Peiminine attenuates inflammatory bowel disease by suppressing TLR4 mediated NFƙB pathway: an integrated network pharmacology and experimental validation

Ulcerative colitis and Crohn’s disease are two of the complex and recurring inflammatory conditions that comprise inflammatory bowel disease. There are currently relatively few therapeutic alternatives available for its treatment, and those that are available have serious side effects. It is also in a very progressive and prevalent phase. Therefore, it is necessary to find safer and more effective therapeutics for its treatment. Targeting different molecular pathways, peiminine has antioxidant and anti-inflammatory qualities. Integrated network pharmacology and molecular docking depicted various targets, amongst them NFƙB and TNF-α were the targets where peiminine elicited maximum binding affinity. Validating the in silico data, further in in vivo study, mice were randomly allocated into six groups: Normal control (NC), Disease control (DC-TNBS, 2,4,6-trinitrobenzene sulfonic acid), STD (TNBS + sulfasalazine 100 mg/kg, p.o.), PEI1, PEI2 & PEI3 (TNBS + Peiminine 1, 2.5, & 5 mg/kg, p.o.), respectively. A sharp fall in disease activity index (DAI) and changes in histopathological examination revealed the colonoprotective effect of peiminine. It also depicted anti-oxidant activity through reducing the levels of myeloperoxidase (MPO) and nitric oxide (NO) and elevating superoxide dismutase (SOD), and catalase (CAT). It downregulated various pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in in vitro and in vivo studies, depicting its anti-inflammatory activity. Peiminine has also been shown to have strong anti-inflammatory properties by downregulating the gene expression of TLR4 (1.96-fold), NFƙB (1.70-fold), iNOS (1.27-fold), COX-2 (2.40-fold), and IL-1β (0.80-fold). Meanwhile, it increases the expression of anti-inflammatory mediator IL-10 (2.55-fold). Collectively, peiminine likely decreased colon damage and TNBS-induced colitis through the TLR4-mediated NFƙB pathway.