排序方式: 共有45条查询结果,搜索用时 0 毫秒
41.
Horan M Newsway V Yasmin Lewis MD Easter TE Rees DA Mahto A Millar DS Procter AM Scanlon MF Wilkinson IB Hall IP Wheatley A Blakey J Bath PM Cockcroft JR Krawczak M Cooper DN 《Human genetics》2006,119(5):527-540
An increased prevalence of both hypertension and cerebrovascular stroke is apparent in growth hormone (GH) deficiency whilst hypertension is a frequent complication in acromegaly. This has suggested a possible link between GH, stature and arterial function. Since the risk of both hypertension and stroke also appears to be inversely correlated with adult height, we have instigated an exploratory study to assess whether inter-individual variation in the genes encoding human growth hormone (GH1) and the GH receptor (GHR) might be associated with an increased risk of hypertension and stroke. GH1 promoter haplotypes were found to differ significantly not only between hypertensive patients (n=111) and controls (n=121) but also between stroke patients (n=155) and controls (n=158). Intriguingly, the association between GH1 promoter haplotype and risk of hypertension was much greater in females than in males. An inverse correlation between height and central systolic blood pressure was apparent in both hypertensive patients and normal controls but was much stronger in individuals carrying at least one GH1 promoter risk haplotype. The GH1 genotype therefore constitutes a risk factor for hypertension that interacts with stature. A strong association was found between the presence of at least one GH1 risk haplotype and a family history of stroke at an early age (odds ratio: 9.07, 95% confidence interval: 1.14–72.22). Three novel GH variants (Arg16His, Phe176Cys, Cys189Arg) were identified during the course of this study. Although two exhibited markedly reduced biological activity in vitro, their clinical significance remains unclear. No association was found between GHR genotype and either hypertension or stroke, nor was any interaction noted between GHR and GH1 genotypes in terms of a disease association. However, an association between GHRd3 genotype and hypertension was observed among stroke patients, particularly females. Elevated HDL was found to be a risk factor for hypertension in individuals lacking a copy of the GHRd3 allele. Weak associations with GHR genotype were also noted for peripheral systolic and diastolic blood pressure in hypertensive patients. Although the underlying mechanisms are still unclear, our findings are consistent with a complex relationship between height, hypertension, GH1 promoter haplotype, GHR polymorphism and the risk of stroke. 相似文献
42.
Shelley F. Stone Geoffrey K. Isbister Seyed Shahmy Fahim Mohamed Chandana Abeysinghe Harendra Karunathilake Ariaranee Ariaratnam Tamara E. Jacoby-Alner Claire L. Cotterell Simon G. A. Brown 《PLoS neglected tropical diseases》2013,7(7)
Background
Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell''s viper) and antivenom treatment.Methodology/Principal Findings
Plasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor α (TNFα), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine.Conclusions/Significance
We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast cell degranulation but not further complement activation. Anaphylaxis is probably triggered by non allergen-specific activation of mast cells and may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself. 相似文献43.
44.
Khunza Meraj Manoj Kumar Mahto N Blessy Christina Nidhi Desai Sajad Shahbazi Matcha Bhaskar 《Bioinformation》2012,8(23):1139-1146
The sodium “channelopathies” are the first among the ion channel diseases identified and have attracted widespread clinical and
scientific interests. Human voltage gated sodium channels are sites of action of several antiarrhythmic drugs, local anesthetics and
related antiepileptic drugs. The present study aims to optimize the activity of Disopyramide, by modification in its structures
which may improve the drug action by reducing its side effects. Herein, we have selected Human voltage-gated sodium channel
protein type 5 as a potent molecular target. Nearly eighty analogs of Disopyramide are designed and optimized. Thirty are selected
for energy minimization using Discovery studio and the LigPrep 2.5. Prior to docking, the active sites of all the proteins are
identified. The processing, optimization and minimization of all the proteins is done in Protein preparation wizard. The docking
study is performed using the GLIDE. Finally top five ranked lead molecules with better dock scores are identified as having strong
binding affinity to 2KAV protein than Disopyramide based on XP G scores. These five leads are further docked with other similar
voltage gated sodium channel proteins (PDB IDs: 2KBI, 4DCK, 2L53 and 4DJC) and the best scoring analog with each protein is
identified. Drug likeliness and comparative bioactivity analysis for all the analogs is done using QikProp 3.4. Results have shown
that the top five lead molecules would have the potential to act as better drugs as compared to Disopyramide and would be of
interest as promising starting point for designing compounds against various Sodium channelopathies. 相似文献
45.
Manoj kumar Mahto Nanda Kumar Yellapu Ravendra Babu Kilaru Naga Raju Chamarthi Matcha Bhaskar 《Bioinformation》2014,10(4):221-226
Darunavir is a synthetic nonpeptidic protease inhibitor which has been tested for anticancer properties. To deduce and enhance the
anticancer activity of the Darunavir, we have modified its reactive moiety in an effective way. We designed 9 analogues in
ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. These analogues can obstruct the activity of other
signalling pathways which are implicated in many tumors. Results of the QikProp showed that all the analogues lied in the
specified range of all the pharmacokinetic (ADMET) properties required to become the successful drug. Docking study was
performed to test its anticancer activity against the biomarkers of the five main types of cancers i.e. bone, brain, breast, colon and
skin cancer. Grid was generated for each oncoproteins by specifying the active site amino acids. The binding model of best scoring
analogue with each protein was assessed from their G-scores and disclosed by docking analysis using the XP visualizer tool. An
analysis of the receptor-ligand interaction studies revealed that these nine Darunavir analogues are active against all cancer
biomarkers and have the features to prove themselves as anticancer drugs, further to be synthesized and tested against the cell
lines. 相似文献