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Jahidur Rashid, Kamrun Nahar, Snehal Raut, Ali Keshavarz, Fakhrul Ahsan
We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long acting nitric oxide donorboth loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC)in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified- and CAR-modified-liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia induced PAH rats...
March 12, 2018: Molecular Pharmaceutics
Morane Le Hiress, Bernardin Akagah, Guillaume Bernadat, Ly Tu, Raphaël Thuillet, Alice Huertas, Carole Phan, Elie Fadel, Gérald Simonneau, Marc Humbert, Gaël Jalce, Christophe Guignabert
Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5-32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure-activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent...
March 10, 2018: Journal of Medicinal Chemistry
Amelia S Power, Anthony J Hickey, David J Crossman, Denis S Loiselle, Marie-Louise Ward
Currently, there are no tailored therapies available for the treatment of right ventricular (RV) hypertrophy, and the cellular mechanisms that underlie the disease are poorly understood. We investigated the cellular changes that occur early in the progression of the disease, when RV hypertrophy is evident, but prior to the onset of heart failure. Intracellular Ca2+ ([Ca2+ ]i ) handling was examined in a rat model of monocrotaline (MCT)-induced pulmonary hypertension and subsequent RV hypertrophy. [Ca2+ ]i and stress production were measured in isolated RV trabeculae under baseline conditions (1-Hz stimulation, 1...
March 10, 2018: Pflügers Archiv: European Journal of Physiology
Yanjiao Li, Li Li, Zhengjiang Qian, Boya Lin, Jidong Chen, Yixuan Luo, Junle Qu, J Usha Raj, Deming Gou
BACKGROUND: Platelet-derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet-derived growth factor BB-treated PASMCs found a significantly downregulated microRNA, miR-1281, but it has not been associated with any cellular function, and we investigated the possibility. METHODS AND RESULTS: Real-time quantitative reverse transcription-polymerase chain reaction assay proved that downregulation of miR-1281 was a conserved phenomenon in human and rat PASMCs...
March 7, 2018: Journal of the American Heart Association
Martin Connolly, Benjamin E Garfield, Alexi Crosby, Nick W Morrell, Stephen J Wort, Paul R Kemp
Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here, we show that miR-322-5p (the rodent orthologue of miR-424-5p) expression is decreased in the right ventricle of monocrotaline-treated rats, a model of PAH, whereas a putative target insulin-like growth factor 1 (IGF-1) is increased. IGF-1 mRNA was enriched 16-fold in RNA immunoprecipitated with Ago2, indicating binding to miR-322-5p. In cell transfection experiments, miR-322-5p suppressed the activity of a luciferase reporter containing a section of the IGF-1 3' untranslated region (UTR) as well as IGF-1 mRNA and protein levels...
March 2018: FEBS Open Bio
Lei Gao, Jun Liu, Yongmei Hao, Zengren Zhao, Huilian Tan, Jie Zhang, Ning Meng, Qinghou Zheng, Zhen Wang, Yi Zhang
Objectives: Inflammation is involved in various forms of pulmonary arterial hypertension (PAH). Although the pathophysiology of PAH remains uncertain, NF-κB and p38 mitogen-activated protein kinase (p38 MAPK) has been reported to be associated with many inflammatory mediators of PAH. This study aimed to evaluate the effect of chronic intermittent hypobaric hypoxia (CIHH) on pulmonary inflammation and remodeling in monocrotaline (MCT) induced PAH in rats. Materials and Methods: An in vivo model of PAH induced by MCT was employed...
March 2018: Iranian Journal of Basic Medical Sciences
Ying-Ju Lai, I-Chen Chen, Hsin-Hsien Li, Chung-Chi Huang
Right ventricular (RV) hypertrophy is characterized by cardiac fibrosis due to endothelial-mesenchymal transition (EndMT) and increased collagen production in pulmonary arterial hypertension (PAH) patients, but the mechanisms for restoring RV function are unclear. Prostanoid agonists are effective vasodilators for PAH treatment that bind selective prostanoid receptors to modulate vascular dilation. The importance of prostanoid signaling in the RV is not clear. We investigated the effects of the EP4-specific agonist L-902,688 on cardiac fibrosis and TGF-β-induced EndMT...
March 3, 2018: International Journal of Molecular Sciences
Fangzheng Chen, Heng Wang, Junjie Yan, Jiadan Lai, Shujing Cai, Linbo Yuan, Situo Zheng
Heat shock protein 70 (HSP70) is a molecular chaperone which has a low content in cytoplasm under normal physiological conditions. A higher intracytoplasmic HSP70 level can be observed in pulmonary arterial smooth muscle cell (PASMC) in pulmonary arterial hypertension (PAH), and this up-regulation can promote pho-IκBα expression, which is an NF-κB signaling pathway inhibitor. NF-κB signaling pathway up-regulation can promote PASMC proliferation and pulmonary vascular remodeling in PAH, resulting in elevation of pulmonary pressure and the subsequent right heart failure caused by right ventricular hypertrophy...
February 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Xiaoqi Jing, Jiaqi Zhang, Zhenlin Huang, Yuchen Sheng, Lili Ji
Hepatic sinusoidal obstruction syndrome (HSOS) is a rare and life-threatening liver disease. (+)-catechin is a natural dietary flavonol with high antioxidant capacity. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway in the protection of (+)-catechin hydrate (CAT) against monocrotaline (MCT)-induced HSOS. Results of serum alanine/aspartate aminotransferases (ALT/AST) activities, total bilirubin (TBil) and bile acids (TBA) amounts, liver histological observation, scanning electron microscope evaluation and hepatic metalloproteinase-9 (MMP-9) expression all demonstrated the protection of CAT against MCT-induced HSOS in rats...
February 20, 2018: Free Radical Research
Laxminarayan Bhat, Jon Hawkinson, Marc Cantillon, Dasharatha G Reddy, Seema R Bhat, Charles-E Laurent, Annie Bouchard, Marzena Biernat, Dany Salvail
Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT 2/2B/7 . In a rat model of monocrotaline (MCT)-induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5-HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice-daily [b.i.d.]), RP (10mg/kg; gavage b...
February 14, 2018: European Journal of Pharmacology
Yanjiang Xing, Shuang Zhao, Qingxia Wei, Shiqiang Gong, Xin Zhao, Fang Zhou, Rafia Ai-Lamki, Daniel Ortmann, Mingxia Du, Roger Pedersen, Guangdong Shang, Shuyi Si, Nicholas W Morrell, Jun Yang
Genetic defects in bone morphogenetic protein type-II receptor (BMPRII) signalling and inflammation contribute to the pathogenesis of pulmonary arterial hypertension (PAH). The receptor is activated by BMP ligands, which also enhance BMPR2 transcription. A small molecule BMP upregulator with selectivity on vascular endothelium would represent a desirable therapeutic intervention for PAH.We assayed compounds identified in the screening of BMP2 upregulators for their ability to increase expression of Inhibitor of DNA binding 1 (Id1), using a dual reporter driven specifically in human embryonic stem cell (hESC)-derived endothelial cells (ECs)...
February 15, 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Sébastien J Dumas, Gilles Bru-Mercier, Audrey Courboulin, Marceau Quatredeniers, Catherine Rücker-Martin, Fabrice Antigny, Morad K Nakhleh, Benoit Ranchoux, Elodie Gouadon, Maria-Candida Vinhas, Matthieu Vocelle, Nicolas Raymond, Peter Dorfmüller, Elie Fadel, Frédéric Perros, Marc Humbert, Sylvia Cohen-Kaminsky
Background -Excessive proliferation and apoptosis resistance in pulmonary vascular cells underlie vascular remodeling in pulmonary arterial hypertension (PAH). Specific treatments for PAH exist, mostly targeting endothelial dysfunction, but high pulmonary arterial pressure still causes heart failure and death. Pulmonary vascular remodeling may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production. The N-methyl-D-aspartate receptor (NMDAR), a major neuronal glutamate receptor, is also expressed on vascular cells, but its role in PAH is unknown...
February 14, 2018: Circulation
Ying Pang, Ming-Ting Liang, Ying Gong, Yong Yang, Pei-Li Bu, Mei Zhang, Heng-Chen Yao
The purpose of the present study was to investigate the anti-inflammatory effect of hepatocyte growth factor (HGF) on pulmonary artery hypertension (PAH) in a rat model and underlying mechanisms. Wistar rats were treated with monocrotaline intravenously to induce PAH and then treated with vehicle or HGF for 2 weeks, respectively. The mean pulmonary artery pressure (mPAP), the index of right heart ventricular hypertrophy (RHVI), pathological changes, and inflammation in the lungs of individual rats were measured...
February 13, 2018: Inflammation
Kuang-Hueih Chen, Asish Dasgupta, Jianhui Lin, Francois Potus, Sebastien Bonnet, James Iremonger, Jennifer Fu, Jeffrey Mewburn, Danchen Wu, Kimberly Dunham-Snary, Anne L Theilmann, Zhi-Cheng Jing, Charles Hindmarch, Mark L Ormiston, Allan Lawrie, Stephen L Archer
Background -Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator, dynamin related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore their dysregulation in PAH...
February 5, 2018: Circulation
Z Feng, Y Hu, N N An, W J Feng, T Hu, Y J Mao
Objective: To observe the effects of acidic oligosaccharides (AOS) on P-selectin levels in the serum and the pulmonary arteries of pulmonary hypertensive rats induced by monocrotaline. Methods: Sixty healthy adult male Sprague-Dawley rats were randomly divided into control group (n=10), model group (n=10), Alprostadil group (n=10), low-dose AOS group (AOS-L, n=10), medium-dose AOS group (AOS-M, n=10) and high-dose AOS group (AOS-H, n=10). The rat model of pulmonary arterial hypertension was made by a single intraperitoneal injection of monocrotaline(60 mg/kg)...
February 12, 2018: Chinese Journal of Tuberculosis and Respiratory Diseases
Jesse W Gerringer, Julie C Wagner, Daniela Vélez-Rendón, Daniela Valdez-Jasso
A longitudinal study of monocrotaline-induced pulmonary arterial hypertension (PAH) was carried out in Sprague-Dawley rats to investigate the changes in impedance (comprising resistance and compliance) produced by elevated blood pressure. Using invasively measured blood flow as an input, blood pressure was predicted using 3- and 4-element Windkessel (3WK, 4WK) type lumped-parameter models. Resistance, compliance, and inductance model parameters were obtained for the five different treatment groups via least-squares errors...
February 2018: Physiological Reports
Olivier Boucherat, Thibaut Peterlini, Alice Bourgeois, Valérie Nadeau, Sandra Breuils-Bonnet, Stéphanie Boilet-Molez, François Potus, Jolyane Meloche, Sophie Chabot, Caroline Lambert, Eve Tremblay, Young Chan Chae, Dario C Altieri, Gopinath Sutendra, Evangelos D Michelakis, Roxane Paulin, Steeve Provencher, Sébastien Bonnet
RATIONALE: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a poor prognosis and limited therapeutic option. Although the mechanisms contributing to vascular remodeling in PAH are still unclear, several features, including hyper-proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs), have led to the emergence of the cancer-like concept. The molecular chaperone heat shock protein 90 (HSP90) is directly associated with malignant growth and proliferation under stress conditions...
February 2, 2018: American Journal of Respiratory and Critical Care Medicine
Fengjiao Sun, Zhiqiang Lu, Yidan Zhang, Shihan Geng, Mengxi Xu, Liman Xu, Yingying Huang, Pengwei Zhuang, Yanjun Zhang
Right ventricular (RV) remodeling coupled with extensive apoptosis in response to unrestrained biomechanical stress may lead to RV failure (RVF), which is the immediate cause of death in the majority of patients with pulmonary arterial hypertension (PAH). Overexpression of β2‑adrenergic receptor (β2‑AR) signaling has been reported to induce myocardiotoxicity in patients with left heart failure. However, the role of β2‑AR signaling in the pathophysiology of PAH development has remained elusive. To address this issue, the present study investigated the changes in cardiopulmonary function and structure, as well as the expression of regulators of fibrosis and apoptosis in RVF following monocrotaline (MCT; 60 mg/kg, i...
February 1, 2018: International Journal of Molecular Medicine
Daniel J Lachant, David F Meoli, Deborah Haight, Jason A Lyons, Robert F Swarthout, R James White
Purpose/Aim: Low doses (30-80 mg/kg) of monocrotaline are commonly used to create experimental models of pulmonary hypertension in rats. At these doses, monocrotaline causes pulmonary endothelial apoptosis and acute lung injury which ultimately results in pulmonary vascular disease. Higher doses of monocrotaline (300 mg/kg) are known to create severe liver injury, but previous investigations with lower doses have not reported histology in other organs to determine whether the vascular injury with monocrotaline is pulmonary-selective or generalized...
January 30, 2018: Experimental Lung Research
Yusheng Cheng, Yan Gong, Shuai Qian, Yi Mou, Hanrui Li, Xijing Chen, Hui Kong, Weiping Xie, Hong Wang, Yihua Zhang, Zhangjian Huang
Given that the clinical therapeutic efficacy of oral-dosed bardoxolone methyl (1) and the selective vasodilatory effect caused by inhalation of nitric oxide (NO) on pulmonary arterial hypertension (PAH) patients, a new hybrid (CDDO-NO, 2) from 1 and NO donor isosorbide 5-mononitrate (3) was designed and synthesized. This hybrid could liberate 1 and NO in the lungs of rats after trachea injection. Significantly, 2 lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), decreased right ventricular hypertrophy (RVH), as well as attenuated pulmonary artery medial thickness (PAMT) and vascular muscularization in monocrotaline (MCT)-induced PAH rats...
January 29, 2018: Journal of Medicinal Chemistry
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