Alterations in reproductive hormone levels among farm women and their children occupationally exposed to organophosphate pesticides.

Exposure to organophosphorus pesticides may lead to reproductive hormone dysfunction. Even among children of pubertal age, the exposure may disrupt growth, development, and maturation. The present study was conducted to assess the alterations in the reproductive hormone levels, among farm women (24-45 years, n = 129) and their children (9-12 years, n = 66 and 13-15 years, n = 63) and compare them with age and gender-matched control group [women (n = 134) and their children (9-12 years, n = 69 and 13-15 years, n = 65)] belonging to villages of Ranga Reddy District, Telangana, India. Blood pesticide residues and reproductive hormone (follicle-stimulating hormone-FSH, luteinizing hormone-LH, estradiol, and testosterone) levels were analyzed. The detected pesticide residues (ng/mL) were chlorpyrifos, diazinon, malathion, and monocrotophos among the farm women, while the farm children of 9-12 years age groups were detected with residues of chlorpyrifos, diazinon, malathion, monocrotophos, and phosalone. The farm children of 13-15 years age group were detected with residues of chlorpyrifos, diazinon, malathion, monocrotophos, and phosalone. However, no residues were detected among the samples of women and children of control groups. Significantly lower levels of FSH (in follicular phase) were observed among the farm women than the control group. Significant alterations in FSH and LH levels of farm women were observed with a significant correlation between the chlorpyrifos residue levels and estradiol hormone. While no such significant change in hormone levels was observed among the farm children of both age groups of both genders. Though the present study showed pesticide-induced alterations in hormone levels among the farm women, research is needed to elucidate the critical windows during which exposure may adversely affect the reproductive system in children at the pubertal stage and women at reproductive age and subsequently their progeny's health at a later stage of life.

Understanding the early host immune response against Mycobacterium tuberculosis.

Generation of immune response is a crucial activity of host defense against any microbial attack. When facultative organism Mycobacterium tuberculosis (MTB) invades its host, various pathways are activated in the host to mount immune responses against invading pathogen for nullifying its actions. During this host-pathogen interaction, interplay of complex network of cytokines and chemokines, initiation of phagocytosis, and formation of granuloma play an important role in containing MTB infections at host side. Simultaneously, MTB also evolves a plethora of specialized mechanisms to evade the host's killing cascades on other side, and during this bilateral cross-talk, many mycobacterial products play crucial role in survival of MTB inside the host. Hence, a better understanding of these phenomena is necessary not only for getting clear picture of pathogenesis of MTB, but also for developing effective, preventive, and therapeutic modalities against the pathogen. With some suggestions on future work, an insight into diversity of immune response of host against MTB was provided in the present review.

How homeopathic medicine works in cancer treatment: deep insight from clinical to experimental studies.

OBJECTIVE: In the current scenario of medical sciences, homeopathy, the most popular system of therapy, is recognized as one of the components of complementary and alternative medicine (CAM) across the world. Despite, a long debate is continuing whether homeopathy is just a placebo or more than it, homeopathy has been considered to be safe and cost-effectiveness therapeutic modality. A number of human ailments ranging from common to serious have been treated with homeopathy. However, selection of appropriate medicines against a disease is cumbersome task as total spectrum of symptoms of a patient guides this process. Available data suggest that homeopathy has potency not only to treat various types of cancers but also to reduce the side effects caused by standard therapeutic modalities like chemotherapy, radiotherapy or surgery. Although homeopathy has been widely used for management of cancers, its efficacy is still under question. In the present review, the anti-cancer effect of various homeopathic drugs against different kinds of cancers has been discussed and future course of action has also been suggested.

Small Heat Shock Protein16.3 of Mycobacterium tuberculosis: After Two Decades of Functional Characterization.

Small heat shock proteins (sHSPs) are one of the five families of proteins acting as molecular chaperone. sHSPs possess a universally conserved alpha-crystallin domain, hence, also known as alpha-crystallin family. Mycobacterium tuberculosis (MTB) is an etiological agent of tuberculosis, a disease claiming million of lives every year across the world. MTB has two sHSPs: sHSP16.3 (a 16.3 kDa protein) and Acr2 (a 17.8 kDa protein). Of these, sHSP16.3 has been reported to be crucial for survival of MTB during prolonged period of dormancy, in addition to indispensable role in its growth, virulence and cell wall thickening. Additionally, this mycobacterial protein is also beneficial for host as well. Due to strong immunogenic properties and consistent presence in patients sera, sHSP16.3 has largely been implicated in vaccine development and diagnosis of latent and active infections of MTB in the clinical cases of TB. Recently, our study provided the substantial evidence to exploit this mycobacterial protein as a good drug target for developing novel therapeutic intervention. In the present review, a comprehensive analysis of various attributes of sHSP16.3 has been done and major gaps in area have been highlighted for future course of action.

Curcumin Suppresses the Production of Pro-inflammatory Cytokine Interleukin-18 in Lipopolysaccharide Stimulated Murine Macrophage-Like Cells.

Curcumin is a major bioactive compound of turmeric that exerts its anti-inflammatory effects by suppressing the many pro-inflammatory cytokines and chemokines in a number of cell types and pathologic conditions. Interleukin-18 (IL-18) is a novel pro-inflammatory cytokine which plays an important role not only in generating Th1 responses but also in inducing severe inflammatory reactions. As curcumin induced inhibition of IL-18 production in keratinocytes and mice is well known, effect of curcumin on IL-18 release in macrophages remains unknown. Hence, this present study has been designed to evaluate the effect of curcumin on IL-18 production and necrotic cell death in murine macrophages-like cells treated with or without lipopolysaccharide (LPS). The IL-18 secretion in cell culture supernatants was assayed by enzyme-linked immunosorbent assay and cytotoxicity was determined by lactate dehydrogenase release assay. Our results demonstrate that curcumin significantly inhibited the production of pro-inflammatory cytokine IL-18 in E.coli LPS stimulated murine macrophage-like cells RAW264.7 in a concentration-dependent manner. Interestingly, curcumin had no cytotoxic effect on murine macrophage-like cells. Our findings suggest that curcumin may be used as a potential therapeutic agent for the treatment of inflammatory diseases.

Prevalence, risk factors and genotype distribution of human papillomavirus infection among women with and without invasive cervical cancer: Findings from a hospital-based study in Bihar, India.

Background Human papillomavirus (HPV) infection is largely responsible for the development of invasive cervical cancer (ICC). Its prevalence, risk factors and genotype distribution among women residing in Bihar (third most populous Indian state) with and without ICC are not well known. Methods In this hospital-based study, we followed up 1439 participants with cytology and HPV report. HPV detection and genotyping were performed using the TaqMan-based real-time PCR method. Clinical and sociodemographic data were collected and analysed using statistical methods. Results The overall prevalence of HPV infection was 37.3% (537/1439) and 11 different types of HPV genotypes were observed. Higher HPV positivity was found in premalignant, intraepithelial and invasive malignant lesions of the cervix; 73.8% (93/126) of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) and high-grade squamous intraepithelial lesions (HSIL) and 93.4% (114/122) of invasive malignancies were infected with HPV in comparison to only 26.1% (245/938) of negative for intraepithelial lesion or malignancy (NILM) cytology. Moreover, HPV was found in 95.2% (236/248) of histologically confirmed cases of carcinoma cervix. HPV16 and HPV18 infections were reported in 78.2% (194/248) and 8.9% (22/248), respectively. The remaining patients had infection with other high-risk strains/co-infection with multiple strains or were HPV-negative. Various socio-demographic factors including women >50 years of age, >10 years of marriage and high parity were significantly associated with HPV infection. Conclusion Our data suggest that HPV16 infection may be the major cause for ICC among women residing in Bihar. Our findings may serve as a baseline for developing an appropriate screening and vaccination strategy for Bihar.

Lysosomal storage disorders: from biology to the clinic with reference to India.

Lysosomal storage disorders (LSDs) are a group of seventy different metabolic storage diseases due to accumulation of substrate mainly in the form of carbohydrate, lipids, proteins, and cellular debris. They occur due to variant in different genes that regulate lysosomal enzymes synthesis, transport, and secretion. In recent years, due to an increased availability of various therapies to treat these disorders, and increased diagnostic tools, there has been an escalated awareness of LSDs. Due to heterogeneous population and various social reasons, India is likely to have a high frequency of LSDs. Therefore, to understand the burden of various LSDs, its molecular spectrum, and understanding the phenotype-genotype correlation, Indian Council of Medical Research (ICMR) and Department of Health Research (DHR), Government of India had set up a task force in the year 2015. It has resulted in identifying common LSDs, and founder variant for some of the storage disorders and molecular spectrum of various LSDs across the country. This review describes in detail the spectrum of LSDs, its molecular epidemiology and prevention in context to Indian population.

Genetic Polymorphism in Xenobiotic Metabolising Genes and Increased Oxidative Stress among Pesticides Exposed Agricultural Workers Diagnosed with Cancers.

BACKGROUND: Oxidative stress combined with nullity of xenobiotic metabolizing GSTT1/GSTM1/CYP2E1 genes may increase the susceptibility of agricultural workers to adverse health effects including cancer. The present study was conducted to determine; the prevalence of polymorphisms in GSTM1, GSTT1 and CYP2E1 genes, serum 8-hydroxy-2'-deoxygunosine levels, and the role of these markers in risk of cancer among agricultural workers occupationally exposed to pesticides. METHODS: A total of 360 participants, of which 180 belonging to farming group diagnosed with leukemia (n=60), lymphoma (n=60) and breast cancers (n=60), 90 in non-farming group diagnosed with similar cancers and the other 90 as healthy controls with neither history of occupational exposure nor diagnosed with any type of cancers were recruited. Following the questionnaire survey, serum 8-OHdG and genetic polymorphisms in the three genes were determined using ELISA and PCR methods respectively. RESULTS: The results of the study revealed that farm workers carrying GSTT1 null genotype had increased risk for lymphoma (OR = 5.34; 95% CI = 1.80-15.82) and breast cancer (OR=4.04; 95% CI = 1.24-13.07). For farm workers carrying GSTM1 null genotype, the risk was six-fold for breast cancer (OR = 6.88; 95% CI =1.88-25.99). Further, there found a significant difference between 8-OHdG and nullity of CYP2E1 among the farm workers diagnosed with leukemia. CONCLUSION: The findings of the present study suggest that the polymorphisms in detoxifying genes among farm workers occupationally exposed to pesticides and the oxidative stress may likely be responsible for triggering the mechanism of malignancy.

Natural Metabolite Ursolic Acid as an Inhibitor of Dormancy Regulator DosR of Mycobacterium tuberculosis: Evidence from Molecular Docking, Molecular Dynamics Simulation and Free Energy Analysis.

BACKGROUND: DosR is a transcriptional regulator of Mycobacterium tuberculosis (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB. OBJECTIVE: We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico approaches. METHODS: The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB. RESULTS: Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature. CONCLUSION: The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.

Knowledge, attitude and practices related to pesticide usage among farmers: Findings from a hospital based cross-sectional study.

BACKGROUND: In India, where agriculture is the prime occupation among the rural population, farmers are extensively using pesticides in crop production without taking adequate precautions. OBJECTIVE: The current study aimed to examine pesticide usage patterns, usage of personal protective equipment (PPE), knowledge on pesticide toxicity, and attitude towards occupational safety among farmers diagnosed with leukaemia (n = 60), lymphoma (n = 33), and breast cancer (n = 30) visiting a tertiary cancer care hospital in Hyderabad, India. METHODS: Face-to-face interviews were conducted using a pre-tested questionnaire and the data collected were analysed with statistical software SPSS 23. RESULTS: The survey revealed that the participants had an average of 19.6 years of farming experience and women were predominantly involved in the mixing of pesticides and other agricultural work apart from spraying. All of them were not using any PPE and the majority of them did not have any knowledge on the route of exposure, toxicity symbols, and safe handling of pesticides. Statistical analysis showed no significant association between educational status and knowledge, attitude and practices (p > 0.05). CONCLUSION: Even though the majority of the farmers were educated, their lack of adequate knowledge on pesticides had enabled them to adopt risky behaviours in handling and storage of pesticides. There is a need for continuous training programs for farmers to promote awareness and minimize the hazards of occupational exposure.

Residual Dialkyl Phosphate Metabolite Concentrations of Organophosphate Pesticides Among Indian Farmworkers: Implication of Exposure and Hazard Assessment.

OBJECTIVE: Biomonitoring of urinary dialkyl phosphate (DAP) metabolites, a sensitive biomarker to assess pesticides exposure and also to study the impact of the use of personal protective equipment (PPE). METHODS: A preintervention-postintervention study to biomonitor dimethylphosphate, diethylphosphate, diethylthiophosphate, and diethyl-dithiophosphate using liquid chromatography with tandem mass spectrometry among Indian farmworkers (n = 120). RESULTS: Dimethylphosphate was detected in all samples at a mean concentration of 74.91 µg · L -1 (17.616 µg · g -1 creatinine), whereas diethylthiophosphate and diethyl-dithiophosphate were detected in 88% and 82% of samples, respectively, among farmworkers who adopted unsafe pesticide-handling practices. Intervention studies showed a significant reduction in the urinary DAP metabolites detected among the farmworkers using PPE provided to them ( P < 0.01). CONCLUSIONS: Study confirms the exposure to pesticides among farmworkers and highlights the importance of the use of PPE to minimize exposure.

Mitigation of pesticide residue levels in the exposed dermal regions of occupationally exposed farmworkers by use of personal protective equipment.

Unsafe pesticide handling practices with the limited use of personal protective equipment (PPE) by the Indian farming groups lead to an increased risk of exposure to pesticides. Therefore, a community-based follow-up study based on dosimeters, wipes, and hand-wash technique was carried out to evaluate the dermal exposure to pesticides and to analyze the impact of the usage of PPE on minimizing the exposure among the farmworkers of Rangareddy district, Telangana, India. Risk in terms of hazard quotient (HQ), hazard index (HI), and safety analysis as margins of safety was assessed. Farmworkers averaged 18 years of farming experience and showed resistance to adopting good agricultural practices. Ten pesticide residues were detected in concentrations ranging from 0.000 to 246 mg ml-1 in hand-wash, 0.000 to 198.33 ng cm-2 in patch dosimeter, and 0.000 to 1,740 ng cm-2 in wipe samples collected from farmworkers not using PPE. The second phase includes the intervention study results that revealed a significant reduction both in the concentrations and the number of pesticide residues detected in the hand-wash, patch, and wipe samples of the farmworkers who have used the PPE provided to them (p < 0.01). Furthermore, the probabilistic health risk assessment in terms of the HQ values ranged from 0.02 to 1029.82, and HI was >1, suggesting the non-carcinogenic risks associated with dermal exposure to pesticides among them. Additionally, the safety risk assessment in terms of the margin of safety suggests that they follow risky handling practices. The study confirms that farmworkers are exposed to pesticides and emphasizes the significance of using PPE in reducing the risk.

The impact of the use of personal-protective-equipment on the minimization of effects of exposure to pesticides among farm-workers in India.

Introduction: Although excessive use of pesticides and unsafe agricultural practices may contribute to numerous intoxications, the role of PPE (personal-protective-equipment) in the minimization of toxicological effects due to pesticide exposure has not been addressed so far. The present study aimed to assess the impact of the use of PPE on the minimization of effects of exposure to pesticides among farm-workers. Methods: A community-based follow-up study with questionnaire-based survey and field observations was undertaken among farm-workers (n = 180) of Rangareddy district, Telangana, India. Biomarkers of exposure such as cholinesterase activity, inflammatory markers (TNF-α, IL-1ß, IL-6, cortisol, and hs-C reactive protein), nutrients (vitamins A, E), liver function (total protein and A/G ratio, AST and ALT levels) were investigated in the laboratory by following the standard protocols. Results: Farm-workers who had a mean farming exposure of 18 years of and who neither followed safe pesticide handling practices nor used PPE and also showed reluctance to obey good agricultural practices (GAPs). Inhibition of AChE (acetylcholine esterase) with increased inflammation was found among farm-workers as compared to their respective normal values when they have not used PPE. Linear regression statistical analysis revealed a profound effect on inhibition in the AChE activity and various inflammatory markers with the increase in the duration of pesticide exposure. Further, there was no effect of the duration of pesticide exposure on the levels of vitamins A, E, ALT, AST, total protein, and A/G ratio. Further, intervention studies carried out on the use of PPE provided (commercially available and cost-effective) for 90 days showed a significant reduction in the biomarker levels (p < 0.01). Conclusion: This study demonstrated the importance of the use of PPE during pesticide applications and other agricultural tasks to minimize pesticide-associated adverse health effects.

Organophosphate pesticide exposure among farm women and children: Status of micronutrients, acetylcholinesterase activity, and oxidative stress.

Nutritional status plays a major role in determining the possible adverse health outcomes due to pesticide toxicity. The objective of the present study was to assess the organophosphorus pesticide residue levels among farm women (FW) (24-45years) and farm children (FC) (9-12 and 13-15years) belonging to the Rangareddy district (Telangana, India) along with their micronutrient status, inhibition of acetylcholinesterase activity, and oxidative stress levels. Residues of Chlorpyrifos, Diazinon, Malathion, Monocrotophos and Phosalone were found in the serum samples of FW and FC along with significantly low levels of vitamins and minerals. Inhibition of AChE activity was observed in FW and FC and altered oxidative stress parameters among FW. Correlation studies have found significant associations between the pesticide residues, micronutrients and antioxidant enzymes. The study suggests an association between pesticide exposure coupled with micronutrient deficiency, induced AChE inhibition, and oxidative stress.

Impact of Micronutrient Supplementation on Pesticide Residual, Acetylcholinesterase Activity, and Oxidative Stress Among Farm Children Exposed to Pesticides.

The present interventional study aimed to assess the impact of micronutrient supplementation on pesticide-residues concentrations, vitamins, minerals, acetylcholinesterase activity and oxidative stress among 129 farm children (9-12 years, n = 66 and 13-15 years, n = 63) involved in farming activities in Ranga Reddy district, Telangana, India. Our data showed the presence of five organophosphorus pesticide residues (chlorpyrifos, diazinon, malathion, monocrotophos, and phosalone) among children before-supplementation (both age-groups); while post-supplementation, only two pesticide residues (chlorpyrifos and diazinon) were detected indicating improved metabolic rate. Vitamin E, copper, magnesium and zinc levels were also improved in both the age-groups and manganese levels were significantly increased only among children of 13-15 years age group. Further, post-supplementation also showed an improvement in acetylcholinesterase activity and a decrease in lipid peroxidation among both the age groups of children. However, further research for ascertaining the ameliorating effect of micronutrients in preventing adverse effects of organophosphorus pesticides must be conducted.

Effect of organophosphorus pesticide exposure on the immune cell phenotypes among farm women and their children.

Epidemiological studies suggest suppression of the lymphocytes function through cholinergic stimulation due to organophosphorus pesticide exposure. The study aimed to assess the alteration in the levels of immune cell phenotypes among farm women (FW) and farm children (FC) who were occupationally exposed to pesticides and age/gender-matched control subjects belonging to Rangareddy district (Telangana, India). A total of 129 FW, 129 FC and 268 age/gender-matched controls were recruited. Blood samples were collected from the selected subjects to estimate the levels of nine organophosphorus pesticide residues and CD (CD3+, CD4+, CD8+, CD16+ and CD19+) cell markers using LC-MS/MS and flow cytometry, respectively. Independent t-test analysis was conducted to compare the immune cell phenotypes between exposed and control groups. Spearman's rank correlation test was further carried out to identify any possible correlation between the pesticide residues and CD markers. The mean percentage for CD4+, CD8+ and CD16+ was found to be significantly low, while for CD19 + itwas significantly high in the FW as compared to the CW group (p < 0.01). Further, the residues of chlorpyrifos and monocrotophos among FW were found to be significantly correlating with the mean percentages of CD19+ and CD8+ markers, respectively. The cell marker subsets of CD4+ and CD8+ were significantly low in FC children 9-12 years and 13-15 years age groups, respectively (p < 0.05). Also, these levels were significantly correlating with the residues of malathion and monocrotophos. The present study could indicate an alteration in the lymphocytes' subpopulations, which may thereby infer the toxicity in the first phase assessment of immunotoxicity. Therefore, further studies may be conducted to understand the suspected pesticides' mechanism along with various other factors in causing immune suppression coupled with nutritional and other related disorders.

Dysregulated Exosomes Result in Suppression of the Immune Response of Pregnant COVID-19 Convalescent Women.

A successful pregnancy outcome is dependent on a delicate balance between inflammatory and anti-inflammatory processes throughout the different trimesters. Interruption in this balance can lead to an adverse outcome resulting in pregnancy loss. Since late 2019, the emergence of the new SARS-CoV-2 virus has affected lives worldwide, including pregnant women; therefore, there is an urgent need to address different approaches in relation to prevention, diagnostics, and therapeutics. Early pregnancy is affected by SARS-CoV-2 infection leading to fetal demise. Available evidence also suggests that 90% of pregnant women infected with the SARS-CoV-2 virus seem to be asymptomatic. Nonetheless, it is still unclear how COVID-19 affects exosome production in pregnant women recovered from COVID-19 and how these exosomes regulate the adaptive immune response. In this study, we found several exosomes including CD9, CD31, CD40, CD45, CD41b, CD42a, CD62P, CD69, CD81, CD105, and HLA-DRDPDQ in the plasma of COVID-19-recovered pregnant women were significantly less abundant than the control group. Furthermore, to understand how these exosomes affect the adaptive immune response, we co-cultured the peripheral blood mononuclear cells (PBMCs) from healthy control (HC) pregnant women with exosomes of either Preg-HC or Preg-recovered COVID-19 women. We identified that Preg-recovered COVID-19 women have reduced capacity for the inflammatory cytokine TNF-α from cytotoxic CD8+ T cells. In summary, our study highlights that pregnant recovered COVID-19 women have reduced production of several exosomes and possess fewer immunogenic properties. Our study implicates that exosomes can control inflammation and antigen presentation capacity of immune cells, thus limiting the infection in pregnant women.

Is hepatocellular carcinoma complicated with portal vein tumor thrombosis potentially curable by radiotherapy in the form of stereotactic body radiation therapy?

PURPOSE: The prognosis of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is dismal. Despite best treatment and care, the patients with this malignancy only showed 2.7-4 months of overall survival. It is debatable whether liver transplantation helps PVTT sufferers. The effectiveness of radiation therapy in treating HCC patients with PVTT should not be undervalued. By limiting the high dosage region to a small planning target volume, stereotactic radiation delivery has shifted toward hypofractionation, limiting the radiation exposure to healthy organs and tissues. Stereotactic body radiotherapy (SBRT) has a local control rate of 75-100%, depending on the treatment. The major limitation in SBRT for hepatocellular carcinoma with PVTT is the paucity of prospective evidence for longer periods beyond the first two years after treatment. More prospective studies/randomized clinical trials with a longer follow-up, larger sample size, and adequate statistical power are the dire need of the present situation to ascertain the curative effect of SBRT as primary therapy for advanced HCC with PVTT. CONCLUSION: SBRT can improve survival, particularly for patients receiving multidisciplinary treatment. This review sums up our most current understanding of how radiation therapy, notably SBRT, can be used to treat hepatocellular carcinoma when combined with PVTT. Recent research has led us to believe that irradiation in the form of SBRT may cure hepatocellular carcinoma complicated by PVTT.

Assessment of dermal exposure to pesticides among farmers using dosimeter and hand washing methods.

Inappropriate use of pesticides followed by unsafe handling practices to control the insect infestation among the farming groups in developing countries has resulted in a high exposure risk. The use of personal protective equipment is also negligible among Indian farmers due to their affordability to access the same. Very little research has been conducted to establish an exposure assessment procedure through dermal penetration of pesticide residues. Therefore, to quantify the contamination of pesticide residues through dermal exposure along with detailed field observations and pesticide management practices, a field study was conducted in Rangareddy district, Telangana, Southern India, to assess the dermal exposure based on dosimeter and hand washing methods. The analytical method was modified and validated in-house for performance parameters such as limit of detection, quantification, linear range, recovery, and precision. The potential dermal exposure values ranged from 0.15 to 13.45 µg, while a reduction was found in exposure levels as actual dermal exposure values ranged from 0 to 0.629 µg. Contamination through hand washing was the major contributor to overall dermal exposure. Statistical analysis revealed a significant difference in the exposed dermal regions of the leg and torso after the use of PPE. Penetration factor for each anatomical region and risk evaluation in terms of the Margin of Safety implies unsafe handling of pesticides. The findings of the present study confirm the increased exposure to organophosphate pesticides among operators and highlight the importance of the use of protective measures, especially among those that focus on dermal exposure mitigation.

Computational study of novel inhibitory molecule, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea, with high potential to competitively block ATP binding to the RNA dependent RNA polymerase of SARS-CoV-2 virus.

For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an essential enzyme that catalyses the replication from RNA template and therefore remains an attractive therapeutic target for anti-COVID drug discovery. In the present study, we performed a comprehensive in silico screening for 16,776 potential molecules from recently established drug libraries based on two important pharmacophores (3-amino-4-phenylbutan-2-ol and piperazine). Based on initial assessment, 4042 molecules were obtained suitable as drug candidates, which were following Lipinski's rule. Molecular docking implemented for the analysis of molecular interactions narrowed this number of compounds down to 19. Subsequent to screening filtering criteria and considering the critical parameters viz. docking score and MM-GBSA binding free energy, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea (compound 1) was accomplished to score highest in comparison to the remaining 18 shortlisted drug candidates. Notably, compound 1 displayed higher docking score (-8.069 kcal/mol) and MM-GBSA binding free energy (-49.56 kcal/mol) than the control drug, remdesivir triphosphate, the active form of remdesivir as well as adenosine triphosphate. Furthermore, a molecular dynamics simulation was carried out (100 ns), which substantiated the candidacy of compound 1 as better inhibitor. Overall, our systematic in silico study predicts the potential of compound 1 to exhibit a more favourable specific activity than remdesivir triphosphate. Hence, we suggest compound 1 as a novel potential drug candidate, which should be considered for further exploration and validation of its potential against SARS-CoV-2 in wet lab experimental studies.Communicated by Ramasawamy H. Sarma.