scholarly journals Dual PPARα/γAgonism Normalizes Lipoprotein Profile of Renal Dyslipidemia

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
O. Samuelsson ◽  
P. O. Attman ◽  
I. Gause-Nilsson ◽  
M. K. Svensson ◽  
P. Alaupovic
Keyword(s):  
Insulin Sensitivity ◽  
Plasma Lipids ◽  
Peroxisome Proliferators ◽  
Improve Insulin Sensitivity ◽  
Once Daily ◽  
Lipoprotein Subclasses ◽  
End Of Treatment ◽  
Baseline Levels ◽  
Dual Activation ◽  
Peroxisome Proliferators Activated Receptors

Chronic kidney disease (CKD) is characterised by specific lipoprotein abnormalities and insulin resistance. Dual activation of the peroxisome proliferators-activated receptors (PPAR)αandγcan significantly improve insulin sensitivity. The aim of the study was to investigate the effects of a dual PPARα/γagonist on lipoprotein abnormalities in patients with CKD. One mg of the dual PPARα/γagonist tesaglitazar was given once daily during six weeks to CKD patients, and to healthy subjects. Plasma lipids, apolipoproteins (apo) and discrete lipoprotein subclasses were measured at baseline and end of treatment. In the CKD patients apoA-I increased significantly by 9%, and apoB decreased by 18%. There was an increase of apoC-III in HDL by 30%, and a parallel decrease of apoC-III in VLDL + LDL by 13%. Both the apoB-containing cholesterol-rich and the triglyceride-rich subclasses decreased significantly. With the exception of ApoC-III,all plasma lipids apolipoproteins and lipoprotein subclasses were reduced by treatment down to similar levels as the baseline levels of a healthy group of reference subjects. This study suggests that by improving insulin sensitivity a dual PPARα/γagonist has the potential to normalise most of the lipoprotein abnormalities in patients with CKD.

DESIGN OF NEW PEROXISOME PROLIFERATORS GAMMA ACTIVATED RECEPTOR AGONISTS (PPARγ) VIA QSAR BASED MODELING

2018 ◽  
pp. 23-26 ◽  
Author(s):  
Tripathi RB ◽  
Jain J ◽  
Siddiqui AW
Keyword(s):  
Molecular Descriptor ◽  
Binding Pocket ◽  
Peroxisome Proliferators ◽  
Qsar Study ◽  
Qsar Analysis ◽  
Qsar Models ◽  
Artery Disease ◽  
Peroxisome Proliferators Activated Receptors ◽  
Recent Attention

The Peroxisome proliferators-activated receptors (PPARs) are one of the nuclear fatty acid receptors, which contain a type II zincfinger DNA binding pattern and a hydrophobic ligand binding pocket. These receptors are thought to play an essential role in metabolic diseasessuch as obesity, insulin resistance, and coronary artery disease. Therefore Peroxisome Proliferators-Activated Receptor (PPARγ) activators havedrawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize newPPARγ activators. Objective: The aim of the study was to finding new selective human PPARγ (PPARγ) modulators that are able to improveglucose homeostasis with reduced side effects compared with TZDs and identify the specific molecular descriptor and structural constraint toimprove the agonist activity of PPARγ analogs. Material and Method: Software’s that was used for this study include S.P. Gupta QSARsoftware (QSAR analysis), Valstat (Comparative QSAR analysis and calculation of L-O-O, Q2, r2, Spress), BILIN (Comparative QSAR analysisand calculation of Q2, r, S, Spress, and F), etc., allowing directly performing statistical analysis. Then multiple linear regression based QSARsoftware (received from BITS-Pilani, India) generates QSAR equations. Result and Discussion: In this study, we explored the quantitativestructure–activity relationship (QSAR) study of a series of meta-substituted Phenyl-propanoic acids as Peroxisome Proliferators Gamma activatedreceptor agonists (PPARγ).The activities of meta-substituted Phenyl-propanoic acids derivatives correlated with various physicochemical, electronic and steric parameters.Conclusion: The identified QSAR models highlighted the significance of molar refractivity and hydrophobicity to the biological activity.

Do ACE inhibitors improve insulin sensitivity?

The Lancet ◽  
1995 ◽  
Vol 346 (8974) ◽  
pp. 583-584 ◽  
Author(s):  
JohnR. Petrie ◽  
AndrewD. Morris ◽  
Shinichiro Ueda ◽  
HenryL. Elliott ◽  
JohnM.C. Connell ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Ace Inhibitors ◽  
Improve Insulin Sensitivity

505 Efficacy of Pitolisant in the Treatment of Cataplexy in Adults With Narcolepsy

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A199-A199
Author(s):  
Craig Davis ◽  
Donna Zarycranski ◽  
Markiyan Doliba ◽  
Jeffrey Dayno ◽  
Jean-Charles Schwartz
Keyword(s):  
Placebo Group ◽  
Washout Period ◽  
Excessive Daytime Sleepiness ◽  
Daytime Sleepiness ◽  
Symptom Burden ◽  
Pooled Analysis ◽  
Once Daily ◽  
High Burden ◽  
Treatment Assessment ◽  
End Of Treatment

Abstract Introduction Pitolisant was initially approved by the FDA in 2019 for the treatment of excessive daytime sleepiness in adult patients with narcolepsy; in 2020, the indication was expanded to include the treatment of cataplexy. Methods Cataplexy data from 7- or 8-week, randomized, placebo-controlled studies (HARMONY-CTP, HARMONY-1) are reviewed and summarized. In HARMONY-CTP, all patients were required to have ≥3 cataplexy attacks per week at baseline; HARMONY-1 enrolled patients with narcolepsy with or without cataplexy. Pitolisant was individually titrated to a maximum potential dose of 35.6 mg/day. The weekly (WRC) or daily (DRC) rate of cataplexy attacks was calculated from patient diaries. Results In HARMONY-CTP (pitolisant, n=54; placebo, n=51), mean baseline WRC was 11.7 in the pitolisant group and 9.6 in the placebo group. In the subset of HARMONY-1 patients with cataplexy (pitolisant, n=17; placebo, n=11), mean baseline DRC was 1.5 and 1.2, respectively. In HARMONY-CTP, least-squares (LS) mean change in WRC was significantly greater for pitolisant versus placebo at Week 2 (-4.1 vs 1.2; P=0.004) and continued through end of treatment (Week 7; -6.5 vs -0.1; P<0.001). In HARMONY-CTP, treatment response was observed in 66.7% of pitolisant-treated versus 25.5% of placebo-treated patients (P<0.001) for WRC reduction ≥50%, and 77.8% versus 33.3% of patients (P<0.001) for WRC reduction ≥25%. In HARMONY-1, LS mean change in DRC was significantly greater for pitolisant versus placebo at Week 5 (-1.04 vs 0.17; P=0.047) and continued through end of treatment (Week 8; -0.96 vs 0.35; P=0.035). In a pooled analysis of patients with high burden of cataplexy (≥15 attacks/week) at baseline (pitolisant, n=20; placebo, n=11), LS mean change in WRC at end-of-treatment assessment was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) versus placebo (-0.1; baseline, 23.1; final, 23.0; P=0.004). There was no evidence of rebound cataplexy after a 1-week placebo washout period. Conclusion Pitolisant, at once-daily doses of up to 35.6 mg, demonstrated a statistically significant and clinically meaningful reduction in the frequency of cataplexy attacks in adults with narcolepsy, including patients with a high symptom burden. Onset of response was observed within the first few weeks of pitolisant treatment. Support (if any) Bioprojet Pharma and Harmony Biosciences, LLC.

scholarly journals SO022VITAMIN D RECEPTOR ACTIVATION DOES NOT IMPROVE INSULIN SENSITIVITY IN PATIENTS WITH STAGE 3 TO 4 CHRONIC KIDNEY DISEASE

2017 ◽  
Vol 32 (suppl_3) ◽  
pp. iii13-iii13
Author(s):  
Belinda Spoto ◽  
Patrizia Pizzini ◽  
Sebastiano Cutrupi ◽  
Giovanni Tripepi ◽  
Giuseppe Curatola ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Insulin Sensitivity ◽  
Kidney Disease ◽  
Receptor Activation ◽  
Improve Insulin Sensitivity

scholarly journals Myricetin Increases Hepatic Peroxisome Proliferator-Activated ReceptorαProtein Expression and Decreases Plasma Lipids and Adiposity in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Chia Ju Chang ◽  
Thing-Fong Tzeng ◽  
Shorong-Shii Liou ◽  
Yuan-Shiun Chang ◽  
I-Min Liu
Keyword(s):  
Plasma Lipids ◽  
Regulatory Element ◽  
Plasma Lipid ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Down Regulation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Once Daily ◽  
Sterol Regulatory Element ◽  
Lowered Body

The aim of this study was to investigate the antiobesity and antihyperlipidaemic effects of myricetin. Myricetin exhibited a significant concentration-dependent decrease in the intracellular accumulation of triglyceride in 3T3-L1 adipocytes. The high-fat diet (HFD)-fed rats were dosed orally with myricetin or fenofibrate, once daily for eight weeks. Myricetin (300 mg kg−1per day) displayed similar characteristics to fenofibrate (100 mg kg−1per day) in reducing lowered body weight (BW) gain, visceral fat-pad weights and plasma lipid levels of HFD-fed rats. Myricetin also reduced the hepatic triglyceride and cholesterol contents, as well as lowered hepatic lipid droplets accumulation and epididymal adipocyte size in HFD-fed rats. Myricetin and fenofibrate reversed the HFD-induced down-regulation of the hepatic peroxisome proliferator activated receptor (PPAR)α. HFD-induced decreases of the hepatic protein level of acyl-CoA oxidase and cytochrome P450 isoform 4A1 were up-regulated by myricetin and fenofibrate. The elevated expressions of hepatic sterol regulatory element binding proteins (SREBPs) of HFD-fed rats were lowered by myricetin and fenofibrate. These results suggest that myricetin suppressed BW gain and body fat accumulation by increasing the fatty acid oxidation, which was likely mediated via up-regulation of PPARαand down-regulation of SREBP expressions in the liver of HFD-fed rats.

Contractile activity per se induces transcriptional activation of SLC2A4 gene in soleus muscle: involvement of MEF2D, HIF-1a, and TRα transcriptional factors

2009 ◽  
Vol 296 (1) ◽  
pp. E132-E138 ◽  
Author(s):  
Guilherme Alves Lima ◽  
Gabriel Forato Anhê ◽  
Gisele Giannocco ◽  
Maria Tereza Nunes ◽  
Maria Lucia Correa-Giannella ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Sensitivity ◽  
Soleus Muscle ◽  
Contractile Activity ◽  
Binding Activity ◽  
Transcriptional Factors ◽  
Chronic Exercise ◽  
Improve Insulin Sensitivity ◽  
Glut 4 ◽  
Per Se

Skeletal muscle is a target tissue for approaches that can improve insulin sensitivity in insulin-resistant states. In muscles, glucose uptake is performed by the GLUT-4 protein, which is encoded by the SLC2A4 gene. SLC2A4 gene expression increases in response to conditions that improve insulin sensitivity, including chronic exercise. However, since chronic exercise improves insulin sensitivity, the increased SLC2A4 gene expression could not be clearly attributed to the muscle contractile activity per se and/or to the improved insulin sensitivity. The present study was designed to investigate the role of contractile activity per se in the regulation of SLC2A4 gene expression as well as in the participation of the transcriptional factors myocyte enhancer factor 2D (MEF2D), hypoxia inducible factor 1a (HIF-1a), and thyroid hormone receptor-α (TRα). The performed in vitro protocol excluded the interference of metabolic, hormonal, and neural effects. The results showed that, in response to 10 min of electrically induced contraction of soleus muscle, an early 40% increase in GLUT-4 mRNA (30 min) occurred, with a subsequent 65% increase (120 min) in GLUT-4 protein content. EMSA and supershift assays revealed that the stimulus rapidly increased the binding activity of MEF2D, HIF-1a, and TRα into the SLC2A4 gene promoter. Furthermore, chromatin immunoprecipitation assay confirmed, in native nucleosome, that contraction induced an approximate fourfold ( P < 0.01) increase in MEF2D and HIF-1a-binding activity. In conclusion, muscle contraction per se enhances SLC2A4 gene expression and that involves MEF2D, HIF-1a, and TRα transcription factor activation. This finding reinforces the importance of physical activity to improve glycemic homeostasis independently of other additional insulin sensitizer approaches.

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