Journal
FRONTIERS IN PHARMACOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.1020670
Keywords
ganciclovir; colitis; microbiome; STING; macrophage
Categories
Funding
- National Natural Science Foundation of China [81870874, 82171229, 81672970]
- Health and Family Planning Commission of China Jiangsu Province [CXTDA2017016]
- Laboratory of Radiation Medicine and radiation protection of Soochow University [GZK1202010]
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This study found that ganciclovir can improve DSS-induced ulcerative colitis by inhibiting the STING signaling pathway. The therapeutic effect of this drug on UC in mice is promising.
Ganciclovir (GCV) is a prodrug nucleoside analogue and is clinically used as antiviral drug for the treatment of cytomegalovirus (CMV) and other infections. Based on the potential anti-inflammatory activity of GCV, this study aimed to investigate the therapeutic effects of ganciclovir on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC), which may involve cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways. Our results demonstrated that incubation of GCV (50 mu M) inhibited cGAS-STING pathway in macrophage RAW264.7 cells. Then, it was found that intestinal cGAS-STING pathways were upregulated in UC patients, Crohn's disease colitis (CD) patients, and DSS-induced colitis mice. Intraperitoneal injection of low-dose GCV (10 mg/kg/day) attenuated DSS-induced colitis and abdominal pain in mice. GCV treatment significantly inhibited the upregulation of cGAS-STING pathway in DSS-induced colitis mice. Moreover, DSS-induced colitis and gut dysbiosis was markedly attenuated in STING deficient mice compared with that of wild-type (WT) mice. Finally, there was lacking therapeutic effect of GCV on DSS-induced colitis in STING deficient mice. Together, our results indicated that low-dose GCV ameliorated DSS-induced UC in mice, possibly through inhibiting STING signaling in colonic macrophages, indicating that GCV may be useful for the treatment of UC.
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