Platelet-derived sTLT-1 is associated with platelet-mediated inflammation in coronary artery disease patients.

The development of coronary artery disease (CAD) depends heavily on platelet activation, and inflammation plays a major role in all stages of atherosclerosis. Platelet-specific soluble triggering receptor expressed on myeloid cells like transcript 1 (sTLT-1) facilitate clot formation and have been linked to chronic inflammation. In this study, we explored the role of platelet-derived sTLT-1 in platelet-mediated inflammation in CAD patients. Plasma levels of sTLT-1 were measured using enzyme-linked immunosorbent assay in CAD patients (n = 163) and healthy controls (n = 99). Correlation analysis was performed to determine the circulatory sTLT-1 levels with platelet activation markers, immune cells, and inflammatory cytokines/chemokines. Increased plasma sTLT-1 levels were observed in CAD patients compared with those in healthy controls (p < 0.0001). A positive correlation was observed between sTLT-1 and platelet activation markers (P-selectin, PAC-1), CD14++ CD16- cells (classical monocytes), Natural killer T (NKT) cells, and platelet-immune cell aggregates with monocytes, neutrophils, dendritic cells, CD11c+ cells, and NKT cells. In contrast, a significant negative correlation was observed with CD8 cells. Furthermore, a significant positive correlation was observed between sTLT-1 and inflammatory markers (TNF-α, IL-1ß, IL-2, IL-6, IL-12p70, IL-18, CXCL-12, and CCL-11). Logistic regression analysis identified sTLT-1 and triglycerides as predictors of CAD. Receiver operating characteristic curve (ROC) analysis showed that sTLT-1 had a higher sensitivity and specificity for predicting CAD. Our findings suggest that platelet activation induces the release of sTLT-1 into the circulation in CAD patients, which aggregates with immune cells and enhances inflammatory responses.

Integrative Placental Multi-Omics Analysis Reveals Perturbed Pathways and Potential Prognostic Biomarkers in Gestational Hypertension.

BACKGROUND: Gestational hypertension (GH) is a severe complication that occurs after 20 weeks of pregnancy; however, its molecular mechanisms are not yet fully understood. OBJECTIVE: Through this case-control discovery phase study, we aimed to find disease-specific candidate placental microRNAs (miRNAs) and metabolite markers for differentiating GH by integrating next-generation sequencing and metabolomics multi-omics analysis of placenta. Using small RNA sequencing and metabolomics of placental tissues of healthy pregnant (HP, n = 24) and GH subjects (n = 20), the transcriptome and metabolome were characterized in both groups. RESULTS: The study identified a total of 44 downregulated placental miRNAs which includes three novel, three mature and 38 precursor miRNAs. Six miRNAs including three mature (hsa-miR-181a-5p, hsa-miR-498-5p, and hsa-miR-26b-5p) and three novel (NC_000016.10_1061, NC_000005.10_475, and NC_000001.11_53) were considered for final target prediction and functional annotation. Integrative analysis of differentially expressed miRNAs and metabolites yielded five pathways such as purine, glutathione, glycerophospholipid, inositol phosphate and ß-alanine to be significantly perturbed in GH. We present fourteen genes (LPCAT1, LPCAT2, DGKH, PISD, GPAT2, PTEN, SACM1L, PGM2, AMPD3, AK7, AK3, CNDP1, IDH2, and ODC1) and eight metabolites (xanthosine, xanthine, spermine, glycine, CDP-Choline, glyceraldehyde 3-phosphate, ß-alanine, and histidine) with potential to distinguish GH and HP. CONCLUSION: The differential expression of miRNAs, their target genes, altered metabolites and metabolic pathways in GH patients were identified for the first time in our study. Further, the altered miRNAs and metabolites were integrated to build their inter-connectivity network. The findings obtained from our study may be used as a valuable source to further unravel the molecular pathways associated with GH and also for the evaluation of prognostic markers.

Circulatory bone morphogenetic protein (BMP) 8B is a non-invasive predictive biomarker for the diagnosis of non-alcoholic steatohepatitis (NASH).

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a complex disease which is characterized by the deposition of fats in the hepatocytes. Further, it progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. The increasing prevalence of NAFLD urges to find the non-invasive predictive biomarkers. In this study, we sought to determine increased BMP8B levels as predictors for the progression of NAFLD. METHODS: In the present cross-sectional study, circulatory BMP8B levels were measured in healthy controls (n = 56), NAFL patients (n = 72) and NASH patients (n = 77) by using an ELISA kit. Human hepatic BMP8B mRNA expression was measured in the liver tissue of control and NASH patients. In addition, BMP8B expression was confirmed by immunohistochemistry analysis. Furthermore, hepatic BMP8B mRNA expression was measured in wild type (WT) mice, WT mice fed with choline deficient high fat diet (WT+CDHF), iNOS (inducible nitric oxide synthase) knockout (iNOS-/-) mice, iNOS-/- fed with CDHF diet (iNOS-/-+CDHF). RESULTS: Increased circulatory BMP8B levels and BMP8B mRNA expression in hepatic tissue were significantly higher in NASH patients as compared with the control subjects. BMP8B expression was increased parallel to the fibrosis score in the hepatic tissues of NASH patients. It was observed that increased BMP8B levels have shown a significant positive correlation between aspartate aminotransferase (r = 0.31, p = 0.005), alanine aminotransferase (r = 0.23, p = 0.045), APRI (r = 0.30, p = 0.009), and Fib-4 score (r = 0.25, p = 0.036) in NASH patients. BMP8B has maintained a significant association with NASH and shown high sensitivity (92.91%) and specificity (92.73%) in NASH patients. Furthermore, increased BMP8B mRNA expression levels were observed in iNOS-/-+CDHF mice. CONCLUSION: Our study findings confirmed that BMP8B increases with the severity of the disease and BMP8B shows potential as a non-invasive predictive biomarker to identify NAFLD progression. However, future studies should investigate circulatory BMP8B levels in a large number of patients and also its impact on liver during NAFLD progression.

Machine learning-based protein signatures for differentiating hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy (HDP) result in major maternal and fetal complications. Our study aimed to find a panel of protein markers to identify HDP by applying machine-learning models. The study was conducted on a total of 133 samples, divided into four groups, healthy pregnancy (HP, n = 42), gestational hypertension (GH, n = 67), preeclampsia (PE, n = 9), and ante-partum eclampsia (APE, n = 15). Thirty circulatory protein markers were measured using Luminex multiplex immunoassay and ELISA. Significant markers were screened for potential predictive markers by both statistical and machine-learning approaches. Statistical analysis found seven markers such as sFlt-1, PlGF, endothelin-1(ET-1), basic-FGF, IL-4, eotaxin and RANTES to be altered significantly in disease groups compared to healthy pregnant. Support vector machine (SVM) learning model classified GH and HP with 11 markers (eotaxin, GM-CSF, IL-4, IL-6, IL-13, MCP-1, MIP-1α, MIP-1ß, RANTES, ET-1, sFlt-1) and HDP with 13 markers (eotaxin, G-CSF, GM-CSF, IFN-gamma, IL-4, IL-5, IL-6, IL-13, MCP-1, MIP-1ß, RANTES, ET-1, sFlt-1). While logistic regression (LR) model classified PE with 13 markers (basic FGF, IL-1ß, IL-1ra, IL-7, IL-9, MIP-1ß, RANTES, TNF-alpha, nitric oxide, superoxide dismutase, ET-1, PlGF, sFlt-1) and APE by 12 markers (eotaxin, basic-FGF, G-CSF, GM-CSF, IL-1ß, IL-5, IL-8, IL-13, IL-17, PDGF-BB, RANTES, PlGF). These markers may be used to diagnose the progression of healthy pregnant to a hypertensive state. Future longitudinal studies with large number of samples are needed to validate these findings.

Untargeted metabolomics reveals altered branch chain amino acids, glucose and fat metabolism contributing to coronary artery disease among Indian diabetic patients.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by increased blood glucose levels. Patients with T2DM have a high risk of developing atherosclerotic coronary artery disease (CAD). CAD with T2DM has a complex etiology and the understanding of the pathophysiology of coronary artery disease (CAD) in the presence of diabetes is poor. Here, we have used LC-MS/MS-based untargeted metabolomics to unveil the alterations of metabolites in the serum of South-Indian patients diagnosed with T2DM, CAD and T2DM along with CAD (T2DM-CAD) compared with the healthy subjects (CT). Using untargeted metabolomics and network-based approaches, a set of metabolites highly co-expressed with T2DM-CAD pathogenesis were identified. Our results revealed that these metabolites belong to essential pathways such as amino acid metabolism, fatty acid metabolism and carbohydrate metabolism. The candidate metabolites identified by metabolomics study are branch chain amino acids, L-arginine, linoleic acid, L-serine, L-cysteine, fructose-6-phosphate, glycerol, creatine and 3-phosphoglyceric acid, and explain the pathogenesis of T2DM-assisted CAD. The identified metabolites could be used as potential prognostic markers to predict CAD in patients diagnosed with T2DM.

Effect of garlic extract on markers of lipid metabolism and inflammation in coronary artery disease (CAD) patients: A systematic review and meta-analysis.

Several preclinical studies have focused on the beneficial effects of garlic on cardiovascular diseases, but the results were inconsistent. We performed a systematic review and meta-analysis on the effect of garlic powder tablets and aged garlic extract (AGE) in CAD patients, mainly focusing on blood pressure, coronary artery calcification, lipid profile, and inflammatory markers. We searched PubMed, Cochrane CENTRAL, and Google Scholar to identify randomized controlled trials which examined garlic's effect on CAD patients. The standardized mean difference with 95% CI was calculated using fixed-effect or random-effect models. Garlic has shown statistically significant changes of HDL (SMD = 0.18; 95% CI = -0.00 to 0.37; p = .05); LDL (SMD = -0.27; 95% CI = -0.46 to -0.08; p = .004), apolipoprotein-A (SMD = 0.68; 95% CI = 0.24 1.13; p = .002), C-RP (SMD = -0.59; 95% CI = -0.92 to -0.25; p = .0007), IL-6 (SMD = -1.08; 95% CI = -2.17 to 0.01; p = .05), homocysteine (SMD = -0.66; 95% CI = -1.04 to -0.28; p = .0007) and CAC score (SMD = -1.61; 95% CI = -2.66 to -0.57; p = .003). In the case of subgroup analysis, the overall effect was significantly effective in reducing TC, LDL levels and improving HDL levels in CV risk patients. Our study findings provide consistent evidence that intake of garlic reduces CVD risk factors. However, garlic could be considered a safe natural medicine to debilitate inflammation in CAD patients.

Disrupted placental vitamin D metabolism and calcium signaling in gestational diabetes and pre-eclampsia patients.

INTRODUCTION: Gestational diabetes (GDM) and pre-eclampsia (PE) represents the unrecognized risk factors for reduced bone content in neonates. The present study is planned to explore the components of vitamin D metabolism and calcium transport in placenta of GDM and PE cases and its effect on the neonatal bone mass determination using bone densitometry system. METHODS: We have collected serum and placenta tissues from GDM (n = 20), PE (n = 20), and healthy pregnancies (n = 20). In the present study, we found mRNA expression of oxidative stress markers, vitamin D metabolic components and calcium channels, calcium channel binding proteins, plasma membrane calcium ATPase, ATP synthase and Ca2+ release genes; Ryanodine receptors genes were assessed by quantitative real-time PCR (qRT-PCR) in placental tissue of GDM, PE, and healthy pregnancies. RESULTS: We observed high level of oxidative stress in both GDM and PE placenta compared to normal pregnancies. CYP2R1 and VDR mRNA expression was significantly downregulated and upregulation of CYP27B1 and CYP24A1 in GDM and PE compared with healthy cases. Similarly, calcium transporters were downregulated in GDM and PE placental tissues. In addition, CYP24A1, VDR, CaBP28K, TRPV5 and PMCA3 mRNA expression were correlated with BMC of neonates. DISCUSSION: Oxidative stress is probably relevant to disrupted vitamin D homeostasis and calcium transport in the placenta of GDM and PE cases. The altered regulatory mechanism of CYP24A1 and VDR could indicates more pronounced serum 25(OH)D reduction. Additionally, reduced BMC in the neonates of these cases might be as consequences of modified CYP24A1, VDR, CaBP28K, TRPV5 and PMCA3 mRNA expression.

Integrated metabolomics and machine learning approach to predict hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy account for 3% to 10% of maternal-fetal morbidity and mortality worldwide. This condition has been considered one of the leading causes of maternal deaths in developing countries, such as India. OBJECTIVE: This study aimed to discover hypertensive disorders of pregnancy-specific candidate urine metabolites as markers for hypertensive disorders of pregnancy by applying integrated metabolomics and machine learning approaches. STUDY DESIGN: The targeted urinary metabolomics study was conducted in 70 healthy pregnant controls and 133 pregnant patients having hypertension as cases. Hypertensive disorders of pregnancy-specific metabolites for disease prediction were further extracted using univariate and multivariate statistical analyses. For machine learning analysis, 80% of the data were used for training (79 for hypertensive disorders of pregnancy and 42 for healthy pregnancy) and validation (27 for hypertensive disorders of pregnancy and 14 for healthy pregnancy), and 20% of the data were used for test sets (27 for hypertensive disorders of pregnancy and 14 for healthy pregnancy). RESULTS: The statistical analysis using an unpaired t test revealed 44 differential metabolites. Pathway analysis showed mainly that purine and thiamine metabolism were altered in the group with hypertensive disorders of pregnancy compared with the healthy pregnancy group. The area under the receiver operating characteristic curves of the 5 most predominant metabolites were 0.98 (adenosine), 0.92 (adenosine monophosphate), 0.89 (deoxyadenosine), 0.81 (thiamine), and 0.81 (thiamine monophosphate). The best prediction accuracies were obtained using 2 machine learning models (95% for the gradient boost model and 98% for the decision tree) among the 5 used models. The machine learning models showed higher predictive performance for 3 metabolites (ie, thiamine monophosphate, adenosine monophosphate, and thiamine) among 5 metabolites. The combined accuracies of adenosine from all models were 98.6 in the training set and 95.6 in the test set. Moreover, the predictive performance of adenosine was higher than other metabolites. The relative feature importance of adenosine was also observed in the decision tree and the gradient boost model. CONCLUSION: Among other metabolites, adenosine and thiamine metabolites were found to differentiate participants with hypertensive disorders of pregnancy from participants with healthy pregnancies; hence, these metabolites can serve as a promising noninvasive marker for the detection of hypertensive disorders of pregnancy.

Exposure to endocrine-disrupting chemicals and risk of gestational hypertension and preeclampsia: A systematic review and meta-analysis.

Prenatal exposure to endocrine-disrupting chemicals has been linked to gestational hypertension (GH) and preeclampsia (PE). However, the results were conflicting and inconclusive. We conducted a systematic review and meta-analysis for an overview of these relationships. We searched PubMed, and Google Scholar for studies investigating bisphenol A, phthalates, and per or poly-fluoroalkyl substances and GH or PE. Pooled odds ratio (OR) with a 95% confidence interval (CI) were calculated for risk estimate using the generic inverse variance method. A total of 14 studies were included in the present analysis. The pooled results demonstrated that perfluorooctanoic acid (PFOA, OR:1.20, 95% CI: 1.04, 1.39), perfluoro octane sulfonic acid (PFOS, (OR:1.23, 95% CI: 1.10, 1.38), and perfluononanoic acid (PFNA, OR:1.20, 95% CI: 1.03, 1.40) were significantly associated with an increased risk of PE. There was no significant association observed with perfluoro hexane sulfonic acid (PFHxS), perfluoro decanoic acid (PFDA), perfluoro heptanoic acid (PFHpA), and perfluoro undecanoic acid (PFUnDA) and PE. For GH, a statistically significant positive association was found with PFOA (OR:1.18, 95% CI: 1.01, 1.39) and PFHxS (OR:1.15, 95% CI: 1.02, 1.29). Among various phthalates analysed only mono-ethyl phthalate (MEP, OR:1.37, 95% CI: 1.11, 1.70) showed an association with GH. From our analysis, bisphenol A exposure during pregnancy did not show a significant association with the risk of PE. Our findings indicated that exposure to PFASs such as PFOA, PFOS, and PFNA during pregnancy is associated with an increased risk of PE and PFOA and PFHxS with GH. We also found that MEP was associated with GH. Most of the results were unstable in sensitivity analysis. Since most of these associations have limited evidence, more research is needed to confirm these findings.

Efficacy and Safety of Saroglitazar in Patients with Cardiometabolic Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVE: The incidence of cardiometabolic diseases is increasing because of an increase in the standard of living. Currently, clinical treatment strategies for cardiometabolic diseases mainly focus on maintaining glycemic and lipid profiles. The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of saroglitazar in patients with metabolic disease and provide evidence for clinical decision making. METHODS: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials [CENTRAL], and Google Scholar) for randomized controlled trials that examined saroglitazar for the treatment of patients with cardiometabolic disease. A total of seven randomized controlled trials were included for the qualitative and quantitative synthesis. Mean difference (MD) and risk ratio with a 95% confidence interval (CI) were applied for continuous and dichotomous data, respectively. RESULTS: The overall effect of saroglitazar showed significant changes in triglycerides, total cholesterol, low-density lipoprotein, non-high-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, alkaline phosphatase, and gamma-glutamyl transferase levels [MD: - 40.50; 95% CI - 58.09 to - 22.92; p < 0.00001; I2 = 78%], [MD: - 7.49; 95% CI - 11.33 to - 3.65; p = 0.0001; I2 = 41%], [MD: - 3.53; 95% CI - 6.91 to - 0.15; p = 0.04; I2 = 19%], [MD: - 8.08; 95% CI - 15.63 to - 0.54; p = 0.04; I2 = 58%], [MD: 2.04; 95% CI 0.17 to 3.92; p = 0.03; I2 = 69%], [MD: - 6.10; 95% CI - 9.40 to - 2.80; p = 0.0003; I2 = 65%], [MD: - 5.89; 95% CI - 7.50 to - 4.28; p < 0.00001; I2 = 98%], and [MD: - 1.64; 95% CI - 2.83 to - 0.45; p = 0.007; I2 = 95%], respectively. A subgroup analysis showed favorable outcomes with sarogiltazar 4 mg. There was a statistically non-significant reduced risk of adverse event occurrence in the saroglitazar treatment group. CONCLUSIONS: Our study results conclude that the overall effect of saroglitazar was beneficial only in terms of lipid profiles and liver function parameters, whereas saroglitazar 4 mg showed a better therapeutic role in maintaining lipid and glycemic parameters in patients with cardiometabolic disease.

Pregestational diabetes alters cardiac structure and function of neonatal rats through developmental plasticity.

Pregestational diabetes (PGDM) leads to developmental impairment, especially cardiac dysfunction, in their offspring. The hyperglycemic microenvironment inside the uterus alters the cardiac plasticity characterized by electrical and structural remodeling of the heart. The altered expression of several transcription factors due to hyperglycemia during fetal development might be responsible for molecular defects and phenotypic changes in the heart. The molecular mechanism of the developmental defects in the heart due to PGDM remains unclear. To understand the molecular defects in the 2-days old neonatal rats, streptozotocin-induced diabetic female rats were bred with healthy male rats. We collected 2-day-old hearts from the neonates and identified the molecular basis for phenotypic changes. Neonates from diabetic mothers showed altered electrocardiography and echocardiography parameters. Transcriptomic profiling of the RNA-seq data revealed that several altered genes were associated with heart development, myocardial fibrosis, cardiac conduction, and cell proliferation. Histopathology data showed the presence of focal cardiac fibrosis and increased cell proliferation in neonates from diabetic mothers. Thus, our results provide a comprehensive map of the cellular events and molecular pathways perturbed in the neonatal heart during PGDM. All of the molecular and structural changes lead to developmental plasticity in neonatal rat hearts and develop cardiac anomalies in their early life.

Comparative efficacy and safety of oral nifedipine with other antihypertensive medications in the management of hypertensive disorders of pregnancy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hypertensive disorders of pregnancy are the most frequently occurring medical condition during pregnancy, resulting in fetal and/or maternal morbidity and mortality. This meta-analysis compared the efficacy and safety of nifedipine with other antihypertensive medications used in hypertensive disorders of pregnancy. METHODOLOGY: A comprehensive search was performed using PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar. The meta-analysis was carried out using Review Manager Software, and the pooled effect estimate was generated as standardized mean difference and odds ratio with 95% confidence interval and two-sided P -value. RESULTS: The meta-analysis was comprised of 22 randomized control trials with 2595 participants. It was found that meantime and number of doses required to achieve target blood pressure were lower in the nifedipine group ( P  < 0.05). Even though it is statistically insignificant, fetal APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) scores less than seven favors nifedipine intervention. Furthermore, none of the fetal or maternal secondary outcomes were found significant. CONCLUSION: Nifedipine was found to be more effective than other antihypertensive medications to reduce blood pressure, particularly in patients with severe hypertension. However, future clinical studies, including real-world data are necessary to establish the safety profile of nifedipine concerning the fetal outcomes in hypertensive pregnant women.

Implications of endocrine-disrupting chemicals on polycystic ovarian syndrome: A comprehensive review.

Polycystic ovarian syndrome (PCOS) is a complex multifactorial disorder of unknown pathogenesis in which genetic and environmental factors contribute synergistically to its phenotypic expressions. Endocrine-disrupting chemicals (EDCs), a group of widespread pollutants freely available in the environment and consumer products, can interfere with normal endocrine signals. Extensive evidence has shown that EDCs, environmental contributors to PCOS, can frequently induce ovarian and metabolic abnormalities at low doses. The current research on environmental EDCs suggests that there may be link between EDC exposure and PCOS, which calls for more human bio-monitoring of EDCs using highly sophisticated analytical techniques for the identification and quantification and to discover the underlying pathophysiology of the disease. This review briefly elaborated on the general etiology of PCOS and listed various epidemiological and experimental data from human and animal studies correlating EDCs and PCOS. This review also provides insights into various analytical tools and sample preparation techniques for biomonitoring studies for PCOS risk assessment. Furthermore, we highlight the role of metabolomics in disease-specific biomarker discovery and its use in clinical practice. It also suggests the way forward to integrate biomonitoring studies and metabolomics to underpin the role of EDCs in PCOS pathophysiology.

Vitamin D Supplementation Modulates Platelet-Mediated Inflammation in Subjects With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Recently, our group identified increased platelet-mediated inflammation in type 2 diabetes (T2DM) patients, and it is a well-established risk factor for diabetes complications, particularly for the development of cardiovascular diseases (CVD). Furthermore, vitamin D is reported to play an important role in the modulation of platelet hyperactivity and immune function, although the effect of vitamin D on platelet-mediated inflammation is not well studied. Hence, we aimed to investigate the effect of vitamin D supplementation on platelet-mediated inflammation in T2DM patients. Methods: After screening a total of 201 subjects, our randomized, double-blind, placebo-controlled trial included 59 vitamin-D-deficient T2DM subjects, and the participants were randomly assigned to placebo (n = 29) or vitamin D3 (n = 30) for 6 months. Serum vitamin D metabolite levels, immunome profiling, platelet activation, and platelet-immune cell aggregate formation were measured at baseline and at the end of the study. Similarly, the serum levels of inflammatory cytokines/chemokines were assessed by a multiplex assay. Results: Six months of vitamin D supplementation increases the serum vitamin D3 and total 25(OH)D levels from the baseline (p < 0.05). Vitamin D supplementation does not improve glycemic control, and no significant difference was observed in immune cells. However, platelet activation and platelet immune cell aggregates were altered after the vitamin D intervention (p < 0.05). Moreover, vitamin D reduces the serum levels of IL-18, TNF-α, IFN-γ, CXCL-10, CXCL-12, CCL-2, CCL-5, CCL-11, and PF-4 levels compared to the baseline levels (p < 0.05). Our ex vivo experiment confirms that a sufficient circulating level of vitamin D reduces platelet activation and platelet intracellular reactive oxygen species. Conclusion: Our study results provide evidence that vitamin D supportive therapy may help to reduce or prevent the disease progression and cardiovascular risk in T2DM patients by suppressing oxidative stress and platelet-mediated inflammation. Clinical Trial Registration: Clinical Trial Registry of India: CTRI/2019/01/016921.

Paricalcitol Attenuates Metabolic Syndrome-Associated Heart Failure through Enhanced Mitochondrial Fusion.

Objectives: Transition from cardiac hypertrophy to failure involves adverse metabolic reprogramming involving mitochondrial dysfunction. We have earlier shown that vitamin D deficiency induces heart failure, at least in part, through insulin resistance. However, whether activation of vitamin D receptor (VDR) can attenuate heart failure and underlying metabolic phenotype requires investigation. Thus, we aimed to assess the cardioprotective potential of paricalcitol, a vitamin D receptor-activator, against cardiac hypertrophy and failure in high-fat high-fructose-fed rats. Methods: Male Sprague Dawley rats were fed control (Con) or high-fat high-fructose (HFHFrD) diet for 20 weeks. After 12 weeks, rats from HFHFrD group were divided into the following: HFHFrD, HFHFrD+P (paricalcitol i.p. 0.08 µg/kg/day) and HFHFrD+E (enalapril maleate i.p. 10 mg/kg/day). Intraperitoneal glucose tolerance test, blood pressure measurement, and 2D echocardiography were performed. Cardiac fibrosis was assessed by Masson's trichrome staining of paraffin-embedded heart sections. Mitochondrial DNA and proteins, and citrate synthase activity were measured in rat hearts. VDR was silenced in H9c2 cardiomyoblasts, and immunoblotting was performed. Results: Paricalcitol improved glucose tolerance, serum lipid profile, and blood pressure in high-fat high-fructose-fed rats. Paricalcitol reduced cardiac wall thickness and increased ejection fraction in high-fat high-fructose-fed rats but had no effect on perivascular fibrosis. PGC1-α was upregulated in the HFHFrD+P group compared to the HFHFrD group, but there was no significant difference in mitochondrial content. Citrate synthase activity was significantly higher in the HFHFrD+P group compared to the HFHFrD group. Rat hearts of the HFHFrD+P group had significantly higher expression of mitofusins. H9c2 cells with VDR knockdown showed significantly lower expression of Mfn2. Improvement in the HFHFrD+P group was comparable with that in the HFHFrD+E group. Conclusions: Paricalcitol reverses cardiac dysfunction in rats with metabolic syndrome by enhancing mitochondrial fusion. We demonstrate repurposing potential of the drug currently used in end-stage kidney disease.

Circulatory hepcidin levels association with gestational diabetes mellitus: a meta-analysis of observational studies.

OBJECTIVES: Hepcidin is linked to glucose metabolism in women with gestational diabetes mellitus (GDM). This systematic review and meta-analysis was conducted to determine the association between hepcidin levels and GDM. A literature search was performed using different databases to identify potential studies investigating hepcidin association in GDM patients. The effect sizes were calculated based on the standardized mean difference (SMD) and Fisher's Z value with a 95% confidence interval (CI). KEY FINDINGS: Out of 827 articles, only 7 case-control studies satisfied the inclusion and exclusion criteria. The pooled SMD of circulatory hepcidin levels in GDM patients was considerably higher than normal pregnant women (SMD = 1.69; 95% CI, 0.86 to 2.53; P < 0.0001). This study also observed that hepcidin levels were positively correlated with ferritin levels (r = 0.264; Z = 0.27; P < 0.0001). Furthermore, a subgroup analysis of serum and plasma groups revealed significantly higher hepcidin levels in serum (SMD = 2.12; 95% CI, 0.44 to3.79; P = 0.001) than in the plasma group (SMD = 1.28; 95% CI, 0.32 to 2.2; I2 = 96%). SUMMARY: Our findings suggest that hepcidin levels may be elevated in GDM patients, making it a viable marker for GDM diagnosis, and regular monitoring of its levels could be helpful in aiding clinical decisions.

Levels of parabens and bisphenols in personal care products and urinary concentrations in Indian young adult women: Implications for human exposure and health risk assessment.

Limited information is available about the levels of exposure of paraben and bisphenols emerging from personal care products (PCPs) use in Indian women and the risk associated with it. In this study, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the concentrations of six parabens (methyl-, ethyl-, propyl-, butyl, benzyl-, and heptyl-parabens) and 8 bisphenols (Bisphenol A, B, F, P, S, Z, AP, and AF) in PCPs samples (n = 114) obtained from Indian market and in the urine samples of young adult females (n = 52). The concentrations measured in PCPs and urine samples were used to determine the estimated daily intake. The mean concentrations of 6 parabens and 8 bisphenols in PCPs ranged from 38.3 to 2.38 × 105 ng/g and 2.71-148 ng/g, respectively. In urine samples analysed, the mean concentrations of 6 parabens and 8 bisphenols ranged from 0.007 to 293 ng/mL and 0.10-10.8 ng/mL, respectively. There was no significant correlation of EDCs with age, BMI and waist-to-hip ratio (WHR), but significant correlations (p < 0.05) were observed between urinary paraben and bisphenol concentrations. A statistically significant difference (p < 0.05) exists between the BMI and WHR groups by bisphenol concentrations. Estimated daily intake and exposure risks for parabens and bisphenols revealed no possible concerns for Indian young adult females. Hitherto, this is the first study to show that Indian young adult females were exposed to parabens and bisphenols. This study provides evidence on PCPs usage contribute to the urinary concentrations of EDCs.

Estimation of parabens and bisphenols in maternal products and urinary concentrations in Indian pregnant women: daily intake and health risk assessment.

The presence of parabens and bisphenols in maternal products and usage during pregnancy have raised serious concern about their possible harm to pregnant women. The concentrations of six parabens and eight bisphenols were quantified by high-performance liquid chromatography-tandem mass spectrometry in the samples of commercially available herbal-based ayurvedic maternal products and urine of healthy pregnant women from Assam, India. Methyl paraben (MP) and bisphenol AF (BPAF) were found to be more dominant in the maternal products, whereas MP, bisphenol A (BPA), and BPAF were dominant in urine samples of healthy pregnant women. The sum of the mean concentrations of all forms of parabens and bisphenols in maternal products were 48,308.50 ng/g and 542.42 ng/g, respectively, and urine 101.33 ng/mL and 23.42 ng/mL, respectively. The estimated daily intake (EDI) of total parabens and bisphenols in maternal products were 7378.02 and 19.78 ng/kg body weight/day, respectively. EDI of total parabens and bisphenols from urinary concentrations were 690.12 and 111.33 µg/kg body weight/day, respectively. The concentrations of butyl (BP) and heptyl (HP) parabens have a significant positive correlation with birth weight. The hazard quotient (HQ) value of MP, EP, and BPA was less than 1, and margin of exposure (MOE) identified potential risk associated with propyl paraben. Results from Monte-Carlo risk assessment analysis did not exceed the acceptable daily intake (ADI). Our results showed that higher concentrations of parabens and bisphenols are present in maternal products and the urine of healthy pregnant women. Hence maternal products containing bisphenols and parabens should be used cautiously during pregnancy to avoid maternal and fetal complications.