Gastrointestinal disease is the most common health concern that occurs due to environmental, infectious, immunological, psychological, and genetic stress. Among them, the most frequent diseases are gastric ulcer (GU) and ulcerative colitis (UC). DSS-induced UC and ethanol-stimulated GU models resemble the pathophysiology of human gastrointestinal disease. The current study was designed to explore the anti-oxidation, anti-inflammation, anti-cell death properties of terazosin, an α-adrenergic receptor antagonist, in vivo and in vitro. Our results indicate that terazosin dramatically activates Pgk1, and upregulates glycose metabolism, evidenced by the enhanced ATP production and higher LDH enzymatic activity. Also, terazosin significantly enhances p-AKT expression and inhibits NF-κB p65 activation through abrogating the phosphorylation of IKBα, as well as lowers Caspase-1 and GSDMD expression. The findings in this study demonstrate that terazosin exhibits anti-inflammatory effects by downregulating NF-κB-GSDMD signal pathway, along with enhancing glycolysis for gastrointestinal disease treatment. Meanwhile, we also find terazosin ameliorates ethanol-induced gastric mucosal damage in mice. Collectively, as a clinical drug, terazosin should be translated into therapeutics for gastrointestinal disease soon.

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Stroke is the second leading cause of death worldwide and the leading cause of long-term disability that seriously endangers health and quality of human life. Tissue-type fibrinogen activator is currently the only drug approved by FDA for the treatment of ischemic stroke. Neuroprotection is theoretically a common strategy for the treatment of both ischemic and hemorrhagic stroke; therefore, the development of neuroprotective agent has been the focus of research. However, no ideal neuroprotective drug is clinically available. Phosphoglycerate kinase-1 (PGK1) activator has the effect of inhibiting apoptosis and protecting tissue damage, and therefore could be a potential neuroprotective agent. To obtain effective PGK1 activators, we virtually screened a large chemical database and their evaluated the efficacy by the Drosophila oxidative stress model, PGK1 enzymatic activity assay, and oxygen-glucose stripping reperfusion (OGD/R) model. The results showed that compounds 7979989, Z112553128 and AK-693/21087020 are potential PGK1 activators with protective effects against PQ-induced oxidative stress in the Drosophila model and could effectively ameliorate apoptosis induced by OGD/R-induced neuronal cell injury. Additionally, compounds 7979989 and Z112553128 are effective in alleviating LPS-induced cellular inflammation. This study indicated that these compounds are promising lead compounds that provide theoretical and material basis to the neuroprotective drug discovery.

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