Agomelatine alleviates steroid-induced osteoporosis by targeting SIRT1/RANKL/FOXO1/OPG signalling in rats.

One of the major contributors to secondary osteoporosis is long-term glucocorticoid usage. Clinically used antidepressant agomelatine also has anti-inflammatory properties. Our research aimed to inspect the probable defensive effect of agomelatine against steroid-promoted osteoporosis. There were four groups of rats; group I had saline as a negative control; rats of group II had dexamethasone (0.6 mg/kg, s.c.), twice weekly for 12 weeks; rats of group III had agomelatine (40 mg/kg/day, orally), as a positive control, daily for 12 weeks; and rats of group IV had dexamethasone + agomelatine in the same previous doses combined for 12 weeks. Finally, biochemical as well as histopathological changes were evaluated and dexamethasone treatment caused osteoporosis, as evidenced by discontinuous thin cancellous bone trabeculae, minor fissures and fractures, irregular eroded endosteal surface with elevated alkaline phosphate, tartarate resistant acid phosphate (TRACP) and osteocalcin levels. Osteoprotegerin (OPG), calcium, and phosphorus levels decreased with disturbed receptor activator of nuclear factor κ B ligand (RANKL), forkhead box O1 (FOXO1), and silent information regulator 1 (SIRT1) protein expression. However, treatment with agomelatine restored the normal levels of biochemical parameters to a great extent, supported by SIRT activation with an improvement in histopathological changes. Here, we concluded that agomelatine ameliorates steroid-induced osteoporosis through a SIRT1/RANKL/FOXO1/OPG-dependent pathway.

1,25-Dihydroxycholecalciferol down-regulates 3-mercaptopyruvate sulfur transferase and caspase-3 in rat model of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of liver morbidity and mortality and has multiple unclear pathogenic mechanisms. Vitamin D deficiency was associated with increased incidence and severity of NAFLD. Increased hepatic expression of 3-mercaptopyruvate sulfur transferase (MPST) and dysregulated hepatocyte apoptosis were involved in NAFLD pathogenesis. We aimed to explore the protective effect of 1,25-Dihydroxycholecalciferol (1,25-(OH)2 D3) against development of NAFLD and the possible underlying mechanisms, regarding hepatic MPST and caspase-3 expression. 60 male adult rats were divided into 4 and 12 week fed groups; each was subdivided into control, high-fat diet (HFD), and HFD + VD. Serum levels of lipid profile parameters, liver enzymes, insulin, glucose, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and hepatic levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and reactive oxygen species (ROS) were measured. BMI and HOMA-IR were calculated, and liver tissues were processed for histopathological and immunohistochemical studies. The present study found that 1,25-(OH)2 D3 significantly decreased BMI, HOMA-IR, serum levels of glucose, insulin, liver enzymes, lipid profile parameters, CRP, TNF-α, hepatic levels of MDA, ROS, hepatic expression of MPST, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and caspase-3; and significantly increased hepatic TAC in both HFD-fed groups. In conclusion: Administration of 1,25-(OH)2 D3 with HFD abolished the NAFLD changes associated with HFD in 4-week group, and markedly attenuated the changes in 12-week group. The anti-apoptotic effect via decrement of caspase-3 and MPST expression are novel mechanisms suggested to be implicated in the protective effect of 1,25-(OH)2 D3.