How to Increase the Safety and Efficacy of Compounds against Neurodegeneration? A Multifunctional Approach

Successful drug design requires not only the detailed knowledge of the pharmacokinetic and pharmacodynamic profiles of the drug candidate portfolio but also a thorough documentation of the possible toxic effects on humans and the environment. Thus, experimental and computational strategies able to measure or predict specific profiles of designed compounds related to their potential toxicity are highly desired. Moreover, a strategy to avoid toxic effects thus enhancing the potential efficacy of drug candidates is of great interest. To fulfil this aim, the pharmacochemistry research unit at the EPGL has recently developed and improved methodologies that detect the potential human health and environmental hazards of compounds active against neurodegeneration at an early stage. A three-step strategy is presented herein. In particular, i) an alternative index to model the bioconcentration of chemicals in the environment was determined; ii) the antioxidant activity of chemical species against free radicals was evaluated. Moreover, since antioxidants play a key role in both toxicity prevention and neuroprotection, iii) the potential interaction of such compounds with enzymatic targets involved in the neurodegenerative cascade was investigated in silico

Detecting, Quantifying, and Discriminating the Mechanism of Mosaic Chromosomal Aneuploidies Using MAD-seq

Current approaches to detect and characterize mosaic chromosomal aneuploidy are limited by sensitivity, efficiency, cost, or the need to culture cells. We describe the mosaic aneuploidy detection by massively parallel sequencing (MAD-seq) capture assay and the MADSEQ analytical approach that allow low

Development of cross metathesis for the design of HDAC inhibitors

Epigenetic histones post translational modifications are key players in the regulation of gene expression. Amongst all possible modifications, the N-acetylation of the lysine side chains located at the N-terminal tail of histones is involved in the relaxation of chromatine and contributes to gene transcription. This acetylation status is controlled by histone acetyl transferases (HAT) and histone deacetylases (HDAC and SIRT). The abnormal expression of HDAC has been linked to the progression of several human diseases such as cancers. Therefore, the development of HDAC inhibitors has emerged as a valuable therapeutic strategy, with currently four compounds approved by the FDA and a fifth one in China. Recent data suggested that combination therapies with HDAC inhibitors may contribute to better clinical results. HDACs are zinc-dependant enzymes grouped in a family of 11 proteins (HDAC1-11), grouped in three classes: class I (HDAC1-3,8), class Il (HDAC4-7,9,10) and class IV (HDAC11). The fourth group of deacetylases contains the class Ill NADH+-dependent sirtuins (SIRT1-7). The standard pharmacophore for HDAC inhibitors involves a zinc-binding group (ZBG) linked through a spacer to a “cap” group in interaction with the external solvent accessible surface. We were interested in alternative chemistries to access HDAC inhibitors in which the intermediate spacer could be build out of two similar building blocks, one bearing the ZBG and on bearing the cap group. By selecting linear alkyl-based spacer, cross metathesis appeared to be a short and flexible strategy, provided it supports the presence of highly oxophile functional groups such as carbonyl groups. This poster summarizes our findings in the application of cross metathesis and the biological evaluations of some of the compounds obtained

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Encyclopedia of Analytical Chemistry

International audienceThin‐layer chromatography (TLC) is a simple and cost‐effective technique, extensively used in natural products analysis. It is suitable for chemical and biological screening of herbal products and useful in monitoring bioguided isolation of active components. When coupled with appropriate detection methods, this versatile technique can provide qualitative or semi‐quantitative information on the chemical constituents of a complex mixture. For this purpose, the main advances in TLC include the development of highly efficient and reproducible methods, as in the case of high‐performance thin‐layer chromatography (HPTLC), and the development of several hyphenated techniques, including mass spectrometry (MS), Raman spectroscopy, and densitometry. Besides, several bioassays have been developed in combination with TLC separation for the on‐plate investigation of biological activity of natural products, a procedure known as bioautography. The major advantage of this technique is the ability to locate active substances from a complex mixture before compound purification. Overall, the recent advances in TLC analysis are a major contribution in avoiding time‐consuming and tedious isolation of already‐known or inactive phytochemicals. In this chapter, a comprehensive overview of TLC with chemical and biological detection is presented, with a focus on up‐to‐date bioautographic assays, their mechanisms, pitfalls, and recent advances in the field of natural products

Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana

Classical pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate–amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant

Study of Leaf Metabolome Modifications Induced by UV-C Radiations in Representative Vitis, Cissus and Cannabis Species by LC-MS Based Metabolomics and Antioxidant Assays

UV-C radiation is known to induce metabolic modifications in plants, particularly to secondary metabolite biosynthesis. To assess these modifications from a global and untargeted perspective, the effects of the UV-C radiation of the leaves of three different model plant species, Cissus antarctica Vent. (Vitaceae), Vitis vinifera L. (Vitaceae) and Cannabis sativa L. (Cannabaceae), were evaluated by an LC-HRMS-based metabolomic approach. The approach enabled the detection of significant metabolite modifications in the three species studied. For all species, clear modifications of phenylpropanoid metabolism were detected that led to an increased level of stilbene derivatives. Interestingly, resveratrol and piceid levels were strongly induced by the UV-C treatment of C. antarctica leaves. In contrast, both flavonoids and stilbene polymers were upregulated in UV-C-treated Vitis leaves. In Cannabis, important changes in cinnamic acid amides and stilbene-related compounds were also detected. Overall, our results highlighted phytoalexin induction upon UV-C radiation. To evaluate whether UV-C stress radiation could enhance the biosynthesis of bioactive compounds, the antioxidant activity of extracts from control and UV-C-treated leaves was measured. The results showed increased antioxidant activity in UV-C-treated V. vinifera extracts

Collaborative brazilian pediatric renal transplant registry (CoBrazPed-RTx) : a report from 2004 to 2018

The Brazilian collaborative registry for pediatric renal transplantation began in 2004 as a multicenter initiative aimed at analyzing, reporting, and disseminating the results of pediatric renal transplantation in Brazil. Data from all pediatric renal transplants performed from January 2004 to May 2018 at the 13 participating centers were analyzed. A total of 2744 pediatric renal transplants were performed in the thirteen participating centers. The median age at transplantation was 12.2 years, with the majority being male recipients (56%). The main underlying diseases were CAKUT (40.5%) and glomerulopathy (28%). 1981 (72%) of the grafts were from deceased donors (DD). Graft survival at one year (censored by death) was 94% in the live donor group (LD) and 91% in the DD group (log-rank test P < 0.01). The patient's survival at one and 5 years was 97% and 95% for the LD group and 96% and 93% for the DD group (log-rank test P = 0.02). The graft loss rate was 19% (n = 517), more frequently caused by vascular thrombosis (n = 102) and chronic graft nephropathy (n = 90). DD recipients had 1.6 (1.0-2.2) times greater chance of death and 1.5 (1.2-1.8) times greater chance of graft loss compared to LD recipients. The mortality rate was 5.4% (n = 148), mainly due to infection (n = 69) and cardiovascular disease (n = 28). The results of this collaborative pediatric renal transplant record are comparable to other international registries, although we still have a high infection rate as a cause of death23