TMAO), hippurate, phenylacetylglycine (PAG), and phenylacetate. The putative gut microbial function may also contribute to the assembly and secretion of very-low-density lipoproteins from the liver to the plasma. Our work provides important insights on the metabolic responses of mequindox.
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