No abstract

Sunitinib has been associated with several cardiotoxic effects such as cardiac fibrosis. The present study was designed to explore the role of interleukin (IL)-17 in sunitinib-induced myocardial fibrosis (MF) in rats and whether its neutralization and/or administration of black garlic (BG), a form of fermented raw garlic (Allium sativum L.), could extenuate this adverse effect. Male Wistar albino rats received sunitinib (25 mg/kg three times a week, orally) and were co-treated with secukinumab (3 mg/kg, subcutaneously, three times total) and/or BG (300 mg/kg/day, orally) for four weeks. Administration of sunitinib induced significant increase in cardiac index, cardiac inflammatory markers, and cardiac dysfunction that were ameliorated by both secukinumab and BG, and to a preferable extent, with the combined treatment. Histological examination revealed disruption in the myocardial architecture and interstitial fibrosis in cardiac sections of the sunitinib group, which were reversed by both secukinumab and BG treatments. Both drugs and their co-administration restored normal cardiac functions, downregulated cardiac inflammatory cytokines, mainly IL-17 and NF-κB, along with increasing the MMP1/TIMP1 ratio. Additionally, they attenuated sunitinib-induced upregulation of the OPG/RANK/RANKL axis. These findings highlight another new mechanism through which sunitinib can induce interstitial MF. The current results propose that neutralizing IL-17 by secukinumab and/or supplementation with BG can be a promising therapeutic approach for ameliorating sunitinib-induced MF.

Bone is a mineralized structure that is mainly made of a matrix that supports the various types of bone cells; osteoblasts, osteoclasts, osteocytes and bone lining cells. Bone mass is preserved as a result of the balance between bone forming osteoblasts and bone resorbing osteoclasts, in a process known as bone remodeling. Bone remodeling process occurs mainly in three steps: resorption, reversal and formation. These steps are controlled locally and systemically by numerous regulatory factors. Among these regulatory factors, wingless-related MMTV integration site (Wnt) signaling pathway plays a significant role in maintainig bone mass as well as regulating many cellular processes. Based on whether β-catenin is involved or not, Wnt signaling is categorized into two main pathways; the canonical and the non-canonical pathways. The actions exerted by the Wnt signaling pathway are achieved when Wnt ligands bind to specific transmembrane receptors such as the Frizzled family (Frz) members and low density lipoprotein receptor-related proteins (LRPs) and are inhibited when these ligands or receptors bind to Wnt signaling inhibitors such as Wnt inhibitory factor 1 (WIF1), secreted Frizzledrelated proteins (sFRPs), Dickkopf 1 (DKK1) and sclerostin. Improper synthesis of any of these ligands, receptors or inhibitors leads to disruption of different body functions and progression of various diseases including skeletal diseases. Therefore, the components of the Wnt signaling pathway can be targeted for developing novel therapeutic agents to manage different diseases.