The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform
Aline Tatiane Toneto - One of the best experts on this subject based on the ideXlab platform.
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nutritional leucine supplementation attenuates cardiac failure in tumour bearing cachectic animals
Journal of Cachexia Sarcopenia and Muscle, 2016Co-Authors: Aline Tatiane Toneto, Luiz Alberto Ferreira Ramos, Emilianne Miguel Salomao, Rebeka Tomasin, Miguel Arcanjo Aereas, Maria Cristina Cintra GomesmarcondesAbstract:Background The condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer-cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer-cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart. Methods Male Wistar rats were fed either a leucine-rich or a normoprotein diet and implanted or not with subcutaneous Walker-256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT-c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase-8, -9, -3, and -7 activity. Results Both groups of tumour-bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour-bearing group but not their leucine-supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase-3 and -7 activity. Conclusions Our data suggest that a leucine-rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer-cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.
Maria Cristina Cintra Gomesmarcondes - One of the best experts on this subject based on the ideXlab platform.
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nutritional leucine supplementation attenuates cardiac failure in tumour bearing cachectic animals
Journal of Cachexia Sarcopenia and Muscle, 2016Co-Authors: Aline Tatiane Toneto, Luiz Alberto Ferreira Ramos, Emilianne Miguel Salomao, Rebeka Tomasin, Miguel Arcanjo Aereas, Maria Cristina Cintra GomesmarcondesAbstract:Background The condition known as cachexia presents in most patients with malignant tumours, leading to a poor quality of life and premature death. Although the cancer-cachexia state primarily affects skeletal muscle, possible damage in the cardiac muscle remains to be better characterized and elucidated. Leucine, which is a branched chain amino acid, is very useful for preserving lean body mass. Thus, this amino acid has been studied as a coadjuvant therapy in cachectic cancer patients, but whether this treatment attenuates the effects of cachexia and improves cardiac function remains poorly understood. Therefore, using an experimental cancer-cachexia model, we evaluated whether leucine supplementation ameliorates cachexia in the heart. Methods Male Wistar rats were fed either a leucine-rich or a normoprotein diet and implanted or not with subcutaneous Walker-256 carcinoma. During the cachectic stage (approximately 21 days after tumour implantation), when the tumour mass was greater than 10% of body weight, the rats were subjected to an electrocardiogram analysis to evaluate the heart rate, QT-c, and T wave amplitude. The myocardial tissues were assayed for proteolytic enzymes (chymotrypsin, alkaline phosphatase, cathepsin, and calpain), cardiomyopathy biomarkers (myeloperoxidase, tissue inhibitor of metalloproteinases, and total plasminogen activator inhibitor 1), and caspase-8, -9, -3, and -7 activity. Results Both groups of tumour-bearing rats, especially the untreated group, had electrocardiography alterations that were suggestive of ischemia, dilated cardiomyopathy, and sudden death risk. Additionally, the rats in the untreated tumour-bearing group but not their leucine-supplemented littermates exhibited remarkable increases in chymotrypsin activity and all three heart failure biomarkers analysed, including an increase in caspase-3 and -7 activity. Conclusions Our data suggest that a leucine-rich diet could modulate heart damage, cardiomyocyte proteolysis, and apoptosis driven by cancer-cachexia. Further studies must be conducted to elucidate leucine's mechanisms of action, which potentially includes the modulation of the heart's inflammatory process.
C. Robert Matthews - One of the best experts on this subject based on the ideXlab platform.
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Interplay between drying and stability of a TIM barrel protein: a combined simulation-experimental study.
Journal of the American Chemical Society, 2013Co-Authors: Payel Das, Kevin T. Halloran, Divya Kapoor, Ruhong Zhou, C. Robert MatthewsAbstract:Recent molecular dynamics simulations have suggested important roles for nanoscale dewetting in the stability, function, and folding dynamics of proteins. Using a synergistic simulation–experimental approach on the αTS TIM barrel protein, we validated this hypothesis by revealing the occurrence of drying inside hydrophobic amino acid clusters and its manifestation in experimental measures of protein stability and structure. Cavities created within three clusters of branched aliphatic amino acids [isoleucine, leucine, and valine (ILV) clusters] were found to experience strong water density fluctuations or intermittent dewetting transitions in simulations. Individually substituting 10 residues in the large ILV cluster at the N-terminus with less hydrophobic alanines showed a weakening or diminishing effect on dewetting that depended on the site of the mutation. Our simulations also demonstrated that replacement of buried Leucines with isosteric, polar asparagines enhanced the wetting of the N- and C-termina...
Payel Das - One of the best experts on this subject based on the ideXlab platform.
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Interplay between Drying and Stability of a TIM Barrel Protein: A Combined Simulation–Experimental Study
2016Co-Authors: Payel Das, Divya Kapoor, Ruhong Zhou, Kevin T. Halloran, Robert C. MatthewsAbstract:Recent molecular dynamics simulations have suggested important roles for nanoscale dewetting in the stability, function, and folding dynamics of proteins. Using a synergistic simulation–experimental approach on the αTS TIM barrel protein, we validated this hypothesis by revealing the occurrence of drying inside hydrophobic amino acid clusters and its manifestation in experimental measures of protein stability and structure. Cavities created within three clusters of branched aliphatic amino acids [isoleucine, leucine, and valine (ILV) clusters] were found to experience strong water density fluctuations or intermittent dewetting transitions in simulations. Individually substituting 10 residues in the large ILV cluster at the N-terminus with less hydrophobic alanines showed a weakening or diminishing effect on dewetting that depended on the site of the mutation. Our simulations also demonstrated that replacement of buried Leucines with isosteric, polar asparagines enhanced the wetting of the N- and C-terminal clusters. The experimental results on the stability, secondary structure, and compactness of the native and intermediate states for the asparagine variants are consistent with the preferential drying of the large N-terminal cluster in the intermediate. By contrast, the region encompassing the small C-terminal cluster experiences only partial drying in the intermediate, and its structure and stability are unaffected by the asparagine substitution. Surprisingly, the structural distortions required to accommodate the replacement of leucine by asparagine in the N-terminal cluster revealed the existence of alternative stable folds in the native basin. This combined simulation–experimental study demonstrates the critical role of drying within hydrophobic ILV clusters in the folding and stability of the αTS TIM barrel
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Interplay between drying and stability of a TIM barrel protein: a combined simulation-experimental study.
Journal of the American Chemical Society, 2013Co-Authors: Payel Das, Kevin T. Halloran, Divya Kapoor, Ruhong Zhou, C. Robert MatthewsAbstract:Recent molecular dynamics simulations have suggested important roles for nanoscale dewetting in the stability, function, and folding dynamics of proteins. Using a synergistic simulation–experimental approach on the αTS TIM barrel protein, we validated this hypothesis by revealing the occurrence of drying inside hydrophobic amino acid clusters and its manifestation in experimental measures of protein stability and structure. Cavities created within three clusters of branched aliphatic amino acids [isoleucine, leucine, and valine (ILV) clusters] were found to experience strong water density fluctuations or intermittent dewetting transitions in simulations. Individually substituting 10 residues in the large ILV cluster at the N-terminus with less hydrophobic alanines showed a weakening or diminishing effect on dewetting that depended on the site of the mutation. Our simulations also demonstrated that replacement of buried Leucines with isosteric, polar asparagines enhanced the wetting of the N- and C-termina...
Kevin Struhl - One of the best experts on this subject based on the ideXlab platform.
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Role of the conserved Leucines in the leucine zipper dimerization motif of yeast GCN4
Nucleic acids research, 1992Co-Authors: Willem J. Van Heeckeren, Joan W. Sellers, Kevin StruhlAbstract:Yeast GCN4 belongs to the class of eukaryotic transcription factors whose bZIP DNA-binding domains dimerize via a leucine zipper motif that structurally resembles a coiled coil. The leucine zipper contains 4-5 highly conserved leucine residues spaced exactly 7 residues apart that are located within the alpha-helical hydrophobic interface between protein monomers. Here, we investigate the role of the four canonical Leucines in the GCN4 leucine zipper by analyzing a series of mutated derivatives for their ability to activate transcription in vivo and to bind DNA in vitro. The GCN4 leucine zipper is surprisingly tolerant of mutations, with a wide variety of single substitutions at any of the four Leucines including basic and acidic amino acids behaving indistinguishably from wild-type GCN4. Moreover, some derivatives containing two leucine substitutions display detectable though reduced function. These results indicate that other residues within the coiled coil are crucial for efficient dimerization, and they suggest that some eukaryotic transcriptional regulatory proteins lacking the conserved leucine repeat will dimerize through a structurally homologous motif. Interestingly, our results differ in several respects from those obtained by analyzing mutations in the GCN4 leucine zipper in the context of a lambda repressor-GCN4 zipper hybrid protein. These apparent differences may reflect a functional interrelationship between the leucine zipper and basic region subdomains for DNA-binding by bZIP proteins.