Small Interfering RNA against Transcription Factor STAT6 Leads to Increased Cholesterol Synthesis in Lung Cancer Cell Lines

STAT6 transcription factor has become a potential molecule for therapeutic intervention because it regulates broad range of cellular processes in a large variety of cell types. Although some target genes and interacting partners of STAT6 have been identified, its exact mechanism of action needs to be elucidated. In this study, we sought to further characterize the molecular interactions, networks, and functions of STAT6 by profiling the mRNA expression of STAT6 silenced human lung cells (NCI-H460) using microarrays. Our analysis revealed 273 differentially expressed genes after STAT6 silencing. Analysis of the gene expression data with Ingenuity Pathway Analysis (IPA) software revealed Gene expression, Cell death, Lipid metabolism as the functions associated with highest rated network. Cholesterol biosynthesis was among the most enriched pathways in IPA as well as in PANTHER analysis. These results have been validated by real-time PCR and cholesterol assay using scrambled siRNA as a negative control. Similar findings were also observed with human type II pulmonary alveolar epithelial cells, A549. In the present study we have, for the first time, shown the inverse relationship of STAT6 with the cholesterol biosynthesis in lung cancer cells. The present findings are potentially significant to advance the understanding and design of therapeutics for the pathological conditions where both STAT6 and cholesterol biosynthesis are implicated viz. asthma, atherosclerosis etc

The discourse of tradition and modernity in contemporary Indian culture

This paper examines the binary between tradition and modernity in contemporary India through the use of film. It focuses specifically on the Hindu/Indian woman, and the way in which this discourse plays out on her body. I argue that the Victorian morality that the British colonisers of India imposed on their colonised subjects has affected the way in which tradition and modernity are viewed in contemporary India, and because of this influence, the historical concepts of tradition and modernity have been skewed. In this paper, I argue that the binary between tradition and modernity does not exist in the context of the Hindu/Indian society, but rather, the Indian society has come to appropriate these concepts to suit their culture.Bachelor of Art

Polyalanine polymorphism in the signal peptide of Glutathione peroxidase 1 (GPX1) gene & its association with osteoporosis

Background & objectives: Osteoporosis is a systemic skeletal disease, characterized by a low bone mass leading to increased bone fragility and hence, a greater susceptibility to the risk of fracture. Since age-related oxidative stress is one of the factors that has been implicated in developing low bone mineral density (BMD), leading to osteoporosis, this study wanted to explore the expression of antioxidant enzymes in individuals with osteoporosis. The present study focused on mapping polymorphism in an important antioxidant enzyme glutathione peroxidase 1 (GPx1) among osteoporosis and healthy Asian Indians. Methods: Dual-energy X-ray absorptiometry was used to assess BMD of individuals and was classified into normal (n=96) and osteoporotic (n=88) groups. Biochemical parameters such as vitamin D, total oxidant status (TOS), and GPx1 enzyme activity were estimated from plasma samples of recruited individuals. Quantitative real-time qRT-PCR was carried out using GAPDH as an endogenous control. Genomic DNA was isolated from whole blood, and polymorphisms were evaluated by sequencing. Results: The BMD was lower in osteoporotic individuals, and further analysis of biochemical parameters indicated significantly low 25-hydroxy vitamin D and GPx1 with higher TOS levels in osteoporotic as compared to healthy individuals. Furthermore, qRT-PCR revealed low expression of GPX1 in osteoporotic individuals. GPX1 sequence analysis of the promoter and two exons revealed the lower frequency of five alanine repeats in the osteoporotic individuals. Interpretation & conclusions: In this study, the in silico analysis revealed the lower frequency of five alanine repeats in exon 1 of GPX1 and high TOS to be associated with osteoporosis. However, no polymorphism was found in exon 2 of GPX1 among the two study groups

Effect of vaccination on the HRCT profile of COVID-19 patients – A single-center experience

Introduction: Vaccination against the global pandemic coronavirus disease 2019 (COVID-19) is a promising way out of the havoc caused by the disease. The clinico-radiological profile of COVID-19 patients in relation to the vaccination status is depicted in the present study. Materials and Methods: This is a retrospective observational imaging and hospital data-based study performed on 214 confirmed and clinically suspicious patients of COVID-19 who underwent high-resolution computed tomography (HRCT) scan of the thorax at the Department of Radio-Diagnosis of a tertiary medical center in the Himalayan foothills. The present study aims to evaluate the effect of vaccination on HRCT findings of COVID-19 populations. Results: Forty-three percent of the non-vaccinated population presented with severe HRCT scores (19–25) in comparison to only 11.5% of the study population who had taken both doses of vaccine (P = 0.018). Two doses of vaccination had a negative Pearson correlation coefficient with severe HRCT scores (–0.146). Co-morbidities had a significant correlation with HRCT severity score, with 61.5% diabetics and 63.33% of hypertensive patients showing scores >19 on HRCT. Conclusion: Vaccination proves to be a game changer in the pandemic with two doses of vaccination having a significant negative correlation with COVID-19-induced severe pneumonitis on HRCT of the thorax

Next generation designer virus-like particle vaccines for dengue

Introduction: A safe and efficacious vaccine for dengue continues to be an unmet public health need. The recent licensing of a dengue vaccine (Dengvaxia) developed by Sanofi has brought to the fore the safety issue of vaccine-induced infection enhancement. Areas covered: This article focuses on two new yeast-produced tetravalent dengue envelope domain III-displaying virus-like particulate vaccine candidates reported in early 2018 and reviews the rationale underlying their design, and pre-clinical data which suggest that these may offer promising alternate options. Expert commentary: These are the only vaccine candidates so far to have demonstrated the induction of primarily serotype-specific neutralizing antibodies to all dengue virus serotypes in experimental animals. Interestingly, these antibodies lack infection-enhancing potential when evaluated using the AG129 mouse model

Sinococuline, a bioactive compound of Cocculus hirsutus has potent anti-dengue activity

Abstract Dengue virus (DENV) infection has increased worldwide, with over 400 million infections annually, and has become a serious public health concern. Several drug candidates, new and repurposed, have failed to meet the primary efficacy endpoints. We have recently shown that Aqueous Extract of the stem of Cocculus hirsutus (AQCH) was effective in vitro and in vivo against DENV and was safe in humans. We now report that an active ingredient of AQCH, Sinococuline, protects against the antibody-mediated secondary-DENV infection in the AG129 mouse model. DENV infection markers were assessed, viz. serum viremia and vital organs pathologies-viral load, proinflammatory cytokines and intestinal vascular leakage. The treatment with Sinococuline at 2.0 mg/kg/day; BID (twice a day), was the most effective in protecting the severely DENV-infected AG129 mice. Also, this dose effectively reduced serum viremia and tissue-viral load and inhibited the elevated expression levels of proinflammatory cytokines (TNF-α and IL-6) in several vital organs. Based on these findings, it could be explored further for pre-clinical and clinical developments for the treatment of dengue

Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis

The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of Mtb to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when Mtb infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant Mtb, ameliorated lung pathology, and reduced post-chemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (C-max and AUC(last)) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure