|
1
|
Rallidis LS, Katsimardos A, Kosmas N, Rallidi T, Kountouri A. Prognostic value of adiponectin in patients with stable coronary artery disease in the era of statins. Eur J Intern Med 2020; 79:118-119. [PMID: 32359977 DOI: 10.1016/j.ejim.2020.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 04/03/2020] [Indexed: 11/28/2022]
Affiliation(s)
- Loukianos S Rallidis
- Second Department of Cardiology, University General Hospital, "Attikon", 1 Rimini Street, Chaidari 12462, Athens, Greece.
| | - Andreas Katsimardos
- Second Department of Cardiology, University General Hospital, "Attikon", 1 Rimini Street, Chaidari 12462, Athens, Greece
| | - Nikolaos Kosmas
- Second Department of Cardiology, University General Hospital, "Attikon", 1 Rimini Street, Chaidari 12462, Athens, Greece
| | | | | |
Collapse
|
|
2
|
Flees J, Greene E, Ganguly B, Dridi S. Phytogenic feed- and water-additives improve feed efficiency in broilers via modulation of (an)orexigenic hypothalamic neuropeptide expression. Neuropeptides 2020; 81:102005. [PMID: 31926603 DOI: 10.1016/j.npep.2020.102005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/17/2019] [Accepted: 01/02/2020] [Indexed: 12/12/2022]
Abstract
Fueled by consumer preference for natural and antibiotic-free products, phytogenics have become the fastest growing segment of the animal feed additives. Yet, their modes of action are not fully understood. This study was undertaken to determine the effect of 5 phytogenics (3 feed- and 2 water-supplements) on the growth performance of commercial broilers, and their potential underlying molecular mechanisms. Day-old male Cobb 500 chicks (n = 576) were randomly assigned into 48 pens consisting of 6 treatments (Control; AVHGP; SCP; BHGP; AVSSL; SG) in a complete randomized design (12 birds/pen, 8 pens/treatment, 96 birds/treatment). Chicks had ad libitum access to feed and water. Individual body weight (BW) was recorded weekly and feed intake was measured daily. Core body temperatures were continuously recorded using thermo-loggers. At d 35, hypothalamic tissues were excised from the thermo-logger-equipped chickens (n = 8 birds/treatment) to determine the expression of feeding-related neuropeptides. Both feed (AVHGP, SCP, BHGP) and water-supplemented (AVSSL, SG) phytogenics significantly improved feed efficiency (FE) compared to the control birds. This higher FE was achieved via a reduction in core body temperature and improvement of market BW, without changes in feed intake in broilers supplemented with phytogenic water additives as compared to the control group. Broilers fed dietary phytogenics, however, attained higher feed efficiency via a reduction in feed intake while maintaining similar BW as the control group. At the molecular levels, the effects of the phytogenic water additives seemed to be mediated by the activation of the hypothalamic AgRP-ORX-mTOR-S6k1 and inhibition of CRH pathways. The effect of the phytogenic feed additives appeared to be exerted through the activation of AdipoQ, STAT3, AMPK, and MC1R pathways. This is the first report describing the likely central mechanisms through which phytogenic additives improve the growth performance and feed efficiency in broilers.
Collapse
Affiliation(s)
- Joshua Flees
- Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, United States of America
| | - Elizabeth Greene
- Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, United States of America
| | - Bhaskar Ganguly
- Clinical Research, Ayurvet Limited, Baddi, Himachal Pradesh 173205, India
| | - Sami Dridi
- Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, AR 72701, United States of America.
| |
Collapse
|
|
3
|
Tanaka S, Imaeda A, Matsumoto K, Maeda M, Obana M, Fujio Y. β2-adrenergic stimulation induces interleukin-6 by increasing Arid5a, a stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts. Pharmacol Res Perspect 2020; 8:e00590. [PMID: 32302067 PMCID: PMC7164407 DOI: 10.1002/prp2.590] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 03/19/2020] [Accepted: 03/24/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND PURPOSE In cardiovascular diseases, cardiac fibroblasts (CFs) participate in the myocardial inflammation by producing pro-inflammatory cytokines, worsening the prognosis. β2-adrenergic receptor (AR) and β3AR are expressed in CFs, and β-adrenergic stimulation promotes CFs to produce pro-inflammatory cytokines. However, the mechanism of the expression of pro-inflammatory cytokines in response to β-adrenergic stimulation remains to be fully elucidated. EXPERIMENTAL APPROACH CFs were isolated from adult wild-type or AT-rich interactive domain-containing protein 5A (Arid5a) knockout mice. The expression of mRNA was measured by real-time RT-PCR. Interleukin (IL)-6 protein was measured by ELISA. The activity of nuclear factor-κB (NF-κB) and cyclic AMP (cAMP) response element binding protein (CREB) was assessed by ELISA-like assay or Western blotting. KEY RESULTS The β-adrenergic stimulation remarkably induced IL-6 mRNA and protein through β2AR in CFs. The activation of adenylate cyclase and the enhancement of intracellular cAMP resulted in the upregulation of IL-6 mRNA expression. The induction of IL-6 transcript by β2AR signaling was independent of NF-κB. Concomitant with IL-6, the expression of Arid5a, an IL-6 mRNA stabilizing factor, was enhanced by β2-adrenergic stimulation and by cAMP increase. Importantly, β2AR signaling-mediated IL-6 induction was suppressed in Arid5a knockout CFs. Finally, β2AR stimulation phosphorylated CREB via PKA pathway, and the activation of CREB was essential for the induction of Arid5a and IL-6 mRNA. CONCLUSION AND IMPLICATIONS β2-adrenergic stimulation post-transcriptionally upregulates the expression of IL-6 by the induction of Arid5a through cAMP/PKA/CREB pathway in adult CFs. β2AR/Arid5a/IL-6 axis could be a therapeutic target against cardiac inflammation.
Collapse
Affiliation(s)
- Shota Tanaka
- Laboratory of Clinical Science and BiomedicineGraduate School of Pharmaceutical SciencesOsaka UniversitySuita CityOsakaJapan
| | - Atsuki Imaeda
- Laboratory of Clinical Science and BiomedicineGraduate School of Pharmaceutical SciencesOsaka UniversitySuita CityOsakaJapan
| | - Kotaro Matsumoto
- Laboratory of Clinical Science and BiomedicineGraduate School of Pharmaceutical SciencesOsaka UniversitySuita CityOsakaJapan
| | - Makiko Maeda
- Project of Clinical Pharmacology and TherapeuticsGraduate School of Pharmaceutical SciencesOsaka UniversitySuita CityOsakaJapan
| | - Masanori Obana
- Laboratory of Clinical Science and BiomedicineGraduate School of Pharmaceutical SciencesOsaka UniversitySuita CityOsakaJapan
| | - Yasushi Fujio
- Laboratory of Clinical Science and BiomedicineGraduate School of Pharmaceutical SciencesOsaka UniversitySuita CityOsakaJapan
- Project of Clinical Pharmacology and TherapeuticsGraduate School of Pharmaceutical SciencesOsaka UniversitySuita CityOsakaJapan
- Integrated Frontier Research for Medical Science DivisionInstitute for Open and Transdisciplinary Research InitiativesOsaka UniversitySuita CityOsakaJapan
| |
Collapse
|
|
4
|
Zimta AA, Tigu AB, Muntean M, Cenariu D, Slaby O, Berindan-Neagoe I. Molecular Links between Central Obesity and Breast Cancer. Int J Mol Sci 2019; 20:ijms20215364. [PMID: 31661891 PMCID: PMC6862548 DOI: 10.3390/ijms20215364] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/21/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Worldwide, breast cancer (BC) is the most common malignancy in women, in regard to incidence and mortality. In recent years, the negative role of obesity during BC development and progression has been made abundantly clear in several studies. However, the distribution of body fat may be more important to analyze than the overall body weight. In our review of literature, we reported some key findings regarding the role of obesity in BC development, but focused more on central adiposity. Firstly, the adipose microenvironment in obese people bears many similarities with the tumor microenvironment, in respect to associated cellular composition, chronic low-grade inflammation, and high ratio of reactive oxygen species to antioxidants. Secondly, the adipose tissue functions as an endocrine organ, which in obese people produces a high level of tumor-promoting hormones, such as leptin and estrogen, and a low level of the tumor suppressor hormone, adiponectin. As follows, in BC this leads to the activation of oncogenic signaling pathways: NFκB, JAK, STAT3, AKT. Moreover, overall obesity, but especially central obesity, promotes a systemic and local low grade chronic inflammation that further stimulates the increase of tumor-promoting oxidative stress. Lastly, there is a constant exchange of information between BC cells and adipocytes, mediated especially by extracellular vesicles, and which changes the transcription profile of both cell types to an oncogenic one with the help of regulatory non-coding RNAs.
Collapse
Affiliation(s)
- Alina-Andreea Zimta
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
| | - Adrian Bogdan Tigu
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
- Babeș-Bolyai University, Faculty of Biology, and Geology, 42 Republicii Street, 400015 Cluj-Napoca, Romania.
| | - Maximilian Muntean
- Department of Plastic Surgery, University of Medicine and Pharmacy "Iuliu Hatieganu", 400337 Cluj-Napoca, Romania.
| | - Diana Cenariu
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University, 62100 Brno, Czech Republic.
- Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, 60200 Brno, Czech Republic.
| | - Ioana Berindan-Neagoe
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine, and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
- Department of Functional Genomics, and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuta", Republicii 34th street, 400015 Cluj-Napoca, Romania.
| |
Collapse
|
|
5
|
Dziemidowicz M, Bonda TA, Litvinovich S, Taranta A, Winnicka MM, Kamiński KA. The role of interleukin-6 in intracellular signal transduction after chronic β-adrenergic stimulation in mouse myocardium. Arch Med Sci 2019; 15:1565-1575. [PMID: 31749886 PMCID: PMC6855166 DOI: 10.5114/aoms.2019.89452] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 07/01/2017] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Inflammatory mediators play an important role in development and progression of cardiovascular disease. Both adrenergic stimulation and high levels of interleukin-6 (IL-6) indicate an unfavorable outcome in patients with myocardial infarction or heart failure. Understanding the interaction between β-adrenergic stimulation and IL-6 in the myocardium may contribute to developing more effective treatments. The aim of this study was to verify the role of IL-6 in the effects of β-adrenergic stimulation in activating selected intracellular signaling pathways in mouse myocardium. MATERIAL AND METHODS Experiments were performed on 12-week-old male mice: 16 C57BL/6JIL6‑/‑TMKopf (IL-6 KO) and 17 C57BL/6J (WT). Animals received intraperitoneal injections of isoproterenol (ISO, 50 mg/kg) or placebo (0.9% NaCl) once a day for 16 days. The phosphorylation of STAT3 (signal transducer and activator of transcription 3), ERK1/2 (extracellular-regulated kinases 1/2), Akt1/2/3, p-38, c-Raf and expression of SOCS3 (suppressor of cytokine signaling 3), PIAS1/3 (protein inhibitors of activated STAT) was assessed by western blotting in the myocardium 24 h after the last injection. Evaluation of gene expression downstream of these pathways was performed by real-time PCR. RESULTS Chronic ISO treatment leads to increased fibrosis of the myocardium in mice lacking IL-6, which is accompanied by increased activity of ERK1/2, p38 and reduced expression of SOCS3. Administration of ISO in IL-6 KO animals intensified gene expression of proteins activated by MAPK/ERK (myc; CEBPB; BMP4; Fasn; Tank), while it reduced expression of genes repressed by ERK 1/2 (Wisp1, Wnt1). CONCLUSIONS IL-6 plays an important role in regulating the activation of MAPK pathways in the mouse myocardium in response to chronic β-adrenergic stimulation.
Collapse
Affiliation(s)
- Magdalena Dziemidowicz
- Department of General and Experimental Pathology, Medical University of Bialystok, Bialystok, Poland
| | - Tomasz A. Bonda
- Department of General and Experimental Pathology, Medical University of Bialystok, Bialystok, Poland
| | | | - Andrzej Taranta
- Department of General and Experimental Pathology, Medical University of Bialystok, Bialystok, Poland
| | - Maria M. Winnicka
- Department of General and Experimental Pathology, Medical University of Bialystok, Bialystok, Poland
| | - Karol A. Kamiński
- Department of Cardiology, Medical University of Bialystok, Bialystok, Poland
- Department of Population Medicine and Civilization Diseases Prevention, Medical University of Bialystok, Bialystok, Poland
| |
Collapse
|
|
6
|
Di Zazzo E, Polito R, Bartollino S, Nigro E, Porcile C, Bianco A, Daniele A, Moncharmont B. Adiponectin as Link Factor between Adipose Tissue and Cancer. Int J Mol Sci 2019; 20:ijms20040839. [PMID: 30781341 PMCID: PMC6412253 DOI: 10.3390/ijms20040839] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/09/2019] [Accepted: 02/11/2019] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue is a key regulator of energy balance playing an active role in lipid storage as well as in synthesizing several hormones directly involved in the pathogenesis of obesity. Obesity represents a peculiar risk factor for a growing list of cancers and is frequently associated to poor clinical outcome. The mechanism linking obesity and cancer is not completely understood, but, amongst the major players, there are both chronic low-grade inflammation and deregulation of adipokines secretion. In obesity, the adipose tissue is pervaded by an abnormal number of immune cells that create an inflammatory environment supporting tumor cell proliferation and invasion. Adiponectin (APN), the most abundant adipokine, shows anti-inflammatory, anti-proliferative and pro-apoptotic properties. Circulating levels of APN are drastically decreased in obesity, suggesting that APN may represent the link factor between obesity and cancer risk. The present review describes the recent advances on the involvement of APN and its receptors in the etiology of different types of cancer.
Collapse
Affiliation(s)
- Erika Di Zazzo
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso 86100, Italy.
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples 80131, Italy.
| | - Rita Polito
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Università degli Studi della Campania "Luigi Vanvitelli", Caserta 81100, Italy.
- CEINGE-Biotecnologie Avanzate Scarl, Napoli 80145, Italy.
| | - Silvia Bartollino
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso 86100, Italy.
| | - Ersilia Nigro
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Università degli Studi della Campania "Luigi Vanvitelli", Caserta 81100, Italy.
- Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Università degli Studi della Campania "Luigi Vanvitelli", Napoli 80131, Italy.
| | - Carola Porcile
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso 86100, Italy.
| | - Andrea Bianco
- Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Università degli Studi della Campania "Luigi Vanvitelli", Napoli 80131, Italy.
| | - Aurora Daniele
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche Farmaceutiche, Università degli Studi della Campania "Luigi Vanvitelli", Caserta 81100, Italy.
- CEINGE-Biotecnologie Avanzate Scarl, Napoli 80145, Italy.
| | - Bruno Moncharmont
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso 86100, Italy.
| |
Collapse
|
|
7
|
Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia–reperfusion injury: role of RISK and SAFE pathways interaction. Apoptosis 2016; 21:809-24. [DOI: 10.1007/s10495-016-1246-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
|
|
8
|
Szewczyk-Golec K, Woźniak A, Reiter RJ. Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity. J Pineal Res 2015; 59:277-91. [PMID: 26103557 DOI: 10.1111/jpi.12257] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 06/19/2015] [Indexed: 12/15/2022]
Abstract
Obesity and its medical complications represent a significant problem throughout the world. In recent decades, mechanisms underlying the progression of obesity have been intensively examined. The involvement of both the behavioral aspects, such as calorie-rich diet, low physical activity and sleep deprivation, and the intrinsic factors, including adipose tissue deregulation, chronic inflammation, oxidative stress, and chronodisruption, has been identified. The circadian disturbances of the adipose tissue endocrine function have been correlated with obesity. Leptin and adiponectin are adipokines strongly associated with glucose and lipid metabolism and with energy balance. Their synthesis and secretion display circadian rhythms that are disturbed in the obese state. Hyperleptinemia resulting in leptin resistance, and hypo-adiponectinemia have been linked to the pathophysiology of the obesity-related disorders. A deficiency of melatonin, one of the consequences of sleep deprivation, has also been demonstrated to correlate with obesity. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti-inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications. In the current review, the results of studies related to the interactions between melatonin, and both leptin and adiponectin are discussed. Despite the existence of some inconsistencies, melatonin has been found to normalize the expression and secretion patterns of both adipokines. These results support the concept of melatonin as a potential therapeutic agent for obesity and related disorders.
Collapse
Affiliation(s)
- Karolina Szewczyk-Golec
- The Chair of Medical Biology, Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
| | - Alina Woźniak
- The Chair of Medical Biology, Nicolaus Copernicus University, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
| |
Collapse
|
|
9
|
Zheng P, Liu J, Mai S, Yuan Y, Wang Y, Dai G. Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by betaine attenuates isoproterenol-induced acute myocardial injury in rats. Hum Exp Toxicol 2014; 34:538-47. [PMID: 25080425 DOI: 10.1177/0960327114543936] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The present study was designed to investigate the cardioprotective effects of betaine on acute myocardial ischemia induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 (STAT3) and apoptotic pathways as the potential mechanism underlying the drug effect. Male Sprague Dawley rats were treated with betaine (100, 200, and 400 mg/kg) orally for 40 days. Acute myocardial ischemic injury was induced in rats by subcutaneous injection of isoproterenol (85 mg/kg), for two consecutive days. Serum cardiac marker enzyme, histopathological variables and expression of protein levels were analyzed. Oral administration of betaine (200 and 400 mg/kg) significantly reduced the level of cardiac marker enzyme in the serum and prevented left ventricular remodeling. Western blot analysis showed that isoproterenol-induced phosphorylation of STAT3 was maintained or further enhanced by betaine treatment in myocardium. Furthermore, betaine (200 and 400 mg/kg) treatment increased the ventricular expression of Bcl-2 and reduced the level of Bax, therefore causing a significant increase in the ratio of Bcl-2/Bax. The protective role of betaine on myocardial damage was further confirmed by histopathological examination. In summary, our results showed that betaine pretreatment attenuated isoproterenol-induced acute myocardial ischemia via the regulation of STAT3 and apoptotic pathways.
Collapse
Affiliation(s)
- P Zheng
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China
| | - J Liu
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China
| | - S Mai
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China
| | - Y Yuan
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China
| | - Y Wang
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China
| | - G Dai
- Department of Pharmaceutical Engineering, College of Chemical and Materials Engineering, Kaili University, Kaili, Guizhou, People's Republic of China
| |
Collapse
|
|
10
|
Fiaschi T, Magherini F, Gamberi T, Lucchese G, Faggian G, Modesti A, Modesti PA. Hyperglycemia and angiotensin II cooperate to enhance collagen I deposition by cardiac fibroblasts through a ROS-STAT3-dependent mechanism. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2603-10. [PMID: 25072659 DOI: 10.1016/j.bbamcr.2014.07.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 07/18/2014] [Accepted: 07/21/2014] [Indexed: 01/09/2023]
Abstract
Cardiac fibroblasts significantly contribute to diabetes-induced structural and functional changes in the myocardium. The objective of the present study was to determine the effects of high glucose (alone or supplemented with angiotensin II) in the activation of the JAK2/STAT3 pathway and its involvement in collagen I production by cardiac fibroblasts. We observed that the diabetic environment 1) enhanced tyrosine phosphorylation of JAK2 and STAT3; 2) induced nuclear localization of tyrosine phosphorylated STAT3 through a reactive oxygen species-mediated mechanism, with angiotensin II stimulation further enhancing STAT3 nuclear accumulation; and 3) stimulated collagen I production. The effects were inhibited by depletion of reactive oxygen species or silencing of STAT3 in high glucose alone or supplemented with exogenous angiotensin II. Combined, our data demonstrate that increased collagen I deposition in the setting of high glucose occurred through a reactive oxygen species- and STAT3-dependent mechanism. Our results reveal a novel role for STAT3 as a key signaling molecule of collagen I production in cardiac fibroblasts exposed to a diabetic environment.
Collapse
Affiliation(s)
- Tania Fiaschi
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Francesca Magherini
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Tania Gamberi
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Gianluca Lucchese
- Institute of Thoracic and Cardiovascular Surgery, University of Verona, Verona, Italy
| | - Giuseppe Faggian
- Institute of Thoracic and Cardiovascular Surgery, University of Verona, Verona, Italy
| | - Alessandra Modesti
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
| | - Pietro Amedeo Modesti
- Department of Clinical and Experimental Medicine, University of Florence, School of Medicine, Florence, Italy.
| |
Collapse
|
|
11
|
Melatonin attenuates dextran sodium sulfate induced colitis with sleep deprivation: possible mechanism by microarray analysis. Dig Dis Sci 2014; 59:1134-41. [PMID: 24429513 DOI: 10.1007/s10620-013-3013-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 12/20/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract. It can be aggravated by stress, like sleep deprivation, and improved by anti-inflammatory agents, like melatonin. We aimed to investigate the effects of sleep deprivation and melatonin on inflammation. We also investigated genes regulated by sleep deprivation and melatonin. METHODS In the 2% DSS induced colitis mice model, sleep deprivation was induced using modified multiple platform water bath. Melatonin was injected after induction of colitis and colitis with sleep deprivation. Also mRNA was isolated from the colon of mice and analyzed via microarray and real-time PCR. RESULTS Sleep deprivation induced reduction of body weight, and it was difficult for half of the mice to survive. Sleep deprivation aggravated, and melatonin attenuated the severity of colitis. In microarrays and real-time PCR of mice colon tissues, mRNA of adiponectin and aquaporin 8 were downregulated by sleep deprivation and upregulated by melatonin. However, mRNA of E2F transcription factor (E2F2) and histocompatibility class II antigen A, beta 1 (H2-Ab1) were upregulated by sleep deprivation and downregulated by melatonin. CONCLUSION Melatonin improves and sleep deprivation aggravates inflammation of colitis in mice. Adiponectin, aquaporin 8, E2F2 and H2-Ab1 may be involved in the inflammatory change aggravated by sleep deprivation and attenuated by melatonin.
Collapse
|
|
12
|
Song X, Fan X, Song X, Zhang J, Zhang W, Li X, Gao J, Harrington A, Ziedonis D, Lv L. Elevated levels of adiponectin and other cytokines in drug naïve, first episode schizophrenia patients with normal weight. Schizophr Res 2013; 150:269-73. [PMID: 23968860 DOI: 10.1016/j.schres.2013.07.044] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 07/20/2013] [Accepted: 07/24/2013] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The study was to examine the levels of adiponectin (APN) and other cytokines, and body metabolism in drug naïve, first episode schizophrenia patients with normal weight. METHODS Ninety-six drug naïve, first episode schizophrenia patients with normal weight (SZ group), 60 healthy individuals with normal weight (control group), and 60 overweight or obese but otherwise healthy individuals (obesity group) were enrolled in the study. Serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and APN were measured using enzyme linked immunosorbent assay (ELISA). Glucose oxidase was used to measure plasma glucose level. Lipid levels were measured using the enzymatic colorimetric method. RESULTS Serum levels of IL-1β, IL-6 and TNF-α in both the SZ group and the obesity group were significantly higher than those in the control group (p's<0.001). There were no significant differences between the SZ group and the obesity group on those cytokines (p's>0.05). In addition, the levels of APN were significantly higher in the SZ group (p<0.001), and significantly lower in the obesity group (p<0.01) compared with the control group. Further, there were significant positive relationships between levels of APN and levels of other cytokines within the SZ group (p's<0.05); in contrast, there were significant negative relationships between levels of APN and levels of other cytokines within the obesity group (p's<0.05). Fasting serum levels of glucose, LDL, triglycerides and total cholesterol were significantly higher, and fasting serum levels of HDL were significantly lower in the obesity group compared with the other two groups (p's<0.01). There were no significant differences in any of the metabolic parameters between the control group and the SZ group (p's>0.05). CONCLUSIONS Drug naïve, first episode schizophrenia patients with normal weight seem to present an up-regulated inflammatory status as reflected by elevated levels of IL-1β, IL-6, and TNF-α. APN may play a unique pro-inflammatory role in this patient population. Implications of the findings in relation to the pathogenesis of schizophrenia and the vulnerability for metabolic problems were discussed.
Collapse
Affiliation(s)
- Xueqin Song
- The First Affiliated Hospital/Zhengzhou University, Zhengzhou, China; Henan Province Biological Psychiatry Key Laboratory, Xinxiang Medical University, Xinxiang, China; Psychotic Disorders Program, UMass Memorial Medical Center/University of Massachusetts Medical School, Worcester, MA, United States
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Wang T, Yao S, Xia Z, Irwin MG. Adiponectin: mechanisms and new therapeutic approaches for restoring diabetic heart sensitivity to ischemic post-conditioning. Front Med 2013; 7:301-5. [PMID: 23904036 DOI: 10.1007/s11684-013-0283-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 06/03/2013] [Indexed: 12/17/2022]
Abstract
Systemic inflammatory response following myocardial ischemia-reperfusion injury (IRI) to a specific organ may cause injuries. Ischemic post-conditioning (IPostC) has emerged as a promising method for myocardial protection against IRI both in experimental and in clinical settings. Enhancement of endogenous nitric oxide (NO) is one of the major mechanisms by which IPostC confers cardioprotection. However, the sensitivity of the diabetic heart to IPostC is impaired and the underlying mechanism is unknown. Adiponectin (APN) is an adipocytederived plasma protein with anti-diabetic and anti-inflammatory properties. Plasma levels of APN are decreased in obese subjects and in patients with type 2 diabetes. APN supplementation has been shown to increase NO production and attenuate myocardial IRI in normal (non-diabetic) animals. However, the effect of APN on myocardial injury in diabetic subjects, especially its potential in restoring the sensitivity of the diabetic heart to IPostC has not been investigated. In the current paper, we discussed the possible reasons why the myocardium of diabetic subjects loses sensitivity to IPostC and also highlighted the potential effectiveness and mechanism of APN in restoring IPostC cardioprotection in diabetes. This review proposes to conduct studies that may facilitate the development of novel and optimal therapies to enhance cardioprotection in patients with severe diseases such as diabetes.
Collapse
Affiliation(s)
- Tingting Wang
- Department of Anesthesiology and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | | | | | | |
Collapse
|
|
14
|
SUN GANG, HU HAI, TIAN XUYANG, YUE JIANWEI, YU HUI, YANG XIAOMIN, WANG ZHANLI. Identification and analysis of microRNAs in the left ventricular myocardium of two-kidney one-clip hypertensive rats. Mol Med Rep 2013; 8:339-44. [DOI: 10.3892/mmr.2013.1549] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 06/11/2013] [Indexed: 11/06/2022] Open
|
|
15
|
Jiang B, Li D, Deng Y, Teng F, Chen J, Xue S, Kong X, Luo C, Shen X, Jiang H, Xu F, Yang W, Yin J, Wang Y, Chen H, Wu W, Liu X, Guo DA. Salvianolic acid A, a novel matrix metalloproteinase-9 inhibitor, prevents cardiac remodeling in spontaneously hypertensive rats. PLoS One 2013; 8:e59621. [PMID: 23533637 PMCID: PMC3606118 DOI: 10.1371/journal.pone.0059621] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 02/15/2013] [Indexed: 01/19/2023] Open
Abstract
Cardiac fibrosis is a deleterious consequence of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9) contributes to the underlying mechanism. Therefore, new therapeutic strategies to attenuate the effects of MMP-9 are urgently needed. In the present study, we characterize salvianolic acid A (SalA) as a novel MMP-9 inhibitor at molecular, cellular and animal level. We expressed a truncated form of MMP-9 which contains only the catalytic domain (MMP-9 CD), and used this active protein for enzymatic kinetic analysis and Biacore detection. Data generated from these assays indicated that SalA functioned as the strongest competitive inhibitor of MMP-9 among 7 phenolic acids from Salvia miltiorrhiza. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM), interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as collagen induced by MMP-9 CD. Functional effects of SalA inhibition on MMP-9 was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR) in vivo. Moreover, SalA treatment in SHR resulted in decreased heart fibrosis and attenuated heart hypertrophy. These results indicated that SalA is a novel inhibitor of MMP-9, thus playing an inhibitory role in hypertensive fibrosis. Further studies to develop SalA and its analogues for their potential clinical application of cardioprotection are warranted.
Collapse
Affiliation(s)
- Baohong Jiang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- * E-mail: (DG); (BJ)
| | - Defang Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- College of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, China
| | - Yanping Deng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Fukang Teng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Shenyang Pharmaceutical University, Shenyang, China
| | - Jing Chen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Song Xue
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiangqian Kong
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Cheng Luo
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Xu Shen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Hualiang Jiang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Feng Xu
- Shenyang Pharmaceutical University, Shenyang, China
| | - Wengang Yang
- Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jun Yin
- Shenyang Pharmaceutical University, Shenyang, China
| | - Yanhui Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Shenyang Pharmaceutical University, Shenyang, China
| | - Hui Chen
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Shenyang Pharmaceutical University, Shenyang, China
| | - Wanying Wu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Xuan Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - De-an Guo
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- * E-mail: (DG); (BJ)
| |
Collapse
|
|
16
|
|
|
17
|
Northcott JM, Yeganeh A, Taylor CG, Zahradka P, Wigle JT. Adipokines and the cardiovascular system: mechanisms mediating health and disease. Can J Physiol Pharmacol 2012; 90:1029-59. [DOI: 10.1139/y2012-053] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.
Collapse
Affiliation(s)
- Josette M. Northcott
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Institute of Cardiovascular Sciences, and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Azadeh Yeganeh
- Department of Physiology, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R3T 2N2, Canada
| | - Carla G. Taylor
- Department of Physiology, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R3T 2N2, Canada
| | - Peter Zahradka
- Department of Physiology, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R3T 2N2, Canada
| | - Jeffrey T. Wigle
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E OJ9, Canada
- Institute of Cardiovascular Sciences, and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
| |
Collapse
|
|
18
|
Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol 2012; 18:3635-61. [PMID: 22851857 PMCID: PMC3406417 DOI: 10.3748/wjg.v18.i28.3635] [Citation(s) in RCA: 193] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 03/26/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
Collapse
|
|
19
|
Abstract
Numerous lines of evidence implicate a role for adipose tissue in the development of a systemic inflammatory state that contributes to metabolic, cardiovascular, and autoimmune disorders. Serum levels of adiponectin, a cytokine that is mainly produced by adipocytes, are paradoxically decreased in individuals with obesity, type 2 diabetes, and cardiovascular disease compared with healthy individuals. Mounting experimental data have revealed that adiponectin exhibits beneficial effects on energy homeostasis and cardiovascular functions that are attributed to its direct modulation of a proinflammatory factor, interleukin-6. However, some recent studies indicate that adiponectin appears to function as an inducer of proinflammatory factors and the elevated adiponectin level aggravates inflammation response in autoimmune disease. In this review, we focus on the action of adiponectin in chronic inflammation-associated metabolic, cardiovascular, and autoimmune disorders. In particular, we discuss the interaction between adiponectin and interleukin-6 in adipocytes and cardiovascular cells.
Collapse
Affiliation(s)
- Li Li
- Department of Physiology and Pathophysiology, Peking University Health Science Center and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | | |
Collapse
|
|
20
|
Wang T, Qiao S, Lei S, Liu Y, Ng KFJ, Xu A, Lam KSL, Irwin MG, Xia Z. N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats. PLoS One 2011; 6:e23967. [PMID: 21912612 PMCID: PMC3166050 DOI: 10.1371/journal.pone.0023967] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 07/28/2011] [Indexed: 01/17/2023] Open
Abstract
Background Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. Methodology/Principal Findings Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes. Conclusions/Significance NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats.
Collapse
Affiliation(s)
- Tingting Wang
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China
| | - Shigang Qiao
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China
| | - Shaoqing Lei
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China
| | - Yanan Liu
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China
| | - Kwok F. J. Ng
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China
- Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong SAR, China
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
| | - Aimin Xu
- Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong SAR, China
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Karen S. L. Lam
- Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong SAR, China
- Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Michael G. Irwin
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China
- Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong SAR, China
- * E-mail: (ZX); (MGI)
| | - Zhengyuan Xia
- Department of Anaesthesiology, The University of Hong Kong, Hong Kong SAR, China
- Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kong SAR, China
- * E-mail: (ZX); (MGI)
| |
Collapse
|
|
21
|
Park HG, Bak EJ, Kim JH, Lee YS, Choi SH, Cha JH, Yoo YJ. Effect of globular adiponectin on interleukin-6 and interleukin-8 expression in periodontal ligament and gingival fibroblasts. J Periodontal Implant Sci 2011; 41:149-56. [PMID: 21811691 PMCID: PMC3139049 DOI: 10.5051/jpis.2011.41.3.149] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Accepted: 05/21/2011] [Indexed: 11/25/2022] Open
Abstract
Purpose Globular adiponectin (gAd) is a type of adipocytokine, which is mainly produced by adipose tissue. It has been reported that gAd acts as a pro- as well as an anti-inflammatory factor. Interleukin (IL)-6 and IL-8 are pro-inflammatory cytokines. To investigate the role of gAd on periodontal tissues, the expression of adiponectin receptor 1 (AdipoR1) and the effect of gAd on the expression of IL-6 and IL-8 were investigated in periodontal ligament (PDL) and gingival fibroblasts. Methods PDL and gingival fibroblasts were cultured from human periodontal tissues. gAd derived from Escherichia coli and murine myeloma cells were used. The expression of AdipoR1 was estimated by reverse transcription-polymerase chain reaction and western blot. The expression of cytokines was measured by enzyme-linked immunosorbent assay. Results PDL and gingival fibroblasts expressed both mRNA and protein of AdipoR1. gAd derived from E. coli increased the production of IL-6 and IL-8, but polymyxin B, an inhibitor of lipopolysaccharide (LPS), inhibited IL-6 and IL-8 production induced by gAd in both types of cells. gAd derived from murine myeloma cells did not induce IL-6 and IL-8 production in those cells. gAd derived from E. coli contained higher levels of LPS than gAd derived from murine myeloma cells. LPS increased production of IL-6 and IL-8 in PDL and gingival fibroblasts, but pretreatment of cells with gAd derived from murine myeloma cells did not inhibit LPS-induced IL-6 and IL-8 expression. Conclusions Our results suggest that PDL and gingival fibroblasts express AdipoR1 and that gAd does not act as a modulator of IL-6 and IL-8 expression in PDL and gingival fibroblasts.
Collapse
Affiliation(s)
- Hong Gyu Park
- Department of Oral Biology, BK21 Project, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Korea
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Fan D, Li L, Wang C, Cui XB, Zhou Y, Wu LL. Adiponectin induces interleukin-6 production and its underlying mechanism in adult rat cardiac fibroblasts. J Cell Physiol 2011; 226:1793-802. [PMID: 21069809 DOI: 10.1002/jcp.22512] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
It has been reported that adiponectin enhances interleukin-6 (IL-6) production in cardiac fibroblasts derived from neonatal rats and adult mice, but the mechanisms involved remain unknown. In the present study, we explored the effect and mechanisms of adiponectin on IL-6 production in adult rat cardiac fibroblasts. Globular adiponectin (gAd) increased IL-6 mRNA expression and protein secretion in cultured adult rat cardiac fibroblasts. gAd-induced IL-6 release was attenuated after RNA interference inhibition of adiponectin receptor 1 (AdipoR1), but not AdipoR2 or an adaptor protein APPL1. gAd increased the phosphorylation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun-N-terminal kinase (JNK). Inhibitors of AMPK (araA), p38MAPK (SB202190), and ERK1/2 (PD98059 and U0126) but not JNK (SP600125) suppressed gAd-induced IL-6 production. In transient transfection assays of IL-6 promoter/luciferase reporter plasmids, gAd increased the transcriptional activity of the full-length IL-6 promoter. Deletion analysis of the IL-6 promoter indicated that activator protein-1 (AP-1), nuclear factor for IL-6 (NF-IL-6) and nuclear factor κB (NF-κB) binding sites were important for gAd-induced IL-6 transcription. Our data suggest that gAd enhances IL-6 synthesis and release in adult rat cardiac fibroblasts through AdipoR1. Activation of AMPK, p38MAPK, and ERK1/2 mediates the intracellular signal transduction. AP-1, NF-IL-6, and NF-κB cis-elements are required for gAd-induced IL-6 transcription.
Collapse
Affiliation(s)
- Dong Fan
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | | | | | | | | | | |
Collapse
|
|
23
|
Ponemone V, Keshavarzian A, Brand MI, Saclarides T, Abcarian H, Cabay RJ, Fletcher E, Larsen B, Durstine LJ, Fantuzzi G, Fayad R. Apoptosis and inflammation: role of adipokines in inflammatory bowel disease. Clin Transl Gastroenterol 2010; 1:e1. [PMID: 23238652 PMCID: PMC3365665 DOI: 10.1038/ctg.2010.1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 08/10/2010] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Leptin and adiponectin (APN) are adipokines produced by adipocytes that participate in the modulation of immune and inflammatory responses. In Crohn's disease (CD), fat wrapping surrounding the inflamed intestine produces high levels of leptin and APN. In inflammatory bowel disease (IBD), apoptosis resistance of lamina propria T lymphocytes (LPL-T) is one of the mechanisms that maintains chronic inflammation. We addressed the mechanism by which leptin and APN regulate inflammation and apoptosis in IBD. METHODS Immune cell infiltration, several factors expressed by adipose tissue (AT), and spontaneous release of cytokines by adipocytes were measured. The presence of APN and leptin in intestinal mucosa was detected and their effect on LPL-T apoptosis, signal transducer and activator of transcription 3 (STAT3), Suppressor of Cytokine Signaling 3 (SOCS3), Bcl-2 and Bcl-xL expression, and cytokine production was studied. In addition, the effects of globular and high-molecular-weight (HMW) APN on LPL-T cytokine production and apoptosis were studied. RESULTS Higher levels of several chemokines, cytokines, and growth factors were present in AT near active than near inactive disease. A significantly higher amount of inflammatory infiltrate was present in AT near active CD than near ulcerative colitis, controls, and near the inactive area of CD. There were no changes in the ratios of APN molecular weight in control and IBD adipocyte products. Leptin and APN inhibited anti-CD3-stimulated-LPL-T apoptosis and potentiated STAT3 phosphorylation, Bcl-2, and Bcl-xL expression in IBD and control mucosa. However, SOCS3 expression was suppressed only in IBD. Both globular and HMW APN have similar effects on LPL-T cytokine production and apoptosis. Leptin and APN enhanced interleukin (IL)-10 production by anti-CD3-stimulated LPL-T in IBD only. APN, but not leptin, increased anti-CD3-induced IL-6 levels in LPL-T only in IBD patients. IL-10 exerts its anti-inflammatory activity in the presence of SOCS3 suppression by leptin or APN. CONCLUSION Leptin and APN maintain the inhibition of anti-CD3-stimulated LPL-T apoptosis by enhancing Bcl-2 and Bcl-xL overexpression and promoting STAT3 phosphorylation while suppressing SOCS3.
Collapse
Affiliation(s)
- Venkatesh Ponemone
- Kinesiology and Nutrition Department, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ali Keshavarzian
- Gastroenterology and General Surgery Departments, Rush University, Chicago, Illinois, USA
| | - Marc I Brand
- Gastroenterology and General Surgery Departments, Rush University, Chicago, Illinois, USA
| | - Theodore Saclarides
- Gastroenterology and General Surgery Departments, Rush University, Chicago, Illinois, USA
| | - Herand Abcarian
- General Surgery Department, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Robert J Cabay
- Pathology Department, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Emma Fletcher
- Exercise Science Department, Applied Physiology Division, University of South Carolina, Columbia, South Carolina, USA
| | - Bianca Larsen
- Exercise Science Department, Applied Physiology Division, University of South Carolina, Columbia, South Carolina, USA
| | - Larry J Durstine
- Exercise Science Department, Applied Physiology Division, University of South Carolina, Columbia, South Carolina, USA
| | - Giamila Fantuzzi
- Kinesiology and Nutrition Department, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Raja Fayad
- Kinesiology and Nutrition Department, University of Illinois at Chicago, Chicago, Illinois, USA
- Exercise Science Department, Applied Physiology Division, University of South Carolina, Columbia, South Carolina, USA
| |
Collapse
|
|
24
|
Akifusa S, Kamio N, Shimazaki Y, Yamaguchi N, Nonaka K, Yamashita Y. Involvement of the JAK-STAT pathway and SOCS3 in the regulation of adiponectin-generated reactive oxygen species in murine macrophage RAW 264 cells. J Cell Biochem 2010; 111:597-606. [DOI: 10.1002/jcb.22745] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
|
|
25
|
Jones HN, Jansson T, Powell TL. Full-length adiponectin attenuates insulin signaling and inhibits insulin-stimulated amino Acid transport in human primary trophoblast cells. Diabetes 2010; 59:1161-70. [PMID: 20150288 PMCID: PMC2857896 DOI: 10.2337/db09-0824] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Maternal adiponectin levels are reduced and placental nutrient transporters are upregulated in obesity and gestational diabetes mellitus; however, the effects of adiponectin on placental function are unknown. We hypothesized that adiponectin regulates placental amino acid transport. RESEARCH DESIGN AND METHODS Human primary trophoblast cells were cultured and incubated with globular adiponectin (gAd) or full-length adiponectin (fAd) alone or in combination with insulin. System A and L amino acid transport and SNAT1, SNAT2, and SNAT4 isoform expression was measured. The activity of the AMP-activated protein kinase (AMPK), phosphatidylinositol 3 kinase-AKT, and peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling pathways was determined. RESULTS In the absence of insulin, gAd stimulated AMPK Thr172 phosphorylation, SNAT2 protein expression, and system A activity. This effect appeared to be mediated by interleukin-6 release and signal transducer and activator of transcription 3 (STAT3) signaling because gAd failed to stimulate system A in cells in which STAT3 had been silenced using small interfering RNA. fAd alone had no effect on system A activity or SNAT expression. Insulin increased AKT and insulin receptor substrate 1 (IRS-1) phosphorylation, system A activity, and SNAT2 expression. When combined with insulin, gAd did not affect system A activity or SNAT expression. In contrast, fAd abolished insulin-stimulated AKT Thr308 and IRS-1 Tyr612 phosphorylation, system A activity, and SNAT2 expression. Furthermore, fAd increased PPARalpha expression and PPARalpha (Ser21) phosphorylation. CONCLUSIONS In contrast to the insulin-sensitizing actions of adiponectin in liver and muscle reported in the literature, fAd attenuates insulin signaling in primary human trophoblast cells. As a result, fAd inhibits insulin-stimulated amino acid transport, which may have important implications for placental nutrient transport and fetal growth in pregnancy complications associated with altered maternal adiponectin levels.
Collapse
Affiliation(s)
- Helen N Jones
- Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio, USA.
| | | | | |
Collapse
|
|
26
|
Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake. Brain Res 2010; 1339:1-10. [PMID: 20388501 DOI: 10.1016/j.brainres.2010.03.063] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Accepted: 03/17/2010] [Indexed: 12/30/2022]
Abstract
Adaptations in the anterior cingulate cortex (ACC) have been implicated in alcohol and drug addiction. To identify genes that may contribute to excessive drinking, here we performed microarray analyses in laser microdissected rat ACC after a single or repeated administration of an intoxicating dose of alcohol (3 g/kg). Expression of the small G protein K-ras was differentially regulated following both single and repeated alcohol administration. We also observed that voluntary alcohol intake in K-ras heterozygous null mice (K-ras(+/-)) did not increase after withdrawal from repeated cycles of intermittent ethanol vapor exposure, unlike in their wild-type littermates. To identify K-ras regulated pathways, we then profiled gene expression in the ACC of K-ras(+/-), heterozygous null mice for the K-ras negative regulator Nf1 (Nf1(+/-)) and wild-type mice following repeated administration of an intoxicating dose of alcohol. Pathway analysis showed that alcohol differentially affected various pathways in a K-ras dependent manner - some of which previously shown to be regulated by alcohol - including the insulin/PI3K pathway, the NF-kappaB, the phosphodiesterases (PDEs) pathway, the Jak/Stat and the adipokine signaling pathways. Altogether, the data implicate K-ras-regulated pathways in the regulation of excessive alcohol drinking after a history of dependence.
Collapse
|
|
27
|
Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice. J Transl Med 2009; 89:1043-52. [PMID: 19564844 DOI: 10.1038/labinvest.2009.63] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Liver regeneration is a very complex and well-orchestrated process associated with signaling cascades involving cytokines, growth factors, and metabolic pathways. Adiponectin is an adipocytokine secreted by mature adipocytes, and its receptors are widely distributed in many tissues, including the liver. Adiponectin has direct actions in the liver with prominent roles to improve hepatic insulin sensitivity, increase fatty acid oxidation, and decrease inflammation. To test the hypothesis that adiponectin is required for normal progress of liver regeneration, 2/3 partial hepatectomy (PH) was performed on wild-type and adiponectin-null mice. Compared to wild-type mice, adiponectin-null mice displayed decreased liver mass regrowth, impeded hepatocyte proliferation, and increased hepatic lipid accumulation. Gene expression analysis revealed that adiponectin regulated the gene transcription related to lipid metabolism. Furthermore, the suppressed hepatocyte proliferation was accompanied with reduced signal transducer and activator of transcription protein 3 (STAT3) activity and enhanced suppressor of cytokine signaling 3 (Socs3) transcription. In conclusion, adiponectin-null mice exhibit impaired liver regeneration and increased hepatic steatosis. Increased expression of Socs3 and subsequently reduced activation of STAT3 in adiponectin-null mice may contribute to the alteration of the liver regeneration capability and hepatic lipid metabolism after PH.
Collapse
|
|
28
|
Wanninger J, Neumeier M, Weigert J, Bauer S, Weiss TS, Schäffler A, Krempl C, Bleyl C, Aslanidis C, Schölmerich J, Buechler C. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. Am J Physiol Gastrointest Liver Physiol 2009; 297:G611-8. [PMID: 19608729 DOI: 10.1152/ajpgi.90644.2008] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
Collapse
Affiliation(s)
- Josef Wanninger
- Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, Germany
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 2009; 123:255-78. [PMID: 19460403 DOI: 10.1016/j.pharmthera.2009.05.002] [Citation(s) in RCA: 779] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2009] [Accepted: 05/05/2009] [Indexed: 12/24/2022]
Abstract
Cardiac fibroblasts are the most prevalent cell type in the heart and play a key role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs with hypertension, myocardial infarction and heart failure. Many of the functional effects of cardiac fibroblasts are mediated through differentiation to a myofibroblast phenotype that expresses contractile proteins and exhibits increased migratory, proliferative and secretory properties. Cardiac myofibroblasts respond to proinflammatory cytokines (e.g. TNFalpha, IL-1, IL-6, TGF-beta), vasoactive peptides (e.g. angiotensin II, endothelin-1, natriuretic peptides) and hormones (e.g. noradrenaline), the levels of which are increased in the remodeling heart. Their function is also modulated by mechanical stretch and changes in oxygen availability (e.g. ischaemia-reperfusion). Myofibroblast responses to such stimuli include changes in cell proliferation, cell migration, extracellular matrix metabolism and secretion of various bioactive molecules including cytokines, vasoactive peptides and growth factors. Several classes of commonly prescribed therapeutic agents for cardiovascular disease also exert pleiotropic effects on cardiac fibroblasts that may explain some of their beneficial outcomes on the remodeling heart. These include drugs for reducing hypertension (ACE inhibitors, angiotensin receptor blockers, beta-blockers), cholesterol levels (statins, fibrates) and insulin resistance (thiazolidinediones). In this review, we provide insight into the properties of cardiac fibroblasts that underscores their importance in the remodeling heart, including their origin, electrophysiological properties, role in matrix metabolism, functional responses to environmental stimuli and ability to secrete bioactive molecules. We also review the evidence suggesting that certain cardiovascular drugs can reduce myocardial remodeling specifically via modulatory effects on cardiac fibroblasts.
Collapse
|
|
30
|
Pini M, Gove ME, Fayad R, Cabay RJ, Fantuzzi G. Adiponectin deficiency does not affect development and progression of spontaneous colitis in IL-10 knockout mice. Am J Physiol Gastrointest Liver Physiol 2009; 296:G382-7. [PMID: 19074637 PMCID: PMC2643903 DOI: 10.1152/ajpgi.90593.2008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The goal of this study was to investigate the role of the adipokine adiponectin (APN) in development of spontaneous colitis in IL-10 knockout (KO) mice. To this aim, we generated double IL-10 APN KO mice and compared their disease development to that of single IL-10 KO mice. Both IL-10 KO and double IL-10 APN KO mice spontaneously developed colitis of comparable severity. No significant differences in inflammatory infiltrate or crypt elongation were observed in colonic tissue obtained from IL-10 KO and double IL-10 APN KO mice at either 12 or 20 wk of age. A comparable increase in circulating levels of serum amyloid A and IFN-gamma was observed in IL-10 KO and double IL-10 APN KO mice as disease progressed. In vitro stimulation of lymphocytes from mesenteric lymph nodes with anti-CD3 and anti-CD28 induced a significantly higher production of IL-17 and TNF-alpha in IL-10 KO and double IL-10 APN KO mice compared with their healthy littermates. No significant differences in cytokine production from lymphocytes or colonic mRNA expression of cytokines were observed between IL-10 KO and double IL-10 APN KO mice. Both IL-10 KO and double IL-10 APN KO mice had a similar decrease in body weight and bone mass compared with their respective healthy littermates. Finally, APN deficiency did not lead to development of insulin resistance, either in APN KO or double IL-10 APN KO mice. In conclusion, lack of APN does not play a significant role in the pathogenesis of spontaneous colonic inflammation in the IL-10 KO model.
Collapse
Affiliation(s)
- Maria Pini
- Departments of Kinesiology and Nutrition and Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Melissa E. Gove
- Departments of Kinesiology and Nutrition and Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Raja Fayad
- Departments of Kinesiology and Nutrition and Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Robert J. Cabay
- Departments of Kinesiology and Nutrition and Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Giamila Fantuzzi
- Departments of Kinesiology and Nutrition and Pathology, University of Illinois at Chicago, Chicago, Illinois
| |
Collapse
|