β‐adrenergic blockade attenuates cardiac dysfunction and myofibrillar remodelling in congestive heart failure

Although β‐adrenoceptor (β‐AR) blockade is an important mode of therapy for congestive heart failure (CHF), subcellular mechanisms associated with its beneficial effects are not clear. Three weeks after inducing myocardial infarction (MI), rats were treated daily with or without 20 and 75 mg/kg atenolol, a selective β₁‐AR antagonist, or propranolol, a non‐selective β‐AR antagonist, for 5 weeks. Sham operated rats served as controls. All animals were assessed haemodynamically and echocardiographically and the left ventricle (LV) was processed for the determination of myofibrillar ATPase activity, α‐ and β‐myosin heavy chain (MHC) isoforms and gene expression as well as cardiac troponin I (cTnI) phosphorylation. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated cardiac hypertrophy and lung congestion in addition to increasing LV ejection fraction and LV systolic pressure as well as decreasing heart rate, LV end‐diastolic pressure and LV diameters in the infarcted animals. Treatment of infarcted animals with these agents also attenuated the MI‐induced depression in myofibrillar Ca²⁺‐stimulated ATPase activity and phosphorylated cTnI protein content. The MI‐induced decrease in α‐MHC and increase in β‐MHC protein content were attenuated by both atenolol and propranolol at low and high doses; however, only high dose of propranolol was effective in mitigating changes in the gene expression for α‐MHC and β‐MHC. Our results suggest that improvement of cardiac function by β‐AR blockade in CHF may be associated with attenuation of myofibrillar remodelling.     

High Diabetes Prevalence among Tuberculosis Cases in Kerala,India

Background

While diabetes mellitus (DM) is a known risk factor for tuberculosis, the prevalence among TB patients in India is unknown. Routine screening of TB patients for DM may be an opportunity for its early diagnosis and improved management and might improve TB treatment outcomes. We conducted a cross-sectional survey of TB patients registered from June–July 2011 in the state of Kerala, India, to determine the prevalence of DM.

Methodology/Principal Findings

A state-wide representative sample of TB patients in Kerala was interviewed and screened for DM using glycosylated hemoglobin (HbA1c); patients self-reporting a history of DM or those with HbA1c ≥6.5% were defined as diabetic. Among 552 TB patients screened, 243(44%) had DM – 128(23%) had previously known DM and 115(21%) were newly diagnosed - with higher prevalence among males and those aged >50years. The number needed to screen(NNS) to find one newly diagnosed case of DM was just four. Of 128 TB patients with previously known DM, 107(84%) had HbA1c ≥7% indicating poor glycemic control.

Conclusions/Significance

Nearly half of TB patients in Kerala have DM, and approximately half of these patients were newly-diagnosed during this survey. Routine screening of TB patients for DM using HbA1c yielded a large number of DM cases and offered earlier management opportunities which may improve TB and DM outcomes. However, the most cost-effective ways of DM screening need to be established by futher operational research.     

Prey habitat selection under shared predation: tradeoffs between risk and competition?

An individual's choice of habitat should optimize amongst conflicting demands in a way that maximizes its fitness. Habitat selection by one species will often be influenced by presence and abundance of competitors that interact directly and indirectly with each other (such as through shared predators). The optimal habitat choice will thus depend on competition for resources by other species that can also modify predation risk. It may be possible to disentangle these two effects with careful analysis of density‐dependent habitat selection by a focal prey species. We tested this conjecture by calculating habitat isodars (graphs of density assuming ideal habitat selection) of chital deer living in two adjoining dry‐forest habitats in Gir National Park and Sanctuary, western India. The habitats differed only in presence (Sanctuary) and absence (National Park) of domestic prey (cattle and buffalo). Both species are preyed on by Asiatic lions. The habitat isodar revealed at low densities, that chital live in small groups and prefer habitat co‐occupied by livestock that reduce food resources, but also reduce predation risk. At higher densities, chital form larger groups and switch their preference toward risky habitat without livestock. The switch in chital habitat use is consistent with theories predicting that prey species should trade off safety in favor of food as population density increases.     

Sphingosine analogue AAL-R increases TLR7-mediated dendritic cell responses via p38 and type I IFN signaling pathways

Sphingosine analogues display immunosuppressive activities and thus have therapeutic potential in the treatment of autoimmune diseases. In this study, we investigated the effects of the sphingosine analogue AAL-R (FTY720 derivative) on dendritic cell (DC) response upon TLR stimulation. Unlike its known immunosuppressive activity, AAL-R increased TLR7-mediated DC responses by elevating the levels of MHC class I and costimulatory molecules and type I IFN expression and by enhancing the capacity of DCs to induce CD8(+) T cell proliferation. Importantly, the stimulatory activity of AAL-R was dependent on type I IFN signaling, as type I IFN receptor-deficient DCs failed to respond to AAL-R. Also, AAL-R activated p38 MAPK to increase type I IFN synthesis and TLR7-mediated DC maturation. These findings enhance our understanding of sphingosine regulation of the host immune system, in particular upon pathogenic infections.     

Crowding,molecular volume and plasticity: An assessment involving crystallography,NMR and simulations

The discrepancy between the X-ray and NMR structures of Mycobacterium tuberculosis peptidyl-tRNA hydrolase in relation to the functionally important plasticity of the molecule led to molecular dynamics simulations. The X-ray and the NMR studies along with the simulations indicated an inverse correlation between crowding and molecular volume. A detailed comparison of proteins for which X-ray and the NMR structures appears to confirm this correlation. In consonance with the reported results of the investigations in cellular compartments and aqueous solution, the comparison indicates that the crowding results in compaction of the molecule as well as change in its shape, which could specifically involve regions of the molecule important in function. Crowding could thus influence the action of proteins through modulation of the functionally important plasticity of the molecule.     

Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study

Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.     

Heme Oxygenase-1 Inhibits HLA Class I Antibody-Dependent Endothelial Cell Activation

Antibody-mediated rejection (AMR) is a key limiting factor for long-term graft survival in solid organ transplantation. Human leukocyte antigen (HLA) class I (HLA I) antibodies (Abs) play a major role in the pathogenesis of AMR via their interactions with HLA molecules on vascular endothelial cells (ECs). The antioxidant enzyme heme oxygenase (HO)-1 has anti-inflammatory functions in the endothelium. As complement-independent effects of HLA I Abs can activate ECs, it was the goal of the current study to investigate the role of HO-1 on activation of human ECs by HLA I Abs. In cell cultures of various primary human macro- and microvascular ECs treatment with monoclonal pan- and allele-specific HLA I Abs up-regulated the expression of inducible proinflammatory adhesion molecules and chemokines (vascular cell adhesion molecule-1 [VCAM-1], intercellular cell adhesion molecule-1 [ICAM-1], interleukin-8 [IL-8] and monocyte chemotactic protein 1 [MCP-1]). Pharmacological induction of HO-1 with cobalt-protoporphyrin IX reduced, whereas inhibition of HO-1 with either zinc-protoporphyrin IX or siRNA-mediated knockdown increased HLA I Ab-dependent up-regulation of VCAM-1. Treatment with two carbon monoxide (CO)-releasing molecules, which liberate the gaseous HO product CO, blocked HLA I Ab-dependent EC activation. Finally, in an in vitro adhesion assay exposure of ECs to HLA I Abs led to increased monocyte binding, which was counteracted by up-regulation of HO-1. In conclusion, HLA I Ab-dependent EC activation is modulated by endothelial HO-1 and targeted induction of this enzyme may be a novel therapeutic approach for the treatment of AMR in solid organ transplantation.     

Role of neurotransmitters and neuropeptides in the control of gonadotropin release: A review

Rapid progress has been recorded recently in the understanding of the role of neuro-transmitters and neuropeptides in the control of reproduction and on their apparent potential in the regulation of fertility. Peptides, as well as monoamines, are important in the control of lutinizing hormone releasing hormone and gonadotropin release. The input from brainstem noradrenergic neurons as well as dopamine mediated stimulated release of lutinizing hormone. In addition considerable evidence exist for the occurrence of a specific follicle stimulating hormone-releasing factor. A large number of brain peptides affect the secretion of lutinizing hormone releasing hormone and the endogenous opioid peptides appear to have a physiologically important function in restraining the influence on lutinizing hormone releasing hormone release under most circumstances. Vasoactive intestinal peptide and substanceP stimulate whereas cholecystokinin, neurotensin, gastrin, secretin, somatostatin α-melanosite stimulating hormone and vasotocin inhibit lutinizing hormone release. Of the inhibitory peptides, cholecystokinin and arg-vasotocin are the most potent. Inhibin injected into the ventricle selectively suppresses follicle stimulating hormone release by a hypothalamic action. Thus the control of gonadotropin release is complex and a number of aminergic and peptidergic transmitters are involved.     

Structure,dynamics, and interactions of jacalin. Insights from molecular dynamics simulations examined in conjunction with results of X‐ray studies

Molecular dynamics simulations have been carried out on all the jacalin–carbohydrate complexes of known structure, models of unliganded molecules derived from the complexes and also models of relevant complexes where X‐ray structures are not available. Results of the simulations and the available crystal structures involving jacalin permit delineation of the relatively rigid and flexible regions of the molecule and the dynamical variability of the hydrogen bonds involved in stabilizing the structure. Local flexibility appears to be related to solvent accessibility. Hydrogen bonds involving side chains and water bridges involving buried water molecules appear to be important in the stabilization of loop structures. The lectin–carbohydrate interactions observed in crystal structures, the average parameters pertaining to them derived from simulations, energetic contribution of the stacking residue estimated from quantum mechanical calculations, and the scatter of the locations of carbohydrate and carbohydrate‐binding residues are consistent with the known thermodynamic parameters of jacalin–carbohydrate interactions. The simulations, along with X‐ray results, provide a fuller picture of carbohydrate binding by jacalin than provided by crystallographic analysis alone. The simulations confirm that in the unliganded structures water molecules tend to occupy the positions occupied by carbohydrate oxygens in the lectin–carbohydrate complexes. Population distributions in simulations of the free lectin, the ligands, and the complexes indicate a combination of conformational selection and induced fit. Proteins 2009. © 2009 Wiley‐Liss, Inc.