Notes

Electrocardiographic Compared to Echocardiographic Quit Ventricular Hypertrophy throughout Severe Aortic Stenosis.
Exposure to chronic hyperglycemia due to diabetes mellitus can lead to the development and progression of diabetic kidney disease (DKD). We have recently reported that reduced superoxide production is associated with mitochondrial dysfunction in the kidneys of mouse models of type 1 DKD. We also demonstrated that humans with DKD have significantly reduced levels of mitochondrion-derived metabolites in their urine. Here, we examined renal superoxide production in a type 2 diabetes animal model, the db/db mouse, and the role of a mitochondrial-protectant, MTP-131 (also called elamipretide, SS-31, or Bendavia) in restoring renal superoxide production and ameliorating DKD. We found that18-week-old db/db mice have reduced renal and cardiac superoxide levels, as measured by dihydroethidium oxidation, and increased levels of albuminuria, mesangial matrix accumulation, and urinary hydrogen peroxide (H2O2). Administration of MTP-131 significantly inhibited the increases in albuminuria, urinary H2O2, and mesangial matrix accumulation in the db/db mice, and fully preserved levels of renal superoxide production in these mice. MTP-131 also reduced total renal lysocardiolipin (lysoCL) and major lysoCL subspecies, and preserved lysocardiolipin acyltransferase 1 (LCLAT1) expression in the db/db mice. These results indicate that in type 2 diabetes, DKD is associated with reduced renal and cardiac superoxide levels and that MTP-131 protects against DKD and preserves physiological superoxide levels possibly by regulating cardiolipin remodeling. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Angiogenesis is a hallmark of tumorigenesis, and hepatocellular carcinoma (HCC) is hypervascular and therefore very dependent on angiogenesis for tumor development and progression. Findings from previous studies suggest that in HCC cells, hypoxia-induced factor 1 alpha (HIF1A) and zinc finger homeobox 3 (ZFHX3) transcription factors functionally interact in the regulation of genes in HCC cells. Here, we report that hypoxia increases the transcription of the ZFHX3 gene and enhances the binding of HIF1A to the ZFHX3 promoter in the HCC cell lines HepG2 and Huh-7. Moreover, ZFHX3, in turn, physically associated with and was functionally indispensable for HIF1A to exert its angiogenic activity, as indicated by in vitro migration and tube formation assays of human umbilical vein endothelial cells (HUVECs) and microvessel formation in xenograft tumors of HCC cells. Mechanistically, ZFHX3 was required for HIF1A to transcriptionally activate the vascular endothelial growth factor A (VEGFA) gene by binding to its promoter. Functionally, down-regulation of ZFHX3 in HCC cells slowed their tumor growth, and addition of VEGFA to conditioned medium from ZFHX3-silenced HCC cells partially rescued the inhibitory effect of this medium on HUVEC tube formation. In human HCC, ZFHX3 expression was up-regulated, and this up-regulation correlated with both HIF1A up-regulation and worse patient survival, confirming a functional association between ZFHX3 and HIF1A in human HCC. We conclude that ZFHX3 is an angiogenic transcription factor that is integral to the HIF1A-VEGFA signaling axis in HCC cells. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The double helical structure of genomic DNA is both elegant and functional in that it serves both to protect vulnerable DNA bases and to facilitate DNA replication and compaction. However, these design advantages come at the cost of having to evolve and maintain a cellular machinery that can manipulate a long polymeric molecule that readily becomes topologically entangled whenever it has to open for translation, replication, or repair. If such a machinery fails to eliminate detrimental topological entanglements, utilization of the information stored in the DNA double helix is compromised. As a consequence, the use of B-form DNA as the carrier of genetic information must have co-evolved with a means to manipulate its complex topology. This duty is performed by DNA topoisomerases, which therefore are, unsurprisingly, ubiquitous in all kingdoms of life. In this review, we focus on how DNA topoisomerases catalyze their impressive range of DNA-conjuring tricks, with a particular emphasis on DNA topoisomerase III (TOP3). Once thought to be the most unremarkable of topoisomerases, the many lives of these type IA topoisomerases are now being progressively revealed. This research interest is driven by a realization that their substrate versatility and their ability to engage in intimate collaborations with translocases and other DNA-processing enzymes are far more extensive and impressive than was thought hitherto. This, coupled with the recent associations of TOP3s with developmental and neurological pathologies in humans, is clearly making us reconsider their undeserved reputation as being unexceptional enzymes. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Genetic screening has identified several variants of the endosomal solute carrier family 9 member A6 (SLC9A6)/(Na+, K+)/H+ exchanger 6 (NHE6) gene that cause Christianson syndrome, a debilitating X-linked developmental disorder associated with a range of neurological, somatic and behavioral symptoms. see more Many of these variants cause complete loss of NHE6 expression, but how subtler missense substitutions or nonsense mutations that partially truncate its C-terminal cytoplasmic regulatory domain impair NHE6 activity and endosomal function are poorly understood. Here, we describe the molecular and cellular consequences of six unique mutations located in the N-terminal cytoplasmic segment (A9S), the membrane ion translocation domain (L188P and G383D) and the C-terminal regulatory domain (E547*, R568Q, W570*) of human NHE6 that purportedly cause disease. Using a heterologous NHE6-deficient cell expression system, we show that the biochemical, catalytic, and cellular properties of the A9S and R568Q variants were largely indistinguishable from those of the wild-type transporter which obscured their disease significance. By contrast, the L188P, G383D, E547* and W570* mutants exhibited variable deficiencies in biosynthetic post-translational maturation, membrane sorting, pH homeostasis in recycling endosomes, and cargo trafficking, and also triggered apoptosis. These findings broaden our understanding of the molecular dysfunctions of distinct NHE6 variants associated with Christianson syndrome. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
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