ROLE OF AMYLOID BETA ASSEMBLY STATE IN THE HUMAN IMMUNE RESPONSE

Alzheimer’s disease (AD) is a slowly progressing neurodegenerative disease that leads to dementia. Histopathological hallmarks that characterize AD are senile plaques formed by extracellular deposition of Amyloid beta (Aβ) peptide and intracellular aggregates of hyperphosphorylated tau protein. The plaques, which are found in the brain parenchyma, comprise both 40 and 42 residue Aβ. Aggregation of Aβ is an established pathogenic mechanism in AD, but little is known about the initiation of this process in vivo. Several studies have revealed significant inflammatory markers such as activated microglia and cytokines surrounding the plaques. Plaques are a hallmark of AD, but they are only part of an array of Aβ aggregate morphologies observed in vivo. Structural polymorphism is a prominent feature of Aβ aggregation both in vitro and in vivo. The molecular relationship between the different forms of Aβ remains to be determined. Inflammatory processes are believed to contribute to AD pathophysiology, and may play an important role in the disease progression. Not all Aβ deposits evoke a proinflammatory response, making it all the more important to probe into structural details of the Aβ aggregation pathway. This research was aimed at investigating what Aβ morphology or aggregation species induce the strongest proinflammatory response in human THP-1 monocytes as a model system. Our results indicate that an intermediate fibrillar aggregation species formed when Aβ(1-42) is reconstituted in water (100 μM, pH 3.6) and incubated at 4oC under quiescent conditions was capable of stimulating maximum tumor necrosis factor alpha (TNFα). Modulating conditions that accelerated or increased Aβ(1-42) fibril formation such as temperature, peptide concentration, or pH diminished the ability to activate the cells. Immunodepletion of Aβ(1-42) solution with fibril specific antibody (OC immune serum) reduced the ability to induce TNFα production. Characterization by SEC showed an included peak that appeared immediately after the void volume and stimulated the maximum proinflammatory response. We have also shown that the shorter peptide Aβ(1-40) could not stimulate a proinflammatory response under similar aggregation conditions. Overall, the data suggest that an intermediate Aβ(1-42) fibrillar precursor species is optimal for inducing maximum proinflammatory activity in THP-1 monocytes

PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR PLANT-BASED ANTI-OXIDANT DRUGS

ABSTRACTObjective: A pharmacokinetic study is a cumbersome process in clinical research. It is very important in target validation and in shifting a leadcompound into a drug. Our major objective was to reveal the most important physiochemical characters of the plant-based anti-oxidants in align withhuman physiology. The in silico studies can preferably be the best solution to identify the physiologically-based pharmacokinetic (PBPK) behavior ofthe anti-oxidants.Methods: Anti-oxidants are found in many foods including fruits and vegetables. Few of the important anti-oxidants, i.e. around 10 plant-based antioxidantcompounds were taken for this research. These compounds were evaluated based on their pharmacokinetic parameters. The properties suchas Lipinski's rule of 5, absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the compounds were screened thoroughly with thehelp of tools such as molinspiration and gastroplus.Results: The physiological studies of these compounds had shown different compartmental absorptions of the compound in the human gastrointestinaltract. Certain compounds were found to pass the physiological barriers and had the ability to become a drug. The compounds were filtered using therisk and toxicity factors. These risk factors caused the compounds to fail in the process of becoming a drug.Conclusion: The compounds which passed the PBPK studies were eligible to become a drug. Of the 10 compounds investigated, eugenol, gingerol,zingerone, and geraniol were found to have higher fraction of absorption to become a drug. Out of these compounds, the compounds gingerol andeugenol have shown the best factor of absorption, and hence, have a better probability of becoming a drug.Keywords: Anti-oxidants, Lipinski, Absorption, Distribution, Metabolism, Excretion and toxicity, Physiological properties, GastroPlus, In silico

Increased Th1 and suppressed Th2 serum cytokine levels in subjects with diabetic coronary artery disease

BACKGROUND: The role played by T helper cytokines under chronic, low grade inflammation as seen in type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) co-morbidity is less well studied. In the present study, we measured the serum levels of both Th1 and Th2 cytokines and correlated it with clinical risk factors for T2DM (Insulin Resistance (IR), Glycated haemoglobin (HbA1c)) and CAD (C-Reactive Protein (CRP), Intima Media Thickness (IMT) and Augmentation index (AGI)) in T2DM subjects with/without CAD. METHODOLOGY: The study subjects were recruited from Chennai Urban Rural Epidemiology Study (CURES). Serum cytokine profile was determined by multiplex cytokine assay in Control (n = 61), T2DM (n = 60), CAD (n = 23) and T2DM-CAD (n = 21) subjects. RESULTS: T2DM subjects showed a mixed Th1-Th2 profile. CAD subjects presented a Th1 profile with modest Th2 suppression while T2DM-CAD subjects showed enhanced Th1 profile with strong suppression of Th2 cytokines. Both Th1 and Th2 cytokines showed a positive correlation with FPG, HbA1c, hsCRP, IMT and AGI. Logistic regression analysis revealed a significant association of IL-12 (OR = 9.3; 95% CI = 3.2-70.7; p = 0.016), IFN-γ (OR = 2.8; 95% CI = 2.7-2.9, p = 0.010), IL-4 (OR = 2.7; 95% CI 2.7-2.7, p = 0.010), IL-5 (OR = 1.1; 95% CI = 1.0-1.4; p = 0.003) and IL-13 (OR = 2; 95% CI = 1.7-2.6; p = 0.017) with T2DM-CAD. CONCLUSION: In conclusion, from the present study it appears that transition from T2DM or CAD to T2DM-CAD co-morbidity is associated with strong down regulation of Th2 cytokines and enhancement of Th1 responses

Increased risk of type 2 diabetes with ascending social class in urban South Indians is explained by obesity: The Chennai urban rural epidemiology study (CURES-116).

AIM: The aim of this study is to determine the factors responsible for differences in the prevalence of diabetes mellitus (DM) in subjects of different social class in an urban South Indian population. MATERIALS AND METHODS: Analyses were based on the cross-sectional data from the Chennai Urban Rural Epidemiology Study of 1989 individuals, aged ≥20 years. Entered in the analyses were information obtained by self-report on (1) household income; (2) family history of diabetes; (3) physical activity; (4) smoking status; (5) alcohol consumption. Biochemical, clinical and anthropometrical measurements were performed and included in the analyses. Social class was classified based on income as low (Rs. <2000) intermediate (Rs. 2000-5000`) and high (Rs. 5000-20000). RESULTS: The prevalence rates of DM were 12.0%, 18.4% and 21.7% in low, intermediate and high social class, respectively (P < 0.001). A significant increase in the risk of diabetes was found with ascending social class (Intermediate class: Odds ratio [OR], 1.7 [confidence interval [CI], 1.2-2.3]; High class: OR, 2.0 [CI-1.4-2.9]). The multivariable adjusted logistic regression analysis revealed that the effect of social class on the risk of diabetes remained significant (P = 0.016) when age, family history of diabetes and blood pressure were included. However, with the inclusion of abdominal obesity in the model, the significant effect of social class disappeared (P = 0.087). CONCLUSION: An increased prevalence of DM was found in the higher social class in this urban South Indian population, which is explained by obesity

Effect of Filarial Infection on Serum Inflammatory and Atherogenic Biomarkers in Coronary Artery Disease (CURES-121)

Helminth infections can potentially confer protection against metabolic disorders, possibly through immunomodulation. In this study, the baseline prevalence of lymphatic filariasis (LF) among subjects without (N = 236) and with (N = 217) coronary artery disease (CAD) was examined as part of the Chennai Urban Rural Epidemiological Study (CURES). The prevalence of LF was not significantly different between CAD(−) and CAD(+) subjects. The LF antigen load and antibody levels indicated comparable levels of infection and exposure between the groups. Within the CAD group, LF(+) and LF(−) subjects had no significant difference in the intimal medial thickness and high-sensitivity C-reactive protein values. However, LF infection was associated with augmented levels of tumor necrosis factor-α and interleukin-6 among CAD(+) subjects. The LF infection had no effect on serum adipocytokine profile. In conclusion, unlike type-2 diabetes, there is no association between the prevalence of LF and CAD and also no evidence of protective immunomodulation of LF infection on CAD in the Asian Indian population

Prevalence of prediabetes and type 2 diabetes mellitus in south and southeast Asian women with history of gestational diabetes mellitus: Systematic review and meta-analysis

Background The burden of Gestational Diabetes Mellitus (GDM) is very high in south Asia (SA) and southeast Asia (SEA). Thus, there is a need to understand the prevalence and risk factors for developing prediabetes and type 2 diabetes mellitus (T2DM) postpartum, in this high-risk population. Aim To conduct a systematic review and meta-analysis to estimate the prevalence of prediabetes and T2DM among the women with history of GDM in SA and SEA. Methods A comprehensive literature search was performed in the following databases: Medline, EMBASE, Web of Knowledge and CINHAL till December 2021. Studies that had reported greater than six weeks of postpartum follow-up were included. The pooled prevalence of diabetes and prediabetes were estimated by random effects meta-analysis model and I2 statistic was used to assess heterogeneity. Results Meta-analysis of 13 studies revealed that the prevalence of prediabetes and T2DM in post-GDM women were 25.9% (95%CI 18.94 to 33.51) and 29.9% (95%CI 17.02 to 44.57) respectively. Women with history of GDM from SA and SEA seem to have higher risk of developing T2DM than women without GDM (RR 13.2, 95%CI 9.52 to 18.29, p Conclusion The conversion to T2DM and prediabetes is very high among women with history of GDM in SA and SEA. This highlights the need for follow-up of GDM women for early identification of dysglycemia and to plan interventions to prevent/delay the progression to T2DM

Prevalence and incidence of hypertension: Results from a representative cohort of over 16,000 adults in three cities of south Asia

Background: Despite high projected burden, hypertension incidence data are lacking in South Asian population. We measured hypertension prevalence and incidence in the Center for cArdio-metabolic Risk Reduction in South Asia (CARRS) adult cohort.Methods: The CARRS Study recruited representative samples of Chennai, Delhi, and Karachi in 2010/11, and socio-demographic and risk factor data were obtained using a standard common protocol. Blood pressure (BP) was measured in the sitting position using electronic sphygmomanometer both at baseline and two year follow-up. Hypertension and control were defined by JNC 7 criteria.Results: In total, 16,287 participants were recruited (response rate=94.3%) and two year follow-up was completed in 12,504 (follow-up rate=79.2%). Hypertension was present in 30.1% men (95% CI: 28.7-31.5) and 26.8% women (25.7-27.9) at baseline. BP was controlled in 1 in 7 subjects with hypertension. At two years, among non-hypertensive adults, average systolic BP increased 2.6mm Hg (95% CI: 2.1-3.1), diastolic BP 0.7mm Hg (95% CI: 0.4-1.0), and 1 in 6 developed hypertension (82.6 per 1000 person years, 95% CI: 80.8-84.4). Risk for developing hypertension was associated with age, low socio-economic status, current alcohol use, overweight, pre-hypertension, and dysglycemia. Risk of incident hypertension was highest (RR=2.95, 95% CI: 2.53-3.45) in individuals with pre-hypertension compared to normal BP. Collectively, 4 modifiable risk factors (pre-hypertension, overweight, dysglycemia, and alcohol use) accounted for 78% of the population attributable risk of incident hypertension.Conclusion: High prevalence and poor control of hypertension, along with high incidence, in South Asian adult population call for urgent preventive measures

Potentially Heterogeneous Cross-Sectional Associations of Seafood Consumption with Diabetes and Glycemia in Urban South Asia.

Aims: In this study, we aimed to estimate cross-sectional associations of fish or shellfish consumption with diabetes and glycemia in three South Asian mega-cities. Methods: We analyzed baseline data from 2010-2011 of a cohort (n = 16,287) representing the population ≥20 years old that was neither pregnant nor on bedrest from Karachi (unweighted n = 4017), Delhi (unweighted n = 5364), and Chennai (unweighted n = 6906). Diabetes was defined as self-reported physician-diagnosed diabetes, fasting plasma glucose ≥126 mg/dL (7.0 mmol/L), or glycated hemoglobin A1c (HbA1c) ≥6.5% (48 mmol/mol). We estimated adjusted and unadjusted odds ratios for diabetes using survey estimation logistic regression for each city, and differences in glucose and HbA1c using survey estimation linear regression for each city. Adjusted models controlled for age, gender, body mass index, waist-height ratio, sedentary lifestyle, educational attainment, tobacco use, an unhealthy diet index score, income, self-reported physician diagnosis of high blood pressure, and self-reported physician diagnosis of high cholesterol. Results: The prevalence of diabetes was 26.7% (95% confidence interval: 24.8, 28.6) in Chennai, 36.7% (32.9, 40.5) in Delhi, and 24.3% (22.0, 26.6) in Karachi. Fish and shellfish were consumed more frequently in Chennai than in the other two cities. In Chennai, the adjusted odds ratio for diabetes, comparing more than weekly vs. less than weekly fish consumption, was 0.81 (0.61, 1.08); in Delhi, it was 1.18 (0.87, 1.58), and, in Karachi, it was 1.30 (0.94, 1.80). In Chennai, the adjusted odds ratio of prevalent diabetes among persons consuming shellfish more than weekly versus less than weekly was 1.08 (95% CI: 0.90, 1.30); in Delhi, it was 1.35 (0.90, 2.01), and, in Karachi, it was 1.68 (0.98, 2.86). Conclusions: Both the direction and the magnitude of association between seafood consumption and glycemia may vary by city. Further investigation into specific locally consumed seafoods and their prospective associations with incident diabetes and related pathophysiology are warranted

Clinico-pathological association of delineated miRNAs in uveal melanoma with monosomy 3/Disomy 3 chromosomal aberrations

PURPOSE: To correlate the differentially expressed miRNAs with clinico-pathological features in uveal melanoma (UM) tumors harbouring chromosomal 3 aberrations among South Asian Indian cohort. METHODS: Based on chromosomal 3 aberration, UM (n = 86) were grouped into monosomy 3 (M3; n = 51) and disomy 3 (D3; n = 35) by chromogenic in-situ hybridisation (CISH). The clinico-pathological features were recorded. miRNA profiling was performed in formalin fixed paraffin embedded (FFPE) UM samples (n = 6) using Agilent, Human miRNA microarray, 8x15KV3 arrays. The association between miRNAs and clinico-pathological features were studied using univariate and multivariate analysis. miRNA-gene targets were predicted using Target-scan and MiRanda database. Significantly dys-regulated miRNAs were validated in FFPE UM (n = 86) and mRNAs were validated in frozen UM (n = 10) by qRT-PCR. Metastasis free-survival and miRNA expressions were analysed by Kaplen-Meier analysis in UM tissues (n = 52). RESULTS: Unsupervised analysis revealed 585 differentially expressed miRNAs while supervised analysis demonstrated 82 miRNAs (FDR; Q = 0.0). Differential expression of 8 miRNAs: miR-214, miR-149*, miR-143, miR-146b, miR-199a, let7b, miR-1238 and miR-134 were studied. Gene target prediction revealed SMAD4, WISP1, HIPK1, HDAC8 and C-KIT as the post-transcriptional regulators of miR-146b, miR-199a, miR-1238 and miR-134. Five miRNAs (miR-214, miR146b, miR-143, miR-199a and miR-134) were found to be differentially expressed in M3/ D3 UM tumors. In UM patients with liver metastasis, miR-149* and miR-134 expressions were strongly correlated. CONCLUSION: UM can be stratified using miRNAs from FFPE sections. miRNAs predicting liver metastasis and survival have been identified. Mechanistic linkage of de-regulated miRNA/mRNA expressions provide new insights on their role in UM progression and aggressiveness