Highlights of Natural Products in Prostate Cancer Drug Discovery

The remarkable impact of natural products (NPs) in the quest for new agents and new directions in medicinal discovery is well established. The exploration of Nature as a source of novel active agents that may serve as leads and scaffolds for drugs targeting a myriad of diseases and the use of synthetic organic chemistry to modify them have been a driving force for drug discovery. Worldwide, prostate cancer (PC) is the second leading cause of death after lung cancer on both USA and Australia, and the third after lung and colo-rectal cancers in Europe

Steroidal CYP17 Inhibitors for Prostate Cancer Treatment: From Concept to Clinic

The successful application of therapeutic strategies to block the known growth stimulation property of estrogen in breast cancer, namely the aromatase (CYP19) inhibitors formestane (4-OH) and exemestane (Aromasin) [1], has paved the way for the investigation of inhibitors of other P450 enzymes that might impart the growth of hormone-dependent cancers [2]. Cytochrome P450 17α-hydroxylase,C17,20-lyase (CYP17) is at the crossroads of androgen and corticoid biosynthesis and has become a valuable target in prostate cancer (PC) treatment [3-8]. Androgens, which are produced in steroidogenic tissues, bind to the androgen receptor (AR) and initiate transcription which in turn results in the synthesis of prostate-specific proteins, as well as in cell proliferation. Systemic ablation of androgen by castration, either surgical or chemical, is highly effective in treating PC when the disease is hormone-dependent

Recent Highlights in Green Oxidative Chemical Processes Applied to Steroid Chemistry

Steroids and their oxidation products are widely distributed in living organisms and are important intermediates for the synthesis of many biologically active molecules. Due to their pharmacological and synthetic relevance, several oxidative chemical processes for the functionalization of the steroid nucleus have been developed. Green chemistry principles have been incorporated in some oxidative transformations of steroids, allowing significant advances in synthetic chemistry applied to these compounds. This chapter presents a selection of relevant applications of pharmaceutical green chemistry to steroid’s oxidative processes. Special emphasis is given to catalytic processes encompassing heterogeneous nanocatalysts, whose application in this context is increasing over the past years. This chapter is organized according to the reaction type that includes alcohol oxidation, epoxidation of alkenes, and allylic oxidation of alkenes to enones, among other relevant oxidative transformations. Biocatalytic oxidative methods applied to steroid synthesis are not included in this review

Aboriginal Women Against Violence Project Evaluation Report

In 2008 Joan Harrison’s Support Services for Women received funding under the National Community Crime Prevention Programme (NCCPP) in relation to the Aboriginal Women Against Violence Project. The overall aim of the project was ‘to address family violence in Aboriginal and Torres Strait Islander communities in Liverpool and Campbelltown areas’ (Attorney General’s Funding schedule). The project identified two specific strategies to achieve this general aim: to train local Aboriginal and Torres Strait Islander women to become trainer, mentors and advocates in their own communities;to establish an Aboriginal Women Against Violence Committee. This evaluation reports on the agreed outcomes identified in the funding agreement as well as identifying broader lessons arising from the project in relation to addressing violence in Aboriginal and Torres Strait Islander communities.Joan Harrison’s Support Services for Wome

Synthesis and Biological Evaluation of New Madecassic Acid Derivatives Targeting ERK Cascade Signaling

In the present study, a series of novel madecassic acid derivatives was synthesized and screened against the National Cancer Institute's 60 human cancer cell line panel. Among them, compounds 5, 12, and 17 displayed potent and highly differential antiproliferative activity against 80% of the tumor cells harboring the B-RafV600E mutation within the nanomolar range. Structure-activity analysis revealed that a 5-membered A ring containing an α,β-unsaturated aldehyde substituted at C-23 with a 2-furoyl group seems to be crucial to produce this particular growth inhibition signature. In silico analysis of the cytotoxicity pattern of these compounds identified two highly correlated clinically approved drugs with known B-RafV600E inhibitory activity. Follow-up analysis revealed inhibition of the ERK signaling pathway through the reduction of cellular Raf protein levels is a key mechanism of action of these compounds. In particular, 17 was the most potent compound in suppressing tumor growth of B-RafV600E-mutant cell lines and displayed the highest reduction of Raf protein levels among the tested compounds. Taken together, this study revealed that modifications of madecassic acid structure can provide molecules with potent anticancer activity against cell lines harboring the clinically relevant B-RafV600E mutation, with compound 17 identified as a promising lead for the development of new anticancer drugs

Validation of models with constant bias: an applied approach

Objective. This paper presents extensions to the statistical validation method based on the procedure of Freese when a model shows constant bias (CB) in its predictions and illustrate the method with data from a new mechanistic model that predict weight gain in cattle. Materials and methods. The extensions were the hypothesis tests and maximum anticipated error for the alternative approach, and the confidence interval for a quantile of the distribution of errors. Results. The model evaluated showed CB, once the CB is removed and with a confidence level of 95%, the magnitude of the error does not exceed 0.575 kg. Therefore, the validated model can be used to predict the daily weight gain of cattle, although it will require an adjustment in its structure based on the presence of CB to increase the accuracy of its forecasts. Conclusions. The confidence interval for the 1-α quantile of the distribution of errors after correcting the constant bias, allows determining the top limit for the magnitude of the error of prediction and use it to evaluate the evolution of the model in the forecasting of the system. The confidence interval approach to validate a model is more informative than the hypothesis tests for the same purpose

High pressure pre-treatments promote higher rate and degree of enzymatic hydrolysis of cellulose

The effect of high pressure (HP) pre-treatments on the subsequent enzymatic hydrolysis of cellulose from bleached kraft Eucalyptus globulus pulp by cellulase from Tricoderma viride was evaluated. Pressure pre-treatments of 300 and 400 MPa during 5–45 min, lead to both an increased rate and degree of hydrolysis, reaching values ranging from 1.5- to 1.9-fold, quantified by the formation of reducing sugars. Both the pressure and time under pressure influenced the enzymatic hydrosability of the cellulosic pulps, with the former being more important. The results indicate that the pressure pre-treatments promoted an increased accessibility of cellulose towards cellulase in the cell wall. The results obtained open promising possibilities, to contribute to overcome conventional limitations of enzymatic cellulose hydrolysis for the production of fermentable glucose, for the production of second generation bioethanol and chemicals by enhancement of both rate and yield of hydrolysis. The results are also of interest for the preparation of “pressure engineered” celullose with incremented tailored hydrolysis patterns

6β-Chloro-5α-hydr­oxy-20-oxopregnan-3β-yl acetate

The title steroid, C23H35ClO4, is a pregnane derivative prepared by ring opening of the corresponding 5α,6α-ep­oxy steroid with BiCl3. There are two symmetry-independent mol­ecules in the asymmetric unit that show no significant differences concerning bond lengths and angles. The conformation of the six-membered rings in both mol­ecules is close to a chair form, while the five-membered ring adopts an envelope conformation. All rings in both mol­ecules are trans-fused. The mol­ecules are held together by an extensive O—H⋯O hydrogen-bonding network

Aislaciones en climas fríos

Independientemente de la fuente que provee energía térmica a un edificio, es necesario aislarlo a fin de aumentar su eficiencia energética. En el presente trabajo se evalúa el comportamiento de los cerramientos aislados de los edificios ante la acción de los procesos de transferencia de masa y de calor que en ellos ocurren. En función de este conocimiento y la aplicación de un modelo apropiado se pretende configurar una estructura de aislaciones que permita la predicción de los efectos perjudiciales que producen la condensación de vapor de agua interna o la formación destructiva de hielo. Se incluyen aplicaciones a sistemas de aislación habituales con materiales de uso corriente en la construcción local, que contradicen viejos preconceptos sobre el tema.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES

A Bioinformatics-Assisted Review on Iron Metabolism and Immune System to Identify Potential Biomarkers of Exercise Stress-Induced Immunosuppression

The immune function is closely related to iron (Fe) homeostasis and allostasis. The aim of this bioinformatics-assisted review was twofold; (i) to update the current knowledge of Fe metabolism and its relationship to the immune system, and (ii) to perform a prediction analysis of regulatory network hubs that might serve as potential biomarkers during stress-induced immunosuppression. Several literature and bioinformatics databases/repositories were utilized to review Fe metabolism and complement the molecular description of prioritized proteins. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to build a protein-protein interactions network for subsequent network topology analysis. Importantly, Fe is a sensitive double-edged sword where two extremes of its nutritional status may have harmful effects on innate and adaptive immunity. We identified clearly connected important hubs that belong to two clusters: (i) presentation of peptide antigens to the immune system with the involvement of redox reactions of Fe, heme, and Fe trafficking/transport; and (ii) ubiquitination, endocytosis, and degradation processes of proteins related to Fe metabolism in immune cells (e.g., macrophages). The identified potential biomarkers were in agreement with the current experimental evidence, are included in several immunological/biomarkers databases, and/or are emerging genetic markers for different stressful conditions. Although further validation is warranted, this hybrid method (human-machine collaboration) to extract meaningful biological applications using available data in literature and bioinformatics tools should be highlighted.The ‘Bioinformatics-assisted Review’ is a project developed and supported by the Research Division at the Dynamical Business and Science Society—DBSS International SAS. The APC was funded by the Exercise & Sport Nutrition Laboratory (ESNL) at Texas A&M University, the POWER LAB at University of Central Florida and the Sport Genomics Research Group at University of the Basque Country UPV/EHU