In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates

CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. By analyzing 30 crystal structures of the HA-binding domain (CD44HAbd), we characterized a subdomain that binds to 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds and is adjacent to residues essential for HA interaction. By computational combinatorial chemistry (CCC), we designed 168,190 molecules and compared their conformers to a pharmacophore containing the key features of the crystallographic THQ binding mode. Approximately 0.01% of the compounds matched the pharmacophore and were analyzed by computational docking and molecular dynamics (MD). We identified two compounds, Can125 and Can159, that bound to human CD44HAbd (hCD44HAbd) in explicit-solvent MD simulations and therefore may elicit CD44 blockage. These compounds can be easily synthesized by multicomponent reactions for activity testing and their binding mode, reported here, could be helpful in the design of more potent CD44 antagonists

Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis.

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis

Impact of common cardio-metabolic risk factors on fatal and non-fatal cardiovascular disease in Latin America and the Caribbean: an individual-level pooled analysis of 31 cohort studies

Background: Estimates of the burden of cardio-metabolic risk factors in Latin America and the Caribbean (LAC) rely on relative risks (RRs) from non-LAC countries. Whether these RRs apply to LAC remains un- known. Methods: We pooled LAC cohorts. We estimated RRs per unit of exposure to body mass index (BMI), systolic blood pressure (SBP), fasting plasma glucose (FPG), total cholesterol (TC) and non-HDL cholesterol on fatal (31 cohorts, n = 168,287) and non-fatal (13 cohorts, n = 27,554) cardiovascular diseases, adjusting for regression dilution bias. We used these RRs and national data on mean risk factor levels to estimate the number of cardiovascular deaths attributable to non-optimal levels of each risk factor. Results: Our RRs for SBP, FPG and TC were like those observed in cohorts conducted in high-income countries; however, for BMI, our RRs were consistently smaller in people below 75 years of age. Across risk factors, we observed smaller RRs among older ages. Non-optimal SBP was responsible for the largest number of attributable cardiovascular deaths ranging from 38 per 10 0,0 0 0 women and 54 men in Peru, to 261 (Dominica, women) and 282 (Guyana, men). For non-HDL cholesterol, the lowest attributable rate was for women in Peru (21) and men in Guatemala (25), and the largest in men (158) and women (142) from Guyana. Interpretation: RRs for BMI from studies conducted in high-income countries may overestimate disease burden metrics in LAC; conversely, RRs for SBP, FPG and TC from LAC cohorts are similar to those esti- mated from cohorts in high-income countries

EDUCACIÓN AMBIENTAL Y SOCIEDAD. SABERES LOCALES PARA EL DESARROLLO Y LA SUSTENTABILIDAD

Este texto contribuye al análisis científico de varias áreas del conocimiento como la filosofía social, la patología, la educación para el cuidado del medio ambiente y la sustentabilidad que inciden en diversas unidades de aprendizaje de la Licenciatura en Educación para la Salud y de la Maestría en Sociología de la SaludLas comunidades indígenas de la sierra norte de Oaxaca México, habitan un territorio extenso de biodiversidad. Sin que sea una área protegida y sustentable, la propia naturaleza de la región ofrece a sus visitantes la riqueza de la vegetación caracterizada por sus especies endémicas que componen un paisaje de suma belleza

Guide for Selection of Relevant Cell Lines During the Evaluation of new Anti-Cancer Compounds

Background: Human cancer cell lines are valuable models for anti-cancer drug development. Although all cancer cells share common biological features, each cancer cell line has unique genotypic/phenotypic characteristics that affect drug response. Thus, the information obtained with a specific cancer cell line cannot be easily extrapolated to other cancer cells. Consequently, cell line selection during experimental design is critical for providing proper and clinically relevant structure-activity analysis. Methods: Herein, we critically review the use of cancer cell lines as tools for activity analysis by comparing two different scenarios: i) the use of multiple cancer cell lines, with the NCI-60 Program as the most representative example; and, ii) the selection of a single cell line with specific biological characteristics that match the rationale of compound design. Results: Considering that most laboratories evaluate the activity of new compounds using few cell lines, we provide a systematic strategy for selection based on the expression levels and genetic status of the target and the effectiveness of target inhibition or silencing. We exemplify the use of public databases for data retrieval and analysis as well as the critical comparison of such information with published results. Conclusion: This approach refines cell line selection, avoiding the perpetuation of published poor selection and enhancing the relevance of the results

Clinical and Experimental Immunomodulation 2016

Inflammatory response (IR), which is crucial in injuries or infected anatomical regions, also generates systemic effects, regulating multiple physiological processes. Those effects depend on the concentration of soluble mediators likecytokines, chemokines, and other inflammatory molecules. For example, concentrations of soluble mediators around 10nM are enough to induce a neuroendocrine response. The diverse systemic effects triggered by IR are plastic and continuously modified by fluctuations of circulatory levels ofhormones, neurotransmitters, and mediators of inflammation. These feedback loops are possible by the constitutive expression of receptors for hormones, neurotransmitters, and cytokines on leukocytes, which modulate key cellularfunctions like proliferation, differentiation, and the secretion profile.That is the reason whereby the constant research on clinical and experimental parameters that modulate is of great importance. This third special issue on clinical and experimental immunomodulation compiles a selection of high quality works on the field.Fil: Pavón, Lenin. Instituto Nacional de Psiquiatría Ramón de la Fuente; MéxicoFil: Besedosky, Hugo. Universitat Phillips; AlemaniaFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Velasco Velázquez, Marco A.. Universidad Nacional Autónoma de México; MéxicoFil: Bauer, Moisés E.. Pontificia Universidade Católica do Rio Grande do Sul; Brasi