Decreased Glomerular Filtration Rate Is Associated with Mortality and Cardiovascular Events in Patients with Hypertension: A Prospective Study

BACKGROUND: Few studies reported the associations between decreased glomerular filtration rate (GFR) and mortality, coronary heart disease (CHD), and stroke in hypertensive patients. We aim to assess the associations between GFR and mortality, CHD, and stroke in hypertensive patients and to evaluate whether low GFR can improve the prediction of these outcomes in addition to conventional cardiovascular risk factors. METHODS AND FINDINGS: This is an observational prospective study and 3,711 eligible hypertensive patients aged ≥5 years from rural areas of China were used for the present analysis. The associations between eGFR and outcomes, followed by a median of 4.9 years, were evaluated using Cox proportional hazards models adjusting for other potential confounders. Low eGFR was independently associated with risk of all-cause mortality, cardiovascular mortality, and incident stroke [multivariable adjusted hazard ratios (95% confidence intervals) for eGFR <60 ml/min/1.73 m(2) relative to eGFR ≥90 ml/min/1.73 m(2) were 1.824 (1.047-3.365), 2.371 (1.109-5.068), and 2.493 (1.193-5.212), respectively]. We found no independent association between eGFR and the risk of CHD. For 4-year all-cause and cardiovascular mortality, integrated discrimination improvement (IDI) was positive when eGFR were added to traditional risk factors (1.51%, P = 0.016, and 1.99%, P = 0.017, respectively). For stroke and CHD events, net reclassification improvements (NRI) were 5.9% (P = 0.012) and 1.8% (P = 0.083) for eGFR, respectively. CONCLUSIONS: We have established an inversely independent association between eGFR and all-cause mortality, cardiovascular mortality, and stroke in hypertensive patients in rural areas of China. Further, addition of eGFR significantly improved the prediction of 4-year mortality and stroke over and above that of conventional risk factors. We recommend that eGFR be incorporated into prognostic assessment for patients with hypertension in rural areas of China. LIMITATIONS: We did not have sufficient information on atrial fibrillation to control for the potential covariate. These associations should be further confirmed in future

CADDIE - An online knowledge base for network-based mechanism exploration and drug repurposing in oncolog

Drug repurposing is the use of previously developed and tested pharmaceutical agents in new application cases and lately often used as a solution to the increasing drug development costs. Cancers are extremely heterogeneous disorders demonstrating a wide variability of drug responses due to diverse subtypes, quickly evolving and acquiring drug resistance. Therefore, the identification of compounds that can effectively combat a specific tumor type is crucial. Drug candidates that are potentially effective against a specific tumor can be chosen based on the set of driver mutations acquired by this tumor. For optimal treatment, it is important to consider targeted anti-cancer therapies and drugs initially developed to treat non-cancerous diseases. To overcome this hurdle, we present CADDIE (Cancer Driver Drug Interaction Explorer), a web platform to identify oncological drug repurposing candidates. CADDIE’s biomedical knowledge base integrates a multitude of gene-gene and drug-gene interaction datasets, detailed anticancer drug information and cancer biology data such as cancer driver genes, mutation frequencies and gene expressions. For the purpose of locating drug targets and candidates for drug repurposing, CADDIE makes network medicine algorithms available to the researchers. It guides the users from the choice of seed genes through the discovery of therapeutic targets or drug candidates. Network medicine also provides indirect strategies that take into account other functionally relevant targets in the gene interaction network since potential cancer driver genes may be inaccessible for direct targeting. We demonstrate the application of CADDIE in different cancer subtypes such as sarcoma and ovarian cancer with a detailed analysis of the found drug targets and chemical compounds. CADDIE is available online at https://exbio.wzw.tum.de/caddie/ and as a python package at https://pypi.org/project/caddiepy/.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202

Antitubercular therapy decreases nitric oxide production in HIV/TB coinfected patients

BACKGROUND: Nitric oxide (NO) production is increased among patients with human immunodeficiency virus (HIV) infection and also among those with tuberculosis (TB). In this study we sought to determine if there was increased NO production among patients with HIV/TB coinfection and the effect of four weeks chemotherapy on this level. METHODS: 19 patients with HIV/TB coinfection were studied. They were treated with standard four drug antitubercular therapy and sampled at baseline and four weeks. 20 patients with HIV infection, but no opportunistic infections, were disease controls and 20 individuals were healthy controls. Nitrite and citrulline, surrogate markers for NO, were measured spectrophotometrically. RESULTS: The mean age of HIV/TB patients was 28.4 ± 6.8 years and CD4 count was 116 ± 36.6/mm. Mean nitrite level among HIV/TB coinfected was 207.6 ± 48.8 nmol/ml. This was significantly higher than 99.7 ± 26.5 nmol/ml, the value for HIV infected without opportunistic infections and 46.4 ± 16.2 nmol/ml, the value for healthy controls (p value < 0.01). The level of HIV/TB coinfected NO in patients declined to 144.5 ± 34.4 nmol/ml at four weeks of therapy (p value < 0.05). Mean citrulline among HIV/TB coinfected was 1446.8 ± 468.8 nmol/ml. This was significantly higher than 880.8 ± 434.8 nmol/ml, the value for HIV infected without opportunistic infections and 486.6 ± 212.5 nmol/ml, the value for healthy controls (p value < 0.01). Levels of citrolline in HIV/TB infected declined to 1116.2 ± 388.6 nmol/ml at four weeks of therapy (p value < 0.05). CONCLUSIONS: NO production is elevated among patients with HIV infection, especially so among HIV/TB coinfected patients, but declines significantly following 4 weeks of antitubercular therapy

LRP1 Regulates Architecture of the Vascular Wall by Controlling PDGFRβ-Dependent Phosphatidylinositol 3-Kinase Activation

Low density lipoprotein receptor-related protein 1 (LRP1) protects against atherosclerosis by regulating the activation of platelet-derived growth factor receptor beta (PDGFRbeta) in vascular smooth muscle cells (SMCs). Activated PDGFRbeta undergoes tyrosine phosphorylation and subsequently interacts with various signaling molecules, including phosphatidylinositol 3-kinase (PI3K), which binds to the phosphorylated tyrosine 739/750 residues in mice, and thus regulates actin polymerization and cell movement.In this study, we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1-deficient (LRP1-/-) SMCs. Marfan syndrome-like phenotypes such as tortuous aortas, disrupted elastic layers and abnormally activated transforming growth factor beta (TGFbeta) signaling are present in smooth muscle-specific LRP1 knockout (smLRP1-/-) mice. To investigate the role of LRP1-regulated PI3K activation by PDGFRbeta in atherogenesis, we generated a strain of smLRP1-/- mice in which tyrosine 739/750 of the PDGFRbeta had been mutated to phenylalanines (PDGFRbeta F2/F2). Spontaneous atherosclerosis was significantly reduced in the absence of hypercholesterolemia in these mice compared to smLRP1-/- animals that express wild type PDGFR. Normal actin organization was restored and spontaneous SMC migration as well as PDGF-BB-induced chemotaxis was dramatically reduced, despite continued overactivation of TGFbeta signaling, as indicated by high levels of nuclear phospho-Smad2.Our data suggest that LRP1 regulates actin organization and cell migration by controlling PDGFRbeta-dependent activation of PI3K. TGFbeta activation alone is not sufficient for the expression of the Marfan-like vascular phenotype. Thus, regulation of PI3 Kinase by PDGFRbeta is essential for maintaining vascular integrity, and for the prevention of atherosclerosis as well as Marfan syndrome

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Catalytic receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15541. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

The Concise guide to pharmacology 2019/20: Enzymes

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14752. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors,ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.Molecular Physiolog

Inhibition of fetal lung maturation by indomethacin in pregnant rabbits

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