LC-MS proteomics analysis of the iInsulin/IGF-1-deficient Caenorhabditis elegans daf-2(e1370) mutant reveals extensive restructuring of intermediary metabolism

The insulin/IGF-1 receptor is a major known determinant of dauer formation, stress resistance, longevity, and metabolism in Caenorhabditis elegans. In the past, whole-genome transcript profiling was used extensively to study differential gene expression in response to reduced insulin/IGF-1 signaling, including the expression levels of metabolism-associated genes. Taking advantage of the recent developments in quantitative liquid chromatography mass spectrometry (LC-MS)-based proteomics, we profiled the proteomic changes that occur in response to activation of the DAF-16 transcription factor in the germline-less glp-4(bn2);daf-2(e1370) receptor mutant. Strikingly, the daf-2 profile suggests extensive reorganization of intermediary metabolism, characterized by the upregulation of many core intermediary metabolic pathways. These include glycolysis/gluconeogenesis, glycogenesis, pentose phosphate cycle, citric acid cycle, glyoxylate shunt, fatty acid beta-oxidation, one-carbon metabolism, propionate and tyrosine catabolism, and complexes I, II, III, and V of the electron transport chain. Interestingly, we found simultaneous activation of reciprocally regulated metabolic pathways, which is indicative of spatiotemporal coordination of energy metabolism and/or extensive post-translational regulation of these enzymes. This restructuring of daf-2 metabolism is reminiscent to that of hypometabolic dauers, allowing the efficient and economical utilization of internal nutrient reserves and possibly also shunting metabolites through alternative energy-generating pathways to sustain longevity

Prevention of occupational diseases in Turkey : deriving lessons from journey of surveillance

Introduction: To prevent and manage the societal and economic burden of occupational diseases (ODs), countries should develop strong prevention policies, health surveillance and registry systems. This study aims to contribute to the improvement of OD surveillance at national level as well as to identify priority actions in Turkey. Methods: The history and current status of occupational health studies were considered from the perspective of OD surveillance. Interpretative research was done through literature review on occupational health at national, regional and international level. Analyses were focused on countries' experiences in policy development and practice, roles and responsibilities of institutions, multidisciplinary and intersectoral collaboration. OD surveillance models of Turkey, Belgium and the Netherlands were examined through exchange visits. Face-to-face interviews were conducted to explore the peculiarities of legislative and institutional structures, the best and worst practices, and approach principles. Results: Some countries are more focused on exploring OD trends through effective and cost-efficient researches, with particular attention to new and emerging ODs. Other countries try to reach every single case of OD for compensation and rehabilitation. Each practice has advantages and shortcomings, but they are not mutually exclusive, and thus an effective combination is possible. Conclusion: Effective surveillance and registry approaches play a key role in the prevention of ODs. A well-designed system enables monitoring and assessment of OD prevalence and trends, and adoption of preventive measures while improving the effectiveness of redressing and compensation. A robust surveillance does not only provide protection of workers' health but also advances prevention of economic losses

THADA regulates the organismal balance between energy storage and heat production

Human susceptibility to obesity is mainly genetic, yet the underlying evolutionary drivers causing variation from person to person are not clear. One theory rationalizes that populations that have adapted to warmer climates have reduced their metabolic rates, thereby increasing their propensity to store energy. We uncover here the function of a gene that supports this theory. THADA is one of the genes most strongly selected during evolution as humans settled in different climates. We report here that THADA knockout flies are obese, hyperphagic, have reduced energy production, and are sensitive to the cold. THADA binds the sarco/ER Ca2+ ATPase (SERCA) and acts on it as an uncoupler. Reducing SERCA activity in THADA mutant flies rescues their obesity, pinpointing SERCA as a key effector of THADA function. In sum, this identifies THADA as a regulator of the balance between energy consumption and energy storage, which was selected during human evolution

Phase 1 Study of the Effect of Icosapent Ethyl on Warfarin Pharmacokinetic and Anticoagulation Parameters

Abstract Background and Objective Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved to reduce triglyceride levels in patients with severe (C5.65 mmol/L) hypertriglyceridemia. EPA, the active metabolite of IPE, is mainly metabolized via b-oxidation, and studies suggest that omega-3 fatty acids such as EPA may have antithrombotic effects. The objective of this study was to evaluate the effect of IPE on the pharmacokinetic and anticoagulation pharmacodynamics of warfarin, a substrate of cytochrome P450 2C9-mediated metabolism. Methods Healthy adults received oral warfarin (25 mg) on day 1, oral IPE (4 g/day) on days 8-35, and coadministration on Day 29. Primary pharmacokinetic end points were area under the concentration-versus-time curve from zero to infinity (AUC 0-? ) and maximum plasma concentration (C max ) for R-and S-warfarin; pharmacodynamic end points were area under the international normalized ratio (INR) effect-time curve after the warfarin dose (AUC INR ) and maximum INR (INR max ). Results Twenty-five subjects completed the study. AUC 0-? and C max ratios of geometric means for both Rand S-warfarin following co-administration of warfarin with versus without IPE were within the 90 % confidence intervals of 0.80-1.25. AUC INR , INR max , and ratios were also similar. Conclusions IPE 4 g/day did not significantly change the single-dose AUC 0-? or C max of R-and S-warfarin or the anticoagulation pharmacodynamics of warfarin when coadministered as racemic warfarin at 25 mg. Co-administration of these drugs was safe and well tolerated in this study of healthy adult subjects. Key Points Patients who are candidates for icosapent ethyl therapy may also be receiving warfarin anticoagulation therapy. Icosapent ethyl 4 g/day did not have an effect on the pharmacokinetics or anticoagulation pharmacodynamics of warfarin. Co-administration of icosapent ethyl and warfarin was safe and well tolerated