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Multifaceted Physiological Roles of Adiponectin in Inflammation And
International Journal of Molecular Sciences Review Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases Hyung Muk Choi 1, Hari Madhuri Doss 1,2 and Kyoung Soo Kim 1,2,* 1 Department of Clinical Pharmacology and Therapeutics, Kyung Hee University School of Medicine, Seoul 02447, Korea; [email protected] (H.M.C.); [email protected] (H.M.D.) 2 East-West Bone & Joint Disease Research Institute, Kyung Hee University Hospital at Gangdong, Gandong-gu, Seoul 02447, Korea * Correspondence: [email protected]; Tel.: +82-2-961-9619 Received: 3 January 2020; Accepted: 10 February 2020; Published: 12 February 2020 Abstract: Adiponectin is the richest adipokine in human plasma, and it is mainly secreted from white adipose tissue. Adiponectin circulates in blood as high-molecular, middle-molecular, and low-molecular weight isoforms. Numerous studies have demonstrated its insulin-sensitizing, anti-atherogenic, and anti-inflammatory effects. Additionally, decreased serum levels of adiponectin is associated with chronic inflammation of metabolic disorders including Type 2 diabetes, obesity, and atherosclerosis. However, recent studies showed that adiponectin could have pro-inflammatory roles in patients with autoimmune diseases. In particular, its high serum level was positively associated with inflammation severity and pathological progression in rheumatoid arthritis, chronic kidney disease, and inflammatory bowel disease. Thus, adiponectin seems to have both pro-inflammatory and anti-inflammatory effects. This indirectly indicates that adiponectin has different physiological roles according to an isoform and effector tissue. Knowledge on the specific functions of isoforms would help develop potential anti-inflammatory therapeutics to target specific adiponectin isoforms against metabolic disorders and autoimmune diseases. -
Adiporon, an Orally Active, Synthetic Agonist of Adipor1 and Adipor2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice
molecules Article AdipoRon, an Orally Active, Synthetic Agonist of AdipoR1 and AdipoR2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice Hubert Zatorski 1,2, Maciej Salaga 1 , Marta Zieli ´nska 1, Kinga Majchrzak 1, Agata Binienda 1 , Radzisław Kordek 3, Ewa Małecka-Panas 2 and Jakub Fichna 1,4,* 1 Department of Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; [email protected] (H.Z.); [email protected] (M.S.); [email protected] (M.Z.); [email protected] (K.M.); [email protected] (A.B.) 2 Department of Digestive Tract Diseases, Medical University of Lodz, 93-281 Lodz, Poland; [email protected] 3 Department of Pathology, Medical University of Lodz, 92-215 Lodz, Poland; [email protected] 4 Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland * Correspondence: jakub.fi[email protected]; Tel.: +48-42-272-57-07 Citation: Zatorski, H.; Salaga, M.; Abstract: Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin- Zieli´nska,M.; Majchrzak, K.; sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and Binienda, A.; Kordek, R.; AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 Małecka-Panas, E.; Fichna, J. and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate AdipoRon, an Orally Active, the possible underlying mechanism. Methods: We used two well-established mouse models of Synthetic Agonist of AdipoR1 and gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac AdipoR2 Receptors Has (30 mg/kg, p.o.). -
(12) United States Patent (10) Patent No.: US 7,723,342 B2 Palani Et Al
US007723342B2 (12) United States Patent (10) Patent No.: US 7,723,342 B2 Palani et al. (45) Date of Patent: *May 25, 2010 (54) HETEROCYCLES AS NICOTINIC ACID FOREIGN PATENT DOCUMENTS RECEPTORAGONSTS FOR THE TREATMENT OF DYSLIPIDEMA DE 263 891 A3 1, 1989 DE 265 760 A3 3, 1989 (75) Inventors: Anandan Palani, Bridgewater, NJ (US); FR 256223 * 10, 1985 Jing Su, Scotch Plains, NJ (US); Dong WO WOOO698.29 A1 11, 2000 WO WO 02/084.298 A2 10, 2002 Xiao, Warren, NJ (US); Xianhai Huang, WO WO 2004037159 * 10/2003 Warren, NJ (US); Ashwin U. Rao, WO WO 2004/O37159 A2 5, 2004 Avenel, NJ (US); Xiao Chen, Edison, NJ WO WO 2004/047755 A2 6, 2004 (US); Haiqun Tang, Belle Mead, NJ WO WO 2004/083388 A2 9, 2004 (US); Jun Qin, Edison, NJ (US); Ying WO WO 2004f1 10368 A2 12/2004 Huang, Berkeley Heights, NJ (US); WO WO 2004f1 10375 A2 12/2004 Robert G. Aslanian, Rockaway, NJ WO WO 2005/OOO217 A2 1, 2005 (US); Brian A. McKittrick, New WO WO 2006O78834 * 1 2005 Vernon, NJ (US) WO WO 2005, O7795O A2 8, 2005 WO WO 2005,105097 A2 11/2005 (73) Assignee: Schering Corporation, Kenilworth, NJ WO WO 2006/045564 A1 5, 2006 (US) WO WO 2006/045565 A1 5, 2006 Notice: WO WO 2006/078834 A1 T 2006 (*) Subject to any disclaimer, the term of this WO WO 2006/089009 A2 8, 2006 patent is extended or adjusted under 35 WO WO 2006/092430 A1 9, 2006 U.S.C. 154(b) by 10 days. -
Modifications to the Harmonized Tariff Schedule of the United States To
U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b). -
G Protein-Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. -
G Protein‐Coupled Receptors
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. -
Neurotensin Receptor 1 Antagonist SR48692 Improves Response To
Published OnlineFirst August 8, 2017; DOI: 10.1158/1078-0432.CCR-17-0861 Cancer Therapy: Preclinical Clinical Cancer Research Neurotensin Receptor 1 Antagonist SR48692 Improves Response to Carboplatin by Enhancing Apoptosis and Inhibiting Drug Efflux in Ovarian Cancer Jin Liu1, Mikael€ Agopiantz2,3,Joel€ Poupon4, Zherui Wu1, Pierre-Alexandre Just5, Bruno Borghese6, Evelyne Segal-Bendirdjian 1, Guillaume Gauchotte3,7, Anne Gompel1,8, and Patricia Forgez1 Abstract Purpose: The high affinity receptor 1 (NTSR1) and its agonist, Results: SR48692 enhanced the response to carboplatin in neurotensin (NTS), are correlated with tumor cell aggressiveness ovarian cancer cells and experimental tumors. When SR48692 in most solid tumors. As chemoresistance and tumor aggres- is combined with carboplatin, we noted a major improvement siveness are often related, we decided to study the role of the of platinum-induced DNA damage and cell death, as well as a NTSR1 complex within platinum-based chemotherapy responses. decrease in tumor growth. The relationship of these results In an ovarian model, we studied carboplatin because it is the main to clinical studies was made by the detection of NTS and standard of care for ovarian cancer. NTSR1 in 72% and 74% of ovarian cancer, respectively. Fur- Experimental Design: Experimental tumors and in vitro studies thermore, in a large series of high-grade ovarian cancer, NTSR1 were performed using SKOV3 and A2780 cells treated with mRNA was shown to correlate with higher stages and platinum carboplatin, with or without a very specific NTSR1 antagonist, resistance. SR48692. We measured the effects of these treatments on cell Conclusions: This study strongly suggests that the addition apoptosis and apoptosis-related proteins, platinum accumula- of NTSR1 inhibitor in combination with platinum salt–based tion in the cell and nucleus, and the expression and localization of therapy will improve the response to the drug. -
Adipor Agonist Increases Insulin Sensitivity and Exercise Endurance
ARTICLE https://doi.org/10.1038/s42003-020-01579-9 OPEN AdipoR agonist increases insulin sensitivity and exercise endurance in AdipoR-humanized mice ✉ Masato Iwabu1,2,3,11, Miki Okada-Iwabu 1,3,11 , Hiroaki Tanabe 4,5, Nozomi Ohuchi1, Keiko Miyata1, ✉ Toshiko Kobori6, Sara Odawara1, Yuri Kadowaki1, Shigeyuki Yokoyama 4,5, Toshimasa Yamauchi 1,7 & ✉ Takashi Kadowaki 1,8,9,10 1234567890():,; Adiponectin receptors, AdipoR1 and AdipoR2 exert anti-diabetic effects. Although muscle- specific disruption of AdipoR1 has been shown to result in decreased insulin sensitivity and decreased exercise endurance, it remains to be determined whether upregulation of AdipoR1 could reverse them in obese diabetic mice. Here, we show that muscle-specific expression of human AdipoR1 increased expression levels of genes involved in mitochondrial biogenesis and oxidative stress-detoxification to almost the same extents as treadmill exercise, and concomitantly increased insulin sensitivity and exercise endurance in obese diabetic mice. Moreover, we created AdipoR-humanized mice which express human AdipoR1 in muscle of AdipoR1·R2 double-knockout mice. Most importantly, the small-molecule AdipoR agonist AdipoRon could exert its beneficial effects in muscle via human AdipoR, and increased insulin sensitivity and exercise endurance in AdipoR-humanized mice. This study suggests that expression of human AdipoR1 in skeletal muscle could be exercise-mimetics, and that Adi- poRon could exert its beneficial effects via human AdipoR1. 1 Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 2 PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. -
Insulin Action/Molecular Metabolism
INSULIN ACTION—ADIPOCYTECATEGORY BIOLOGY 1692-P 1694-P Stress in Beta Cells Obtained with Laser Capture Microdissection Biopsy-Proven Insulitis of Clinical Islet Transplantation Is Not from Cadaver Pancreases of Brain Dead Donors Reversed by Steroid Therapy AREF EBRAHIMI, MIN-HO JUNG, JONATHAN M. DREYFUSS, HUI PAN, DENNIS ANNA LAM, BEHRUZ RAHIMI, SHARLEEN IMES, KIM SOLEZ, JAMES SHAPIRO, C. SGROI, SUSAN BONNER-WEIR, GORDON C. WEIR, Boston, MA PETER A. SENIOR, Edmonton, AB, Canada Brain death of pancreas donors is thought to lead to the expression of Gradual decline in islet function remains a challenge in clinical islet infl ammatory, stress and apoptotic pathways in isolated islets resulting in transplantation (CIT), but acute graft loss is relatively uncommon. Here we poor clinical outcomes. To test this hypothesis we obtained cadaveric pan- describe a case of acute decline in graft function with histology suggesting creases from brain dead pancreatic donors (n=7, mean age 5011) and normal an immune mechanism. A 49 year old female (BMI 24.4 kg/m2, insulin 0.3 pancreatic tissue obtained at surgery done for pancreatic neoplasms (n=7, U/kg) with type 1 diabetes for 37 years underwent two CIT (6071 and 6827 age 699). Frozen sections were subjected to laser capture microdissection islet equivalents/kg) following alemtuzumab induction with tacrolimus (TAC, to obtain beta-cell rich islet tissue, from which extracted RNA was analyzed mean 8 ug/L) and mycophenolate mofetil for maintenance. Initial engraft- with Affymetrix arrays. Gene expression of the two groups was evaluated ment was reasonable (β2 score of 12 at 1 week), but β2 score gradually with principle component analysis (PCA), and differential expression anal- declined (Figure 1) rising to 19 after the second CIT. -
GPCR/G Protein
Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33. -
Adiporon Treatment Induces a Dose-Dependent Response in Adult Hippocampal Neurogenesis
International Journal of Molecular Sciences Article AdipoRon Treatment Induces a Dose-Dependent Response in Adult Hippocampal Neurogenesis Thomas H. Lee 1 , Brian R. Christie 2 , Henriette van Praag 3, Kangguang Lin 4, Parco Ming-Fai Siu 5, Aimin Xu 6,7,8, Kwok-Fai So 9,10,11 and Suk-yu Yau 1,* 1 Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong; [email protected] 2 Division of Biomedical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada; [email protected] 3 FAU Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33431, USA; [email protected] 4 Department of Affective Disorder, Guangzhou Brain Hospital, The Brain Affiliated Hospital of Guangzhou Medical University, Guangzhou 510370, China; [email protected] 5 Division of Kinesiology, School of Public Health, The University of Hong Kong, Hong Kong; [email protected] 6 Department of Medicine, The University of Hong Kong, Hong Kong; [email protected] 7 Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong 8 The State Key Laboratory of Pharmacology, The University of Hong Kong, Hong Kong 9 Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China; [email protected] 10 State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong 11 Department of Ophthalmology, The University of Hong Kong, Hong Kong * Correspondence: [email protected]; Tel.: +852-2766-4890 Abstract: AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, Citation: Lee, T.H.; Christie, B.R.; and anti-inflammatory effects on mouse models as adiponectin does. -
Obesity Reduces the Anticancer Effect of Adiporon Against Orthotopic
www.nature.com/scientificreports OPEN Obesity reduces the anticancer efect of AdipoRon against orthotopic pancreatic cancer in diet‑induced obese mice Keizo Takenaga1*, Miho Akimoto2, Nobuko Koshikawa1 & Hiroki Nagase1 The antidiabetic adiponectin receptor agonist AdipoRon has been shown to suppress the tumour growth of human pancreatic cancer cells. Because obesity and diabetes afect pancreatic cancer progression and chemoresistance, we investigated the efect of AdipoRon on orthotopic tumour growth of Panc02 pancreatic cancer cells in DIO (diet‑induced obese) prediabetic mice. Administration of AdipoRon into DIO mice fed high‑fat diets, in which prediabetic conditions were alleviated to some extent, did not reduce either body weight or tumour growth. However, when the DIO mice were fed low‑fat diets, body weight and the blood leptin level gradually decreased, and importantly, AdipoRon became efective in suppressing tumour growth, which was accompanied by increases in necrotic areas and decreases in Ki67‑positive cells and tumour microvessels. AdipoRon inhibited cell growth and induced necrotic cell death of Panc02 cells and suppressed angiogenesis of endothelial MSS31 cells. Insulin and IGF‑1 only slightly reversed the AdipoRon‑induced suppression of Panc02 cell survival but had no efect on the AdipoRon‑induced suppression of MSS31 cell angiogenesis. Leptin signifcantly ameliorated AdipoRon‑induced suppression of angiogenesis through inhibition of ERK1/2 activation. These results suggest that obesity‑associated factors weaken the anticancer efect of AdipoRon, which indicates the importance of weight loss in combating pancreatic cancer. Pancreatic cancer is the most lethal cancer. Most of the tumours are already unresectable at diagnosis, and the 5-year survival rate is quite low1.