The present study was conducted to investigate the potential protective effects of coenzyme Q 10 (CoQ10) administration on methotrexate induced lung and liver fibrosis in rat model, and to explore our hypothesis regarding its possible mechanism of action through reactivation of autophagy pathway. Methotrexate induced fibrosis was achieved by intraperitoneal injections twice a week for 4 weeks. A combined treatment of CoQ10 and methotrexate were used. Blood samples for biochemical analysis, lung and livers tissue for biochemical and histopathological analysis, were investigated. Concomitant treatment of CoQ10 & methotrexate caused improvement in histological picture of the lung and liver tissues, liver function and oxidative stress biomarkers, modulation of autophagy genes [mammalian target of rapamycin (m-TOR), Microtubule-associated proteins 1 A/1B light chain 3 (MAP1LC3B), and Sequestosome 1 ubiquitin-binding protein p62 (p62/SQSTM1)] with simultaneous reduction in High Mobility Group Protein B1 (HMGB1). Based on our results we postulated that CoQ10 up regulates autophagy pathway that could explain its protective properties against lung and liver fibrosis caused by methotrexate treatment in current study rat model.

The Nkx2.5 gene encodes a transcription factor that plays a critical role in heart development. In humans, heterozygous mutations in NKX2.5 result in congenital heart defects (CHDs). However, the molecular mechanisms by which these mutations cause the disease remain unknown. NKX2.5-R142C is a mutation that was reported to be associated with atrial septal defect (ASD) and atrioventricular (AV) block in 13-patients from one family. The R142C mutation is located within both the DNA-binding domain and the nuclear localization sequence of NKX2.5 protein. The pathogenesis of CHDs in humans with R142C point mutation is not well understood. To examine the functional deficit associated with this mutation in vivo, we generated and characterized a knock-in mouse that harbours the human mutation R142C. Systematic structural and functional examination of the embryonic, newborn, and adult mice revealed

Since the discovery of proprotein convertase subtilisin kexin 9 (PCSK9) in 2003, this PC has attracted a lot of attention from the scientific community and pharmaceutical companies. Secreted into the plasma by the liver, the proteinase K–like serine protease PCSK9 binds the low-density lipoprotein (LDL) receptor at the surface of hepatocytes, thereby preventing its recycling and enhancing its degradation in endosomes/lysosomes, resulting in reduced LDL-cholesterol clearance. Surprisingly, in a nonenzymatic fashion, PCSK9 enhances the intracellular degradation of all its target proteins. Rare gain-of-function PCSK9 variants lead to higher levels of LDL-cholesterol and increased risk of cardiovascular disease; more common loss-of-function PCSK9 variants are associated with reductions in both LDL-cholesterol and risk of cardiovascular disease. It took 9 years to elaborate powerful new PCSK9-based therapeutic approaches to reduce circulating levels of LDL-cholesterol. Presently, PCSK9 monoclonal antibodies that inhibit its function on the LDL receptor are evaluated in phase III clinical trials. This review will address the biochemical, genetic, and clinical aspects associated with PCSK9’s biology and pathophysiology in cells, rodent and human, with emphasis on the clinical benefits of silencing the expression/activity of PCSK9 as a new modality in the treatment of hypercholesterolemia and associated pathologies.