Vitamin D modulates hepatic microRNAs and mitigates tamoxifen-induced steatohepatitis in female rats.

Tamoxifen (TAM) is a life-saving and cost-effective drug widely used in the prevention and treatment of breast cancer. However, the adverse effects of tamoxifen can lead to non-adherence and poor patient outcomes. Therefore, exploring novel strategies to improve TAM safety profile is crucial. Given the key role that vitamin D (VD) plays in modulating lipid metabolism and inflammation, in addition to its benefits in reducing risk and progression of breast cancer, we evaluated the protective potential of VD against TAM-induced hepatotoxicity focusing on lipid metabolism and microRNAs (miRNAs) regulation. Female rats were pretreated with VD as cholecalciferol (500 IU/kg/day, po) for 4 weeks before receiving TAM (40 mg/kg/day, po) concurrently with VD during the fifth and sixth weeks. Liver histology, lipid profile and expression of genes, proteins, and miRNAs involved in lipid metabolism and inflammation were examined. TAM-induced steatohepatitis was evidenced by elevated liver triglycerides and cholesterol contents, increased serum miRNA-122 level, and ALT activity, in parallel with accumulation of lipid droplets, focal necrosis, and inflammatory cells infiltration in hepatocytes. Prophylactic use of VD mitigated TAM-induced steatohepatitis by modulating key transcription factors in the liver: PPAR-α, Srebf1, and NF-κB and their downstream genes/proteins Fas, CPT-1A, and TNF-α resulting in reduced hepatic lipids and suppressed pro-inflammatory signaling. Notably, VD pretreatment mitigated TAM-induced alterations in the expression of serum miRNA-122, hepatic miRNA-21, and miRNA-33. The combination therapy of VD and TAM has complementary benefits in terms of safety and not only efficacy and should be further investigated clinically.

Neuroprotective Effects of Telmisartan and Nifedipine Against Cuprizone-Induced Demyelination and Behavioral Dysfunction in Mice: Roles of NF-κB and Nrf2.

Multiple sclerosis is a chronic inflammatory neurodegenerative disease of the central nervous system which injures the myelin sheath. Telmisartan and nifedipine are antihypertensive drugs that recently showed neuroprotective properties against neurodegenerative diseases. This study evaluated the neuroprotective effect of telmisartan or nifedipine in cuprizone-induced demyelination in mice by examining the underlying mechanisms. C57BL/6 mice received a diet containing 0.7% (w/w) cuprizone for 7 days followed by 3 weeks on a 0.2% cuprizone diet. Telmisartan (5 mg/kg/day, p.o.) or nifedipine (5 mg/kg/day, p.o.) was administered for 3 weeks starting from the second week. Telmisartan or nifedipine improved locomotor activity and enhanced motor coordination as demonstrated by open field, rotarod, and grip strength tests. Furthermore, telmisartan or nifedipine restored myelin basic protein mRNA and protein expression and increased luxol fast blue-staining intensity. Telmisartan or nifedipine attenuated cuprizone-induced oxidative stress and apoptosis by decreasing brain malondialdehyde and caspase-3 along with restoring reduced glutathione and brain-derived neurotrophic factor levels. Telmisartan or nifedipine exerted an anti-inflammatory effect by reducing the expression of nuclear factor kappa B (NF-κB p65) as well as pro-inflammatory cytokines and elevating the expression of IκB-α. In parallel, telmisartan or nifedipine upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the levels of heme oxygenase-1 and NADPH quinone oxidoreductase 1 enzymes. In conclusion, the current study provides evidence for the protective effect of telmisartan and nifedipine in cuprizone-induced demyelination and behavioral dysfunction in mice possibly by modulating NF-κB and Nrf2 signaling pathways.