Repurposing of alogliptin to mitigate experimentally-induced ulcerative colitis and its associated pulmonary injury in rats through regulating inflammatory, necroptotic, and ER stress pathways.

Lung injury is one of the clinically reported conditions associated with inflammatory bowel diseases. The purpose of this study was to assess, for the first time, alogliptin's possible therapeutic effect in acetic acid (AA)-induced UC and its associated lung injury in rats, with investigation of the probable molecular mechanisms of protection. To induce UC, rats were given a single intrarectal injection of 1 ml of 4% AA. Following 24 h of induction, rats were treated orally with ALO for 2 weeks at doses of 15 or 30 mg/kg/day. Higher-dose of ALO provided an ancillary improvement towards the treatment of AA-induced UC and its associated lung injury compared to lower-dose of ALO. Notably, ALO improved the rats' overall health, body weights and mitigated the pathological changes induced by AA in the colon and lungs. Besides, ALO enhanced tight junction integrity by modulating the gut DPP-4/GLPs axis, which in turn led to inhibition of systemic inflammation induced by TNF-α/claudin-1 axis. These outcomes subsequently prevented the pulmonary injury associated with TLR4/NF-κB p65/TNF-α, RIPK1/MLKL/HMGB1, IRE-1α/p-JNK, oxidative stress, and TGF-β1/COL1A1/COL3A1 cascades with notable anti-fibrotic effects. In this context, ALO could be a promising nominee for the treatment of UC and its associated pulmonary injury through attenuating colonic inflammation, preserving gut integrity, and preventing systemic inflammation and its associated lung-induced injury.