Immunohistochemical studies on progressive pathology of ischaemia reperfusion acute kidney injury in male Sprague Dawley rats

270-274Acute kidney injury (AKI) is a major problem in ICU patient, majority of the cases even after functional recovery ended with chronic kidney disease. In the present study, we investigated the immunohistochemical change in progressive pathology of ischaemia reperfusion induced acute kidney injury. Male Sprague Dawley (SD) rats were subjected to 35 min of renal ischemia followed by reperfusion periods of day 1, 4, 7, 14 and 28. Renal injury was confirmed by the increase serum creatinine level. The vascular and tubular changes in kidneys were studied by the CD31 and vimentin immunohistochemistry respectively. In this study, no significant changes were observed in CD31 positive cells, though lower densities of capillaries were noticed in the tubulo-interstitial lesion on day 28 of reperfusion. Significant increase in vimentin positive cells, which is a marker of undifferentiated cells, was observed on day 4 and day 7 of reperfusion. The immature cells were also present on day 28 of reperfusion indicating that these cells may would have led further progressive pathological changes in kidney even after the functional and morphological normalization

TRC120038, a Novel Dual AT1/ETA Receptor Blocker for Control of Hypertension, Diabetic Nephropathy, and Cardiomyopathy in ob-ZSF1 Rats

In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT1/ETA receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8 mg/kg bid.) or candesartan cilexetil (0.3 mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat

Immunohistochemical studies on progressive pathology of ischaemia reperfusion acute kidney injury in male Sprague Dawley rats

Acute kidney injury (AKI) is a major problem in ICU patient, majority of the cases even after functional recovery ended with chronic kidney disease. In the present study, we investigated the immunohistochemical change in progressive pathology of ischaemia reperfusion induced acute kidney injury. Male Sprague Dawley (SD) rats were subjected to 35 min of renal ischemia followed by reperfusion periods of day 1, 4, 7, 14 and 28. Renal injury was confirmed by the increase serum creatinine level. The vascular and tubular changes in kidneys were studied by the CD31 and vimentin immunohistochemistry respectively. In this study, no significant changes were observed in CD31 positive cells, though lower densities of capillaries were noticed in the tubulo-interstitial lesion on day 28 of reperfusion. Significant increase in vimentin positive cells, which is a marker of undifferentiated cells, was observed on day 4 and day 7 of reperfusion. The immature cells were also present on day 28 of reperfusion indicating that these cells may would have led further progressive pathological changes in kidney even after the functional and morphological normalization

TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats

Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components

Regional earth system modelling framework for CORDEX-SA: an integrated model assessment for Indian summer monsoon rainfall

An effort is made to implement a regional earth system model (RESM); ROM, over CORDEX-South Asia (SA). The added value of RESM is assessed for mean precipitation, its variability (intraseasonal to interannual), extremes, and associated processes. In this regard, ROM’s fields are compared with the respective fields of its standalone version (REMO), the models belonging coupled model intercomparison project (CMIP5 and CMIP6), and regional climate models of CORDEX-CORE simulations. RESM shows substantial improvement for most of the Indian monsoon’s aspects; however, the magnitude of the value addition varies spatiotemporally and also with different aspects.. The improved representation of intraseasonal variability (active-break spell’s duration and intensity) and Interannual variability attributed to improved mean seasonal precipitation. Additionally, correct representation of sea surface temperature, Indian Ocean Dipole, and its underlying dynamics also contribute to improving the mean precipitation. The notable improvement is seen especially over the south-eastern regions of the Bay of Bengal (BoB) and South-Central India, where increasing (decreasing) low-pressure systems over Central India (BoB) are noticed as a consequence of air-sea coupling, leading to enhanced (reduced) precipitation over Central India (BoB), reducing dry (wet) bias found in REMO and the other models. Despite substantial improvements, RESM has a systematic wet bias in the mean precipitation associated with a warm bias over the western coast of the Arabian Sea. An overestimation of very high extreme precipitation due to the enhanced contribution of low-pressure systems indicates the model’s limitations, suggesting the need for further tuning of the RESM

Immunoprotection in mice immunized with native OmpH, recombinant OmpH and HS alum precipitated vaccine of Pasteurella multocida P52 against P. multocida challenge

436-441Outer membrane proteins (OMPs) of Pasteurella multocida play an important role in virulence and are important for vaccine development due to immunogenicity. Here, we evaluated immunoprotection in mice, immunized with native OmpH, recombinant OmpH and HS alum precipitated vaccine of P. multocida P52 against P. multocida challenge. Protection studies were performed in mice of groups I (OmpH); II (recombinant OmpH); and III (HS alum precipitated vaccine). Group IV was control group administered with sterile PBS. The protection percentage was recorded as 83.33% protection in Gr. I & III, and 66.66% in Gr. II. The control group (Gr. IV) showed 100% mortality. The mean antibodies titers were detected at day 7, 14, 21 and 28 postimmunization, and compared with the control group. All immunized groups showed significantly high immune protection compared to the control group

ENHANCED SOLUBILITY AND DISSOLUTION BY SURFACE-MODIFIED SOLID DISPERSION OF ALECTINIB HYDROCHLORIDE

Objective: Alectinib hydrochloride (AH), a poorly soluble drug, exhibits low solubility thereby very low bioavailability. The present study aims to develop and optimize surface-modified solid dispersion of AH (AH-SMSD) with enhanced solubility and dissolution using Soluplus® (SOL) and Gelucire 44/14 (GEL) as a polymer and surfactant respectively. Methods: Design of Experiments (DoE) was implemented to optimize the weight ratio of SOL (X1), and GEL (X2), keeping the drug weight constant, to maximize the solubility (Y1) and dissolution (Y2). The optimized solid dispersion was subjected to solubility & dissolution in bio-relevant media and characterized using differential scanning calorimetry (DSC), Powder X-ray diffraction (pXRD), Fourier-transform infrared (FTIR), and scanning electron microscopy (SEM). Results: A statistically significant model is obtained for solubility and dissolution through DoE. Formulation (F9) containing AH:SOL:GEL in weight ratios 1:5:5 showed a 547-fold increase in solubility. This solubility enhancement further translated into dissolution improvement with drug release of >80% in 15 min. The optimized formulation also showed improved solubility and dissolution in fasted-state bio-relevant media. DSC and pXRD showed a change in the crystallinity pattern of the drug. FTIR showed the existence of weak intermolecular interactions. Morphological evaluation through SEM demonstrated that the drug particles were dispersed to a hydrophilic carrier matrix, thus, transforming the hydrophobic drug into a hydrophilic form. Conclusion: AH-SMSD with enhanced solubility and dissolution was successfully developed. The optimized formulation also showed improvement in the bio-relevant media and therefore has the potential to improve in-vivo oral bioavailability (however, needs to be experimentally explored)

Heat shock proteins: a therapeutic target worth to consider

Heat shock proteins (HSPs) are the molecular chaperones, that are not only expressed during the normal growth process of cell cycle consecutively, but also get induced in cells during various stress conditions produced by cellular insult, environmental changes, temperature, infections, tumors etc. According to their molecular weight and functions, HSPs are divided into five major families. HSP90, HSP70, HSP60 and HSP100 are the most studied members of the family. Experimental studies have proved that overexpression and/or inhibition of HSPs play an important role in maintaining the tolerance and cell viability under above-described stress conditions. HSP90 is found to be a promising candidate for the diagnosis, prognosis and treatment of cancer. Similarly, HSP70, HSP60 and small HSPs experimentally and clinically have potential for the treatment of neurodegenerative disease, ischemia, cell death, autoimmunity, graft rejection, etc. In a way, exploring, the cytoprotective and immunoregulatory role of HSPs can open a new avenue for the drug discovery and treatment of critical diseases

Delay in seeking medical help in patients with Rheumatoid Arthritis in India: a qualitative study

BackgroundRheumatoid arthritis (RA) is an autoimmune disease with varied articular and extra‐articular manifestations. In developing countries such as India patients with RA often delay seeking medical advice which may impact prognosis and disease burden.AimTo explore perceptions and experiences of patients living in India in seeking medical help for their RA symptoms.MethodsClinician‐diagnosed RA participants from different socioeconomic backgrounds were interviewed using a semi‐structured topic guide. Participants were purposively selected and interviewed following an iterative approach. All interviews were recorded and transcribed by an independent company and analyzed using a thematic framework. Findings were reported in accordance with consolidated criteria for reporting qualitative research guidelines.ResultsTwenty participants (13 male, 7 female) with median age 40 years (35.7‐46.5) were recruited. Three overarching themes demonstrating participants’ experiences and reasons for delay in seeking medical help were identified. (1) “Symptoms perspectives and delay in participants’ journey” narrated participants’ experiences of having RA symptoms, how these were perceived, rationalized and led to delay. (2) “Participants’ experience of the healthcare system” illustrated delay in referral, reaching diagnosis and treatment initiation highlighting their experiences with the health system. (3) “Recommendations for improving care” where participants made recommendations for reducing the delay at local and national levels.ConclusionThis is the first qualitative study which explored perceptions and experiences of RA patients in India resulting in delay. Improved provision of rheumatology care, effective referral system and greater involvement of government at local and national levels are needed to improve the delay in seeking medical help for Indian patients

NMR-based clinical metabolomics revealed distinctive serum metabolic profiles in patients with spondyloarthritis

Spondyloarthritis (SpA) is an umbrella term for autoimmune rheumatic diseases that can affect the back, pelvis, neck and some larger joints, as well as internal organs, like the intestines and eyes. The most common of these diseases is ankylosing spondylitis (ASp) which predominantly affects the spine and sacroiliac joints causing characteristic inflammatory back pain (IBP) and severe spine stiffness. In addition, AsP may involve peripheral joints causing asymmetrical peripheral oligo-arthritis often associated with extra-articular symptoms such as acute anterior uveitis (iritis), psoriasis, enthesitis, dactylitis and chronic inflammatory bowel disease (IBD). These clinical features adversely affect the quality of life in ASp patients owing to restricted spinal/hip mobility, pain, fatigue, disease flares and depression. The clinical management of SpA is marred by delay in diagnosis, and paucity of biomarkers of disease activity. The present study aimed to explore the potential of serum metabolic profiling of patients with SpA to identify biomarker for the diagnosis and assessment of disease activity. The serum metabolic profiles of 81 patients with SpA were compared with that of 86 healthy controls (HC) using nuclear magnetic resonance (NMR) based metabolomics approach. Seventeen patients were followed-up after 3 months of standard treatment and paired sera were analyzed for effects of therapy. Comparisons were done using the multivariate partial least-squares discriminant analysis (PLS-DA) and the discriminatory metabolic entities were identified based on variable importance in projection (VIP) statistics and further evaluated for statistical significance (p-value<0.05). We found that the serum metabolic profiles differed significantly in SpA as compared with healthy controls. Compared to HC, the SpA patients were characterized by increased serum levels of amino-acids, acetate, choline, N-acetyl glycoproteins, N-alpha-acetyllysine, creatine/creatinine etc. and decreased levels of low/very-low density lipoproteins, and poly-unsaturated lipids. PLS-DA analysis also revealed metabolic differences between axial and peripheral SpA patients. Further metabolite profiles were found to differ with disease activity and treatment in responding patients. The results presented in this study demonstrate the potential of serum metabolic profiling of SpA as a useful tool for diagnosis, prediction of peripheral disease, assessment of disease activity, and treatment response.The decreased circulatory levels of glutamine were found to be associated with SpA disease activity