In silico modification of suberoylanilide hydroxamic acid (SAHA) as potential inhibitor for class II histone deacetylase (HDAC)

<p>Abstract</p> <p>Background</p> <p>The cervical cancer is the second most prevalent cancer for the woman in the world. It is caused by the oncogenic human papilloma virus (HPV). The inhibition activity of histone deacetylase (HDAC) is a potential strategy for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is widely known as a low toxicity HDAC inhibitor. This research presents <it>in silico</it> SAHA modification by utilizing triazole, in order to obtain a better inhibitor. We conducted docking of the SAHA inhibitor and 12 modified versions to six class II HDAC enzymes, and then proceeded with drug scanning of each one of them.</p> <p>Results</p> <p>The docking results show that the 12 modified inhibitors have much better binding affinity and inhibition potential than SAHA. Based on drug scan analysis, six of the modified inhibitors have robust pharmacological attributes, as revealed by drug likeness, drug score, oral bioavailability, and toxicity levels.</p> <p>Conclusions</p> <p>The binding affinity, free energy and drug scan screening of the best inhibitors have shown that 1c and 2c modified inhibitors are the best ones to inhibit class II HDAC.</p

Onset of the Thermic Effect of Feeding (TEF): a randomized cross-over trial

<p>Abstract</p> <p>Background</p> <p>The purpose of this investigation was to identify the onset of the thermic effect of feeding (TEF) after ingestion of a high carbohydrate (CHO) and a high protein (PRO) 1255 kJ (300 kcal) drink.</p> <p>Methods</p> <p>Resting metabolic rate (RMR) and TEF were measured over 30-minute periods via indirect calorimetry using a ventilated hood technique. Eighteen subjects (7 men and 11 women) completed two randomized, double-blind trials. Data were collected in 1-minute measurement intervals. RMR was subtracted from TEF and the time of onset was obtained when two consecutive data points exceeded 5% and 10% of resting metabolic rate.</p> <p>Results</p> <p>At 5% above RMR the onset of TEF for CHO was 8.4 ± 6.2 minutes and was not different as compared to PRO, 8.6 ± 5.2 minutes (p = 0.77). Likewise, no differences were found with a 10% increase above RMR: CHO, 14.1 ± 7.5 min; PRO, 16.7 ± 6.7 min (p = 0.36). Several subjects did not show a 10% increase within 30-min.</p> <p>Conclusion</p> <p>We conclude that the onset of TEF is variable among subjects but is initiated within about 5 to 20-min for most subjects after ingestion of a 1255 kJ liquid meal. No differences were found between CHO or PRO liquid meals.</p

Macroscopic heat release in a molecular solar thermal energy storage system

The development of solar energy can potentially meet the growing requirements for a global energy system beyond fossil fuels, but necessitates new scalable technologies for solar energy storage. One approach is the development of energy storage systems based on molecular photoswitches, so-called molecular solar thermal energy storage (MOST). Here we present a novel norbornadiene derivative for this purpose, with a good solar spectral match, high robustness and an energy density of 0.4 MJ kg -1 . By the use of heterogeneous catalyst cobalt phthalocyanine on a carbon support, we demonstrate a record high macroscopic heat release in a flow system using a fixed bed catalytic reactor, leading to a temperature increase of up to 63.4 °C (83.2 °C measured temperature). Successful outdoor testing shows proof of concept and illustrates that future implementation is feasible. The mechanism of the catalytic back reaction is modelled using density functional theory (DFT) calculations rationalizing the experimental observations

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Bio-inspired CO₂ conversion by iron sulfide catalysts under sustainable conditions

The mineral greigite presents similar surface structures to the active sites found in many modern-day enzymes. We show that particles of greigite can reduce CO2 under ambient conditions into chemicals such as methanol, formic, acetic and pyruvic acid. Our results also lend support to the Origin of Life theory on alkaline hydrothermal vents

Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery

Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules

Reflectivity, reflexivity and situated reflective practice

This paper describes an aspect of reflective practice referred to as ‘Situated Reflective Practice’ (SRP). The overarching theory is derived from social theories of structuration and reflexivity. In particular, from Giddens’s (1984) theory of structuration, this sees social life as interplay of agency and structure. Discussion of the research reported here centres on the nature of such situated reflection, considers related literature and presents the data collected in a recent small-scale study. The original purpose of the research was to explore the perceptions of corporate trainers on a course for Preparing to Teach in the Lifelong Learning Sector (PTLLS). As a result of this research the concept of Situated Reflective Practice was generated. It is argued that here exist some situations where a person will find themselves in a position over which they have little control, avoidance or veto. The major conclusion of this study was that key interview themes enabled the delineation of a series of five characteristics representing increasing structural distance in space and time between the reflective practitioner and the professional situation in which they work

Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammatory signature correlating with survival advantage in peritoneal mesothelioma

Background: Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours. Results: We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to similar to 1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a proinflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma. Conclusions: We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner