35 research outputs found
Mammalian Comparative Sequence Analysis of the Agrp Locus
Agouti-related protein encodes a neuropeptide that stimulates food intake. Agrp expression in the brain is restricted to neurons in the arcuate nucleus of the hypothalamus and is elevated by states of negative energy balance. The molecular mechanisms underlying Agrp regulation, however, remain poorly defined. Using a combination of transgenic and comparative sequence analysis, we have previously identified a 760 bp conserved region upstream of Agrp which contains STAT binding elements that participate in Agrp transcriptional regulation. In this study, we attempt to improve the specificity for detecting conserved elements in this region by comparing genomic sequences from 10 mammalian species. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements. Conserved sequences within these elements suggest a role for homeodomain proteins in the regulation of Agrp and provide additional targets for functional evaluation
Can Oxygen Set Thermal Limits in an Insect and Drive Gigantism?
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Efficacy and Safety of Ertugliflozin in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea: A Sub-Study of VERTIS CV.
IntroductionVERTIS CV is the cardiovascular outcome trial for the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU).MethodsPatients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0-10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c < 7%.ResultsOf the 8246 patients enrolled in VERTIS CV, 330 were eligible for this sub-study (ertugliflozin 5 mg, n = 100; ertugliflozin 15 mg, n = 113; placebo, n = 117). This subgroup had a mean (SD) age of 63.2 (8.4) years and T2DM duration of 11.4 (7.4) years. At week 18, ertugliflozin 5 mg and 15 mg were each associated with significantly greater least squares (LS) mean reductions from baseline in HbA1c relative to placebo (placebo-adjusted LS mean [95% CI] - 0.66% [- 0.89, - 0.43] and - 0.75% [- 0.98, - 0.53], respectively, p < 0.001 for each dose vs placebo). Ertugliflozin significantly reduced FPG and BW compared with placebo (p < 0.001), but not systolic BP. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ertugliflozin 5 mg and 15 mg, and placebo groups. The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo).ConclusionsIn patients with T2DM and ASCVD, ertugliflozin added to metformin and SU improved glycemic control, reduced BW, and was generally well tolerated.Trial registrationVERTIS CV ClinicalTrials.gov identifier, NCT01986881
Is leptin protective against heart failure with preserved ejection fraction? A complex interrelationship among leptin, obesity, and left ventricular hypertrophy
In vitro antiplasmodial activity and toxicity assessment of plant extracts used in traditional malaria therapy in the Lake Victoria Region
As part of our program screening the flora of the Lake Victoria Region, a total of 54 organic extracts from seven plant families (8 species) were individually tested for antiplasmodial activity against chloroquine-sensitive [Sierra Leone (D-6)] and chloroquine-resistant [Vietnam (W-2)] strains. Only 22% of these extracts exhibited very high in vitro antiplasmodial activity. Six methanol (MeOH) extracts and one chloroform extract showed in vitro antiplasmodial activity against the D-6 Plasmodium falciparum strain, while only three MeOH extracts were active against the W-2 strain. All of the ethyl acetate extracts proved to be inactive against both strains of P. falciparum. A brine shrimp cytotoxicity assay was used to predict the potential toxicity of the extracts. The cytotoxicity to antiplasmodial ratios for the MeOH extracts were found to be greater than 100, which could indicate that the extracts are of low toxicity
The role of renin–angiotensin–aldosterone system-based therapy in diabetes prevention and cardiovascular and renal protection
UNDERSTANDING THE INTERACTIONS BETWEEN ARTEMISININ AND CYCLODEXTRINS: SPECTROSCOPIC STUDIES AND MOLECULAR MODELING
Artemisinin extracted from Artemisia annua L. proved to be currently, with its derivatives, the most effective drugs against simple and severe malaria, and is also effective on the chloroquine-resistant forms. The advantageous effect of some cyclodextrins (CDs) on artemisinin solubilization was demonstrated by different authors. The present work aims to confirm the effect of several CDs on artemisinin solubilization and to analyse the complexes formed between these CDs and artemisinin in order to understand their solubilization capacities. In this context, solubility studies, liquid-state NMR spectroscopy ( 1H NMR studies and ROESY experiments) as well as theoretical studies (molecular modeling) have been performed. Randomly methylated-βCD, Crysmeb® and hydroxypropylated-γCD were also found to improve the aqueous solubilization of artemisinin as well as βCD, γCD and hydroxypropylated-βCD whose effects were already demonstrated. The best solubilization ability was found with Crysmeb®. The spectroscopic studies showed a lot of interactions between artemisinin and all the CDs studied, but mainly outside the cavity. Molecular modeling confirmed that artemisinin and CDs formed non-inclusion complexe