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β-Citronellol: a potential anti-inflammatory and gastro-protective agent-mechanistic insights into its modulatory effects on COX-II, 5-LOX, eNOS, and ICAM-1 pathways through in vitro, in vivo, in silico, and network pharmacology studies

Iqbal Urooj,Malik Abdul,Sial Nabeela Tabassum,Mehmood Malik Hassan,Nawaz Shoaib,Papadakis Marios,Fouad Dalia,Ateyya Hayam,Welson Nermeen N.,Alexiou Athanasios,Batiha Gaber El-Saber

Background The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of β- Citronellol using in vitro , in vivo assays and in silico approaches. Methods In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of β-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE 2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA). Results β - Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat’s paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE 2 , and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, β - Citronellol (50 and 100 mg/kg) increased gastric PGE 2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues. Conclusions The anti-inflammatory, anti-oxidant, and gastro-protective effects of β - Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE 2, 5-LOX, eNOS, and ICAM-1 inflammatory markers. Graphical abstract