GS-5759, a Bifunctional b 2 -Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells s

) and propranolol, were agonist-dependent, being significantly lower for GS-5759 than b2A. Collectively, these data can be explained by "forced proximity," bivalent binding where the pharmacophore in GS-5759 responsible for PDE4 inhibition also interacts with a nonallosteric domain within the b 2 -adrenoceptor that enhances the affinity of b2A for the orthosteric site. Microarray analyses revealed that, after 2-hour exposure, GS-5759 increased the expression of .3500 genes in BEAS-2B cells that were highly rank-order correlated with gene expression changes produced by indacaterol and GSK 256066 in combination (Ind/GSK). Moreover, the line of regression began close to the origin with a slope of 0.88, indicating that the magnitude of most gene expression changes produced by Ind/GSK was quantitatively replicated by GS-5759. Thus, GS-5759 is a novel compound exhibiting dual b 2 -adrenoceptor agonism and PDE4 inhibition with potential to interact on target tissues in a synergistic manner. Such polypharmacological behavior may be particularly effective in chronic obstructive pulmonary disease and other complex disorders where multiple processes interact to promote disease pathogenesis and progression

A Pharmacodynamics Analysis of Glucocorticoid Receptor-Mediated Gene Expression in BEAS-2B Human Airway Epithelial Cells

International treatment guidelines recommend that inhaled glucocorticoids be used as a monotherapy to control mild-to-moderate asthma. However, a combination of an inhaled glucocorticoid with a long-acting β2-adrenoceptor agonist is recommended for managing moderate-to-severe asthma, which cannot be controlled by glucocorticoids alone. Increasing evidence supports the idea that glucocorticoids acting through the glucocorticoid receptor (GR) can attenuate inflammatory responses either by inducing anti-inflammatory genes (a process called transactivation) or by suppressing pro-inflammatory genes (a process called transrepression). Gene transactivation by glucocorticoids was initially thought to be responsible for causing the metabolic side-effects and, hence, is relatively understudied when compared to transrepression. However, it has become increasingly clear that transactivation plays an important role in the anti-inflammatory actions of glucocorticoids. Moreover, the extent to which clinically-relevant glucocorticoids are equivalent in their ability to promote gene expression is unclear. This thesis describes the first pharmacodynamic approach to evaluate the transactivation potential of a panel of glucocorticoids alone and in combination with indacaterol (Ind), a long-acting β2-adrenoceptor agonist. Pharmacodynamic analyses showed that magnitude of luciferase gene induction was agonist dependent (i.e. seven different glucocorticoids tested displayed varying degrees of agonism). In addition, there were significant differences in agonist potency and, more importantly, the relationship between GR occupancy and response. To complement the reporter studies, similar analyses were performed on four glucocorticoid-inducible candidate genes. Three of these (GILZ, p57kip2 and CRISPLD2) are genes with potential anti-inflammatory activity and a fourth gene, PDK4 is predicted to promote metabolic side-effects. Similar to the luciferase reporter system, the expression of these genes was agonist-dependent and displayed markedly different GR occupancy-response relationships. Furthermore, Ind, when combined with the seven GR agonists tested, synergistically enhanced transactivation, the magnitude of which was agonist and gene dependent. These studies demonstrate that when gene transactivation is used as a functional output, glucocorticoids used to treat asthma are not biologically-equivalent. It is proposed that these differences may be exploited to therapeutic advantage. Thus, the generation of gene expression ‘fingerprints’ in target and off-target human tissues may allow new GR agonists to be rationally designed for asthma with an improved therapeutic index

Prevalence, Regional Variations, and Predictors of Overweight, Obesity, and Hypertension Among Healthy Reproductive-Age Indian Women: Nationwide Cross-Sectional Polycystic Ovary Syndrome Task Force Study

BackgroundA clear understanding of the anthropometric and sociodemographic risk factors related to BMI and hypertension categories is essential for more effective disease prevention, particularly in India. There is a paucity of nationally representative data on the dynamics of these risk factors, which have not been assessed among healthy reproductive-age Indian women. ObjectiveThis cross-sectional polycystic ovary syndrome (PCOS) task force study aimed to assess the anthropometric and sociodemographic characteristics of healthy reproductive-age Indian women and explore the association of these characteristics with various noncommunicable diseases. MethodsWe conducted a nationwide cross-sectional survey from 2018 to 2022 as part of the Indian Council of Medical Research–PCOS National Task Force study, with the primary aim of estimating the national prevalence of PCOS and regional phenotypic variations among women with PCOS. A multistage random sampling technique was adopted, and 7107 healthy women (aged 18-40 years) from 6 representative geographical zones of India were included in the study. The anthropometric indices and sociodemographic characteristics of these women were analyzed. Statistical analysis was performed to assess the association between exposure and outcome variables. ResultsOf the 7107 study participants, 3585 (50.44%) were from rural areas and 3522 (49.56%) were from urban areas. The prevalence of obesity increased from 8.1% using World Health Organization criteria to 40% using the revised consensus guidelines for Asian Indian populations. Women from urban areas showed higher proportions of overweight (524/1908, 27.46%), obesity (775/1908, 40.62%), and prehypertension (1008/1908, 52.83%) categories. A rising trend of obesity was observed with an increase in age. Women aged 18 to 23 years were healthy (314/724, 43.4%) and overweight (140/724, 19.3%) compared with women aged 36 to 40 years with obesity (448/911, 49.2%) and overweight (216/911, 23.7%). The proportion of obesity was high among South Indian women, with 49.53% (531/1072) and 66.14% (709/1072), using both World Health Organization criteria and the revised Indian guidelines for BMI, respectively. BMI with waist circumference and waist-to-height ratio had a statistically significant linear relationship (r=0.417; P<.001 and r=0.422; P<.001, respectively). However, the magnitude, or strength, of the association was relatively weak (0.3<|r|<0.5). Statistical analysis showed that the strongest predictors of being overweight or obese were older age, level of education, wealth quintile, and area of residence. ConclusionsAnthropometric and sociodemographic characteristics are useful predictors of overweight- and obesity-related syndromes, including prehypertension, among healthy Indian women. Increased attention to the health of Indian women from public health experts and policy makers is warranted. The findings of this study can be leveraged to offer valuable insights, informing health decision-making and targeted interventions that mitigate risk factors of overweight, obesity, and hypertension. International Registered Report Identifier (IRRID)RR2-10.2196/2343

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Not AvailableEquine influenza viruses (EIV)—H3N8 continue to circulate in equine population throughout the world. They evolve by the process of antigenic drift that leads to substantial change in the antigenicity of the virus, thereby necessitating substitution of virus strain in the vaccines. This requires frequent testing of the new vaccines in the in vivo system; however, lack of an appropriate laboratory animal challenge model for testing protective efficacy of equine influenza vaccine candidates hinders the screening of new vaccines and other therapeutic approaches. In the present investigation, BALB/c mouse were explored for suitability for conducting pathogenecity studies for EIV. The BALB/c mice were inoculated intranasally @ 2×106.24 EID50 with EIV (H3N8) belonging to Clade 2 of Florida sublineage and monitored for setting up of infection and associated parameters. All mice inoculated with EIV exhibited clinical signs viz. loss in body weights, lethargy, dyspnea, etc, between 3 and 5 days which commensurate with lesions observed in the respiratory tract including rhinitis, tracheitis, bronchitis, bronchiolitis, alveolitis and diffuse interstitial pneumonia. Transmission electron microscopy, immunohistochemistry, virus quantification through titration and qRT-PCR demonstrated active viral infection in the upper and lower respiratory tract. Serology revealed rise in serum lactate dehydrogenase levels along with sero-conversion. The pattern of disease progression, pathological lesions and virus recovery from nasal washings and lungs in the present investigations in mice were comparable to natural and experimental EIV infection in equines. The findings establish BALB/c mice as small animal model for studying EIV (H3N8) infection and will have immense potential for dissecting viral pathogenesis, vaccine efficacy studies, preliminary screening of vaccine candidates and antiviral therapeutics against EIV.Not Availabl