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Ko Fujimori, Kosuke Aritake, Yo Oishi, Nanae Nagata, Toko Maehara, Michael Lazarus, Yoshihiro Urade
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is responsible for the production of PGD2 in adipocytes and is selectively induced by a high-fat diet (HFD) in adipose tissue. In this study, we investigated the effects of HFD on obesity and insulin resistance in two distinct types of adipose-specific L-PGDS gene knockout (KO) mice: fatty acid binding protein 4 (fabp4, aP2)-Cre/L-PGDS flox/flox and adiponectin (AdipoQ)-Cre/L-PGDS flox/flox mice. The L-PGDS gene was deleted in adipocytes in the premature stage of the former strain and after maturation of the latter strain...
February 13, 2019: Scientific Reports
Stoyan Dimitrov, Tanja Lange, Cécile Gouttefangeas, Anja T R Jensen, Michael Szczepanski, Jannik Lehnnolz, Surjo Soekadar, Hans-Georg Rammensee, Jan Born, Luciana Besedovsky
Efficient T cell responses require the firm adhesion of T cells to their targets, e.g., virus-infected cells, which depends on T cell receptor (TCR)-mediated activation of β2 -integrins. Gαs -coupled receptor agonists are known to have immunosuppressive effects, but their impact on TCR-mediated integrin activation is unknown. Using multimers of peptide major histocompatibility complex molecules (pMHC) and of ICAM-1-the ligand of β2 -integrins-we show that the Gαs -coupled receptor agonists isoproterenol, epinephrine, norepinephrine, prostaglandin (PG) E2 , PGD2 , and adenosine strongly inhibit integrin activation on human CMV- and EBV-specific CD8+ T cells in a dose-dependent manner...
February 12, 2019: Journal of Experimental Medicine
Bangrong Cai, Kyung-Joo Seong, Sun-Woong Bae, Min Suk Kook, Changju Chun, Jin Ho Lee, Won-Seok Choi, Ji-Yeon Jung, Won-Jae Kim
Microglia-mediated neuroinflammatory responses are well known to inhibit neurogenesis in the dentate gyrus (DG) of the adult hippocampus, and growing evidence indicates that therapeutic intervention to suppress microglial activation could be an effective strategy for restoring the impaired neurogenesis and memory performance. In the present study, we investigated the effects of water-soluble arginyl-diosgenin analog (Arg-DG) on the adult hippocampal neurogenesis using a central LPS-induced inflammatory mice model, along with the fundamental mechanisms in vivo and in vitro using LPS-stimulated microglial BV2 cells...
February 11, 2019: Molecular Neurobiology
Daiki Horikami, Naoki Toya, Koji Kobayashi, Keisuke Omori, Nanae Nagata, Takahisa Murata
Acute lung injury (ALI) is caused by various stimuli such as acid aspiration and infection, resulting in severe clinical outcomes with high mortality. Prostaglandin D2 (PGD2 ) is a lipid mediator produced in the lungs of patients with ALI. There are two prostaglandin D synthase (PGDS), namely, lipocalin-type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS). We previously reported the anti-inflammatory role of H-PGDS-derived PGD2 in an endotoxin-induced murine ALI model. Therefore, in this study, we investigated the role of L-PGDS-derived PGD2 in ALI in comparison to H-PGDS-derived PGD2 ...
February 8, 2019: Journal of Pathology
Mariana Rezende Alves, Nayra Soares Do Amaral, Fabio Albuquerque Marchi, Felipe Ilelis De Barros Silva, Alexandre André Balieiro Anastácio Da Costa, Kátia Cândido Carvalho, Glauco Baiocchi, Fernando Augusto Soares, Louise De Brot, Rafael Malagoli Rocha
To identify biomarkers that could predict response or lack of response to conventional chemotherapy at the time of diagnosis of high‑grade serous ovarian carcinoma (HGSOC), the present study compared large‑scale gene expression from patients with short or long disease‑free survival times, according to the last cycle of chemotherapy, and validated these findings using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and conventional immunohistochemical (IHC) analysis. Samples were selected for microarray evaluation, at the time of diagnosis, using the following criteria: Identical debulking primary surgery, International Federation of Gynaecology and Obstetrics staging, histological subtype and grade...
January 28, 2019: Oncology Reports
Mengwen Li, Xinsheng Fan, Leilei Ji, Yuhao Fan, Li Xu
With the increasing morbidity and mortality of asthma, asthma aggravated by environmental pollution has drawn more attention. This study investigated the exacerbating effects of trimellitic anhydride (TMA), a typical pollutant, in ovalbumin (OVA)-induced asthmatic mice and the gene and protein expressions of TRPA1, V1, V2 in lung tissue. Female BALB/c mice were respectively administered for 42 days as follow: sensitized and challenged with OVA, sensitized and challenged with TMA, sensitized with OVA and challenged with OVA plus TMA, as well as sensitized and challenged with OVA plus TMA...
February 1, 2019: International Immunopharmacology
Cornelia Pipper, Natalie Bordag, Bernadette Reiter, Kyriakos Economides, Peter Florian, Thomas Birngruber, Frank Sinner, Manfred Bodenlenz, Anita Eberl
Eicosanoids are lipid mediator molecules with key roles in inflammatory skin diseases such as psoriasis. Eicosanoids are released close to the source of inflammation where they elicit local, pleiotropic effects and dysregulations. Monitoring inflammatory mediators directly in skin lesions could provide new insights and new therapeutic possibilities. This study describes the analysis of dermal interstitial fluid (dISF) samples obtained by dermal open flow microperfusion (dOFM) in a rat model of skin inflammation...
January 29, 2019: Journal of Lipid Research
Katelyn J Siegrist, DeeDee Romo, Brad L Upham, Michael Armstrong, Kevin Quinn, Lauren Vanderlinden, Ross S Osgood, Kalpana Velmurugan, Marc Elie, Jonathan Manke, Dominik Reinhold, Nichole Reisdorph, Laura Saba, Alison K Bauer
Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; <206.3 g/mol) are under regulated environmental contaminants (e.g., secondhand smoke) that lead to gap junction dysregulation, p38 MAPK activation, and increased mRNA production of inflammatory mediators, such as cytokines and cyclooxygenase (COX2), in lung epithelial cells. However, the early mechanisms involving lipid signaling through the arachidonic acid pathway and subsequent eicosanoid production leading to these downstream events are not known...
January 25, 2019: Toxicological Sciences: An Official Journal of the Society of Toxicology
Baptiste Buisseret, Owein Guillemot-Legris, Giulio G Muccioli, Mireille Alhouayek
Pain is one of the cardinal signs of inflammation and is present in many inflammatory conditions. Therefore, anti-inflammatory drugs such as NSAIDs also have analgesic properties. We previously showed that prostaglandin D2 -glycerol ester (PGD2 -G), endogenously produced by cyclooxygenase-2 from the endocannabinoid 2-arachidonoylglycerol, has anti-inflammatory effects in vitro and in vivo that are partly mediated by DP1 receptor activation. In this work, we investigated its effect in a model of carrageenan-induced inflammatory pain...
January 23, 2019: Biochimica et biophysica acta. Molecular and cell biology of lipids
Benjamin T Kopp, Rohan Thompson, Jeeho Kim, Robert Konstan, Alejandro Diaz, Bennett Smith, Chandra Shrestha, Lynette K Rogers, Don Hayes, Dmitry Tumin, Frederick W Woodley, Octavio Ramilo, Don B Sanders, Judith A Groner, Asuncion Mejias
BACKGROUND: Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children with CF...
January 19, 2019: Thorax
Jing Zhou, Hongyue Ma, Yuanyuan Wu, Xiang Lv, Jiajia Wang, Shengjin Liu, Dandan Li, Hengbin Wang, Yanqing Yan, Niancui Luo, Quan Li, Huiqin Xu, Qichun Zhang, Li Yu, Hongbo Guo, Uros Kuzmanov, Liuqing Di, Qinan Wu, Jinao Duan
Arsenic sulfide compounds provide nearly all of the world's supply of arsenic. However, the risk of arsenic trisulfide exposure is still not fully investigated. Here, we systemically assessed the toxicology of As4S4 in rats by combining arsenic metabolite detection, routine testing and lipidomic profiling. It was revealed that the oral administration of As4S4 for two months increased the total arsenic content in the liver reaching a saturation level. Further analysis by anion exchange chromatography coupled with inductively coupled plasma mass spectrometry (ICP-MS) technology showed no trace of inorganic arsenic, but there was significant presence of dimethylarsinic acid (DMA), in the livers of rats...
January 16, 2019: Metallomics: Integrated Biometal Science
Elina Jerschow, Matthew L Edin, Yuling Chi, Beth Hurst, Waleed M Abuzeid, Nadeem A Akbar, Marc Gibber, Marvin P Fried, Weiguo Han, Teresa Pelletier, Zhen Ren, Taha Keskin, Gigia Roizen Gottlieb, Fred B Lih, Artiom Gruzdev, J Alyce Bradbury, Victor Schuster, Simon Spivack, David Rosenstreich, Darryl C Zeldin
BACKGROUND: Nasal polyps influence the burden of aspirin exacerbated respiratory disease (AERD) by contributing to eicosanoid production. AERD is diagnosed through graded aspirin challenges. It is not known how sinus surgery affects aspirin challenge outcomes. OBJECTIVE: To investigate the effects of endoscopic sinus surgery (ESS) on aspirin-induced reaction severity and on the levels of eicosanoids associated with these reactions. METHODS: Twenty-eight AERD patients were challenged with aspirin before and 3-4 weeks after ESS...
December 20, 2018: Journal of Allergy and Clinical Immunology in Practice
Jovana Maric, Avinash Ravindran, Luca Mazzurana, Aline Van Acker, Anna Rao, Efthymia Kokkinou, Maria Ekoff, Dominique Thomas, Alexander Fauland, Gunnar Nilsson, Craig E Wheelock, Sven-Erik Dahlén, Nerea Ferreirós, Gerd Geisslinger, Danielle Friberg, Akos Heinemann, Viktoria Konya, Jenny Mjösberg
BACKGROUND: Group 2 innate lymphoid cells (ILC2) play a key role in the initiation and maintenance of type 2 immune responses. The PGD2 -CRTH2 receptor axis potently induces cytokine production and migration of ILC2. OBJECTIVE: We set out to examine prostaglandin production in human ILC2 and the implications of such endogenous production on ILC2 function. METHODS: The effects of the COX-1/2 inhibitor flurbiprofen, the HPGDS inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2 were determined by assessing receptor and transcription factor expression, cytokine production and gene expression by flow cytometry, ELISA and quantitative RT-PCR, respectively...
December 19, 2018: Journal of Allergy and Clinical Immunology
Stanko Skrtic, Björn Tyrberg, Malin Broberg, Hans Ericsson, Volker Schnecke, Magnus Kjaer, Marcus Hompesch, Eva-Marie Andersson, Erik Ryberg, Alexander Aivazidis, Charlotte Wennberg Huldt, Lars Löfgren, Linda Morrow, Joanna Parkinson, Tina Rydén-Bergsten, Elaine Watkins, Maria Sörhede Winzell
AIMS/HYPOTHESIS: GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients. METHODS: We determined the drive on PGD2 secretion by glucose and IL-1beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro...
2018: PloS One
Giancarlo Marone, Maria Rosaria Galdiero, Antonio Pecoraro, Valentina Pucino, Gjada Criscuolo, Maria Triassi, Gilda Varricchi
Prostaglandin D2 (PGD2 ) is a major cyclooxygenase mediator that is synthesized by activated human mast cells and other immune cells. The biological effects of PGD2 are mediated by D-prostanoid (DP1 ), DP2 (CRTH2) and thromboxane prostanoid (TP) receptors that are expressed on several immune and non-immune cells involved in allergic inflammation. PGD2 exerts various proinflammatory effects relevant to the pathophysiology of allergic disorders. Several selective, orally active, DP2 receptor antagonists and a small number of DP1 receptor antagonists are being developed for the treatment of allergic disorders...
January 2019: Expert Opinion on Investigational Drugs
Daniel Elieh Ali Komi, Leif Bjermer
Improving the lung function after experimental allergen challenge by blocking of mast cell (MC) mediators and the capability of MC mediators (including histamine, prostaglandin (PG) D2, and leukotriene (LT) C4) in induction of mucosal edema, bronchoconstriction, and mucus secretion provide evidence that MCs play a key role in pathophysiology of asthma. In asthma, the number of MCs increases in the airways and infiltration of MCs in a variety of anatomical sites including the epithelium, the submucosal glands, and the smooth muscle bundles occurs...
November 30, 2018: Clinical Reviews in Allergy & Immunology
Tanya M Laidlaw
It is well-established that following ingestion of aspirin or any other inhibitor of cyclooxygenase-1, patients with Samter's disease, or aspirin-exacerbated respiratory disease (AERD) develop the sudden onset of worsening respiratory clinical symptoms, which usually involves nasal congestion, rhinorrhea, wheezing and bronchospasm. Gastrointestinal distress, nausea, a pruritic rash and angioedema can also occasionally develop. However, the underlying pathologic mechanism that drives these clinical reactions remains elusive...
September 2018: World Journal of Otorhinolaryngology—Head and Neck Surgery
Zhang L Zhang, Vincent van Suylen, Judith E van Zanden, Caroline Van De Wauwer, Erik A M Verschuuren, Wim van der Bij, Michiel E Erasmus
OBJECTIVES: Despite progress in lung transplantation (LTx) techniques, a shortage of donor lungs persists worldwide. Ex vivo lung perfusion (EVLP) is a technique that evaluates, optimizes and enables transplantation of the lungs that would otherwise have been discarded. Herein, we present our centre's first EVLP experiences between July 2012 and June 2016, when we performed 149 LTxs. METHODS: It was a single-centre, retrospective analysis of a prospectively collected database...
November 29, 2018: European Journal of Cardio-thoracic Surgery
Asheebo Rojas, Di Chen, Thota Ganesh, Nicholas H Varvel, Raymond Dingledine
Introduction:A robust neuroinflammatory response is a prevalent feature of multiple neurological disorders, including epilepsy and acute status epilepticus. One component of this neuroinflammatory reaction is the induction of cyclooxygenase-2 (COX-2), synthesis of several prostaglandins and endocannabinoid metabolites, and subsequent activation of prostaglandin and related receptors. Neuroinflammation mediated by COX-2 and its downstream effectors has received considerable attention as a potential target class to ameliorate the deleterious consequences of neurological injury...
November 28, 2018: Expert Opinion on Therapeutic Targets
Eri Takeshita, Hirofumi Komaki, Yuko Shimizu-Motohashi, Akihiko Ishiyama, Masayuki Sasaki, Shin'ichi Takeda
Objective: Currently, the only approved standard Duchenne muscular dystrophy (DMD) treatment in Japan is oral steroids, which have various disadvantages. Previous work has suggested that hematopoietic-type prostaglandin D synthase (HPGDS), involved in production of the inflammatory mediator prostaglandin D2 (PGD2 ), might have a role in DMD pathology. We therefore investigated the safety, pharmacokinetics (PK), and pharmacodynamics of a highly selective HPGDS inhibitor (TAS-205) in Japanese patients with genetically confirmed DMD...
November 2018: Annals of Clinical and Translational Neurology
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