Natural Killer T cells and the invariant subset promote atherosclerosis: A meta-analysis.

AIMS: Natural Killer T (NKT) cells are reported to be both pro- and anti-atherosclerotic. With this meta-analysis, we evaluated the NKT population and their subsets in regulating the atherosclerotic disease in mice. MAIN METHODS: Eighteen pre-clinical (mice, n = 1276) and 6 clinical observational studies (humans, n = 116) met the eligibility criteria for inclusion. Random effects model was used and standard mean difference (SMD) was calculated for the cell counts and aortic lesion area. KEY FINDINGS: Lesion area decreased in the absence of whole NKT cell population (-1.33[95%CI, -2.14, -0.52]), and in the absence of only iNKT subset (-0.66[95%CI, -1.69, 0.37]). However, lesion area increased after over-expression/activation of iNKTs (1.40[95%CI, 0.28, 2.52]). Atherogenic diet (AD) or high fat diet (HFD) increased the number of NKT cells (2.51[95%CI, 1.42, 3.61]), whereas the iNKT cell numbers and iNKT cell-specific gene expression decreased in mice (-2.04[95%CI, -3.34, -0.75]) and atherosclerotic patients (-1.81[95 % CI, -2.89, -0.74]). SIGNIFICANCE: Here we show that, NKT and iNKT cells promote atherosclerosis. In general, NKT cell population increases with the progression of the plaque in mice and the numbers of iNKT cells reduce once the disease is established both in mice and humans.

Meta-analysis reveals inhibition of the inflammatory cytokine IL-6 affords limited protection post-myocardial ischemia/infarction.

Background: Proinflammatory cytokine cascades play crucial roles in the onset and progression of myocardial ischemia and infarction. Clinically, elevated serum levels of pro-inflammatory cytokine interleukin-6 is a poor prognostic indicator for future cardiac events and cardiac morbidity. Despite several reports, there is no clear evidence of cardiac benefits of inhibiting IL-6 in pre-clinical and clinical settings. Objective: To analyze the available data systematically and perform a meta-analysis to show the evidence of effects of IL-6 inhibition on cardiac remodeling and mortality in ischemic animal models. Methods: We used PICO framework and the quality of the studies was assessed using SYRCLE's risk of bias tool. Studies with interventions i.e., genetic deletion or pharmacological inhibition of IL-6/IL-6R were included for the meta-analysis. Systematic review was synthesized by including pre-clinical as well as randomized clinical trials involving myocardial infarction patients treated with IL-6 inhibitors. The effect size of the pooled data was determined using standard mean difference and 95% confidence intervals. Results: A total of 12 pre-clinical studies were included in the review for analysis. Most of the studies showed an unclear risk of bias as the selection and reporting criteria were poorly described. We observed high heterogeneity in the included studies due to the varying duration of myocardial infarction and the dosage of IL-6 antibodies used in the studies. Overall inhibition of IL-6 significantly increased area at risk [p = 0.001, SMD = 0.49 (95% CI: -0.36, 1.35)] and significantly reduced ejection fraction [p = 0.001, SMD = -0.19 (95% CI: -1.39, 1.01)] and end-diastolic diameter [p = 0.02, SMD = -0.25 (95% CI: -0.87, 0.36)] of left ventricle post-MI, but no effects on infarct size [p < 0.01, SMD = 0.00; 95% CI: -1.34, 0.58). In randomized clinical trials, the overall effect on C-reactive protein remains significantly unchanged on CRP levels (SMD = -0.38; 95% CI: -1.94, 0.55) post-treatment with IL-6R inhibitor tocilizumab. The meta-regression demonstrates a significant positive correlation (p = 0.058) between the increase in ischemic area and duration of ischemia post-surgery in the absence of IL-6. This meta-analysis indicates mixed effect of IL-6 inhibition on cardiac remodeling post-MI, particularly in protecting the myocardium viability from damaging acute inflammation but not significant on cardiac function of ischemic animal models. Conclusion: Despite the well-established pro-inflammatory nature of IL-6 in myocardial ischemia, our meta-analysis reports a limited contribution of IL-6 in the cardiac remodeling of hearts in animal models of myocardial ischemia. Moreover, genetically deleted IL-6 murine models produced contrasting results. Additional pre-clinical studies exploring the pharmacological inhibition of IL-6R are required to determine the beneficial effects of IL-6 inhibitors in regulating cardiac remodeling. The findings from IL-6R inhibition have better clinical relevance compared to genetically inhibited IL-6.

Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology.

Transcription factors as multifaceted modulators of gene expression that play a central role in cell proliferation, differentiation, lineage commitment, and disease progression. They interact among themselves and create complex spatiotemporal gene regulatory networks that modulate hematopoiesis, cardiogenesis, and conditional differentiation of hematopoietic stem cells into cells of cardiovascular lineage. Additionally, bone marrow-derived stem cells potentially contribute to the cardiovascular cell population and have shown potential as a therapeutic approach to treat cardiovascular diseases. However, the underlying regulatory mechanisms are currently debatable. This review focuses on some key transcription factors and associated epigenetic modifications that modulate the maintenance and differentiation of hematopoietic stem cells and cardiac progenitor cells. In addition to this, we aim to summarize different potential clinical therapeutic approaches in cardiac regeneration therapy and recent discoveries in stem cell-based transplantation.

Mitigative effect of Momordica cymbalaria fruit extract against sodium fluoride induced hepatotoxicity in Wistar male albino rats.

OBJECTIVES: The main objective of the present study is to evaluate the mitigative effect of hydroalcoholic extract of Momordica cymbalaria fruits against sodium fluoride (NaF) induced hepatotoxicity. METHODS: In this study, Wistar male albino rats were randomly divided into five groups of six rats each. Group I and II served as normal and toxic controls. Group III as plant control received extract at a dose of 400 mg/kg b. wt, p.o and Groups IV and V as treatment groups received extract at a dose 200 and 400 mg/kg b. wt, p.o for 30 days. All groups except Groups I and III received 100 ppm of NaF through drinking water. After completion of the study, blood collected for the estimation of liver blood serum biomarkers such as aspartate aminotransferases (AST), alanine aminotransferases (ALT), alkaline Phosphatase (ALP), direct and total bilirubin, total protein and albumin. The liver tissue homogenate was for estimation of lipid peroxidation, catalase, and reduced glutathione levels. RESULTS: The results showed that NaF intoxication caused elevation of liver blood serum levels and lipid peroxidation; decreased levels of serum total protein, albumin and liver reduced glutathione, and catalase observed. The treatment groups showed decreased elevated serum biomarkers (ALT, AST, and ALP), liver lipid peroxidation and increased serum total protein and albumin, liver reduced glutathione and catalase levels in a dose-dependent manner. Histopathological studies also further strongly supported for mitigative effects of the plant. CONCLUSIONS: In conclusion, our findings of the study indicated that M. cymbalaria fruits were a potential drug candidate in the treatment of NaF induced hepatotoxicity.

Ex vivo model for studying endothelial tip cells: Revisiting the classical aortic-ring assay.

A drug undergoes several in silico, in vitro, ex vivo and in vivo assays before entering into the clinical trials. In 2014, it was reported that only 32% of drugs are likely to make it to Phase-3 trials, and overall, only one in 10 drugs makes it to the market. Therefore, enhancing the precision of pre-clinical trial models could reduce the number of failed clinical trials and eventually time and financial burden in health sciences. In order to attempt the above, in the present study, we have shown that aortic ex-plants isolated from different stages of chick embryo and different regions of the aorta (pulmonary and systemic) have differential sprouting potential and response to angiogenesis modulatory drugs. Aorta isolated from HH37 staged chick embryo showed 16% (p < 0.001) and 11% (p < 0.001) increase in the number of tip cells at 72 h of culture compared to that of HH35 and HH29 respectively. The ascending order of the number of tip cells was found as central (Gen II), proximal (Gen I) and distal (Gen III) in a virtual zonal segmentation of endothelial sprouting. The HH37 staged aortas displayed differential responses to pro- and anti-angiogenic drugs like Vascular endothelial growth factor (VEGF), nitric oxide donor (spNO), and bevacizumab (avastin), thalidomide respectively. The human placenta tissue-culture however evinced endothelial sprouting only on day 12, with a gradual decrease in the number of tip cells until 21 days. In summary, this study provides an avant-garde angiogenic model emphasized on tip cells that would enhance the precision to test next-generation angiogenic drugs.