Leishmania donovani modulates host miRNAs regulating cholesterol biosynthesis for its survival.

Cholesterol reduction by intracellular protozoan parasite Leishmania donovani (L. donovani), causative agent of leishmaniasis, impairs antigen presentation, pro-inflammatory cytokine secretion and host-protective membrane-receptor signaling in macrophages. Here, we studied the miRNA mediated regulation of cholesterol biosynthetic genes to understand the possible mechanism of L. donovani-induced cholesterol reduction and therapeutic importance of miRNAs in leishmaniasis. System-scale genome-wide microtranscriptome screening was performed to identify the miRNAs involved in the regulation of expression of key cholesterol biosynthesis regulatory genes through miRanda3.0. 11 miRNAs out of 2823, showing complementarity with cholesterol biosynthetic genes were finally selected for expression analysis. These selected miRNAs were differentially regulated in THP-1 derived macrophages and in primary human macrophages by L. donovani. Correlation of expression and target validation through luciferase assay suggested two key miRNAs, hsa-miR-1303 and hsa-miR-874-3p regulating the key genes hmgcr and hmgcs1 respectively. Inhibition of hsa-mir-1303 and hsa-miR-874-3p augmented the expression of targets and reduced the parasitemia in macrophages. This study will also provide the platform for the development of miRNA-based therapy against leishmaniasis.

Predictors of Cardiac Autonomic Dysfunction in Obesity-Related Hypertension.

INTRODUCTION: Cardiac Autonomic Dysfunction (CAD) is an overlooked cardiovascular risk factor in individuals with obesity-related hypertension. Despite its clinical significance, there is a notable lack of clarity regarding the pathophysiological correlates involved in its onset and progression. AIM: The present study aimed to identify potential predictors of CAD in obesity-related hypertension. METHODS: A total of 72 participants (34 men and 38 women) were enrolled. Comprehensive evaluations were conducted, including cardiac autonomic function assessments, body composition estimation and biochemical analysis. Participants were categorized as CAD-positive or CAD-negative based on Ewing's criteria for autonomic dysfunction. Univariate logistic regression analysis was performed to identify potential predictors for CAD. Multivariate logistic regression models were further constructed by adjusting clinically relevant covariates to identify independent predictors of CAD. RESULTS: Multivariate logistic regression analysis revealed that resting heart rate (HRrest), (odds ratio, confidence interval: 0.85, 0.78-0.93; p = 0.001) and percentage body fat (BF%), (odds ratio, confidence interval: 0.78, 0.64-0.96; p = 0.018) were significant independent predictors of CAD. Receiver Operating Characteristic curve analysis depicted optimal cut-off values for HRrest and BF% as > 74.1 bpm and > 33.6%, respectively. Multicolinearity analysis showed variance inflation factors (VIF) below the cautionary threshold of 3. CONCLUSIONS: The HRrest and BF% emerged as significant independent predictors of CAD in obesity-related hypertension. Therapeutic strategies should target HRrest < 74.1 bpm and BF% < 33.6% to mitigate CAD risk in this population. Future trials are required to establish causal relationships and may consider additional confounding variables in obesity-related hypertension.

Role of FTO and MC4R Polymorphisms in Escalating Obesity and Their Indirect Association With Risk of T2D in Indian Population.

INTRODUCTION: Obesity plays a pivotal role in the development of metabolic syndrome-excessive body fat, spikes in blood glucose levels and hypertension-and ultimately leads to cardiovascular diseases and type 2 diabetes (T2D), if left unattended. The present study aimed to investigate the associated risk of T2D with obesity risk alleles of fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes. METHODS: The study includes 400 subjects (300 T2D diabetic cases and 100 healthy controls). Genetic analysis was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The findings of the study show no significant increase in odds of diabetes associated with the prevalence of FTO and MC4R minor alleles. Rare allele frequencies for "A" of FTO rs9939609 were 0.34 and 0.30 in cases and controls, respectively. Rare allele frequencies for A of MC4R rs12970134 were found to be more common in controls (0.45) than cases (0.41), but the difference was insignificant (p 0.246); however, an increase in body weight with the presence of allele "A" of the FTO gene (p value < 0.001) was found, indicating indirect involvement in the development of T2D. In addition, these were also correlated with the demographic/lifestyle and clinico-pathological parameters between T2D cases and controls. We found that T2D patients with a history of smoking and high consumption of alcohol, fast foods and sweetened beverages are at high risk of T2D compared to healthy controls (p < 0.01*). CONCLUSION: The present study concludes that there is no direct association of rs9939609 of the FTO gene with the occurrence of diabetes in the Indian population, but its role in T2D development cannot be overlooked altogether. Furthermore, we conclude that the rs9939609 of FTO carries a potential risk of obesity and because of this FTO rs9939609 T > A is widely considered an obesity-associated allele/single-nucleotide polymorphism (SNP).

Postactivation Potentiation Following Acute Bouts of Plyometric versus Heavy-Resistance Exercise in Collegiate Soccer Players.

Postactivation potentiation is referred to as an acute and temporary enhancement of muscle performance resulting from previous muscle contraction. The purpose of this study was to compare the acute effect of plyometric exercise (PLY) and heavy-resistance exercise (RES) on the blood lactate level (BLa) and physical performance. Fourteen male collegiate soccer players were randomized to perform either RES or PLY first and then crossed over to perform the opposite intervention. PLY consisted of 40 jumps, whereas RES comprised ten single repetitions at 90% of one repetition maximum. BLa and physical performance (countermovement jump height and 20-m sprint) were measured before and at 1 and 10 min following the exercise. No significant difference was observed in the BLa for both exercises (PLY and RES). Relative to baseline, countermovement jump (CMJ) height was significantly better for the PLY group after 1 min (P = 0.004) and after 10 min (P = 0.001) compared to that of the RES group. The 20-m sprint time was significantly better for PLY at 10 min (P = 0.003) compared to that of RES. The present study concluded that, compared to RES, PLY causes greater potentiation, which leads to improved physical performance. This trial is registered with NCT03150277.

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies.

Chikungunya fever is an arboviral infection caused by the Chikungunya virus (CHIKV) and is transmitted by Aedes mosquito. The envelope protein (E2) of Chikungunya virus is involved in attachment of virion with the host cell. The present study was conceptualized to determine the structure of E2 protein of CHIKV and to identify the potential viral entry inhibitors. The secondary and tertiary structure of E2 protein was determined using bioinformatics tools. The mutational analysis of the E2 protein suggested that mutations may stabilize or de-stabilize the structure which may affect the structure-function relationship. In silico screening of various compounds from different databases identified two lead molecules i.e. phenothiazine and bafilomycin. Molecular docking and MD simulation studies of the E2 protein and compound complexes was carried out. This analysis revealed that bafilomycin has high docking score and thus high binding affinity with E2 protein suggesting stable protein-ligand interaction. Further, MD simulations suggested that both the compounds were stabilizing E2 protein. Thus, bafilomycin and phenothiazine may be considered as the lead compounds in terms of potential entry inhibitor for CHIKV. Further, these results should be confirmed by comprehensive cell culture, cytotoxic assays and animal experiments. Certain derivatives of phenothiazines can also be explored in future studies for entry inhibitors against CHIKV. The present investigation thus provides insight into protein structural dynamics of the envelope protein of CHIKV. In addition the study also provides information on the dynamics of interaction of E2 protein with entry inhibitors that will contribute towards structure based drug design.