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The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.

ABSTRACT: ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators.

SUBMITTER: Kharade SV

PROVIDER: S-EPMC4976861 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.

Kharade Sujay V SV Nichols Colin C Denton Jerod S JS

Future medicinal chemistry 20160510 7

ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes ...[more]

PMID: 27161588

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Project description:Abstract Proper knowledge and understanding of climatic variability across different seasons are important in farm management. To learn more about the potential effects of climate change on dairying in Hawaii, we conducted a study on site-specific climate characterization using several variables including rainfall, wind speed (WS), solar radiation, and temperature, at two dairy farms located on Hawai`i Island, Hawai`i, in Ookala named “OK DAIRY” and in Upolu Point named “UP DAIRY.” Temperature–humidity index (THI) and WS variations in the hottest four months (June to September) were analyzed to determine when critical thresholds that affect animal health are exceeded. Rainfall data were used to estimate the capacity of forage production in 6-mo wet (November to April) and dry (May to October) seasons. Future projections of temperature and rainfall were assessed using mid- and end-century gridded data products for low (RCP 4.5) and high emissions (RCP 8.5) scenarios. Our results showed that the “OK DAIRY” site received higher rainfall than the “UP DAIRY” site, favoring grass growth and forage availability. In addition, the “UP DAIRY” site was more stressful for animals during the summer (THI 69 to 73) than the “OK DAIRY” site (THI 67 to 70) as the THI exceeded the critical threshold of 68, which is conducive for high-lactating cattle. On the “UP DAIRY” site, the THI did not drop below 68 during the summer nights, which created fewer opportunities for cattle to recover from heat stress. Future projections indicated that air temperature would increase 1.3 to 1.8 °C by mid-century and 1.6 to 3.2 °C by the end-century at both farms, and rainfall will increase at the “OK DAIRY” site and decrease at the “UP DAIRY” site by the end-century. The agriculture and livestock industries, particularly the dairy and beef subsectors in Hawai`i, are vulnerable to climate changes as higher temperatures and less rainfall will have adverse effects on cattle. The findings in this study demonstrated how both observed and projected changes in climate support the development of long-term strategies for breeding and holistic livestock management practices to adapt to changing climate conditions.

Dataset Information

The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.

Publications

The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics.

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