Crocin attenuates cisplatin-induced hepatotoxicity via TLR4/NF-κBp50 signaling and BAMBI modulation of TGF-β activity: Involvement of miRNA-9 and miRNA-29

TLR4-induced mitigation of the BMP down-regulation and activin membrane bound inhibitor (BAMBI) and the consequent enhancement of the transforming growth factor-beta (TGF-beta) profibrogenic signaling has not yet been studied in cisplatin (CIS)-induced hepatotoxicity. miRNA-9 and29 have been previously reported to modulate TLR4 signaling via either tempering the expression of nuclear factor kappa-B p50 (NF-kappa B p50) or downregulation of extracellular matrix genes respectively. Hence we aimed to investigate the involvement of TLR4-induced modulation of TGF-beta receptor 1 (TGF-beta R1) signaling as well as the implication of miRNA-9 and 29 in CIS-induced hepatotoxicity. Moreover, we examined the ability of the phytochemical; crocin (CROC); to interact with either TLR4 or TGF-beta R1 through a molecular docking study and subsequently explore its capability to attenuate CIS-induced hepatotoxicity. CROC pretreatment ameliorated the CIS-induced enhancement of TLR4 and TGF-beta signaling and enhanced the expression of BAMBI, miRNA-9 and 29. Accordingly, it may be assumed that the protective effect of CROC against CIS-induce hepatotoxicity is mediated via the crosstalk of TLR4/NF-kappa Bp50 signaling and BAMBI modulation of TGF-beta 1 activity in addition to the up-regulation of miRNA-9 and 29. These findings came in alignment with our molecular docking results; emphasizing the molecular antagonistic activity of CROC in both TLR4 and TGF-beta R1.