No abstract

Breast carcinogenesis is a multistep process, involving both genetic and epigenetic modification process of genes, involved in diverse pathways ranging from DNA repair to metabolic processes. This study was undertaken to assess the role of promoter methylation of GSTP1 gene, a member of glutathione-S-transferase family of enzymes, in relation to its expression, polymorphism, and clinicopathological parameters. Tissue samples were taken from breast cancer patients and paired with their normal adjacent tissues. A total of 51 subjects were studied, in which the frequency of promoter methylation in cancerous tissue was 37.25% as against 11% in the normal tissues (p ≤ 0.001). The hypermethylated status of the gene was significantly associated with the loss of the protein expression (r = −0.449, p = 0.001, odds ratio = 7.42, 95% confidence interval = 2.05-26.92). Furthermore, when compared with the clinical parameters, the significant association was found between the promoter hypermethylation and lymph node metastasis (p ≤ 0.001), tumor stage (p = 0.039), tumor grade (p = 0.028), estrogen receptor status (p = 0.018), and progesterone receptor status (p = 0.046). Our study is the first of its kind in Kashmiri population, which indicates that GSTP1 shows aberrant methylation pattern in the breast cancer with the consequent loss in the protein expression. Furthermore, it also shows that the gene polymorphism (Ile105Val) at codon 105 is not related to the promoter methylation and two are the independent events in breast cancer development.

Metazoan genomes have a hierarchal 3-dimensional (3D) organization scaling from nucleosomes, loops, topologically associating domains (TADs), compartments, to chromosome territories. The 3D organization of genome has been linked with development, differentiation and disease. However, the principles governing the 3D chromatin architecture are just beginning to get unraveled. The nucleus has very high concentration of proteins and these proteins are either diffusely distributed throughout the nucleus, or aggregated in the form of foci/bodies/clusters/speckles or in combination of both. Several evidences suggest that the distribution of proteins within the nuclear space is linked to the organization and function of genome. Here, we describe advances made in understanding the relationship between subnuclear distribution of proteins and genome architecture.

Chromatin attains its three-dimensional (3D) conformation by establishing contacts between different noncontiguous regions. Sterile Alpha Motif (SAM)–mediated polymerization of the polyhomeotic (PH) protein regulates subnuclear clustering of Polycomb Repressive Complex 1 (PRC1) and chromatin topology. The mutations that perturb the ability of the PH to polymerize, disrupt long-range chromatin contacts, alter Hox gene expression, and lead to developmental defects. To understand the underlying mechanism, we combined the experiments and theory to investigate the effect of this SAM domain mutation on nucleosome occupancy and accessibility on a genome wide scale. Our data show that disruption of PH polymerization because of SAM domain mutation decreases nucleosome occupancy and alters accessibility. Polymer simulations investigating the interplay between distant chromatin contacts and nucleosome occupancy, both of which are regulated by PH polymerization, suggest that nucleosome density increases when contacts between different regions of chromatin are established. Taken together, it appears that SAM domain–mediated PH polymerization biomechanically regulates the organization of chromatin at multiple scales from nucleosomes to chromosomes and we suggest that higher order organization can have a top–down causation effect on nucleosome occupancy.

Asthma is a complex disorder causing the narrowing of the lung airways and affects people of all ages but is most prevalent during childhood. The main symptoms involved are wheezing, chest tightness, coughing and shortness of breath. Many cells which include eosinophils, lymphocytes, and mast cells are involved in the pathogenesis of asthma. The present drugs that are used to alleviate asthma symptoms are steroidal that has many side effects. In order to develop most effective and nonsteroidal drugs the path physiology need to be explored at biochemical level. The lipoxygenases and their metabolites could be a potential target for the development of new drugs for the treatment of asthma. In this review, we highlight the various path physiological pathways involved in asthma, which could pave for the discovery of novel drugs. Keywords: Asthma, Lung airways, Wheezing, Lymphocytes, Lipoxygenases. I.INTRODUCTION Asthma is a complex disorder that causes the narrowing of the lung airways leading to wheezing, chest tightness, and shortness of breath and coughing. Asthma affects people of all ages but most often in childhood. Asthma is classified into two types: a) Extrinsic (allergic or atopic asthma) is most common in childhood and accounts for about 75% of asthma cases. It is caused by immune response to inhaled allergens such as pollens, dander's and dust mite particles, b) Intrinsic asthma (non-allergic) predominantly affects people of 30 years of age and accounts for about 10% of all cases. It is triggered by cigarette smoke exposure, aspirin intake, laughter, stress, cold air, food preservatives, exercise and myriad of other factors. Genetic makeup of an individual is one of very common predisposing factors for the development of atopic or extrinsic asthma persons. Atopic asthma is considered as a syndrome due to its various phenotypic characteristics such as airway hyper responsiveness, increased IgE production, goblet cell metaplasia, sub epithelial fibrosis, and airway remodeling. The inhaled steroids are the current most effective therapy for asthma though it is not beneficial to all asthmatic patients and on the other hand treatment itself leads to various intolerable side effects. Asthma is a multi cellular process involving many eosinophils, lymphocytes, and mast cells however eosinophilic infiltration is the striking dominant feature. Among lymphocytes both B and T lymphocytes are having crucial roles by generating IgE mediated humoral and Th2 mediated cellular responses respectively. Imbalance between TH-1 and TH-2 immune response with elevation of TH-2 cytokines such as IL-4, IL-13, IL-5, and IL-9 and decrease in Th1 cytokines such as IL-12 and IFN-gamma is the dominant feature in asthma pathogenesis.Th2 cytokines and macrophages also leads to increase the levels chemokines which are responsible for recruiting and activation of various inflammatory cells such as eosinophils in the airway and those inflammatory cells secrete different proinflammatory mediators such as histamine, leukotrienes to...