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Kelly M DeMars, Austin O McCrea, David M Siwarski, Brian D Sanz, Changjun Yang, Eduardo Candelario-Jalil
Ischemic stroke occurs when a clot forms in the brain vasculature that starves downstream tissue of oxygen and nutrients resulting in cell death. The tissue immediately downstream of the blockage, the core, dies within minutes, but the surrounding tissue, the penumbra is potentially salvageable. Prostaglandin E2 binds to four different G-protein coupled membrane receptors EP1-EP4 mediating different and sometimes opposing responses. Pharmacological activation of the EP4 receptor has already been established as neuroprotective in stroke, but the mechanism(s) of protection are not well-characterized...
2018: Frontiers in Neuroscience
Raffaele Pesavento, Paolo Prandoni
Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon and late complication of pulmonary embolism resulting from misguided remodelling of residual pulmonary thromboembolic material and small-vessel arteriopathy. CTEPH is the only form of pulmonary hypertension (PH) potentially curable by pulmonary endarterectomy (PEA). Unfortunately, several patients have either an unacceptable risk-benefit ratio for undergoing the surgical intervention or develop persistent PH after PEA. Novel medical and endovascular therapies can be considered for them...
March 2, 2018: Thrombosis Research
Paul C Norris, Charles N Serhan
Metabolomics enables a systems approach to interrogate the bioactive mediators, their pathways and further metabolites involved in the physiology and pathophysiology of human and animal tissues. New metabololipidomic approaches with mass spectrometry presented in this brief review can now be utilized for the identification and profiling of lipid mediator networks that control inflammation-resolution in human blood and healthy and diseased solid tissues. Coagulation of blood is a protective response that prevents excessive bleeding on injury of blood vessels...
March 7, 2018: Biochemical and Biophysical Research Communications
Nagarajan Muthukaman, Sanjay Deshmukh, Macchindra Tambe, Dnyandeo Pisal, Shital Tondlekar, Mahamadhanif Shaikh, Neelam Sarode, Vidya G Kattige, Pooja Sawant, Monali Pisat, Vikas Karande, Srinivasa Honnegowda, Abhay Kulkarni, Dayanidhi Behera, Satyawan B Jadhav, Ramchandra R Sangana, Girish S Gudi, Neelima Khairatkar-Joshi, Laxmikant A Gharat
In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases...
February 28, 2018: Bioorganic & Medicinal Chemistry Letters
T Nodai, S Hitomi, K Ono, C Masaki, N Harano, A Morii, M Sago-Ito, I Ujihara, T Hibino, K Terawaki, Y Omiya, R Hosokawa, K Inenaga
Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin-1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats...
March 1, 2018: Journal of Dental Research
Marilena Crescente, Laura Menke, Melissa V Chan, Paul C Armstrong, Timothy D Warner
Platelets are important players in thrombosis and haemostasis with their function being modulated by mediators in the blood and the vascular wall. Among these, eicosanoids can both stimulate or inhibit platelet reactivity. Platelet cyclooxygenase (COX)-1 generated thromboxane (TX) A2 is the primary prostanoid that stimulates platelet aggregation; its action is counter-balanced by prostaglandin (PG)I2 (prostacyclin), a product of vascular COX. PGD2 , PGE2 , 12- hydroxyeicosatraenoic acid (HETE) or 15-HETE, are other prostanoid modulators of platelet activity, but some also play a role in carcinogenesis...
March 7, 2018: British Journal of Pharmacology
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
Johannes C Schoeman, Amy C Harms, Michel van Weeghel, Ruud Berger, Rob J Vreeken, Thomas Hankemeier
Oxidative stress and inflammation are underlying pathogenic mechanisms associated with the progression of several pathological conditions and immunological responses. Elucidating the role of signalling lipid classes, which include, among others, the isoprostanes, nitro fatty acids, prostanoids, sphingoid bases and lysophosphatidic acids, will create a snapshot of the cause and effect of inflammation and oxidative stress at the metabolic level. Here we describe a fast, sensitive, and targeted ultra-high-performance liquid chromatography-tandem mass spectrometry metabolomics method that allows the quantitative measurement and biological elucidation of 17 isoprostanes as well as their respective isomeric prostanoid mediators, three nitro fatty acids, four sphingoid mediators, and 24 lysophosphatidic acid species from serum as well as organ tissues, including liver, lung, heart, spleen, kidney and brain...
March 2, 2018: Analytical and Bioanalytical Chemistry
Murtuza Hadianawala, Amarjyoti Das Mahapatra, Jitender K Yadav, Bhaskar Datta
Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques...
February 26, 2018: Journal of Molecular Modeling
Károly Baintner
The first 60-min phase of inflammatory ascites formation was studied by intraperitoneally (i.p.) administered macromolecular inducers: yeast cell wall zymosan binds to specific macrophage receptors, polyethyleneimine (PEI) and concanavalin A (ConA), produces non-covalent cross-links on the surface of various cells, while λ-carrageenan may function as a contact activator. Depletion of peritoneal macrophages was performed by overnight pretreatment with diphtheria toxin in transgenic mice, resulting in a significant (p < 0...
February 23, 2018: Acta Microbiologica et Immunologica Hungarica
Jane A Mitchell, Nicholas S Kirkby
Eicosanoids represent a diverse family of lipid mediators with fundamental roles in controlling physiology and disease. Within the eicosanoid super family are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX-1 and COX-2. COX-2 is the therapeutic target for the nonsteroidal anti-inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir Professor John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one the bodies fundamental cardiovascular protective pathways...
February 21, 2018: British Journal of Pharmacology
José M Centeno, Luis Miranda-Gómez, Mikahela A López-Morales, Teresa Jover-Mengual, María C Burguete, Vannina G Marrachelli, María Castelló-Ruiz, Alicia Aliena-Valero, Enrique Alborch, Francisco J Miranda
Diabetic nephropathy is associated with increased risk of cardiovascular disease. B-type natriuretic peptide (BNP) plays an important role in cardiovascular pathophysiology and therapeutics. The aim of the present study was to investigate the influence of experimental diabetes on the mechanisms that regulate the relaxant response of the rabbit renal artery to BNP. Arterial relaxations to BNP were enhanced in diabetic rabbits. Indomethacin enhanced BNP-induced relaxation in control rabbits but showed no effect in diabetic rabbits...
February 21, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Nobuyuki Nishizawa, Yoshiya Ito, Koji Eshima, Hirotoki Ohkubo, Ken Kojo, Tomoyoshi Inoue, Joan Raouf, Per-Johan Jakobsson, Satoshi Uematsu, Shizuo Akira, Shuh Narumiya, Masahiko Watanabe, Masataka Majima
BACKGROUND & AIMS: Liver repair following hepatic ischemia/reperfusion (I/R) injury is crucial to survival. This study aims to examine the role of endogenous prostaglandin E2 (PGE2 ) produced by inducible microsomal PGE synthase-1 (mPGES-1), a terminal enzyme of PGE2 generation, in liver injury and repair following hepatic I/R. METHODS: mPGES-1 deficient (mPGES-1-/- ) mice or their wild counterparts (WT) were subjected to partial hepatic ischemia followed by reperfusion...
February 16, 2018: Journal of Hepatology
Kai Ding, Ziyuan Zhou, Shuo Zhou, Yaxia Yuan, Kyungbo Kim, Ting Zhang, Xirong Zheng, Fang Zheng, Chang-Guo Zhan
Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2 . Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs)...
February 8, 2018: Bioorganic & Medicinal Chemistry Letters
Andreas Koeberle, Oliver Werz
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostanoid formation and represent prevalent therapeutics for treatment of inflammatory disorders. However, NSAIDs are afflicted with severe side effects, which might be circumvented by more selective suppression of pro-inflammatory eicosanoid biosynthesis. This concept led to dual inhibitors of microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase that are crucial enzymes in the biosynthesis of pro-inflammatory prostaglandin E2 and leukotrienes...
February 15, 2018: Biotechnology Advances
Mária Szekeres, György L Nádasy, Gabriella Dörnyei, Annamária Szénási, Akos Koller
PURPOSE: Exercise elicits early adaptation of coronary vessels enabling the coronary circulation to respond adequately to higher flow demands. We hypothesized that short-term daily exercise induces biomechanical and functional remodeling of the coronary resistance arteries related to pressure. METHODS: Male rats were subjected to a progressively increasing 4-week treadmill exercise program (over 60 min/day, 1 mph in the final step). In vitro pressure-diameter measurements were performed on coronary segments (119 ± 5 μm in diameter at 50 mm Hg) with microarteriography...
February 14, 2018: Journal of Vascular Research
U T Timur, M M J Caron, Y M Bastiaansen-Jenniskens, T J M Welting, L W van Rhijn, G J V M van Osch, P J Emans
OBJECTIVE: The Hoffa's fat pad (HFP) is an intra-articular adipose tissue which is situated under and behind the patella. It contains immune cells next to adipocytes and secretes inflammatory factors during osteoarthritis (OA). In this study, we compared the release profile of prostanoids, which are involved in inflammation, of HFP from OA patients vs patients with a focal cartilage defect (CD) without evidence for OA on MRI and investigated the prostanoid modulatory anti-inflammatory action of celecoxib on HFP...
February 7, 2018: Osteoarthritis and Cartilage
Ahmed A Elmarakby, Mohamed Katary, Jennifer S Pollock, Jennifer C Sullivan
We previously reported that female spontaneously hypertensive rats (SHR) have greater cyclooxygenase-2 (COX-2) expression in the renal medulla and enhanced urinary excretion of prostaglandin (PG) E2 (PGE2) metabolites compared to male SHR. Based on the role of COX-2-derived prostanoids in the regulation of cardiovascular health, the aim of the current study was to test the hypothesis that blood pressure (BP) in female SHR is more sensitive to COX-2 inhibition than in males. Seven week old male and female SHR were implanted with telemetry transmitters for continuous BP recording...
February 6, 2018: Prostaglandins & Other Lipid Mediators
K J Quek, O Z Ameer, J K Phillips
Background: The renin-angiotensin system, in particular Angiotensin II (AngII), plays a significant role in the pathogenesis of hypertension in chronic kidney disease (CKD). Effects of chronic AT1 receptor antagonism were investigated in a genetic hypertensive rat model of CKD, the Lewis polycystic kidney (LPK) rat. Methods: Mixed-sex LPK and Lewis control rats (total n=31) were split between treated (valsartan 60mg/kg/day p.o. from 4-18 weeks) and vehicle groups...
February 7, 2018: American Journal of Hypertension
Éva Pál, Leila Hadjadj, Zoltán Fontányi, Anna Monori-Kiss, Zsuzsanna Mezei, Norbert Lippai, Attila Magyar, Andrea Heinzlmann, Gellért Karvaly, Emil Monos, György Nádasy, Zoltán Benyó, Szabolcs Várbíró
BACKGROUND AND PURPOSE: Vitamin D deficiency (VDD) is a global health problem, which can lead to several pathophysiological consequences including cardiovascular diseases. Its impact on the cerebrovascular system is not well understood. The goal of the present work was to examine the effects of VDD on the morphological, biomechanical and functional properties of cerebral arterioles. METHODS: Four-week-old male Wistar rats (n = 11 per group) were either fed with vitamin D deficient diet or received conventional rat chow with per os vitamin D supplementation...
2018: PloS One
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