Subnational estimates of life expectancy at birth in India: evidence from NFHS and SRS data.

BACKGROUND: Mortality estimates at the subnational level are of urgent need in India for the formulation of policies and programmes at the district level. This is the first-ever study which used survey data for the estimation of life expectancy at birth ([Formula: see text]) for the 640 districts from NFHS-4 (2015-16) and 707 districts from NFHS-5 (2019-21) for the total, male and female population in India. METHODS: This study calculated annual age-specific mortality rates from NFHS-4 and NFHS-5 for India and all 36 states for the total, male and female population. This paper constructed the abridged life tables and estimated life expectancy at birth [Formula: see text] and further estimated the model parameters for all 36 states. This study linked state-specific parameters to the respective districts for the estimation of life expectancy at birth [Formula: see text]for 640 districts from NFHS-4 and 707 districts from NFHS-5 for the total, male and female population in India. RESULTS: Findings at the state level showed that there were similarities between the estimated and calculated [Formula: see text] in most of the states. The results of this article observed that the highest [Formula: see text] varies in the ranges of 70 to 90 years among the districts of the southern region. [Formula: see text] falls below 70 years among most of the central and eastern region districts. In the northern region districts [Formula: see text] lies in the range of 70 years to 75 years. The estimates of life expectancy at birth [Formula: see text] shows the noticeable variations at the state and district levels for the person, male, and female populations from the NFHS (2015-16) and NFHS (2019-21). In the absence of age-specific mortality data at the district level in India, this study used the indirect estimation method of relating state-specific model parameters with the IMR of their respective districts and estimated [Formula: see text] across the 640 districts from NFHS-4 (2015-16) and 707 districts from NFHS-5 (2019-21). The findings of this study have similarities with the state-level estimations of [Formula: see text] from both data sources of SRS and NFHS and found the highest [Formula: see text] in the southern region and the lowest [Formula: see text] in the eastern and central region districts. CONCLUSIONS: In the lack of [Formula: see text] estimates at the district level in India, this study could be beneficial in providing timely life expectancy estimates from the survey data. The findings clearly shows variations in the district level [Formula: see text]. The districts from the southern region show the highest [Formula: see text] and districts from the central and eastern region has lower [Formula: see text]. Females have higher [Formula: see text] as compared to the male population in most of the districts in India.

Cadmium modulates intestinal Wnt/ß-catenin signaling ensuing intestinal barrier disruption and systemic inflammation.

The intricate architecture of the intestinal epithelium, crucial for nutrient absorption, is constantly threatened by environmental factors. The epithelium undergoes rapid turnover, which is essential for maintaining homeostasis, under the control of intestinal stem cells (ISCs). The central regulator, Wnt/ß-catenin signaling plays a key role in intestinal integrity and turnover. Despite its significance, the impact of environmental factors on this pathway has been largely overlooked. This study, for the first time, investigates the influence of Cd on the intestinal Wnt signaling pathway using a mouse model. In this study, male BALB/c mice were administered an environmentally relevant Cd dose (0.98 mg/kg) through oral gavage to investigate the intestinal disruption and Wnt signaling pathway. Various studies, including histopathology, immunohistochemistry, RT-PCR, western blotting, ELISA, intestinal permeability assay, and flow cytometry, were conducted to study Cd-induced changes in the intestine. The canonical Wnt signaling pathway experienced significant downregulation as a result of sub-chronic Cd exposure, which caused extensive damage throughout the small intestine. Increased intestinal permeability and a skewed immune response were also observed. To confirm that Wnt signaling downregulation is the key driver of Cd-induced gastrointestinal toxicity, mice were co-exposed to LiCl (a recognized Wnt activator) and Cd. The results clearly showed that the harmful effects of Cd could be reversed, which is strong evidence that Cd mostly damages the intestine through the Wnt/ß-catenin signalling axis. In conclusion, this research advances the current understanding of the role of Wnt/ß catenin signaling in gastrointestinal toxicity caused by diverse environmental pollutants.

Structural basis for the role of C-terminus acidic tail of Saccharomyces cerevisiae ubiquitin-conjugating enzyme (Rad6) in E3 ligase (Bre1) mediated recognition of histones.

Ubiquitination of histone H2B on chromatin is key to gene regulation. E3 ligase Bre1 and E2 Rad6 in Saccharomyces cerevisiae associate together to catalyze mono-ubiquitination at histone H2BK123. Prior studies identified the role of a highly dynamic C-terminal acidic tail of Rad6 indispensable for H2BK123 mono-ubiquitination. However, the mechanistic basis for the Rad6-acidic tail role remained elusive. Using different structural and biophysical approaches, this study for the first time uncovers the direct role of Rad6-acidic tail in interaction with the Bre1 Rad6-Binding Domain (RBD) and recognition of histones surface to facilitate histone H2B mono-ubiquitination. A combination of NMR, SAXS, ITC, site-directed mutagenesis and molecular dynamics studies reveal that RBD domain of Bre1 interacts with Rad6 to stabilize the dynamics of acidic tail. This Bre1-RBD mediated stability in acidic tail of Rad6 could be one of the key factors for facilitating correct recognition of histone surface and ubiquitin-transfer at H2BK123. We provide biophysical evidence that Rad6-acidic tail and a positivity charged surface on histone H2B are involved in recognition of E2:Histones. Taken together, this study uncovers the mechanistic basis for the role of Rad6-acidic in Bre1-RBD mediated recognition of histone surface that ensure the histone H2B mono-ubiquitination.

Impact of COVID-19 on subnational variations in life expectancy and life disparity at birth in India: evidence from NFHS and SRS data.

BACKGROUND: Measuring life expectancy and life disparity can assist in comprehending how the COVID-19 pandemic has affected the mortality estimates in the Indian population. The present study aims to study the life expectancy and life disparity at birth at the national and subnational levels before and during the COVID-19 pandemic using the NFHS and SRS data. METHODS: The measures Life expectancy at birth ([Formula: see text]) and Life disparity at birth ([Formula: see text]) were computed for the non-pandemic and pandemic years from NFHS (2015-16), SRS (2015) and NFHS (2019-21), SRS (2020) respectively at the national and Subnational level in India. Using NFHS data for the 36 states and SRS data for the 22 states, the study calculates [Formula: see text] and [Formula: see text] by total, male and female population. RESULTS: The [Formula: see text] for male and female decline from 64.3 years and 69.2 years in 2015-16 to 62.9 years and 68.9 years in 2019-21. The [Formula: see text] shows a drop of approximately 1.4 years for males and 0.3 years for females in the pandemic year 2019-21 when compared to the non-pandemic year 2015-16. At the subnational level [Formula: see text] shows a decline for 22 states in person, 23 states in males and 21 states in females in the pandemic year 2019-21 as compared to the non-pandemic years 2015-16. The [Formula: see text] shows a increase for 21 states in person, 24 states in females and 17 states in males in the pandemic year than non-pandemic year. The findings shows a significant losses in [Formula: see text] and gains in [Formula: see text] for males than females in the pandemic year as compared to the non-pandemic year at the subnational level in India. CONCLUSIONS: COVID-19 pandemic has decreased [Formula: see text] and increased [Formula: see text] in the pandemic year 2019-21 at the national and subnational level in India. COVID-19 had a significant impact on the age pattern of mortality for many states and male, female population and delayed the mortality transition in India.

Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders.

WEE1 is a checkpoint kinase critical for mitotic events, especially in cell maturation and DNA repair. Most cancer cells' progression and survival are linked with elevated levels of WEE1 kinase. Thus, WEE1 kinase has become a new promising druggable target. A few classes of WEE1 inhibitors are designed by rationale or structure-based techniques and optimization approaches to identify selective acting anticancer agents. The discovery of the WEE1 inhibitor AZD1775 further emphasized WEE1 as a promising anticancer target. Therefore, the current review provides a comprehensive data on medicinal chemistry, synthetic approaches, optimization methods, and the interaction profile of WEE1 kinase inhibitors. In addition, WEE1 PROTAC degraders and their synthetic procedures, including a list of noncoding RNAs necessary for regulation of WEE1, are also highlighted. From the standpoint of medicinal chemistry, the contents of this compilation serve as an exemplar for the further design, synthesis, and optimization of promising WEE1-targeted anticancer agents.

Machine Learning Algorithms for understanding the determinants of under-five Mortality.

BACKGROUND: Under-five mortality is a matter of serious concern for child health as well as the social development of any country. The paper aimed to find the accuracy of machine learning models in predicting under-five mortality and identify the most significant factors associated with under-five mortality. METHOD: The data was taken from the National Family Health Survey (NFHS-IV) of Uttar Pradesh. First, we used multivariate logistic regression due to its capability for predicting the important factors, then we used machine learning techniques such as decision tree, random forest, Naïve Bayes, K- nearest neighbor (KNN), logistic regression, support vector machine (SVM), neural network, and ridge classifier. Each model's accuracy was checked by a confusion matrix, accuracy, precision, recall, F1 score, Cohen's Kappa, and area under the receiver operating characteristics curve (AUROC). Information gain rank was used to find the important factors for under-five mortality. Data analysis was performed using, STATA-16.0, Python 3.3, and IBM SPSS Statistics for Windows, Version 27.0 software. RESULT: By applying the machine learning models, results showed that the neural network model was the best predictive model for under-five mortality when compared with other predictive models, with model accuracy of (95.29% to 95.96%), recall (71.51% to 81.03%), precision (36.64% to 51.83%), F1 score (50.46% to 62.68%), Cohen's Kappa value (0.48 to 0.60), AUROC range (93.51% to 96.22%) and precision-recall curve range (99.52% to 99.73%). The neural network was the most efficient model, but logistic regression also shows well for predicting under-five mortality with accuracy (94% to 95%)., AUROC range (93.4% to 94.8%), and precision-recall curve (99.5% to 99.6%). The number of living children, survival time, wealth index, child size at birth, birth in the last five years, the total number of children ever born, mother's education level, and birth order were identified as important factors influencing under-five mortality. CONCLUSION: The neural network model was a better predictive model compared to other machine learning models in predicting under-five mortality, but logistic regression analysis also shows good results. These models may be helpful for the analysis of high-dimensional data for health research.

The Manifestation of Anxiety as Repercussion of COVID-19: A Survey of Medical Practitioner's Opinion.

Anxiety is usually transient in nature, but if the symptoms are severe and persistent in the absence of stressor, then it is considered as anxiety disorder. Corona virus disease 2019 (COVID-19) which was declared as pandemic by World Health Organization in March 2020 affected the lives of human beings worldwide. A panic and anxious situation was created due to the outbreak of COVID-19. Medical health practitioners have been connected with the patients and hence can better speculate the psychology of human beings. The present study was designed to find out the manifestation of anxiety as repercussion of COVID-19 on the basis of opinion of medical practitioners. A survey was conducted among the medical practitioners from India and Bangladesh to find out the possibility of anxiety as after-effect of COVID-19 through questionnaires. Results of the study showed that 95% medical practitioners were in the view to have chances of anxiety with more possibility to have social anxiety and post-traumatic stress anxiety disorder as a consequence of COVID-19. Female and male genders have equal chances, whereas transgender have lesser chances to have anxiety disorders as a consequence of COVID-19. Population above 50 years age might have maximum chance of having anxiety as after-effect of COVID-19. The study concludes to have chances of anxiety as repercussion of COVID-19.

Association between physical limitations and depressive symptoms among Indian elderly: marital status as a moderator.

BACKGROUND: Depression among the elderly is well-documented and associated with socio-economic factors, physical and mental health conditions. Few studies have focused on older adults' physical limitations and depressive symptoms. However, very little is known about marital status' role in such associations, especially in India. The present study examines the association between physical limitations and self-reported depressive symptoms and moderating role of marital status in such association separately for men and women. METHODS: The present study used data from the Longitudinal Ageing Study in India (LASI) wave 1, 2017-2018, a nationally and state representative longitudinal large-scale survey of ageing and health. For the present research, a total sample of 20,806 older adults aged 60+ years was selected after excluding missing values. Along with descriptive statistics, binary logistic regression analysis and interaction effect of marital status were applied to examine the association between physical limitations (functional limitations and mobility difficulty) with the depressive symptoms separately for men and women. RESULTS: About 58, 50, and 45% elderly reported having depressive symptoms and had difficulty in 2+ ADLs, 2+ IADLs, and 2+ mobility difficulties, respectively. By the marital status, the prevalence of depressive symptoms was higher among currently unmarried than currently married, irrespective of type and number of physical limitations. The unadjusted, marital and multivariate-adjusted association suggested that elderly with more than two ADLs, IADLs, and mobility difficulty had higher odds of depressive symptoms. The gender stratified interaction effect of marital status and physical limitations on depressive symptoms indicated that currently unmarried elderly, particularly unmarried older women with 2+ ADLs (OR = 2.85; CI 95% = 1.88-3.09), 2+ IADLs (OR = 2.01; CI 95% = 1.74-2.31) and 2+ mobility difficulty (OR = 2.20; CI 95% = 1.86-2.60) had higher odds of depressive symptoms. However, such association was only valid for unmarried men having mobility difficulty. CONCLUSION: The study highlights that the elderly with physical limitations such as ADLs, IADLs, and mobility difficulty require attention and care. Although married elderly are less likely to have depressive symptoms even with all the mentioned physical limitations, unmarried women are more vulnerable to have depressive symptoms with physical limitations.

Impact of COVID-19 on life expectancy at birth in India: a decomposition analysis.

BACKGROUND: Quantifying excess deaths and their impact on life expectancy at birth (e0) provide a more comprehensive understanding of the burden of coronavirus disease of 2019 (COVID-19) on mortality. The study aims to comprehend the repercussions of the burden of COVID-19 disease on the life expectancy at birth and inequality in age at death in India. METHODS: The mortality schedule of COVID-19 disease in the pandemic year 2020 was considered one of the causes of death in the category of other infectious diseases in addition to other 21 causes of death in the non-pandemic year 2019 in the Global Burden of Disease (GBD) data. The measures e0 and Gini coefficient at age zero (G0) and then sex differences in e0 and G0 over time were analysed by assessing the age-specific contributions based on the application of decomposition analyses in the entire period of 2010-2020. RESULTS: The e0 for men and women decline from 69.5 and 72.0 years in 2019 to 67.5 and 69.8 years, respectively, in 2020. The e0 shows a drop of approximately 2.0 years in 2020 when compared to 2019. The sex differences in e0 and G0 are negatively skewed towards men. The trends in e0 and G0 value reveal that its value in 2020 is comparable to that in the early 2010s. The age group of 35-79 years showed a remarkable negative contribution to Δe0 and ΔG0. By causes of death, the COVID-19 disease has contributed - 1.5 and - 9.5%, respectively, whereas cardiovascular diseases contributed the largest value of was 44.6 and 45.9%, respectively, to sex differences in e0 and G0 in 2020. The outcomes reveal a significant impact of excess deaths caused by the COVID-19 disease on mortality patterns. CONCLUSIONS: The COVID-19 pandemic has negative repercussions on e0 and G0 in the pandemic year 2020. It has severely affected the distribution of age at death in India, resulting in widening the sex differences in e0 and G0. The COVID-19 disease demonstrates its potential to cancel the gains of six to eight years in e0 and five years in G0 and has slowed the mortality transition in India.

Overexpression of SlHSP90.2 leads to altered root biomass and architecture in tomato (Solanum lycopersicum).

The Heat shock proteins 90 family plays pivotal roles in root growth and plant development. Its isoforms have been identified in several plant species with transcripts presents in almost all stages of plant growth. However, its functional relevance has not been completely established. Therefore, in this study, we provide evidence about the role of SlHSP90.2 in tomato (Solanum lycopersicum) root development. Using tomato cultivars with differing root phenotypes, we have shown that SlHSP90.2 transcripts are in accordance with root architecture, i.e. high rooting cultivars had more expression of SlHSP90.2 as compared to low rooting cultivars. Moreover, overexpression of SlHSP90.2 gene in transgenic tomato plants showed significant increase in root biomass and architecture, as evident from the analysis of fresh and dry weights of root and shoot samples, primary root length and length and number of lateral roots. The transgenic lines are also more tolerant to salinity and drought stresses. The results of the present study suggest that genetic manipulation of HSP90.2 homologs in other crops can offer promising leads to develop plant with better root biomass and architecture and improved agronomics traits, like better water and mineral absorption, salinity and drought tolerance potential.

Molecular characterization of SlATG18f in response to Tomato leaf curl New Delhi virus infection in tomato and development of a CAPS marker for leaf curl disease tolerance.

KEY MESSAGE: Analysis of autophagy-related genes in tomato shows the involvement of SlATG18f in leaf curl disease tolerance and a CAPS marker developed from this gene demonstrates its usefulness in marker-assisted selection. Autophagy is a highly conserved catabolic process regulating cellular homeostasis and adaptation to different biotic and abiotic stress. Several autophagy-related proteins (ATGs) are reported to be involved in autophagic processes, and considering their importance in regulating growth and stress adaptation, these proteins have been identified and characterized in several plant species. However, there is no information available on the role of autophagy-related proteins regulating the tolerance of tomato to tomato leaf curl disease (ToLCD). Given this, the present genome-wide study identified thirty ATG-encoding genes (SlATG) in tomato, followed by their functional characterization. Expression profiling of the SlATG genes in contrasting tomato cultivars subjected to virus infection showed a 4.5-fold upregulation of SlATG18f in the tolerant cultivar. Further, virus-induced gene silencing of SlATG18f in the tolerant cultivar conferred disease susceptibility, which suggested the role of this gene in Tomato leaf curl New Delhi virus tolerance. Comparison of the gene sequence of both tolerant and susceptible cultivars along with the 5' upstream regions identified an SNP (A/T) at -2916 upstream of the start codon. A cleaved amplified polymorphic sequence (CAPS) marker was developed targeting this region, which showed a significant association with the tolerance characteristics in the tomato germplasm (R2 = 0.1787). Altogether, the study identified a potential gene that could be used to develop ToLCNDV tolerant tomato cultivars using transgene-based or marker-assisted breeding-based approaches.

Disaggregated analysis of birth averted due to family planning use in India: An evidence from NFHS-4 (2015-16).

BACKGROUND AND OBJECTIVE: India contributes a major share of global unintended births. It is established that contraception plays a significant role in preventing unintended pregnancies, maternal mortality and induced abortion. In this study, to analyze the effectiveness of our family welfare program, we tried to give district-level estimates of number of births averted due to contraception. DATA AND METHODS: Data for this study came from the cross-sectional, population-based data from the fourth round of National Family Health Survey (NFHS-4) conducted in 2015-16. Here, we discussed two methods based on robust regression for computing number of births averted at district level. Further, we analyzed the percentage increase in births (PIB) that would be experienced by each district in the absence of contraception. RESULTS: Findings of this study clearly showed that there was a huge variation in the estimates of number of births averted among different districts as well as states of India. Out of 640 districts, 315 districts achieved below-replacement fertility and 365 districts have contraceptive prevalence rate (CPR) more than 50 percent. Method 1 found around 22 percent districts showed less than 15 percent reduction in births while Method 2 suggested nearly 14 percent districts predominantly located in Uttar Pradesh, Bihar, Jharkhand, Arunachal Pradesh, Meghalaya and Manipur exhibited less than 30 percent reduction of births due to use of all forms of contraception. At all India level, an average estimate obtained by two methods, nearly 63 million births would have been averted by the use of contraception or 40 percent more than the number of births occurred during that period. CONCLUSION: The study successfully identified the districts that were not performing well at the front of utilization of various family planning methods for birth control. To achieve objectives of National Population Policy (2000), poor-performing districts must be monitored like the government keeps monitoring of Aspirational districts.

Reciprocal changes in CD11c+CD11b+ and CD11c+CD8α+ dendritic cell subsets determine protective or permissive immune response in murine experimental VL.

CD11c+CD8α+ and CD11c+CD11b+ dendritic cells are two major subsets of murine splenic CD11c+ DCs which play a crucial role in T cell priming and shaping Th1/Th2 responses, but their role in the context of experimental visceral leishmaniasis (VL) is poorly understood. Herein, we showed that L. donovani infection in Balb/c mice preferentially decreased the population abundance of CD11c+CD11b+ DCs and increased relative abundance of splenic CD11c+CD8α +DCs. During infection, splenic CD11c+CD11b+ DCs induced Th1 differentiation whereas CD11c+CD8α+ DCs promoted Th2 differentiation. Additionally, treatment of infected mice with miltefosine as experimental control exhibited host defense allowing the restoration of CD11c+CD11b+ population and decrease in CD11c+CD8α+ subset. Furthermore, reciprocal regulation of immune accessory surface molecules, Sema4A and OX40L critically determined Th1/Th2 response induced by these DC subsets during VL. L. donovani infection significantly induced OX40L expression and slightly downregulated SEMA 4A expression in CD11c+CD8α+ DCs whereas miltefosine treatment significantly downregulated OX40L expression along with pronounced upregulation of SEMA 4A expression in CD11c+CD11b+ DCs. SiRNA mediated knockdown of SEMA 4A markedly reduced CD11c+CD11b+ driven IFN-γ, TNF-α and IL-12 synthesis in miltefosine treated mice whereas functional blocking of OX40L decreased CD11c+CD8α+ induced IL-10, IL-4 and TGF-ß synthesis in L. donovani infected group. Vaccination of Balb/c mice with antigen-pulsed + CpG-ODN-activated DC subsets revealed that only antigen-pulsed CD11c+CD11b+ DCs eliminated parasite load in visceral organ and restored protective Th1 cytokine response. Collectively, our results suggest that differential regulation of splenic CD11c+ subsets by L. donovani is essential for disease progression and specific subtypes may be exploited as prophylactic measures against visceral leishmaniasis.

Dandy-Walker variant with precocious puberty: a rare association.

Precocious puberty is characterised by premature appearance of secondary sexual characteristics before the age of 7 years in girls and 9 years in boys. Dandy-Walker malformation comprises a spectrum of intracranial malformations of the posterior fossa. We present a case of a 7-year-old male child who has presented with features of central precocious puberty and on further evaluation has been found to have Dandy-Walker variant and secondary hypothyroidism. The following case report describes this association which is extremely rare and has never been described in literature.

Dulaglutide-induced cerebral venous thrombosis in a patient with type 2 diabetes mellitus.

Though patients with diabetes mellitus are at a high risk of atherothrombotic events, every such event should not be attributed to the disease itself. We present a case of a patient with diabetes with headache and blurring of vision for 3 days. Brain imaging revealed right transverse sinus thrombosis and acute infarct of the right posterior parieto-occipital region, predominantly in the posterior cortical watershed zone. The patient was on subcutaneous dulaglutide for 3 weeks and was having nausea and vomiting. Various causes of cerebral venous thrombosis were ruled out with appropriate laboratory investigations. Finally, cerebral venous thrombosis was attributed to dulaglutide-induced nausea and vomiting which led to severe dehydration.

Leishmania donovani molecules recognized by sera of filaria infected host facilitate filarial infection.

We earlier found that F6 fraction of human filaria Brugia malayi cross-reacted with sera of Leishmania donovani infected hamsters and immunization with F6 inhibited both filarial and leishmanial infections. In the present study, we identified a 52.9-93.6 kDa fraction (Ld1) of L. donovani that cross-reacted with sera of B. malayi infected animals and investigated effect of Ld1 on filarial infection. Immunization of BALB/c mice with Ld1 facilitated B. malayi infection with remarkable increase in parasite burden. Facilitation of filarial infection was associated with downregulated cell proliferation, IL-5, IL-13, IFN-γ, TNF-α, and IL-2 levels and upregulated IL-4 and TGF-ß. Ld1 exposure also suppressed MHC class-I, MHC class-II, and FcεR1 expression, and phagocytosis in naive mouse macrophages, and CD4+, CD8+, and CD19+ cell population in mouse spleen. Two-dimensional electrophoresis and matrix-assisted laser desorption ionization-time of flight-mass spectrometry revealed eight proteins in Ld1: putative heat shock protein (HSP) 70-related protein 1, HSP70 mitochondrial precursor, alanine aminotransferase, 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, protein disulfide isomerase, putative ATPase beta subunit, trypanothione reductase, and a hypothetical protein. HSP70 protein mitochondrial precursor and trypanothione reductase showed homology with Trypanosoma cruzi and L. donovani, respectively, and the rest 6 proteins including hypothetical protein bear homology with L. infantum. In conclusion, the present study for the first time shows that immunization with filarial cross-reactive Ld1 fraction of L. donovani facilitates filarial infection by modulating Th1 and Th2 responses. Ld1 molecules may therefore facilitate filarial infection in filaria-leishmania co-infection.

Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis.

Earlier we have established a carbazole alkaloid (mahanine) isolated from an Indian edible medicinal plant as an anticancer agent with minimal effect on normal cells. Here we report for the first time that mahanine-treated drug resistant and sensitive virulent Leishmania donovani promastigotes underwent apoptosis through phosphatidylserine externalization, DNA fragmentation and cell cycle arrest. An early induction of reactive oxygen species (ROS) suggests that the mahanine-induced apoptosis was mediated by oxidative stress. Additionally, mahanine-treated Leishmania-infected macrophages exhibited anti-amastigote activity by nitric oxide (NO)/ROS generation along with suppression of uncoupling protein 2 and Th1-biased cytokines response through modulating STAT pathway. Moreover, we have demonstrated the interaction of a few antioxidant enzymes present in parasite with mahanine through molecular modeling. Reduced genetic and protein level expression of one such enzyme namely ascorbate peroxidase was also observed in mahanine-treated promastigotes. Furthermore, oral administration of mahanine in acute murine model exhibited almost complete reduction of parasite burden, upregulation of NO/iNOS/ROS/IL-12 and T cell proliferation. Taken together, we have established a new function of mahanine as a potent antileishmanial molecule, capable of inducing ROS and exploit antioxidant enzymes in parasite along with modulation of host's immune response which could be developed as an inexpensive and nontoxic therapeutics either alone or in combination.

Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.

A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.

Role of Ubiquitin-Mediated Degradation System in Plant Biology.

Ubiquitin-mediated proteasomal degradation is an important mechanism to control protein load in the cells. Ubiquitin binds to a protein on lysine residue and usually promotes its degradation through 26S proteasome system. Abnormal proteins and regulators of many processes, are targeted for degradation by the ubiquitin-proteasome system. It allows cells to maintain the response to cellular level signals and altered environmental conditions. The ubiquitin-mediated proteasomal degradation system plays a key role in the plant biology, including abiotic stress, immunity, and hormonal signaling by interfering with key components of these pathways. The involvement of the ubiquitin system in many vital processes led scientists to explore more about the ubiquitin machinery and most importantly its targets. In this review, we have summarized recent discoveries of the plant ubiquitin system and its involvement in critical processes of plant biology.