GENETIC SUSCEPTIBILITY OF TRANSCRIPTION FACTOR 7-LIKE 2 GENE VARIANT AND RISK OF TYPE 2 DIABETES IN ASIAN INDIANS

Background: The variants of transcription factor 7-like 2 (TCF7L2) gene have been shown to be associated with type 2 diabetes mellitus (T2DM) and its related complications. Objectives: We aimed to explore the possible association of rs7903146 (C/T) variant in TCF7L2 with the risk of T2DM in the North Indian population. Methods: The present case–control study included a total of 638 human subjects (318 T2DM subjects and 320 healthy controls). Various anthropometric, biochemical, and genetic parameters were studies in all the subjects. Genotyping of TCF7L2 gene was carried out using allele-specific polymerase chain reaction method. Results: The results of this study indicate significantly higher values of body mass index, waist circumference, waist-to-hip ratio, and body fat (%) in T2DM subjects than controls (p≤0.001). Dyslipidemia represented by higher levels of triglycerides and reduced values of high-density lipoprotein was more predominant in diabetic subjects compared to healthy subjects. The frequency of risk genotype (TT) frequency was significantly higher in T2DM subjects (16.4%) compared to controls (11.6%). The “T” allele was more dominant in diabetic subjects than controls. Logistic regression analysis of the data revealed a significant association of TT genotype with 2-fold (odds ratio with 95% of confidence interval; 2.09 [1.29–3.42] p=0.003) and CT genotype with 1.7-fold (1.73 [1.23–2.44] p=0.002) increased risk of developing T2DM. Conclusions: The present study demonstrated a significant association of rs7903146 (C/T) variant in TCF7L2 with the augmented risk of T2DM in North Indian population

Metabolic syndrome and risk of major coronary events among the urban diabetic patients: North Indian Diabetes and Cardiovascular Disease Study-NIDCVD-2

Objective: The present study aimed at estimating the prevalence of metabolic syndrome (MetS) and prospectively, evaluating cardiovascular events among Asian Indians type 2 diabetic subjects. Methods: The sample comprised 1522 type 2 diabetic mellitus (T2DM) subjects aged 25-91. years, who participated in the North Indian Diabetes and Cardiovascular Disease Study (NIDCVD). The participants were screened for hypertension, dyslipidemia, obesity and cardiovascular events. Anthropometric, clinical and biochemical measurements were done in all subjects. The prevalence of MetS was estimated in all the subjects according to the harmonized criteria of 2009. Results: The prevalence of MetS among urban Indian diabetic subjects was 71.9% and was significantly higher in females (86%) as compared to males (57.9%). To determine the independent predictors of the MetS in diabetic sample, binary logistic regression analyses were performed using demographic and biochemical parameters. Significant differences in the indices of generalized and abdominal obesity and lipids (total cholesterol, high density lipoprotein) were observed (p <. 0.01) in male:female and MetS and non-MetS comparisons. Regression analysis for prediction of CAD showed that family history, age, body mass index (BMI), SBP, physical inactivity and hypertension independently and significantly predicted the disease outcome. Binary logistic regression analysis revealed that MetS may be an independent risk/predictor of CAD (odd ratio (OR) = 3.44, CI 1.31-9.01, p = 0.012) along with higher age groups, BMI and hypertension in Indian population. Conclusion: The study demonstrated that the high prevalence of MetS and its different components were positively associated with a higher risk of CAD in north Indian diabetic subjects. Nevertheless, MetS is a major health problem in India, comprehensive population studies are warranted for estimation of incidence and prevalence, and education should be provided on its prevention and control to reduce the diabetes-related morbidity and mortality

Paraoxonase 1 gene polymorphisms (Q192R and L55M) are associated with coronary artery disease susceptibility in Asian Indians

Background: Coronary artery disease (CAD) is a complex metabolic disorder in which lifestyle and genetic factors are known to play key roles in pathogenesis. The paraoxonase 1 (PON1) enzyme has a defensive effect against CAD progression, as it safeguards low-density lipoproteins (LDLs) from oxidative modifications. The most extensively studied genetic variants in the PON1 gene are Q192R and L55M, which have been related with LDL antioxidative activity and risk of CAD. Objective: The present case-control study intended to examine the Q192R and L55M polymorphisms and their association with the risk of CAD patients in north Indians. Methods: A total of 872 subjects (412 CAD patients and 460 controls) were recruited from north India. The PON1 gene was amplified and genotypes were studies using PCR-RFLP. χ2 analysis was performed to compare genotype/allele frequencies in patients and controls. Results: The present study indicated abdominal obesity, elevated body mass index, and dyslipidemia with increased levels of total cholesterol and triglycerides as well as reduced high-density lipoprotein cholesterol in CAD subjects compared to healthy controls (p < 0.05). Logistic regression analysis of the data revealed an association of the RR genotype of the Q192R polymorphism with an about 2-fold elevated risk of CAD (OR = 2.23, 95% CI = 1.47–3.37, p = 0.0001). Contrariwise, the L55M polymorphism did not show significant association with CAD (OR = 1.81, 95% CI = 0.66–4.95, p = 0.326). Conclusions: The Q192R polymorphism in the PON1 gene may be a susceptibility gene associated with increased risk of CAD in an Asian Indian population

ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia with metabolic syndrome in Asian Indians

Background: Ectonucleotide pyrophosphatase/phosphodiesterase1 (ENPP1/PC-1) is a key modulator of the insulin signaling pathway, and its common variant, K121Q, increases the susceptibility to diabetes and cardiovascular diseases. Objectives: The main objective of the present study was to investigate the association of ENPP1 K121Q polymorphism with the pathophysiology of metabolic syndrome (MetS) in a north Indian population. Methods: A total of 567 participants (303 MetS subjects and 264 healthy controls) were examined for ENPP1 genotypes and various clinical parameters, including body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressures (SBP/DBP), fasting blood glucose (FBG), cholesterol, triglycerides (TG), highdensity lipoprotein, and insulin. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Statistical analysis of the data was done using SPSS. Results: Significant increases in BMI, WC, SBP, DBP, FBG, TG, low-density lipoprotein, insulin, and Homeostasis Model Assessment of insulin resistance (HOMAIR) and of beta-cell function (HOMA-BF) were observed in MetS patients compared to healthy controls. Logistic regression analysis of data demonstrated a nonsignificant association of QQ and KQ+QQ genotypes with increased risk of MetS (OR [95% CI], 1.583 [0.455–5.507], p = 0.470 for QQ genotypes and 1.097 [0.784–1.540], p = 0.587 for KQ+QQ genotypes). Moreover, MetS subjects carrying Q alleles had significantly higher levels of TG, insulin, body fat percentage, and insulin resistance as evident by higher values of HOMAIR. Conclusions: We conclude that ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia in MetS subjects of an Asian Indian population

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent

Among the small peptides <b>2</b>–<b>31</b>, (H)­Gly-Gly-Phe-Leu­(OMe) (<b>30</b>) reduced prostaglandin production of COX-2 with an IC₅₀ of 60 nM relative to 6000 nM for COX-1. The 5 mg kg^–1 dose of compound <b>30</b> rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound <b>30</b> for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of <b>30</b> with COX-2 were supported by isothermal calorimetry experiments showing a <i>K</i>_a of 6.10 ± 1.10 × 10⁴ M^–1 and Δ<i>G</i> of −100.3 kJ mol^–1 in comparison to a <i>K</i>_a 0.41 × 10³ ± 0.09 M^–1 and Δ<i>G</i> of −19.2 ± 0.06 kJ mol^–1 for COX-1. Moreover, compound <b>30</b> did not show toxicity up to a 2000 mg kg^–1 dose. Hence, we suggest peptide <b>30</b> as a highly potent and promising candidate for further development into an anti-inflammatory drug

Triblock Conjugates: Identification of a Highly Potent Antiinflammatory Agent

Rationally designed conjugates of chrysin, indole, and barbituric acid were synthesized and screened for their antiinflammatory activities through in vitro and in vivo experiments. Improved over the previously reported chrysin–indole–pyrazole conjugates and also in comparison to the chrysin, indole, and barbituric acid based COX-2 inhibitors, the new compounds have displayed significantly better IC₅₀ for COX-2 and some of them also exhibited inhibition of 5-LOX enzyme. For one of the test compounds, IC₅₀ for COX-2 and 5-LOX was 1 and 1.5 nM, respectively. Investigations of Swiss Albino mice through capsaicin induced paw lickings and dextran induced inflammation showed that these compounds possess appreciable analgesic and antiinflammatory activities. <i>K</i>_i, <i>K</i>_a, and Δ<i>G</i> for the enzyme–compound interaction were calculated and found to be in agreement with the biological data. The experimental results were supported by the molecular docking studies of the compounds in the active site of COX-2 and 5-LOX. Overall, a highly promising antiinflammatory agent was identified

Design and Synthesis of Aza-/Oxa Heterocycle-Based Conjugates as Novel Anti-Inflammatory Agents Targeting Cyclooxygenase‑2

A library of hybrid molecules was procured by the combination of triazine–indole adduct with morpholine/piperidine/pyrrolidine and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound <b>6</b> having an IC₅₀ value of 20 nM for COX-2 and 3000 nM for COX-1. The significant reduction in the formation of prostaglandin E₂ in the lipopolysaccharide-treated (COX-2-activated) human whole blood, almost no change in the production of thromboxane B₂ in the calcium ionophore-treated (COX-1-activated) sample of human whole blood, and the mechanistic studies on Swiss albino mice ensured that compound <b>6</b> is selective for COX-2. The association constant (<i>K</i>_a) of compound <b>6</b> with COX-2 was found to be of the order of 0.48 × 10⁶ M^–1. The diffusion spectroscopy experiments and relaxation time (<i>T</i>₁) calculations of compound <b>6</b> in the presence of COX-2 assisted in identifying the site-specific interactions of <b>6</b> with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure–activity relationship studies. With maximum tolerable dose >2000 mg kg^–1, compound <b>6</b> made 68 and 32% reduction in formalin-induced analgesia and carrageenan-induced inflammation in Swiss albino mice

Design and Synthesis of Aza-/Oxa Heterocycle-Based Conjugates as Novel Anti-Inflammatory Agents Targeting Cyclooxygenase‑2

A library of hybrid molecules was procured by the combination of triazine–indole adduct with morpholine/piperidine/pyrrolidine and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound <b>6</b> having an IC₅₀ value of 20 nM for COX-2 and 3000 nM for COX-1. The significant reduction in the formation of prostaglandin E₂ in the lipopolysaccharide-treated (COX-2-activated) human whole blood, almost no change in the production of thromboxane B₂ in the calcium ionophore-treated (COX-1-activated) sample of human whole blood, and the mechanistic studies on Swiss albino mice ensured that compound <b>6</b> is selective for COX-2. The association constant (<i>K</i>_a) of compound <b>6</b> with COX-2 was found to be of the order of 0.48 × 10⁶ M^–1. The diffusion spectroscopy experiments and relaxation time (<i>T</i>₁) calculations of compound <b>6</b> in the presence of COX-2 assisted in identifying the site-specific interactions of <b>6</b> with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure–activity relationship studies. With maximum tolerable dose >2000 mg kg^–1, compound <b>6</b> made 68 and 32% reduction in formalin-induced analgesia and carrageenan-induced inflammation in Swiss albino mice