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File: /var/www/html/application/helpers/my_audit_helper.php
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Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
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Function: simplexml_load_file_from_url
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Function: pubMedSearch_Global
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Function: pubMedGetRelatedKeyword
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Function: require_once
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Function: _error_handler
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedSearch_Global
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Function: pubMedGetRelatedKeyword
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Aims: While Ca signaling plays a vital role in maintaining normal endothelial function and vascular activity, aberrant Ca signaling in endothelial dysfunction is involved in the pathogenesis of inflammation. As a safe anti-psychotic drug to mobilize Ca signaling, we repurposed spiperone as a potential drug for two intestinal epithelial injury related diseases, colitis and sepsis.
Materials And Methods: Spiperone-induced vasorelaxation of human submucosal arterioles and mesenteric arterioles from wide-type and TRPV4 KO mice was determined by Mulvany-style wire myograph. The action of spiperone in HUVEC was tested by Ca imaging and patch clamp, and its action on murine mesenteric arterioles was measured in vivo. LPS- and CLP-induced septic mice and DSS-induced colitic mice were used to examine the anti-inflammatory effects of spiperone.
Key Findings: Spiperone induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of healthy arterioles with EC of ∼50 nM predominately via PLC/IP/IPR pathway to induce endoplasmic reticulum (ER) Ca release and further to promote Ca entry via TRPV4-constituted SOCE. In both LPS- and CLP-induced septic mice, spiperone effectively prevented and treated sepsis by reducing serum proinflammatory factors, alleviating multiple organ dysfunction, rescuing the impaired EDH-mediated vasorelaxation and improving murine survival rate. Similarly, spiperone could also protect against murine colitis.
Significance: We reveal new action mode and mechanism of spiperone to induce EDH-mediated vasorelaxation of both human and murine arterioles to protect against colitis and sepsis by innovatively inducing PLC/IPR/Ca signaling rather than canonically antagonizing GPCR. Spiperone could be repurposed as a potential new drug for the prevention/treatment of colitis and sepsis.
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http://dx.doi.org/10.1016/j.lfs.2024.123268 | DOI Listing |
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