scholarly journals Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

2018 ◽  
Vol 9 ◽  
Author(s):  
Jingwen Xia ◽  
Li Yang ◽  
Liang Dong ◽  
Mengjie Niu ◽  
Shengli Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Virtual Screening ◽  
Therapeutic Efficacy ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Prostacyclin Receptor ◽  
Dual Agonist

scholarly journals Bortezomib alleviates experimental pulmonary hypertension by regulating intracellular calcium homeostasis in PASMCs

2016 ◽  
Vol 311 (3) ◽  
pp. C482-C497 ◽  
Author(s):  
Jun Zhang ◽  
Wenju Lu ◽  
Yuqin Chen ◽  
Qian Jiang ◽  
Kai Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Transient Receptor Potential ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Receptor Potential ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Canonical Transient Receptor Potential ◽  
Transient Receptor

The ubiquitin-proteasome system is considered to be the key regulator of protein degradation. Bortezomib (BTZ) is the first proteasome inhibitor approved by the US Food and Drug Administration for treatment of relapsed multiple myeloma and mantle cell lymphoma. Recently, BTZ treatment was reported to inhibit right ventricular hypertrophy and vascular remodeling in hypoxia-exposed and monocrotaline-injected rats. However, the underlying mechanisms remain poorly understood. We previously confirmed that hypoxia-elevated basal intracellular Ca2+ concentration ([Ca2+]i) and store-operated Ca2+ entry (SOCE) in pulmonary artery smooth muscle cells (PASMCs) are involved in pulmonary vascular remodeling. In this study we aim to determine whether BTZ attenuates the hypoxia-induced elevation of [Ca2+] in PASMCs and the signaling pathway involved in this mechanism. Our results showed that 1) in hypoxia- and monocrotaline-induced rat pulmonary hypertension (PH) models, BTZ markedly attenuated the development and progression of PH, 2) BTZ inhibited the hypoxia-induced increase in cell proliferation, basal [Ca2+]i, and SOCE in PASMCs, and 3) BTZ significantly normalized the hypoxia-upregulated expression of hypoxia-inducible factor-1α, bone morphogenetic protein 4, canonical transient receptor potential isoforms 1 and 6, and the hypoxia-downregulated expression of peroxisome proliferator-activated receptor-γ in rat distal pulmonary arteries and PASMCs. These results indicate that BTZ exerts its protective role in the development of PH potentially by inhibiting the canonical transient receptor potential-SOCE-[Ca2+]i signaling axis in PASMCs.

Triterpenoids from Hibiscus sabdariffa L. with PPARδ/γ Dual Agonist Action: In Vivo, In Vitro and In Silico Studies

Planta Medica ◽  
2019 ◽  
Vol 85 (05) ◽  
pp. 412-423 ◽  
Author(s):  
Abraham Giacoman-Martínez ◽  
Francisco Alarcón-Aguilar ◽  
Alejandro Zamilpa ◽  
Sergio Hidalgo-Figueroa ◽  
Gabriel Navarrete-Vázquez ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Messenger Ribonucleic Acid ◽  
Transporter Protein ◽  
Agonist Action ◽  
Fatty Acid Transporter ◽  
Peroxisome Proliferator Activated Receptors ◽  
Glucose Transporter Type 4 ◽  
Dual Agonist

Abstract Hibiscus sabdariffa is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors δ and γ may play a role in the actions of H. sabdariffa. These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from H. sabdariffa to identify compounds with peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of H. sabdariffa and the dichloromethane extract of H. sabdariffa was performed. The dichloromethane extract of H. sabdariffa exhibited an antihyperglycemic effect. The dichloromethane extract of H. sabdariffa was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor δ/γ dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were α-amyrin and lupeol. These molecules were subjected to molecular docking analysis. α-Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, α-amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, α-amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that α-amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor δ/γ dual agonist action.

scholarly journals Peroxisome proliferator activated receptor-γ-Rho-kinase interactions contribute to vascular remodeling after chronic intrauterine pulmonary hypertension

2014 ◽  
Vol 306 (3) ◽  
pp. L299-L308 ◽  
Author(s):  
Jason Gien ◽  
Nancy Tseng ◽  
Gregory Seedorf ◽  
Gates Roe ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Rho Kinase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Counts ◽  
Expression Activity ◽  
Rock Inhibition ◽  
Rock Activity

Peroxisome proliferator-activated receptor-γ (PPARγ) and Rho-kinase (ROCK) regulate smooth muscle cell (SMC) proliferation and contribute to vascular remodeling in adult pulmonary hypertension. Whether these pathways interact to contribute to the development of vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN) remains unknown. We hypothesized that ROCK-PPARγ interactions increase SMC proliferation resulting in vascular remodeling in experimental PPHN. Pulmonary artery SMCs (PASMCs) were harvested from fetal sheep after partial ligation of the ductus arteriosus in utero (PPHN) and controls. Cell counts were performed daily for 5 days with or without PPARγ agonists and ROCK inhibition. PPARγ and ROCK protein expression/activity were measured by Western blot in normal and PPHN PASMCs. We assessed PPARγ-ROCK interactions by studying the effect of ROCK activation on PPARγ activity and PPARγ inhibition (siRNA) on ROCK activity and PASMC proliferation. At baseline, PPHN PASMC cell number was increased by 38% above controls on day 5. ROCK protein expression/activity were increased by 25 and 34% and PPARγ protein/activity decreased by 40 and 50% in PPHN PASMC. ROCK inhibition and PPARγ activation restored PPHN PASMC growth to normal values. ROCK inhibition increased PPARγ activity by 50% in PPHN PASMC, restoring PPARγ activity to normal. In normal PASMCs, ROCK activation decreased PPARγ activity and PPARγ inhibition increased ROCK activity and cell proliferation, resulting in a PPHN hyperproliferative PASMC phenotype. PPARγ-ROCK interactions regulate SMC proliferation and contribute to increased PPHN PASMC proliferation and vascular remodeling in PPHN. Restoring normal PPARγ-ROCK signaling may prevent vascular remodeling and improve outcomes in PPHN.

scholarly journals Development of a Protocol for Virtual Screening of PPARγ Weak Partial Agonists and Their Metabolites: Case Study on Naturally-derived Oleanane Triterpenoids

2021 ◽  
Vol 25 (2) ◽  
pp. 117-132
Author(s):  
Merilin Al Sharif ◽  
◽  
Petko Alov ◽  
Vessela Vitcheva ◽  
Antonia Diukendjieva ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Molecular Mechanisms ◽  
Partial Agonist ◽  
Mechanistic Explanation ◽  
Binding Mode ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Partial Agonists ◽  
Docking Protocol ◽  
Agonistic Activity

Triterpenoids are well known metabolic syndrome (MetS) modulators. One of the suggested molecular mechanisms of action involves peroxisome proliferator-activated receptor gamma (PPARγ) activation. In this study we aimed to: (i) develop a virtual screening (VS) protocol for PPARγ weak partial agonists, (ii) predict potential metabolic transformations of naturally-derived triterpenoids, and (iii) perform VS of the triterpenoids and their metabolites. The NIH PubMed system was searched for publications about naturally-derived oleanane triterpenoids which are agonists or up-regulators of PPARγ. Structure- and ligand-based methods were combined in the development of the VS protocol. Metabolites were predicted using Meteor Nexus expert system (Lhasa Limited). Two in-house virtual libraries of PPARγ weak partial agonists and naturally-derived triterpenoids with their predicted metabolites were compiled. The pharmacophore-based docking protocol was applied for VS of the collected triterpenoids. Most of the docking poses reproduced the binding mode of caulophyllogenin (a weak partial agonist) in a complex with PPARγ (PDB ID 5F9B). Our results contribute to the mechanistic explanation of the effects of triterpenoids suggesting possible weak partial agonistic activity toward PPARγ. This research can direct further studies on triterpenoids’ role in MetS modulation. The developed protocol can be applied for VS of any PPARγ weak partial agonists.

scholarly journals Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys

2010 ◽  
Vol 31 (3) ◽  
pp. 404-405
Author(s):  
Hong Chen ◽  
Beatriz Dardik ◽  
Ling Qiu ◽  
Xianglin Ren ◽  
Shari L. Caplan ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Plasma Levels ◽  
Energy Homeostasis ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cynomolgus Monkeys ◽  
Dose Dependent ◽  
Dual Agonist

ABSTRACT Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-α and -γ subtypes. Dual activation of PPARα and -γ is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 μg/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.

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