Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China.
Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao 266073, China; Department of Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
Life Sci. 2024 Dec 1;358:123090. doi: 10.1016/j.lfs.2024.123090. Epub 2024 Oct 9.
Although zinc pyrithione (ZPT) has been studied as topical antimicrobial and cosmetic consumer products, little is known about its pharmacological actions in gastrointestinal (GI) health and inflammation. Our aims were to investigate the effects of ZPT on transient receptor potential (TRP) channels and Ca signaling in intestinal epithelial cells (IECs) and its therapeutic potential for colitis.
Digital Ca imaging and patch-clamp electrophysiology were performed on human colonic epithelial cells (HCoEpiC) and rat small intestinal epithelial cells (IEC-6). The transcription levels of proinflammatory cytokines such as IL-1β were detected by RTq-PCR. Dextran sulfate sodium (DSS) was used to induce colitis in mice.
ZPT dose-dependently induced Ca signaling and membrane currents in IECs, which were attenuated by selective blockers of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 4 (TRPV4) channels, respectively. Interestingly, Ca entry via TRPA1 channels inhibited the activity of TRPV4 channels in HCoEpiC, but not vice versa. ZPT significantly promoted migration of IECs by activating TRPA1 and TRPV4 channels. ZPT reversed lipopolysaccharides (LPS)-induced changes in mRNA expression of TRPA1 and TRPV4. Moreover, ZPT decreased mRNA levels of pro-inflammatory factors promoted by LPS in HCoEpiC, which were restored by selective TRPA1 blocker. In whole animal studies in vivo, ZPT significantly ameliorated DSS-induced body weight loss, colon shortening and increases in stool score, serum calprotectin and lactic acid (LD) in mouse model of colitis.
ZPT exerts anti-colitic action likely by anti-inflammation and pro-mucosal healing through TRP channels in IECs. The present study not only expands pharmacology spectrum of ZPT in GI tract, but also repurposes it to a potential drug for colitis therapy.
尽管吡硫鎓（ZPT）已被研究作为局部抗菌和化妆品消费产品，但对于其在胃肠道（GI）健康和炎症中的药理作用知之甚少。我们的目的是研究 ZPT 对肠道上皮细胞（IEC）中瞬时受体电位（TRP）通道和 Ca 信号的影响及其在结肠炎治疗中的潜力。
对人结肠上皮细胞（HCoEpiC）和大鼠小肠上皮细胞（IEC-6）进行数字 Ca 成像和膜片钳电生理学研究。通过 RTq-PCR 检测促炎细胞因子（如 IL-1β）的转录水平。使用葡聚糖硫酸钠（DSS）诱导小鼠结肠炎。
ZPT 剂量依赖性地诱导 IEC 中的 Ca 信号和膜电流，分别被瞬时受体电位锚蛋白 1（TRPA1）和瞬时受体电位香草酸 4（TRPV4）通道的选择性阻滞剂减弱。有趣的是，通过 TRPA1 通道的 Ca 内流抑制了 HCoEpiC 中 TRPV4 通道的活性，但反之则不然。ZPT 通过激活 TRPA1 和 TRPV4 通道显著促进 IEC 的迁移。ZPT 逆转了 LPS 诱导的 HCoEpiC 中 TRPA1 和 TRPV4 通道 mRNA 表达的变化。此外，ZPT 降低了 LPS 诱导的 HCoEpiC 中促炎因子的 mRNA 水平，而选择性 TRPA1 阻断剂可恢复这些水平。在体内动物研究中，ZPT 显著改善了 DSS 诱导的体重减轻、结肠缩短和粪便评分、血清钙卫蛋白和乳酸（LD）增加的小鼠结肠炎模型。
ZPT 通过 IEC 中的 TRP 通道发挥抗结肠炎作用，可能通过抗炎和促进黏膜愈合。本研究不仅扩展了 ZPT 在胃肠道中的药理学谱，还将其重新用于结肠炎治疗的潜在药物。
