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Wen-Liang Song, Emanuela Ricciotti, Xue Liang, Tilo Grosser, Gregory R Grant, Garret A FitzGerald
Prostaglandin (PG) D2 is formed by two distinct prostaglandin D synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD2 producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a sigma glutathione-S-transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of LPGDS and HPGDS dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDSs, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds KO mice...
October 10, 2018: Journal of Pharmacology and Experimental Therapeutics
Natália R T Amorim, Tatiana Luna-Gomes, Marcos Gama-Almeida, Glaucia Souza-Almeida, Claudio Canetti, Bruno L Diaz, Peter F Weller, Patricia Torres Bozza, Clarissa M Maya-Monteiro, Christianne Bandeira-Melo
Leptin is a cytokine, produced mainly by mature adipocytes, that regulates the central nervous system, mainly to suppress appetite and stimulate energy expenditure. Leptin also regulates the immune response by controlling activation of immunomodulatory cells, including eosinophils. While emerging as immune regulatory cells with roles in adipose tissue homeostasis, eosinophils have a well-established ability to synthesize pro-inflammatory molecules such as lipid mediators, a key event in several inflammatory pathologies...
2018: Frontiers in Immunology
Hiroki Kabata, Kazuyo Moro, Shigeo Koyasu
Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up-to-date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL-33, IL-25; MAPK, NF-κB pathways), co-stimulatory cytokines (IL-2, IL-7, IL-9, TSLP; STAT5, IL-4; STAT6, TNF superfamily; MAPK, NF-κB pathways), suppressive cytokines (type1 IFNs, IFN-γ, IL-27; STAT1, IL-10, TGF-β), transdifferentiation cytokines (IL-12; STAT4, IL-1β, IL-18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+ -NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+ -NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell-to-cell interactions (ICOSL-ICOS; STAT5, B7-H6-NKp30, E-cadherin-KLRG1)...
November 2018: Immunological Reviews
Christian Domingo, Oscar Palomares, David A Sandham, Veit J Erpenbeck, Pablo Altman
Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D2 (PGD2 ) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH 2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1 ) and 2 (DP2 )...
September 29, 2018: Respiratory Research
Irina Bobolea, Victoria Del Pozo, Veronica Sanz, Rosario Cabañas, Ana Fiandor, Carolina Alfonso-Carrillo, María Ángeles Salcedo, Rocío Heredia Revuelto, Santiago Quirce
BACKGROUND: Aspirin desensitization (AD) has been the only available modifying treatment in aspirin-exacerbated respiratory disease (AERD). The mechanisms of AD are nonetheless poorly understood. Though very effective, AD is limited by its risks and side-effects. OBJECTIVE: Moving forward to the targeted biologicals era, the aim of this study was to characterize the airway inflammatory response to long-term AD, including TSLP dynamics, in order to assess potential new targets in AERD...
October 2018: Respiratory Medicine
Chuhyon Corwin, Anastasia Nikolopoulou, Allen L Pan, Mariela Nunez-Santos, Shankar Vallabhajosula, Peter Serrano, John Babich, Maria E Figueiredo-Pereira
BACKGROUND: Prostaglandins are products of the cyclooxygenase pathway, which is implicated in Parkinson's disease (PD). Limited knowledge is available on mechanisms by which prostaglandins contribute to PD neurodegeneration. To address this gap, we focused on the prostaglandin PGD2/J2 signaling pathway, because PGD2 is the most abundant prostaglandin in the brain, and the one that increases the most under pathological conditions. Moreover, PGJ2 is spontaneously derived from PGD2. METHODS: In this study, we determined in rats the impact of unilateral nigral PGJ2-microinfusions on COX-2, lipocalin-type PGD2 synthase (L-PGDS), PGD2/J2 receptor 2 (DP2), and 15 hydroxyprostaglandin dehydrogenase (15-PGDH)...
September 20, 2018: Journal of Neuroinflammation
Lei Wang, Dandan Yao, R N V Krishna Deepak, Heng Liu, Qingpin Xiao, Hao Fan, Weimin Gong, Zhiyi Wei, Cheng Zhang
The signaling of prostaglandin D2 (PGD2 ) through G-protein-coupled receptor (GPCR) CRTH2 is a major pathway in type 2 inflammation. Compelling evidence suggests the therapeutic benefits of blocking CRTH2 signaling in many inflammatory disorders. Currently, a number of CRTH2 antagonists are under clinical investigation, and one compound, fevipiprant, has advanced to phase 3 clinical trials for asthma. Here, we present the crystal structures of human CRTH2 with two antagonists, fevipiprant and CAY10471. The structures, together with docking and ligand-binding data, reveal a semi-occluded pocket covered by a well-structured amino terminus and different binding modes of chemically diverse CRTH2 antagonists...
October 4, 2018: Molecular Cell
Xiaoying Li, Xin Hong, Xianshu Gao, Xiaobin Gu, Wei Xiong, Jing Zhao, Hongliang Yu, Ming Cui, Mu Xie, Yun Bai, Shaoqian Sun
Purpose: In our previous study, we found that AKR1C3 was a radioresistance gene in KY170R cells. Downregulating the expression of AKR1C3 could enhance the radiosensitivity of esophageal carcinoma cells. In this study, we investigated whether methyl jasmonate (MeJ), an inhibitor of Aldo-keto reductase family1 member C3 ( AKR1C3 ), could overcome radiation resistance in AKR1C3 highly expressed cells. Patients and methods: We used clone formation assays to detect radiosensitivity effects...
2018: Cancer Management and Research
Wen Yang, Xia Wang, Liuxin Xu, Honglin Li, Rui Wang
Arachidonic acid (AA) metabolic network generates a variety of products that mediate or modulate inflammatory reactions. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. granditlora (Wehrhahn) Grierson, was found as an inhibitor of 5-LOX and 15-LOX in vitro. When evaluated in collagen-induced arthritis (CIA) rats, however, lowdose of HOEC (1 mg/kg) showed better efficacy than that of high dose (10 mg/kg). To study how HOEC interfered the AA metabolic pathway, in this study, we dynamically observed the changes of plasma AA metabolites (LTB4, LTC4, 15-HETE, PGE2, TXB2 and PGD2) in the CIA rats treated with different doses of HOEC by using enzyme-linked immunosorbent assay (ELISA)...
2018: American Journal of Translational Research
Hiromichi Shoji, Toshiaki Shimizu
The metabolic changes that occur during the postnatal weaning period appear to be particularly important for future health, and human breast milk is considered to provide the optimal source of nutrition for infants. Our previous studies examined the effect of feeding type on antioxidative properties, glucose and insulin metabolism, the lipid profile, metabolomics, and prostaglandin (PG) metabolism in term and preterm infants. Levels of a urinary marker of oxidative DNA damage (8-OHdG) were significantly lower in breast-fed term and preterm infants than those in formula-fed infants...
September 8, 2018: Pediatrics International: Official Journal of the Japan Pediatric Society
Yoshihiko Chiba, Wataru Suto, Hiroyasu Sakai
RATIONALE: Augmented smooth muscle contractility of the airways is one of the causes of airway hyperresponsiveness in asthmatics. However, the mechanism of the altered properties of airway smooth muscle cells is not well understood. OBJECTIVES: To identify differentially expressed genes (DEGs) related to the bronchial smooth muscle (BSM) hyper-contractility in a murine asthma model. METHODS: The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction...
2018: PloS One
Dong Sun, Chong Su, Yingze Liu, Xiangjun Meng, John Paul Fawcett, Yingjie Guo, Jingkai Gu
Prostaglandins (PGs) are biologically active metabolites of arachidonic acid containing 20 carbon atoms, a cyclic moiety, and two side chains (A and B) in common. The bioassay of PGs requires high sensitivity because of their low concentration in tissues and blood and has usually been carried out by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the negative ion mode. Chemical derivatization of PG carboxylic acid groups to introduce positive charge-carrying groups is an established strategy to improve the sensitivity and selectivity of such assays...
August 27, 2018: Journal of the American Society for Mass Spectrometry
Karl-Erik Andersson, Christopher Fry, Jalesh Panicker, Kevin Rademakers
AIMS: Update on some molecular targets for new drugs to improve lower urinary tract (LUT) dysfunction. METHODS: Using PubMed, a search for literature on molecular targets in the LUT was performed to identify relevant clinical and animal studies. Keywords were entered as Medical Subject Headings (MeSH) or as text words. The Mesh terms were used in various combinations and usually included the terms lower urinary AND pharmacology. Other Mesh term included: bladder, urethra, CNS, physiology, afferent activity, ATP, prostanoids, cannabinoids, fibrosis...
June 2018: Neurourology and Urodynamics
Chuangjia Hu, Bin Liu, Hui Li, Xiangzhong Wu, Tingting Guo, Wenhong Luo, Yingbi Zhou
Prostaglandin (PG) D2 , a prostanoid known to have hypotensive effect, can evoke increased in vitro prepartum myometrial contraction resulting from up-regulation of the F prostanoid (FP) receptor. The present study further determined postpartum rat uterine responses to PGD2 to evaluate the possibility of the prostanoid becoming a therapeutic for postpartum uterine atony, a major cause of postpartum hemorrhage that can lead to maternal morbidity. In vitro and in vivo postpartum uterine responses to PGD2 were determined and compared to those of prepartum rats...
October 5, 2018: European Journal of Pharmacology
Sachin Kumar, Akanksha Sharma, Rinkesh Kumar Gupta, Ajay Kumar Verma, Premendra D Dwivedi
Tree nuts are among "Big Eight" and have been reported globally for causing allergy. Buchanania lanzan (Bl) is one of the major tree nuts consumed by Indian population. However, very little is known about B. lanzan's induced allergic manifestation. Therefore, evaluation of it's allergenic potential was undertaken. Bl-crude protein extract sensitized BALB/c mice sera were used to identify the allergic proteins by it's IgE binding capability. The major IgE binding proteins found with molecular weight of 11, 20, 23, 25, 48, 54, and 65 kDa...
October 2018: International Immunopharmacology
Juan A Giménez-Bastida, William E Boeglin, Olivier Boutaud, Michael G Malkowski, Claus Schneider
Aspirin (acetylsalicylic acid) inhibits prostaglandin (PG) synthesis by transfer of its acetyl group to a serine residue in the cyclooxygenase (COX) active site. Acetylation of Ser530 inhibits catalysis by preventing access of arachidonic acid substrate in the COX-1 isoenzyme. Acetylated COX-2, in contrast, gains a new catalytic activity and forms 15 R hydroxy-eicosatetraenoic acid (15 R-HETE) as alternate product. Here we show that acetylated COX-2 also retains COX activity, forming predominantly 15 R-configuration PGs (70 or 62% 15 R, respectively, determined using radiolabeled substrate or LC-MS analysis)...
August 10, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
R Stokes Peebles
Prostaglandins are synthesized through the metabolism of arachidonic acid via the cyclooxygenase pathway. There are five primary prostaglandins, PGD2 , PGE2 , PGF2 , PGI2 , and thromboxane B2 , that all signal through distinct seven transmembrane, G-protein coupled receptors. The receptors through which the prostaglandins signal determines their immunologic or physiologic effects. For instance, the same prostaglandin may have opposing properties, dependent upon the signaling pathways activated. In this article, we will detail how inhibition of cyclooxygenase metabolism and regulation of prostaglandin signaling regulates allergic airway inflammation and asthma physiology...
August 3, 2018: Pharmacology & Therapeutics
Jeevan Kumar Jadapalli, Griffin M Wright, Vasundhara Kain, Mohammad Asif Sherwani, Nabiha Yusuf, Ganesh V Halade
Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-months-old male C57BL/6J mice were divided into high and low dose DOX-treated groups maintaining saline control. The first group was injected with high DOX 15mg/kg/week (H-DOX) and the second group was injected with 7.5mg/kg/week as latent low DOX (LL-DOX). Given that H-DOX led to complete mortality in two weeks and 70% survival in LL-DOX were compared with saline controls...
August 3, 2018: American Journal of Physiology. Heart and Circulatory Physiology
S K Kritas, C E Gallenga, C D Ovidio, G Ronconi, Al Caraffa, E Toniato, D Lauritano, P Conti
Molds include all species of microscopic fungi, the spores of which are small molecules, ubiquitous, mostly found in soil with higher rainfall and high humidity, in the atmosphere of urban and rural settings and in decaying vegetation. They originate from pathogenic fungi and have a crucial role in inflammatory response, causing a broad range of diseases. Immune suppressed subjects may develop mycoses caused by opportunistic common pathogenic fungi. Mast cells (MCs) are immune cells involved in the pathophysiology of infected skin, lung, and organs, where there is an increase of angiogenesis...
July 2018: Journal of Biological Regulators and Homeostatic Agents
Dingxin Pan, Kathleen M Buchheit, Sachin K Samuchiwal, Tao Liu, Haley Cirka, Hannah Raff, Joshua A Boyce
BACKGROUND: Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene [LT] C4 , prostaglandin [PG] D2 , and thromboxane A2 ), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms. OBJECTIVES: We sought to determine the regulation and significance of MC-derived eicosanoids synthesized in response to IL-33, a cytokine critical to innate type 2 immunity...
July 12, 2018: Journal of Allergy and Clinical Immunology
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