How Can Molecular Pharmacology Help Understand the Multiple Actions of Melatonin: 20 Years of Research and Trends

Melatonin actions are so numerous that a naive reader might become suspicious at such wonders. In a systematic way, we would like to summarize the various approaches that led to what is scientifically sounded in terms of molecular pharmacology: where and how melatonin is acting as a molecule, what can be its action as an antioxidant per se, and its side effects at a molecular level not as a drug or in vivo. Finally, the nature of the relationship between melatonin and mitochondria should be decrypted as well. The road we took from 1987 up to now, and particularly after 1995, will be mentioned with special considerations to the receptors from various species and our goals beyond that; the synthesis and catabolism of melatonin and their link to other enzymes; the discovery of the MT3 binding sites, and what’s left to understand on this particularly interesting target; and the search for agonists that occulted part of the potential discovery of true and potent antagonists, a situation quite unique among the G-protein-coupled receptors

On the Organization of a Drug Discovery Platform

Some of the most exciting parts of work in the pharmaceutical industry are the steps leading up to drug discovery. This process can be oversimplified by describing it as a screening campaign involving the systematic testing of many compounds in a test relevant to a given pathology. This naïve description takes place without taking into consideration the numerous key steps that led up to the screening or the steps that might follow. The present chapter describes this whole process as it was conducted in our company during our early drug discovery activities. First, the purpose of the procedures is described and rationalized. Next follows a series of mostly published examples from our own work illustrating the various steps of the process from cloning to biophysics, including expression systems and membrane-bound protein purifications. We believe that what is described here presents an example of how pharmaceutical industry research can organize its platform(s) when the goal is to find and qualify a new preclinical drug candidate using cutting-edge technologies and a lot of hard work

Melanin-concentrating hormone receptors in GtoPdb v.2023.1

Melanin-concentrating hormone (MCH) receptors (provisional nomenclature as recommended by NC-IUPHAR [32]) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (PMCH, P20382), which also produces neuropeptide EI and neuropeptide GE

Melanin-concentrating hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Melanin-concentrating hormone (MCH) receptors (provisional nomenclature as recommended by NC-IUPHAR [31]) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (PMCH, P20382), which also produces neuropeptide EI and neuropeptide GE

Functional invalidation of the autotaxin gene by a single amino acid mutation in mouse is lethal

AbstractAutotaxin is a member of the phosphodiesterase family of enzymes, (NPP2). It is an important secreted protein found in conditioned medium from adipocytes. It also has a putative role in the metastatic process. Based on these observation, further validation of this potential target was necessary, apart from the classical biochemical ones. The construction of a knock out mouse strain for ATX was started. In this paper, we report the generation of a mouse line displaying an inactivated ATX gene product. The KO line was designed in order to generate a functional inactivation of the protein. In this respect, the threonine residue T210 was replaced by an alanine (T210A) leading to a catalytically inactive enzyme. If the experimental work was straight forward, we disappointedly discovered at the final stage that the breeding of heterozygous animals, ATX −/+, led to the generation of a Mendelian repartition of wild-type and heterozygous, but no homozygous were found, strongly suggesting that the ATX deletion is lethal at an early stage of the development. This was confirmed by statistical analysis. Although other reported the same lethality for attempted ATX−/− mice generation [van Meeteren, L.A., Ruurs, P., Stortelers, C., Bouwman, P., van Rooijen, M.A., Pradère, J.P., Pettit, T.R., Wakelam, M.J.O., Saulnier-Blache, J.S., Mummery, C.L., Moolenar, W.H. and Jonkers, J. (2006) Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development, Mol. Cell. Biol. 26, 5015–5022; Tanaka, M., Okudaira, S., Kishi, Y., Ohkawa, R., Isei, S., Ota, M., Noji, S., Yatomi, Y., Aoki, J., and Arai, H. (2006) Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid, J. Biol. Chem. 281, 25822–25830], they used more drastic multiple exon deletions in the ATX gene, while we chose a single point mutation. To our knowledge, the present work is the first showing such a lethality in any gene after a point mutation in an enzyme catalytic site

Specific Oncogenic Activity of the Src-Family Tyrosine Kinase c-Yes in Colon Carcinoma Cells

c-Yes, a member of the Src tyrosine kinase family, is found highly activated in colon carcinoma but its importance relative to c-Src has remained unclear. Here we show that, in HT29 colon carcinoma cells, silencing of c-Yes, but not of c-Src, selectively leads to an increase of cell clustering associated with a localisation of β-catenin at cell membranes and a reduction of expression of β-catenin target genes. c-Yes silencing induced an increase in apoptosis, inhibition of growth in soft-agar and in mouse xenografts, inhibition of cell migration and loss of the capacity to generate liver metastases in mice. Re-introduction of c-Yes, but not c -Src, restores transforming properties of c-Yes depleted cells. Moreover, we found that c-Yes kinase activity is required for its role in β-catenin localisation and growth in soft agar, whereas kinase activity is dispensable for its role in cell migration. We conclude that c-Yes regulates specific oncogenic signalling pathways important for colon cancer progression that is not shared with c-Src

Value of syndromic surveillance within the Armed Forces for early warning during a dengue fever outbreak in French Guiana in 2006

<p>Abstract</p> <p>Background</p> <p>A dengue fever outbreak occured in French Guiana in 2006. The objectives were to study the value of a syndromic surveillance system set up within the armed forces, compared to the traditional clinical surveillance system during this outbreak, to highlight issues involved in comparing military and civilian surveillance systems and to discuss the interest of syndromic surveillance for public health response.</p> <p>Methods</p> <p>Military syndromic surveillance allows the surveillance of suspected dengue fever cases among the 3,000 armed forces personnel. Within the same population, clinical surveillance uses several definition criteria for dengue fever cases, depending on the epidemiological situation. Civilian laboratory surveillance allows the surveillance of biologically confirmed cases, within the 200,000 inhabitants.</p> <p>Results</p> <p>It was shown that syndromic surveillance detected the dengue fever outbreak several weeks before clinical surveillance, allowing quick and effective enhancement of vector control within the armed forces. Syndromic surveillance was also found to have detected the outbreak before civilian laboratory surveillance.</p> <p>Conclusion</p> <p>Military syndromic surveillance allowed an early warning for this outbreak to be issued, enabling a quicker public health response by the armed forces. Civilian surveillance system has since introduced syndromic surveillance as part of its surveillance strategy. This should enable quicker public health responses in the future.</p

Proposal of a framework for evaluating military surveillance systems for early detection of outbreaks on duty areas

<p>Abstract</p> <p>Background</p> <p>In recent years a wide variety of epidemiological surveillance systems have been developed to provide early identification of outbreaks of infectious disease. Each system has had its own strengths and weaknesses. In 2002 a Working Group of the Centers for Disease Control and Prevention (CDC) produced a framework for evaluation, which proved suitable for many public health surveillance systems. However this did not easily adapt to the military setting, where by necessity a variety of different parameters are assessed, different constraints placed on the systems, and different objectives required. This paper describes a proposed framework for evaluation of military syndromic surveillance systems designed to detect outbreaks of disease on operational deployments.</p> <p>Methods</p> <p>The new framework described in this paper was developed from the cumulative experience of British and French military syndromic surveillance systems. The methods included a general assessment framework (CDC), followed by more specific methods of conducting evaluation. These included Knowledge/Attitude/Practice surveys (KAP surveys), technical audits, ergonomic studies, simulations and multi-national exercises. A variety of military constraints required integration into the evaluation. Examples of these include the variability of geographical conditions in the field, deployment to areas without prior knowledge of naturally-occurring disease patterns, the differences in field sanitation between locations and over the length of deployment, the mobility of military forces, turnover of personnel, continuity of surveillance across different locations, integration with surveillance systems from other nations working alongside each other, compatibility with non-medical information systems, and security.</p> <p>Results</p> <p>A framework for evaluation has been developed that can be used for military surveillance systems in a staged manner consisting of initial, intermediate and final evaluations. For each stage of the process parameters for assessment have been defined and methods identified.</p> <p>Conclusion</p> <p>The combined experiences of French and British syndromic surveillance systems developed for use in deployed military forces has allowed the development of a specific evaluation framework. The tool is suitable for use by all nations who wish to evaluate syndromic surveillance in their own military forces. It could also be useful for civilian mobile systems or for national security surveillance systems.</p

Genetic polymorphisms and weight loss in obesity: A randomised trial of hypo-energetic high-versus low-fat diets

OBJECTIVES: To study if genes with common single nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet. DESIGN: Randomised, parallel, two-arm, open-label multi-centre trial. SETTING: Eight clinical centres in seven European countries. PARTICIPANTS: 771 obese adult individuals. INTERVENTIONS: 10-wk dietary intervention to hypo-energetic (-600 kcal/d) diets with a targeted fat energy of 20%-25% or 40%-45%, completed in 648 participants. OUTCOME MEASURES: WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants. RESULTS: Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from -0.6 to 0.8 kg, and homozygotes, from -0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to -1.6 kg in heterozygotes, and from 3.8 kg to -2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant. CONCLUSIONS: Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet