Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.
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PMID:A change of heart: oxidative stress in governing muscle function? 2851 Feb 29

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the mutations in survival motor neuron 1 gene (SMN1). The molecular pathology of missense mutations in SMN1 is not thoroughly investigated so far. Therefore, we collected all missense mutations in the SMN1 protein, using all possible search terms, from three databases (PubMed, PMC and Google Scholar). All missense mutations were subjected to in silico pathogenicity, conservation, and stability analysis tools. We used statistical analysis as a QC measure for validating the specificity and accuracy of these tools. PolyPhen-2 demonstrated the highest specificity and accuracy. While PolyPhen-1 showed the highest sensitivity; overall, PolyPhen2 showed better measures in comparison to other in silico tools. Three mutations (D44V, Y272C, and Y277C) were identified as the most pathogenic and destabilizing. Further, we compared the physiochemical properties of the native and the mutant amino acids and observed loss of H-bonds and aromatic stacking upon the cysteine to tyrosine substitution, which led to the loss of aromatic rings and may reduce protein stability. The three mutations were further subjected to Molecular Dynamics Simulation (MDS) analysis using GROMACS to understand the structural changes. The Y272C and Y277C mutants exhibited maximum deviation pattern from the native protein as compared to D44V mutant. Further MDS analysis predicted changes in the stability that may have been contributed due to the loss of hydrogen bonds as observed in intramolecular hydrogen bond analysis and physiochemical analysis. A loss of function/structural impact was found to be severe in the case of Y272C and Y277C mutants in comparison to D44V mutation. Correlating the results from in silico predictions, physiochemical analysis, and MDS, we were able to observe a loss of stability in all the three mutants. This combinatorial approach could serve as a platform for variant interpretation and drug design for spinal muscular dystrophy resulting from missense mutations.
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PMID:Impact of missense mutations in survival motor neuron protein (SMN1) leading to Spinal Muscular Atrophy (SMA): A computational approach. 3000 96


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