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Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi.
Amaral, M, Varela, MT, Kant, R, Christodoulides, M, Fernandes, JPS, Tempone, AG
Life (Basel, Switzerland). 2023;(3)
Abstract
Chagas disease is an endemic tropical disease caused by the protozoan Trypanosoma cruzi, which affects around 7 million people worldwide, mostly in development countries. The treatment relies on only two available drugs, with severe adverse effects and a limited efficacy. Therefore, the search for new therapies is a legitimate need. Within this context, our group reported the anti-Trypanosoma cruzi activity of gibbilimbol B, a natural alkylphenol isolated from the plant Piper malacophyllum. Two synthetic derivatives, LINS03018 (1) and LINS03024 (2), demonstrated a higher antiparasitic potency and were selected for mechanism of action investigations. Our studies revealed no alterations in the plasma membrane potential, but a rapid alkalinization of the acidocalcisomes. Nevertheless, compound 1 exhibit a pronounced effect in the bioenergetics metabolism, with a mitochondrial impairment and consequent decrease in ATP and reactive oxygen species (ROS) levels. Compound 2 only depolarized the mitochondrial membrane potential, with no interferences in the respiratory chain. Additionally, no macrophages response of nitric oxide (NO) was observed in both compounds. Noteworthy, simple structure modifications in these derivatives induced significant differences in their lethal effects. Thus, this work reinforces the importance of the mechanism of action investigations at the early phases of drug discovery and support further developments of the series.
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The Impact of Mobile Health Interventions on Antenatal and Postnatal Care Utilization in Low- and Middle-Income Countries: A Meta-Analysis.
Yadav, P, Kant, R, Kishore, S, Barnwal, S, Khapre, M
Cureus. 2022;(1):e21256
Abstract
Despite many efforts, the utilization of full antenatal and postnatal care remains a significant concern in low- and middle-income countries (LMICs). We planned to retrieve the relevant literature and pooled the data for meta-analysis to evaluate the impact of mobile health (mHealth) intervention on antenatal and postnatal care utilization in low- and middle-income countries. We searched the literature through major electronic databases such as PubMed, MEDLINE, Embase, Cochrane, Scopus, CINAHL, Clinical key, Google Scholar, and Ovid with selected keywords and explored the reference list of articles. Meta-analysis was performed using the RevMan software version 5.4; p-value < 0.05 was considered statistically significant. The effect of variables was measured in odds ratio (OR) with a fixed-effects model. Six published interventional studies were selected as per the eligibility and participants, intervention, comparison, and outcome (PICO) framed for systematic review and meta-analysis. The search was restricted to articles in the English language, articles published online, and preprinted articles until September 2020. Outcome variables include antenatal and postnatal care utilization by pregnant and delivered mothers. The results have been presented in the form of a forest plot. The findings of this meta-analysis depicted the significant increase in four or more antenatal care (ANC) attendance (OR = 1.81, 95% confidence interval (CI) = 1.49-2.19), tetanus toxoid (TT) immunization (OR = 1.63, 95% CI = 1.17-2.27), compliance to iron supplementation (OR = 1.88, 95% CI = 1.18-3.00), and postnatal care attendance (OR = 2.54, 95% CI = 2.15-2.99) among those pregnant mothers who received mHealth intervention compared with the control group. This meta-analysis creates evidence for the effectiveness of mHealth with pooled data of interventional studies with limited sample sizes. Technology is changing, but even with limited support such as short messaging service (SMS), there was an improvement in antenatal and postnatal service utilization. This meta-analysis concluded that mHealth has the potential to increase the utilization of antenatal and postnatal care compared to standard care, although the level of evidence is moderate.
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3.
Effect of non-pharmacological interventions on adults with cardiovascular risk in a rural community.
Kumar, S, Kant, R, Yadav, P, Kumar, B
Journal of family medicine and primary care. 2022;(9):5521-5526
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Abstract
BACKGROUND Non-communicable diseases (NCDs) are the leading cause of morbidity and mortality worldwide, with three-fourth of deaths occurring in low- and middle-income countries (LMICs) like India. Currently, three out of the top five causes of morbidity and mortality in the country are NCDs. OBJECTIVE This study evaluated the impact of non-pharmacological interventions as a comprehensive approach toward adults with cardiovascular risk in Indian rural communities. MATERIAL AND METHODS It was a quasi-experimental study conducted in Rishikesh, a holy city of Uttarakhand known as the world's yoga capital at the foothills of Himalaya. Out of 87 villages, four villages were randomly selected. Eighty-eight participants were enrolled (22 from each village and household). It was a multi-stage random sampling. All the participants with cardiovascular risk and age >30 years were recruited. Pregnant, severely ill, and unwilling to consent were excluded. Non-pharmacological intervention as a comprehensive approach, including yoga, meditation, mental health counseling, dietary counseling, tobacco, and alcohol cessation counseling has been provided to cardiovascular risk participants. RESULTS Data of 76 participants were analyzed as the per-protocol analysis method. The drop-out rate was 13.63%. Male and female participants were 52 (68.4%) and 24 (31.6%) in number. Mean age of the participants was 55.28 ± 13.64 years. Diastolic blood pressure or DBP (P = 0.017*), systolic blood pressure or SBP (P = 0.008**), waist circumference (WC) (P = 0.000**), waist-to-hip ratio (P = 0.000**) and waist-to-height ratio (P = 0.000**) significantly improved in the post intervention group. CONCLUSION Non-pharmacological interventions as a comprehensive approach can significantly reduce modifiable risk factors for cardio-metabolic disease.
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Maturity-Onset Diabetes of the Young: Rapid Evidence Review.
Kant, R, Davis, A, Verma, V
American family physician. 2022;(2):162-167
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Abstract
Maturity-onset diabetes of the young (MODY) is a non-insulin-dependent form of diabetes mellitus that is usually diagnosed in young adulthood. MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14) based on the causative genetic mutation. Subtypes 1 to 3 account for 95% of cases. MODY is often misdiagnosed as type 1 or 2 diabetes and should be suspected in nonobese patients who have diabetes that was diagnosed at a young age (younger than 30 years) and a strong family history of diabetes. Unlike those with type 1 diabetes, patients with MODY have preserved pancreatic beta-cell function three to five years after diagnosis, as evidenced by detectable serum C-peptide levels with a serum glucose level greater than 144 mg per dL and no laboratory evidence of pancreatic beta-cell autoimmunity. Patients with MODY1 and MODY3 have progressive hyperglycemia and vascular complication rates similar to patients with types 1 and 2 diabetes. Lifestyle modification including a low-carbohydrate diet should be the first-line treatment for MODY1 and MODY3. Sulfonylureas are the preferred pharmacologic therapy based on pathophysiologic reasoning, although clinical trials are lacking. Patients with MODY2 have mild stable fasting hyperglycemia with low risk of diabetes-related complications and generally do not require treatment, except in pregnancy. Pregnant patients with MODY may require insulin therapy and additional fetal monitoring for macrosomia.
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Theory for nanoscale curvature induced enhanced inactivation kinetics of SARS-CoV-2.
Kant, R, Mishra, GK, Neha,
Nanoscale. 2022;(14):5600-5611
Abstract
We develop a novel theory for the nanomorphology dependent outer sphere heterogeneous electron transfer (ET) rate constant () based on an energy level alignment approach. is modelled through the activation free energy, which is a product of the water monolayer covered metal work function (WF) and the fractional electronic charge exchanged at the transition state (attained through the alignment of the metal Fermi and HOMO/LUMO energy levels of the electroactive species). The theory shows that is an exponentially increasing and decreasing function of the mean curvature in concave and convex nanomorphologies, respectively, for electroactive species or proteins involving their HOMO energy. For the specific spike protein of SARS-CoV-2, we have estimated the half lifetime (t1/2) and degree of inactivation as a function of the metal WF, nanostructure mean curvature, spike protein HOMO energy, and the environmental temperature (T). By varying the metal from Ag to Au, t1/2 is reduced from 7 h to 4 min, respectively. The reduction in the copper nanoparticle size from 50 to 5 nm increases the degree of inactivation from 60 to 99.6% (with a reduction factor of 10 in t1/2). Similarly, the increase in T from 10 °C to 65 °C causes a 100 times lowering of the t1/2 and t99.9% of SARS-CoV-2 on Cu metal. The theory predicts that involving the HOMO energy level of a protein follows the surface nanostructure shape dependent order as follows: spherical nanoparticle > cylindrical nanorod > cylindrical nanopore > spherical nanocavity, while the opposite trend is observed in the case of the LUMO energy level participation. Finally, the theory shows agreement with the reported experimental data of the degree of inactivation of SARS-CoV-2 on Ag and Cu nanoparticles.
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Impact of Cassia Bark Consumption on Glucose and Lipid Control in Type 2 Diabetes: An Updated Systematic Review and Meta-Analysis.
Mandal, A, Sharma, S, Rani, R, Ranjan, S, Kant, R, Mirza, A
Cureus. 2021;(7):e16376
Abstract
Control of diabetes is a constant challenge and natural remedies are being searched along with modern medicine. The effectiveness of cinnamon in managing it lacks consensus. Besides this, earlier trials had a variant in the type of product they used, quantity, duration, the form of molecules, etc. So, we aimed to measure the impact of cassia ground bark powder consumption, 1-2 gm/day for 90 days, in lowering plasma glucose and lipids among those with type 2 diabetes. The authors searched the PubMed, Medline, Embase, CINAHL, Clinical Key, Ovid, and Scopus databases and the Cochrane Central Register (last search December 30, 2020) with the MeSH terms and keywords of cinnamon, cassia cinnamon, Chinese cinnamon, and type 2 diabetes mellitus to conclude the effects of cassia cinnamon on diabetes based on the evidence of human clinical trials that reported at least one of the following: glycosylated hemoglobin (HbA1C), fasting blood glucose, total cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Weighted mean differences were calculated by using the random-effect model of RevMan software (The Cochrane Collaboration, London, UK), and the pooled analysis found an insignificant reduction of the outcome variable (p>0.05).
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Effect of Vitamin B6, B9, and B12 Supplementation on Homocysteine Level and Cardiovascular Outcomes in Stroke Patients: A Meta-Analysis of Randomized Controlled Trials.
Kataria, N, Yadav, P, Kumar, R, Kumar, N, Singh, M, Kant, R, Kalyani, V
Cureus. 2021;(5):e14958
Abstract
Globally, stroke is the fifth-most leading cause of mortality and also the third leading cause of disability. This study aimed to assess the effect of vitamin B6, B9, and B12 supplementation on homocysteine level, risk of stroke, cardiovascular disorders, and vascular death among stroke participants. An extensive literature search was done through PubMed, Medline, Embase, and Clinical key database from 1 January 2000 to 1 January 2020. Effect of vitamin B (B6, B9, and B12) supplementation on homocysteine was assessed with a mean difference in both vitamin and placebo groups. Risk ratio (RR) was calculated for determining the risk of stroke, major cardiovascular disorder, and vascular death by using a fixed-effect model. A total of eight trials with 8513 participants were included for the final analysis. Vitamin B supplementation intervention was found to have a significant benefit in reducing homocysteine in stroke patients (mean difference -3.84; p<0.00001). The intervention of vitamin B supplementation showed a significant risk reduction of 11% for combined risk of stroke, myocardial infarction, and vascular death among stroke patients, 13% for stroke and 17% for vascular death, whereas no beneficial effect was seen for cardiovascular disorders. This meta-analysis demonstrated up-to-date evidence on the beneficial effect of vitamin B supplementations in reducing homocysteine and preventing the combined risk of stroke, myocardial infarction, and vascular death among stroke patients.
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The Outbreaks of Acute Encephalitis Syndrome in Uttar Pradesh, India (1978-2020) and Its Effective Management: A Remarkable Public Health Success Story.
Srivastava, N, Deval, H, Mittal, M, Kant, R, Bondre, VP
Frontiers in public health. 2021;:793268
Abstract
INTRODUCTION Acute encephalitis syndrome (AES) is a major public health enigma in India and the world. Uttar Pradesh (UP) is witnessing recurrent and extensive seasonal AES outbreaks since 1978. Government of India and UP state government have devised various mitigation measures to reduce AES burden and AES associated mortality, morbidity and disability in Uttar Pradesh. The aim of this study was to describe the public health measures taken in order to control seasonal outbreaks of AES in UP between 1978 and 2020. METHODS We used literature review as a method of analysis, including the Indian government policy documents. This review utilized search engines such as PubMed, Google Scholar, Research Gate, Cochrane, Medline to retrieve articles and information using strategic keywords related to Acute Encephalitis Syndrome. Data was also collected from progress reports of government schemes and websites of Indian Council of Medical Research (ICMR), National Vector Borne Disease Control Programme (NVBDCP) and Integrated Disease Surveillance Programmes (IDSP). RESULTS The incidence of AES cases in UP have declined from 18.2 per million population during 2005-2009 to 15 per million population during 2015-2019 [CI 12.6-20.6, P-value < 0.001] and case fatality rate (CFR) reduced from 33% during 1980-1984 to 12.6% during 2015-2019 [CI 17.4-30.98, P-value < 0.001]. AES incidence was 9 (2019) and 7 (2020) cases per million populations respectively and CFR was 5.8% (2019) and 5% (2020). This decline was likely due to active surveillance programs identifying aetiological agents and risk factors of AES cases. The identified etiologies of AES include Japanese encephalitis virus (5-20%), Enterovirus (0.1-33%), Orientia tsutsugamushi (45-60%) and other viral (0.2-4.2%), bacterial (0-5%) and Rickettsial (0.5-2%) causes. The aggressive immunization programs against Japanese encephalitis with vaccination coverage of 72.3% in UP helped in declining of JE cases in the region. The presumptive treatment of febrile cases with empirical Doxycycline and Azithromycin (EDA) caused decline in Scrub Typhus-AES cases. Decrease in incidence of vector borne diseases (Malaria, Dengue, Japanese Encephalitis and Kala Azar) i.e., 39.6/100,000 population in 2010 to 18/100,000 population in 2017 is highlighting the impact of vector control interventions. Strengthening healthcare infrastructure in BRD medical college and establishment of Encephalitis Treatment Centre (ETC) at peripheral health centres and emergency ambulance services (Dial 108) reduced the referral time and helped in early treatment and management of AES cases. The AES admissions increased at ETC centres to 60% and overall case fatality rate of AES declined to 3%. Under clean India mission and Jal Jeevan mission, proportion of population with clean drinking water increased from 74.3% in 1992 to 98.7% in 2020. The proportion of household having toilet facilities increased from 22.9% in 1992 to 67.4% in 2020. Provisions for better nutritional status under state and national nutrition mission helped in reducing the burden of stunting (52%) and wasting (53.4%) among under five children in 1992 to 38.8% (stunting) and 36.8% (wasting) in year 2018. These factors have all likely contributed to steady AES decline observed in UP. CONCLUSION There is a recent steady decline in AES incidence and CFR since implementation of intensive AES surveillance system and JE immunization campaigns which is highlighting the success of interventions made by central and state government to control seasonal AES outbreaks in UP. Currently, AES incidence is 9 cases per million population (in year 2019) and mortality is 5.8%.
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Efficacy of DPP-4 inhibitors and SGLT2 inhibitors compared to sulphonylureas in adult patients with diabetes with low c-peptide levels with or without anti-GAD65 antibody positivity.
Sudan, A, Kalra, A, Mirza, AA, Kant, R
Diabetes & metabolic syndrome. 2021;(4):102197
Abstract
BACKGROUND AND AIMS Latent Autoimmune Diabetes of Adulthood (LADA) is different from type 2 diabetes. Present treatment protocols do not reflect that. DPP-4 and SGLT2 inhibitors have changed therapy. DPP-4 inhibitor use has shown delayed decline in beta-cell reserve in LADA. We studied patients with low c-peptide to assess relationship between c-peptide and anti-GAD65 antibody levels and compare DPP-4 inhibitors with SGLT2 inhibitors and sulphonylureas. METHODS The study was an open-label trial conducted in 156 participants with low c-peptide (<0.8 ng/mL), age > 25 years, recently diagnosed diabetes with HBA1c ≥ 6.5%. Participants were enrolled into three arms: Group A received sulphonylureas + metformin, Group B received DPP-4 inhibitors + metformin, and Group C received SGLT-2 inhibitors + metformin. Serum anti-GAD-65 antibodies were assessed using sandwich ELISA. Participants were assessed on enrolment and after three months of dual pharmacotherapy. RESULTS The three arms were comparable on enrolment. 52% of participants with low c-peptide had high anti-GAD65 antibody titers. Significant differences were observed after three months - DPP-4 inhibitors reduced HbA1c by 1.1 ± 0.3%, compared to SGLT2 inhibitors (0.8 ± 0.13%) and sulphonylureas (0.7 ± 0.3%) CONCLUSION DPP-4 inhibitors appear to provide better glycemic control than alternate therapeutic options in patients with low serum c-peptide.
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Role of gut microbiota in cardiovascular diseases.
Novakovic, M, Rout, A, Kingsley, T, Kirchoff, R, Singh, A, Verma, V, Kant, R, Chaudhary, R
World journal of cardiology. 2020;12(4):110-122
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Plain language summary
Cardiovascular disease (CVD) is the leading cause of death globally. CVD risk factors such as aging, obesity, dietary patterns and a sedentary lifestyle induce changes in the gut microbiota. The resulting dysbiosis is associated with intestinal inflammation leading to reduced integrity of the gut barrier. When this happens, certain components enter the circulation which may facilitate the development of CVD. Looking at the gut microbiota as a locus of intervention is therefore a novel and relevant avenue for future research. This article reviews the normal function and composition of the gut microbiome, the mechanisms leading to reduced gut barrier integrity (leaky gut syndrome), its link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention. The alteration of the gut microbiome is a potential therapeutic target in managing CVD. However, further experiments are needed to see if the effects observed in animal studies can be translated to humans.
Abstract
The human gut is colonized by a community of microbiota, primarily bacteria, that exist in a symbiotic relationship with the host. Intestinal microbiota-host interactions play a critical role in the regulation of human physiology. Deleterious changes to the composition of gut microbiota, referred to as gut dysbiosis, has been linked to the development and progression of numerous diseases, including cardiovascular disease (CVD). Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Most CVD risk factors, including aging, obesity, dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis. Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier, which in turn increases circulating levels of bacterial structural components and microbial metabolites, including trimethylamine-N-oxide and short-chain fatty acids, that may facilitate the development of CVD. This article reviews the normal function and composition of the gut microbiome, mechanisms leading to the leaky gut syndrome, its mechanistic link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention. As CVD is the leading cause of deaths globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research.