DOCSLIB.ORG

Tetrahydroxydihydroflavonol Binds to Adiponectin Receptors, with a Preference for Adipor1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tetrahydroxydihydroflavonol Binds to Adiponectin Receptors, with a Preference for Adipor1 Page 1 of 56 Diabetes 1 Orally active osteoanabolic agent 6-C-β-D-glucopyranosyl-(2S, 3S)-(+)- 5,7, 3',4'- 2 tetrahydroxydihydroflavonol binds to adiponectin receptors, with a preference for AdipoR1, 3 induces adiponectin-associated signaling and improves metabolic health in a rodent model of 4 diabetes. 5 Running title: GTDF is an orally active adiponectin mimetic 6 Abhishek Kumar Singh1,#, Amit Arvind Joharapurkar2,#, Mohd. Parvez Khan3, Jay Sharan Mishra1, 7 Nidhi Singh1, Manisha Yadav1, Zakir Hossain4, Kainat Khan3, Sudhir Kumar5, Nirav Anilkumar 8 Dhanesha2, Devendra Pratap Mishra5, Rakesh Maurya5, Sharad Sharma6, Mukul Rameshchandra 9 Jain2, Arun Kumar Trivedi1, Madan Madhav Godbole7, Jiaur Rahaman Gayen4 , Naibedya 10 Chattopadhyay2 and Sabyasachi Sanyal1,* 11 12 Authors’ affiliations: 13 1Biochemistry Division, CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 14 226031, UP, India. 2Zydus Research Center, Sarkhej-Bavla NH#8A, Moraiya, Ahmedabad 382210, Gujarat, 15 India. 3Division of Endocrinology, CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, 16 Lucknow 226031, UP, India. 4Division of Phramacokinetics, CSIR-Central Drug Research Institute, 10 17 Janakipuram Extn, Sitapur Road, Lucknow 226031, UP, India. 5Division of Medicinal and Process Chemistry, 18 CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 226031, UP, India. 19 6Division of Toxicology, CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 20 226031, UP, India. 7Department of Molecular Medicine, Sanjay Gandhi Postgraduate Institute of Medical 21 Sciences, Lucknow 226014, UP, India. 22 # These authors contributed equally 23 *Address correspondence to Sabyasachi sanyal, e mail: [email protected], Biochemistry Division, 24 CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 226031, UP, 25 India ; Tel: (+91)-9792366322; Fax: (+91)-(522)-2771941 26 Word Count 5412 27 Number of Figures 7 1 Diabetes Publish Ahead of Print, published online May 21, 2014 Diabetes Page 2 of 56 1 ABSTRACT 2 Adiponectin is an adipocytokine that signals through plasma membrane-bound adiponectin 3 receptors (AdipoR) -1 and -2. Plasma adiponectin depletion is associated with type 2 4 diabetes, obesity and cardiovascular diseases. Adiponectin therapy however, is yet 5 unavailable owing to its large size, complex multimerization and functional differences of the 6 multimers. We report discovery and characterization of 6-C-β-D-glucopyranosyl-(2S, 3S)- 7 (+)- 5,7, 3',4'- tetrahydroxydihydroflavonol (GTDF) as an orally active adiponectin mimetic. 8 GTDF interacted with both AdipoRs, with a preference for AdipoR1. It induced adiponectin- 9 associated signaling and enhanced glucose uptake and fatty acid oxidation in vitro, which 10 were augmented or abolished by AdipoR1 overexpression or silencing respectively. GTDF 11 improved metabolic health, characterized by elevated glucose-clearance, β-cell-survival, 12 reduced steatohepatitis, browning of white adipose tissue and improved lipid profile in an 13 AdipoR1-expressing but not an AdipoR1-depleted strain of diabetic mice. The discovery of 14 GTDF as an adiponectin mimetic provides a promising therapeutic tool for the treatment of 15 metabolic diseases. 16 17 18 19 20 21 22 23 24 25 2 Page 3 of 56 Diabetes 1 The anti-inflammatory adipocytokine adiponectin (1; 2) signals through adiponectin 2 receptors (AdipoR) -1 and -2 (3). T-cadherin, a cadherin family member that lacks 3 transmembrane and cytoplasmic domains also binds adiponectin, and is proposed to affect its 4 bioavailability (4). Plasma adiponectin depletion is associated with type 2 diabetes, obesity 5 and cardiovascular diseases (5-7). Adiponectin administration or overexpression ameliorates 6 insulin resistance, metabolic syndrome and atherosclerosis in animals (3; 8-12) and enhances 7 pancreatic β cell survival (13). These evidences make AdipoRs important therapeutic targets 8 for metabolic diseases. 9 Structurally, adiponectin belongs to the complement 1q family (1; 14; 15). 10 Adipoenctin monomer is a 30 kDa protein consisting of an N-terminal collagenous and a C- 11 terminal globular domains (1). Mammalian plasma adiponectin is present in several 12 multimeric forms; low-molecular-weight dimer or trimers, medium-molecular-weight 13 hexamers or high-molecular-weight (HMW) dodecamers and 18 mers (10; 16-18). The 14 globular domain of adiponectin (gAd) can form trimers and was initially shown to exist as a 15 proteolytic cleavage product in human plasma (10), although subsequent studies failed to 16 detect it in circulation, its ability to modulate AdipoRs is undisputed. All these forms display 17 different levels of physiological activity and the HMW complex is considered the most 18 clinically relevant form (10; 16-18). The HMW full-length adiponectin and gAd 19 preferentially signal through AdipoR2 and AdipoR1 respectively (3). Given the 20 multimerization-related complexities of adiponectin structure and function, it appears that 21 small molecule AdipoR ligands may provide the only viable therapeutic option against 22 diseases associated with defects in adiponectin expression or action. 23 We have previously identified GTDF, a novel natural analog of the dietary flavonoid 24 quercetin, as a potent orally bioavailable osteoanabolic compound that induced proliferation, 25 differentiation and mineralization of cultured primary osteoblasts at a nanomolar 3 Diabetes Page 4 of 56 1 concentration that was 1000 fold less than effective concentration of quercetin or queretin-O- 2 glucoside, and restored trabecular bones of osteopenic rats on a par with parathyroid hormone 3 (19). While studying its mechanism of action, we found that GTDF induced rapid AMP– 4 dependent protein kinase (AMPK), AKT and p38 phosphorylation and elevated PGC-1α 5 expression in osteoblasts. GTDF also deacetylated tumor suppressor P53 via indirect 6 activation of NAD-dependent deacetylase Sirtuin1 (sirt1) [(20), and manuscript in 7 preparation, SS and NC)]. Literature search revealed that adiponectin elicits similar cellular 8 signaling (1; 3; 11). Interestingly, the quercetin group of compounds display functional 9 properties similar to adiponectin, such as AMPK activation, glucose uptake enhancement, 10 induction of fatty acid oxidation-related genes and amelioration of diabetes and insulin 11 resistance in vivo (21-23). We thus asked if GTDF, quercetin or other naturally occurring 12 quercetin analogs could be adiponectin mimetics. Here we report detailed characterization of 13 GTDF as an adiponectin mimetic that improves metabolic health in a rodent model of 14 diabetes. 15 16 RESEARCH DESIGN AND METHODS 17 Materials and kits: All cell culture reagents were from Invitrogen, Life Technologies 18 (Carlsbad, CA). Fine chemicals were from Sigma-Aldrich (St. Louis, MO) unless otherwise 19 indicated. Epoxy agarose beads conjugated with GTDF were constructed at Shantani Biotech 20 (Pune, India). Globular adiponectin (gAd) was purchased from Enzo Life Sciences 21 (Farmingdale, NY) and ATGen Global (Gyeonggi-do, South Korea) and compared; gAd 22 from both sources showed identical activity; gAd from ATGen Global was used in this study. 23 GW7647 was from Sigma-Aldrich, full length human AdipoR1 and AdipoR2 mammalian 24 expression constructs were from Open Biosystems (Huntsville, AL). 125I-gAd was from 25 Phoenix Pharmaceuticals (Burlingame, CA), 125I (20 MBq) used for radiolabeling GTDF was 4 Page 5 of 56 Diabetes 1 from BARC (Mumbai, India). Glycogen assay kit was from Sigma-Aldrich (St. Louis, 2 Missouri). Serum concentrations of triglycerides, nonesterified free fatty acids (NEFA), 3 HDL, LDL,VLDL, total cholesterol, beta-hydroxybutyrate, and creatinine were determined 4 using kits purchased from Pointe Scientific (Canton, MI, USA).Circulating glucagon, insulin, 5 C-peptide, leptin, adiponectin, ghrelin, corticosterone and markers of inflammation (MCP-1, 6 TNF-α, and IL-6) were estimated using enzyme-linked immunosorbent assay (ELISA) assay 7 kits (R&D Systems, Minneapolis, MN). Serum concentrations of sodium and potassium were 8 measured using a Cobas c system (Roche Diagnostics; Indianapolis, IN). TUNEL assay kit 9 was from Roche Applied Science (Indianapolis, IN). Plasma membrane extraction kit was 10 from Biovision (Milpitas, CA). 11 Cell culture and induction of differentiation 12 HEK-293, CHO, C2C12 and 3T3L-1 cell-lines were cultured as reported (24). Mouse stromal 13 vascular fraction (SVF) was prepared from epididymal fat pad by collagenase digestion. 14 Human SVFs were prepared from human lipoaspirates (subcutaneous), collected following 15 approval of Institutional Ethical Committee. Cells were differentiated in presence of GTDF 16 or vehicle for 10d (3T3L-1 and mouse SVF) or 21d (human SVF), using standard procedure, 17 and then analyzed by QPCR, immunoblotting or microscopy. 18 Iodination and purification of 125I-GTDF 19 GTDF was radio-labeled as previously described for quercetin1 with minor modifications. 20 Briefly, 10µl of 125I (20 MBq; BARC, Mumbai, India) was added to 100µg GTDF in 5% 21 acetic acid/methanol, then chloramine-T (4µg in MilliQ H2O) was added, and the mixture 22 was allowed to react at room temperature (240C) for 5 min. The reaction was terminated by 23 adding 60µl sodium metabisulphite (4mg/ml in MilliQ H2O).The reaction mixture was dried 24 by passing nitrogen and was dissolved into methanol (100 µl). Reverse phase TLC (RP-18 5 Diabetes
Load more

Recommended publications
  • 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.
    [Show full text]
  • Trace Amine-Associated Receptor 1 Activation Regulates Glucose-Dependent
    Trace amine-associated receptor 1 activation regulates glucose-dependent insulin secretion in pancreatic beta cells in vitro by ©Arun Kumar A thesis submitted to the School of Graduate Studies in partial fulfillment of the requirements for the degree of Master of Science Department of Biochemistry, Faculty of Science Memorial University of Newfoundland FEBRUARY 2021 St. John’s, Newfoundland and Labrador i Abstract Trace amines are a group of endogenous monoamines which exert their action through a family of G protein-coupled receptors known as trace amine-associated receptors (TAARs). TAAR1 has been reported to regulate insulin secretion from pancreatic beta cells in vitro and in vivo. This study investigates the mechanism(s) by which TAAR1 regulates insulin secretion. The insulin secreting rat INS-1E -cell line was used for the study. Cells were pre-starved (30 minutes) and then incubated with varying concentrations of glucose (2.5 – 20 mM) or KCl (3.6 – 60 mM) for 2 hours in the absence or presence of various concentrations of the selective TAAR1 agonist RO5256390. Secreted insulin per well was quantified using ELISA and normalized to the total protein content of individual cultures. RO5256390 significantly (P < 0.0001) increased glucose- stimulated insulin secretion in a dose-dependent manner, with no effect on KCl-stimulated insulin secretion. Affymetrix-microarray data analysis identified genes (Gnas, Gng7, Gngt1, Gria2, Cacna1e, Kcnj8, and Kcnj11) whose expression was associated with changes in TAAR1 in response to changes in insulin secretion in pancreatic beta cell function. The identified potential links to TAAR1 supports the regulation of glucose-stimulated insulin secretion through KATP ion channels.
    [Show full text]
  • Edinburgh Research Explorer
    Edinburgh Research Explorer International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list Citation for published version: Davenport, AP, Alexander, SPH, Sharman, JL, Pawson, AJ, Benson, HE, Monaghan, AE, Liew, WC, Mpamhanga, CP, Bonner, TI, Neubig, RR, Pin, JP, Spedding, M & Harmar, AJ 2013, 'International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands', Pharmacological reviews, vol. 65, no. 3, pp. 967-86. https://doi.org/10.1124/pr.112.007179 Digital Object Identifier (DOI): 10.1124/pr.112.007179 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Pharmacological reviews Publisher Rights Statement: U.S. Government work not protected by U.S. copyright General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 1521-0081/65/3/967–986$25.00 http://dx.doi.org/10.1124/pr.112.007179 PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:967–986, July 2013 U.S.
    [Show full text]
  • 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.).
    [Show full text]
  • Interplay Between Gating and Block of Ligand-Gated Ion Channels
    brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes.
    [Show full text]
  • In the Porcine Pituitary During the Oestrous Cycle Marta Kiezun, Anna Maleszka, Nina Smolinska, Anna Nitkiewicz and Tadeusz Kaminski*
    Kiezun et al. Reproductive Biology and Endocrinology 2013, 11:18 http://www.rbej.com/content/11/1/18 RESEARCH Open Access Expression of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) in the porcine pituitary during the oestrous cycle Marta Kiezun, Anna Maleszka, Nina Smolinska, Anna Nitkiewicz and Tadeusz Kaminski* Abstract Background: Adiponectin, protein secreted mainly by white adipose tissue, is an important factor linking the regulation of metabolic homeostasis and reproductive processes. The biological activity of the hormone is mediated via two distinct receptors, termed adiponectin receptor 1(AdipoR1) and adiponectin receptor 2 (AdipoR2). The present study analyzed mRNA and protein expression of AdipoR1 and AdipoR2 in the anterior (AP) and posterior (NP) pituitary of cyclic pigs. Methods: The total of 20 animals was assigned to one of four experimental groups (n = 5 per group) as follows: days 2–3 (early-luteal phase), 10–12 (mid-luteal phase), 14–16 (late-luteal phase), 17–19 (follicular phase) of the oestrous cycle. mRNA and protein expression were analyzed using real-time PCR and Western Blot methods, respectively. Results: The lowest AdipoR1 gene expression was detected in AP on days 10–12 relative to days 2–3and14–16 (p < 0.05). In NP, AdipoR1 mRNA levels were elevated on days 10–12 and 14–16 (p < 0.05). AdipoR2 gene expression in AP was the lowest on days 10–12, and an expression peak occurred on days 2–3 (p < 0.05). In NP, the lowest (p < 0.05) expression of AdipoR2 mRNA was noted on days 17–19. The AdipoR1 protein content in AP was the lowest on days 17–19 (p < 0.05), while in NP the variations in protein expression levels during the oestrous cycle were negligible.
    [Show full text]
  • (Title of the Thesis)*
    THE PHYSIOLOGICAL ACTIONS OF ADIPONECTIN IN CENTRAL AUTONOMIC NUCLEI: IMPLICATIONS FOR THE INTEGRATIVE CONTROL OF ENERGY HOMEOSTASIS by Ted Donald Hoyda A thesis submitted to the Department of Physiology In conformity with the requirements for the degree of Doctor of Philosophy Queen‟s University Kingston, Ontario, Canada (September, 2009) Copyright © Ted Donald Hoyda, 2009 ABSTRACT Adiponectin regulates feeding behavior, energy expenditure and autonomic function through the activation of two receptors present in nuclei throughout the central nervous system, however much remains unknown about the mechanisms mediating these effects. Here I investigate the actions of adiponectin in autonomic centers of the hypothalamus (the paraventricular nucleus) and brainstem (the nucleus of the solitary tract) through examining molecular, electrical, hormonal and physiological consequences of peptidergic signalling. RT-PCR and in situ hybridization experiments demonstrate the presence of AdipoR1 and AdipoR2 mRNA in the paraventricular nucleus. Investigation of the electrical consequences following receptor activation in the paraventricular nucleus indicates that magnocellular-oxytocin cells are homogeneously inhibited while magnocellular-vasopressin neurons display mixed responses. Single cell RT-PCR analysis shows oxytocin neurons express both receptors while vasopressin neurons express either both receptors or one receptor. Co-expressing oxytocin and vasopressin neurons express neither receptor and are not affected by adiponectin. Median eminence projecting corticotropin releasing hormone neurons, brainstem projecting oxytocin neurons, and thyrotropin releasing hormone neurons are all depolarized by adiponectin. Plasma adrenocorticotropin hormone concentration is increased following intracerebroventricular injections of adiponectin. I demonstrate that the nucleus of the solitary tract, the primary cardiovascular regulation site of the medulla, expresses mRNA for AdipoR1 and AdipoR2 and mediates adiponectin induced hypotension.
    [Show full text]
  • Metabolite Sensing Gpcrs: Promising Therapeutic Targets for Cancer Treatment?
    cells Review Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment? Jesús Cosín-Roger 1,*, Dolores Ortiz-Masia 2 , Maria Dolores Barrachina 3 and Sara Calatayud 3 1 Hospital Dr. Peset, Fundación para la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, FISABIO, 46017 Valencia, Spain 2 Departament of Medicine, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; [email protected] 3 Departament of Pharmacology and CIBER, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; [email protected] (M.D.B.); [email protected] (S.C.) * Correspondence: [email protected]; Tel.: +34-963851234 Received: 30 September 2020; Accepted: 21 October 2020; Published: 23 October 2020 Abstract: G-protein-coupled receptors constitute the most diverse and largest receptor family in the human genome, with approximately 800 different members identified. Given the well-known metabolic alterations in cancer development, we will focus specifically in the 19 G-protein-coupled receptors (GPCRs), which can be selectively activated by metabolites. These metabolite sensing GPCRs control crucial processes, such as cell proliferation, differentiation, migration, and survival after their activation. In the present review, we will describe the main functions of these metabolite sensing GPCRs and shed light on the benefits of their potential use as possible pharmacological targets for cancer treatment. Keywords: G-protein-coupled receptor; metabolite sensing GPCR; cancer 1. Introduction G-protein-coupled receptors (GPCRs) are characterized by a seven-transmembrane configuration, constitute the largest and most ubiquitous family of plasma membrane receptors, and regulate virtually all known physiological processes in humans [1,2]. This family includes almost one thousand genes that were initially classified on the basis of sequence homology into six classes (A–F), where classes D and E were not found in vertebrates [3].
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,603,526 B2 Tygesen Et Al
    USOO8603526B2 (12) United States Patent (10) Patent No.: US 8,603,526 B2 Tygesen et al. (45) Date of Patent: Dec. 10, 2013 (54) PHARMACEUTICAL COMPOSITIONS 2008. O152595 A1 6/2008 Emigh et al. RESISTANT TO ABUSE 2008. O166407 A1 7/2008 Shalaby et al. 2008/0299.199 A1 12/2008 Bar-Shalom et al. 2008/0311205 A1 12/2008 Habib et al. (75) Inventors: Peter Holm Tygesen, Smoerum (DK); 2009/0022790 A1 1/2009 Flath et al. Jan Martin Oevergaard, Frederikssund 2010/0203129 A1 8/2010 Andersen et al. (DK); Karsten Lindhardt, Haslev (DK); 2010/0204259 A1 8/2010 Tygesen et al. Louise Inoka Lyhne-versen, Gentofte 2010/0239667 A1 9/2010 Hemmingsen et al. (DK); Martin Rex Olsen, Holbaek 2010, O291205 A1 11/2010 Downie et al. (DK); Anne-Mette Haahr, Birkeroed 2011 O159100 A1 6/2011 Andersen et al. (DK); Jacob Aas Hoellund-Jensen, FOREIGN PATENT DOCUMENTS Frederikssund (DK); Pemille Kristine Hoeyrup Hemmingsen, Bagsvaerd DE 20 2006 014131 1, 2007 (DK) EP O435,726 8, 1991 EP O493513 7, 1992 EP O406315 11, 1992 (73) Assignee: Egalet Ltd., London (GB) EP 1213014 6, 2002 WO WO 89,09066 10, 1989 (*) Notice: Subject to any disclaimer, the term of this WO WO91,040 15 4f1991 patent is extended or adjusted under 35 WO WO95/22962 8, 1995 U.S.C. 154(b) by 489 days. WO WO99,51208 10, 1999 WO WOOOf 41704 T 2000 WO WO 03/024426 3, 2003 (21) Appl. No.: 12/701,429 WO WOO3,O24429 3, 2003 WO WOO3,O24430 3, 2003 (22) Filed: Feb.
    [Show full text]
  • Metabolic Syndrome: Is It Time to Add the Central Nervous System?
    nutrients Review Metabolic Syndrome: Is It Time to Add the Central Nervous System? Milagros Rojas 1, Mervin Chávez-Castillo 2, Daniela Pirela 1, Heliana Parra 1 , Manuel Nava 1, Maricarmen Chacín 3, Lissé Angarita 4 , Roberto Añez 5, Juan Salazar 1 , Rina Ortiz 6, Samuel Durán Agüero 7, Marbel Gravini-Donado 8, Valmore Bermúdez 9 and Edgar Díaz-Camargo 9,* 1 Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela; migarocafi@gmail.com (M.R.); [email protected] (D.P.); [email protected] (H.P.); [email protected] (M.N.); [email protected] (J.S.) 2 Psychiatric Hospital of Maracaibo, Maracaibo 4004, Venezuela; [email protected] 3 Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 08002, Colombia; [email protected] 4 Escuela de Nutrición y Dietética, Facultad de Medicina, Universidad Andrés Bello, Sede Concepción 4260000, Chile; [email protected] 5 Departamento de Endocrinología y Nutrición, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; [email protected] 6 Posgrado, Carrera de Medicina, Universidad Católica de Cuenca, Cantón de Cuenca 010101, Ecuador; [email protected] 7 Facultad de Ciencias Para el Cuidado de la Salud, Universidad San Sebastián, Los Leones 8420524, Chile; [email protected] 8 Facultad de Ciencias Jurídicas y Sociales, Universidad Simón Bolívar, Barranquilla 080002, Colombia; [email protected] 9 Facultad de Ciencias Jurídicas y Sociales, Universidad Simón Bolívar, Cúcuta 540006, Colombia; [email protected] * Correspondence: [email protected] Citation: Rojas, M.; Chávez-Castillo, M.; Pirela, D.; Parra, H.; Nava, M.; Abstract: Metabolic syndrome (MS) is a set of cardio-metabolic risk factors that includes central Chacín, M.; Angarita, L.; Añez, R.; obesity, hyperglycemia, hypertension, and dyslipidemias.
    [Show full text]
  • ADIPOQ) and the Type 1 Receptor (ADIPOR1), Obesity and Prostate Cancer in African Americans
    Prostate Cancer and Prostatic Diseases (2010) 13, 362–368 & 2010 Macmillan Publishers Limited All rights reserved 1365-7852/10 www.nature.com/pcan ORIGINAL ARTICLE Genetic variation in adiponectin (ADIPOQ) and the type 1 receptor (ADIPOR1), obesity and prostate cancer in African Americans JL Beebe-Dimmer1, KA Zuhlke2, AM Ray2, EM Lange3 and KA Cooney4 1Department of Population Studies and Prevention, Karmanos Cancer Institute, Department of Internal Medicine, Wayne State University, Detroit, MI, USA; 2Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI, USA; 3Departments of Genetics and Biostatistics, University of North Carolina, Chapel Hill, NC, USA and 4Departments of Internal Medicine and Urology, University of Michigan Medical School, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA Adiponectin is a protein derived from adipose tissue suspected to have an important role in prostate carcinogenesis. Variants in the adiponectin gene (ADIPOQ) and its type 1 receptor (ADIPOR1) have been recently linked to risk of both breast and colorectal cancer. Therefore, we set out to examine the relationship between polymorphisms in these genes, obesity and prostate cancer in study of African-American men. Ten single-nucleotide polymorphisms (SNPs) in ADIPOQ and ADIPOR1 were genotyped in DNA samples from 131 African-American prostate cancer cases and 344 controls participating in the Flint Men’s Health Study. Logistic regression was then used to estimate their association with prostate cancer and obesity. While no significant associations were detected between any of the tested SNPs and prostate cancer, the rs1501299 SNP in ADIPOQ was significantly associated with body mass (P ¼ 0.03).
    [Show full text]
  • The Expanded Endocannabinoid System/Endocannabinoidome As a Potential Target for Treating Diabetes Mellitus
    Current Diabetes Reports (2019) 19:117 https://doi.org/10.1007/s11892-019-1248-9 OBESITY (KM GADDE, SECTION EDITOR) The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus Alain Veilleux1,2,3 & Vincenzo Di Marzo1,2,3,4,5 & Cristoforo Silvestri3,4,5 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease. Recent Findings As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. Summary The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D. Keywords Endocannabinoidome . Bioactive lipids . Peripheral tissues . Glucose . Insulin Introduction: The Endocannabinoid System cannabis-derived natural product, Δ9-tetrahydrocannabinol and its Subsequent Expansion (THC), responsible for most of the psychotropic, euphoric to the “Endocannabinoidome” and appetite-stimulating actions (via CB1 receptors) and immune-modulatory effects (via CB2 receptors) of marijuana, The discovery of two G protein-coupled receptors, the canna- opened the way to the identification of the endocannabinoids binoid receptor type-1 (CB1) and − 2 (CB2) [1, 2], for the (eCBs).
    [Show full text]