DITHIOCARBAMATE SUBSTITUTED PHENOTHIAZINE DERIVATIVES: IN SILICO EXPERIMENTS, SYNTHESIS, AND BIOLOGICAL EVALUATION

Objective: The present study was designed to study the anticancer activity of a series of novel analogs of phenothiazine with dithiocarbamate as a side chain. Methods: A novel series of derivatives containing dithiocarbamate as a side chain at the tenth position of phenothiazine nucleus were synthesized, characterized by spectral analysis, and evaluated for their antimitotic and antioxidant activity using germinated Bengal gram seeds and 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, respectively. A quantitative estimate of drug-likeness was also performed, which calculated the molecular properties and screened the molecules based on drug-likeness rules. Further, molecular docking study was performed for finding the binding affinity with tubulin protein to rationalize their anticancer activity. Results: The results revealed that the antioxidant activity of compounds 3e, 3g, 3i, 3j and standard Ascorbic acid were 10 mmol, 14 mmol, 16 mmol, 16 mmol and 35 mmol, respectively. Further compounds 3e, 3g, 3h and 3i have shown promising antimitotic activity. Compound 3i (-9 K. Cal/mol) showed the highest binding energies towards tubulin protein when compared to standard drug colchicine (-8.6 K. Cal/mol). Among all, compound 3i showed promising antimitotic and antioxidant activity, which correlated with insilico docking studies. Conclusion: Dithiocarbamate substituted phenothiazine derivatives proved to be encouraging leads as tubulin inhibitors

Sensitivity of Planktonic Cells of Staphylococcus aureus to Elevated Hydrostatic Pressure as Affected by Mild Heat, Carvacrol, Nisin, and Caprylic Acid

Current study investigated effects of elevated hydrostatic pressure exposure in the presence of mild heat and natural antimicrobials against Staphylococcus aureus. Hydrostatic pressure of 350 to 550 MPa with nisin (5000 IU/mL), carvacrol, or caprylic acid (0.5% v/v) were applied for the reduction in four-strain mixture of S. aureus in HEPES buffer at 4 and 40 °C for up to 7 min. Results were statistically analyzed by ANOVA and D-values were additionally calculated using best-fitted linear model. Prior to exposure to treatments at 4 °C, counts of the pathogen were 7.95 ± 0.4 log CFU/mL and were reduced (p \u3c 0.05) to 6.44 ± 0.3 log CFU/mL after 7 min of treatment at 450 MPa. D-value associated with this treatment was 5.34 min (R2 = 0.72). At 40 °C, counts were 8.21 ± 0.7 and 5.77 ± 0.3 log CFU/mL before and after the 7-min treatments, respectively. D-value associated with 40 °C treatment was 3.30 min (R2 = 0.62). Application of the antimicrobials provided additional pathogen reduction augmentation for treatments \u3c 5 min. The results of the current study could be incorporated for meeting regulatory requirements such as Food Code, HACCP, and Preventive Control for Human Food of Food Safety Modernization Act for assuring microbiological safety of products against this prevalent pathogen of public health concern

Metabolic Control Analysis in a Cellular Model of Elevated MAO-B: Relevance to Parkinson’s Disease

We previously demonstrated that spare respiratory capacity of the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (KGDH) was completely abolished upon increasing levels of MAO-B activity in a dopaminergic cell model system (Kumar et al., J Biol Chem 278:46432–46439, 2003). MAO-B mediated increases in H2O2 also appeared to result in direct oxidative inhibition of both mitochondrial complex I and aconitase. In order to elucidate the contribution that each of these components exerts over metabolic respiratory control as well as the impact of MAO-B elevation on their spare respiratory capacities, we performed metabolic respiratory control analysis. In addition to KGDH, we assessed the activities and substrate-mediated respiration of complex I, pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and mitochondrial aconitase in the absence and presence of complex-specific inhibitors in specific and mixed substrate conditions in mitochondria from our MAO-B elevated cells versus controls. Data from this study indicates that Complex I and KGDH are the most sensitive to inhibition by MAO-B mediated H2O2 generation, and could be instrumental in determining the fate of mitochondrial metabolism in this cellular PD model system

A study of alterations in DNA epigenetic modifications (5mC and 5hmC) and gene expression influenced by simulated microgravity in human lymphoblastoid cells

Cells alter their gene expression in response to exposure to various environmental changes. Epigenetic mechanisms such as DNA methylation are believed to regulate the alterations in gene expression patterns. In vitro and in vivo studies have documented changes in cellular proliferation, cytoskeletal remodeling, signal transduction, bone mineralization and immune deficiency under the influence of microgravity conditions experienced in space. However microgravity induced changes in the epigenome have not been well characterized. In this study we have used Next-generation Sequencing (NGS) to profile ground-based “simulated” microgravity induced changes on DNA methylation (5-methylcytosine or 5mC), hydroxymethylation (5-hydroxymethylcytosine or 5hmC), and simultaneous gene expression in cultured human lymphoblastoid cells. Our results indicate that simulated microgravity induced alterations in the methylome (~60% of the differentially methylated regions or DMRs are hypomethylated and ~92% of the differentially hydroxymethylated regions or DHMRs are hyperhydroxymethylated). Simulated microgravity also induced differential expression in 370 transcripts that were associated with crucial biological processes such as oxidative stress response, carbohydrate metabolism and regulation of transcription. While we were not able to obtain any global trend correlating the changes of methylation/ hydroxylation with gene expression, we have been able to profile the simulated microgravity induced changes of 5mC over some of the differentially expressed genes that includes five genes undergoing differential methylation over their promoters and twenty five genes undergoing differential methylation over their gene-bodies. To the best of our knowledge, this is the first NGS-based study to profile epigenomic patterns induced by short time exposure of simulated microgravity and we believe that our findings can be a valuable resource for future explorations

SDOCT Imaging to Identify Macular Pathology in Patients Diagnosed with Diabetic Maculopathy by a Digital Photographic Retinal Screening Programme

INTRODUCTION: Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT) clinic to identify macular pathology in this subset of patients. METHODS: A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1) and surrogate markers for diabetic macular edema (M1) attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months. RESULTS: From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009). We analyzed images from 311 patients' SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist. DISCUSSION: This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1) and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1) have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population

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

A Study of Serum Paraoxonase And Malondialdehyde in Pregnancy Induced Hypertension

Background: Pregnancy induced hypertension (PIH) is one of the leading cause of maternal and fetal mortality and morbidity. Treatment is symptomatic till date. Early identification and monitoring of disease progression could prevent adverse complications. Oxidative stress is considered as one of the etiological factor resulting in lipid peroxidation. Malondialdehyde (MDA) is formed as an end product of lipid peroxidation. It causes oxidation of LDL and eventually leads to membrane damage. This could be an indicator of oxidative stress. Paraoxonase (PON1) is a HDL associated esterase enzyme which exhibit antioxidative property by preventing lipoproteins from oxidative damage. Aim& Objective: The objective of the present study was to evaluate serum MDA and PON1 in normotensive pregnant women and in women with PIH and their role in predicting the severity of PIH. Materials and methods:  A case control study was done, in which 50 women were normotensive pregnant women (Group 1) and 50 were women diagnosed with PIH (Group 2). Group 2 was further divided into mild (n=28) and severe PIH(n=22). Serum MDA levels and PON1 activity were estimated. Data was analysed using Graph pad prism version 7.0. Unpaired t-test was performed to test the significance of difference between the two groups and the subgroups.Results: serum MDA levels were significantly elevated in Group 2(5.087 ± 1.245nmol/ml) when compared to Group 1(2.812 ± 0.7395nmol/ml). In subgroups, serum MDA levels were significantly higher in severe PIH than in mild PIH (P < 0.001). Serum PON1 activity was significantly decreased in Group 2(225.3 ± 39.65IU/L) when compared to Group 1(335 ± 71.69IU/L). Also, PON1 levels were significantly decreased in severe PIH than in mild PIH with P < 0.001.Conclusion: Serum MDA was elevated in PIH indicating increased oxidative stress. PON1 activity was decreased resulting in oxidant and antioxidant imbalance. Thus, serum MDA and PON1 can play a significant role in the pathogenesis of PIH and they can aid in detecting the severity of the disease. &nbsp