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Karampatsou SI, Paltoglou G, Genitsaridi SM, Kassari P, Charmandari E. The Effect of a Multidisciplinary Lifestyle Intervention Program on Apelin-12, Vaspin and Resistin Concentrations in Children and Adolescents with Overweight and Obesity. Nutrients 2024; 16:3646. [PMID: 39519480 PMCID: PMC11547676 DOI: 10.3390/nu16213646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Background: Obesity in childhood and adolescence has reached epidemic proportions in recent decades. Methods: In the present study, we determined the concentrations of apelin-12, vaspin and resistin in 106 children and adolescents with overweight or obesity before and after the implementation of a multidisciplinary, personalized lifestyle intervention program of diet, sleep and exercise for 1 year. All subjects attended our Center for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence. Results: Following the lifestyle intervention, there were significant decreases in BMI (p < 0.01), apelin-12 (p < 0.05) and resistin (p < 0.01) concentrations, and an increase in vaspin (p < 0.01) concentration. Glucose was the best positive predictor of apelin-12 (b = 0.236, p < 0.05), and osteopontin was the best negative predictor of changes in apelin-12 (b = -0.299, p < 0.05). Vaspin correlated positively with adiponectin (b = 0.29, p < 0.05), while vitamin D (b = 0.621, p < 0.05) was the best positive predictor of vaspin. BMI z score (b = -0.794, p < 0.05), HDL (b = -0.284, p < 0.05) and HbA1C (b = -0.262, p < 0.05) were the best negative predictors of changes in vaspin. BMI z score was the best positive predictor of resistin (b = 0.437, p < 0.05). Conclusions: These findings suggest that apelin-12, vaspin and resistin correlate with indices of obesity, glucose, lipids and bone metabolism, while interaction with other proteins, such as osteopontin and adiponectin, was also noted. Therefore, apelin-12, vaspin and resistin may be used as biomarkers in children and adolescents with overweight and obesity.
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Affiliation(s)
- Sofia I. Karampatsou
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, 11527 Athens, Greece; (S.I.K.); (G.P.); (S.M.G.); (P.K.)
- Department of Pediatrics, National and Kapodistrian University of Athens Nursing School, “P. and A. Kyriakou” Children’s Hospital, 11527 Athens, Greece
| | - George Paltoglou
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, 11527 Athens, Greece; (S.I.K.); (G.P.); (S.M.G.); (P.K.)
- Second Department of Pediatrics, National and Kapodistrian University of Athens Medical School, “P. and A. Kyriakou” Children’s Hospital, 11527 Athens, Greece
| | - Sofia M. Genitsaridi
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, 11527 Athens, Greece; (S.I.K.); (G.P.); (S.M.G.); (P.K.)
| | - Penio Kassari
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, 11527 Athens, Greece; (S.I.K.); (G.P.); (S.M.G.); (P.K.)
- Division of Endocrinology and Metabolism, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Evangelia Charmandari
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, 11527 Athens, Greece; (S.I.K.); (G.P.); (S.M.G.); (P.K.)
- Division of Endocrinology and Metabolism, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
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Pisarenko OI, Studneva IM. Apelin C-Terminal Fragments: Biological Properties and Therapeutic Potential. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:1874-1889. [PMID: 38105205 DOI: 10.1134/s0006297923110160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 12/19/2023]
Abstract
Creation of bioactive molecules for treatment of cardiovascular diseases based on natural peptides is the focus of intensive experimental research. In the recent years, it has been established that C-terminal fragments of apelin, an endogenous ligand of the APJ receptor, reduce metabolic and functional disorders in experimental heart damage. The review presents literature data and generalized results of our own experiments on the effect of apelin-13, [Pyr]apelin-13, apelin-12, and their chemically modified analogues on the heart under normal and pathophysiological conditions in vitro and in vivo. It has been shown that the spectrum of action of apelin peptides on the damaged myocardium includes decrease in the death of cardiomyocytes from necrosis, reduction of damage to cardiomyocyte membranes, improvement in myocardial metabolic state, and decrease in formation of reactive oxygen species and lipid peroxidation products. The mechanisms of protective action of these peptides associated with activation of the APJ receptor and manifestation of antioxidant properties are discussed. The data presented in the review show promise of the molecular design of APJ receptor peptide agonists, which can serve as the basis for the development of cardioprotectors that affect the processes of free radical oxidation and metabolic adaptation.
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Affiliation(s)
- Oleg I Pisarenko
- Chazov National Medical Research Center of Cardiology, Moscow, 121552, Russia.
| | - Irina M Studneva
- Chazov National Medical Research Center of Cardiology, Moscow, 121552, Russia
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Medrano-Bosch M, Simón-Codina B, Jiménez W, Edelman ER, Melgar-Lesmes P. Monocyte-endothelial cell interactions in vascular and tissue remodeling. Front Immunol 2023; 14:1196033. [PMID: 37483594 PMCID: PMC10360188 DOI: 10.3389/fimmu.2023.1196033] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Monocytes are circulating leukocytes of innate immunity derived from the bone marrow that interact with endothelial cells under physiological or pathophysiological conditions to orchestrate inflammation, angiogenesis, or tissue remodeling. Monocytes are attracted by chemokines and specific receptors to precise areas in vessels or tissues and transdifferentiate into macrophages with tissue damage or infection. Adherent monocytes and infiltrated monocyte-derived macrophages locally release a myriad of cytokines, vasoactive agents, matrix metalloproteinases, and growth factors to induce vascular and tissue remodeling or for propagation of inflammatory responses. Infiltrated macrophages cooperate with tissue-resident macrophages during all the phases of tissue injury, repair, and regeneration. Substances released by infiltrated and resident macrophages serve not only to coordinate vessel and tissue growth but cellular interactions as well by attracting more circulating monocytes (e.g. MCP-1) and stimulating nearby endothelial cells (e.g. TNF-α) to expose monocyte adhesion molecules. Prolonged tissue accumulation and activation of infiltrated monocytes may result in alterations in extracellular matrix turnover, tissue functions, and vascular leakage. In this review, we highlight the link between interactions of infiltrating monocytes and endothelial cells to regulate vascular and tissue remodeling with a special focus on how these interactions contribute to pathophysiological conditions such as cardiovascular and chronic liver diseases.
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Affiliation(s)
- Mireia Medrano-Bosch
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
| | - Blanca Simón-Codina
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
| | - Wladimiro Jiménez
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
- Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Elazer R. Edelman
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Pedro Melgar-Lesmes
- Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
- Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
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Keskin-Aktan A, Kutlay Ö. Exogenous Apelin-13 Administration Ameliorates Cyclophosphamide- Induced Oxidative Stress, Inflammation, and Apoptosis in Rat Lungs. Protein Pept Lett 2023; 30:743-753. [PMID: 37622713 DOI: 10.2174/0929866530666230824142516] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 07/04/2023] [Accepted: 08/08/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND Apelin-13 is an endogenous adipocytokine known for its antioxidant, antiinflammatory, and antiapoptotic properties. OBJECTIVE We aimed to investigate the possible protective effects of exogenous Apelin-13 administration on oxidative stress, inflammation, and apoptosis induced by the cytotoxic agent cyclophosphamide (CP) in the lungs. METHODS Twenty-four male Wistar albino rats were divided into four groups: Control (saline), CP (200 mg/kg), Apelin-13 (10 μg/kg/day), and CP+Apelin-13. CP was administered as a single dose on the fifth day, and apelin-13 was administered intraperitoneally for five days. Total oxidant status (TOS), total antioxidant status (TAS), and lipid peroxidation were determined with spectrophotometry, TNFα and IL1β were determined with ELISA, APJ, Sirt1, NF-κB, and p53 mRNA expressions were determined with qRT-PCR, cytochrome (Cyt) C and caspase-3 protein expressions were studied with western blotting in lung tissues. The oxidative stress index (OSI) was also calculated. Furthermore, serum surfactant protein-D (SP-D) and Krebs von den Lungen-6 (KL-6) levels were measured with ELISA. RESULTS Compared to the control group, TOS, OSI, lipid peroxidation, TNFα, IL1β, cyt C, caspase-3, APJ, NF-κB, and p53 were higher, and Sirt1 was lower in the lung tissue of rats in the CP group. Serum KL-6 and SP-D levels were higher in the CP group. Co-administration of CP with Apelin-13 completely reversed the changes induced by CP administration. CONCLUSION Exogenous Apelin-13 treatment protected lung tissue against injury by inhibiting cyclophosphamide-induced oxidative stress, inflammation, and apoptosis. This protective effect of apelin-13 was accompanied by upregulation of the Sirt1 and downregulation of NF-κB/p53 in the lungs.
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Affiliation(s)
- Arzu Keskin-Aktan
- Department of Physiology, School of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey
| | - Özden Kutlay
- Department of Physiology, School of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey
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The apelin/APJ signaling system and cytoprotection: Role of its cross-talk with kappa opioid receptor. Eur J Pharmacol 2022; 936:175353. [DOI: 10.1016/j.ejphar.2022.175353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 11/18/2022]
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Wang X, Zhang L, Li P, Zheng Y, Yang Y, Ji S. Apelin/APJ system in inflammation. Int Immunopharmacol 2022; 109:108822. [DOI: 10.1016/j.intimp.2022.108822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/23/2022] [Accepted: 04/29/2022] [Indexed: 12/18/2022]
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Alleviation of liver cirrhosis and associated portal-hypertension by Astragalus species in relation to their UPLC-MS/MS metabolic profiles: a mechanistic study. Sci Rep 2022; 12:11884. [PMID: 35831335 PMCID: PMC9279505 DOI: 10.1038/s41598-022-15958-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/01/2022] [Indexed: 11/08/2022] Open
Abstract
Liver cirrhosis is a late-stage liver disease characterized by excessive fibrous deposition triggering portal-hypertension (PH); the prime restrainer for cirrhosis-related complications. Remedies that can dually oppose hepatic fibrosis and lower PH, may prevent progression into decompensated-cirrhosis. Different Astragalus-species members have shown antifibrotic and diuretic actions with possible subsequent PH reduction. However, A.spinosus and A.trigonus were poorly tested for eliciting these actions. Herein, A.spinosus and A.trigonus roots and aerial parts extracts were subjected to comprehensive metabolic-fingerprinting using UHPLC-MS/MS resulting in 56 identified phytoconstituents, followed by chemometric untargeted analysis that revealed variable metabolic profiles exemplified by different species and organ types. Consequently, tested extracts were in-vivo evaluated for potential antifibrotic/anticirrhotic activity by assessing specific markers. The mechanistic prospective to induce diuresis was investigated by analyzing plasma aldosterone and renal-transporters gene-expression. Serum apelin and dimethylarginine-dimethylaminohydrolase-1 were measured to indicate the overall effect on PH. All extracts amended cirrhosis and PH to varying extents and induced diuresis via different mechanisms. Further, An OPLS model was built to generate a comprehensive metabolic-profiling of A.spinosus and A.trigonus secondary-metabolites providing a chemical-based evidence for their efficacious consistency. In conclusion, A.spinosus and A.trigonus organs comprised myriad pharmacologically-active constituents that act synergistically to ameliorate cirrhosis and associated PH.
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Soliman LA, Zayed RA, Omran D, Said F, Darweesh SK, Ghaith DM, Eletreby R, Barakat MS, Bendary MM, Zaky DZ, Amer E, Elmahgoub IR. Apelin Association with Hepatic Fibrosis and Esophageal Varices in Patients with Chronic Hepatitis C Virus. Am J Trop Med Hyg 2022; 107:190-197. [DOI: 10.4269/ajtmh.21-0085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 02/24/2022] [Indexed: 11/07/2022] Open
Abstract
Portal hypertension and esophageal varices complicating hepatitis C virus (HCV)-related chronic liver diseases are some of the most devastating sequelae. Angiogenesis is the hallmark of their pathogenesis. Apelin is one of the recently identified angiogenic and fibrogenic peptides. We studied apelin gene expression, apelin (rs3761581) single-nucleotide polymorphism (SNP), and serum apelin level in patients with chronic HCV, and their association with liver fibrosis and esophageal varices in 112 patients with HCV-related chronic liver disease (40 with liver cirrhosis [LC]/low-grade varices, 33 with LC/high-grade varices, and 39 with fibrotic non-cirrhotic liver/no varices) and 80 healthy control subjects. Real-time polymerase chain reaction was used for apelin gene expression assay and apelin rs3761581 SNP analysis in peripheral blood samples. The serum apelin level was measured by ELISA. Apelin gene expression was undetectable in the studied samples. The SNP analysis revealed a greater frequency of the C (mutant) allele among patients compared with control subjects (P = 0.012; odds ratio, 3.67). The serum apelin level was significantly greater in patients with LC/varices (median, 31.6 ng/L) compared with patients without LC/varices (median, 2.9 ng/L; P < 0.001). A serum apelin level cutoff value of 16.55 ng/L predicted the presence of varices, with an area under the receiver operating characteristic curve value of 0.786. A positive correlation was found between serum apelin level and grade of liver fibrosis (r = 0.346, P < 0.001) and portal hypertension (r = 0.438, P < 0.001). In conclusion, the apelin rs3761581-C allele may be associated with the progression of HCV-related chronic liver disease and varices formation, and can be considered a potential therapeutic target to control fibrosis progression. The serum apelin level provided an accurate prediction of the presence of esophageal varices.
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Affiliation(s)
| | - Rania A. Zayed
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Dalia Omran
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Fadwa Said
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Samar Kamal Darweesh
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Doaa Mohamed Ghaith
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rasha Eletreby
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mahmoud Salama Barakat
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mahmoud M. Bendary
- Department of Microbiology and Immunology, Faculty of Pharmacy, Port Said University, Port Said, Egypt
| | | | - Eman Amer
- Department of Biochemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
| | - Iman Rifaat Elmahgoub
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Huang Y, Zhang S, Weng JF, Huang D, Gu WL. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis. Open Med (Wars) 2022; 17:915-929. [PMID: 35647306 PMCID: PMC9106112 DOI: 10.1515/med-2022-0481] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 03/03/2022] [Accepted: 03/29/2022] [Indexed: 11/17/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a cholangiopathy caused by genetic and microenvironmental changes, such as bile homeostasis disorders and microbiota dysbiosis. Therapeutic options are limited, and proven surveillance strategies are currently lacking. Clinically, PSC presents as alternating strictures and dilatations of biliary ducts, resulting in the typical “beaded” appearance seen on cholangiography. The pathogenesis of PSC is still unclear, but cholangiocytes play an essential role in disease development, wherein a reactive phenotype is caused by the secretion of neuroendocrine factors. The liver–gut axis is implicated in the pathogenesis of PSC owing to the dysbiosis of microbiota, but the underlying mechanism is still poorly understood. Alterations in cholangiocyte responses and related signalling pathways during PSC progression were elucidated by recent research, providing novel therapeutic targets. In this review, we summarise the currently known underlying mechanisms of PSC pathogenesis caused by the dysbiosis of microbiota and newly reported information regarding cholangiocytes in PSC. We also summarise recently reported in vitro and in vivo models for studying the pathogenesis of PSC.
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Affiliation(s)
- Yu Huang
- Department of Surgery, Guangzhou First People's Hospital, No. 1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 510180, People's Republic of China
| | - Shuai Zhang
- Department of Surgery, Guangzhou First People's Hospital, Guangdong 510180, People's Republic of China
| | - Jie-Feng Weng
- Department of Surgery, Guangzhou First People's Hospital, Guangdong 510180, People's Republic of China
| | - Di Huang
- Department of Surgery, Guangzhou First People's Hospital, Guangdong 510180, People's Republic of China
| | - Wei-Li Gu
- Department of Surgery, Guangzhou First People's Hospital, No. 1 Panfu Road, Yuexiu District, Guangzhou, Guangdong 510180, People's Republic of China
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Yurtcu N, Caliskan CS, Guvey H, Celik S, Hatirnaz S, Tinelli A. Predictive and Diagnostic Value of Serum Adipokines in Pregnant Women with Intrahepatic Cholestasis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19042254. [PMID: 35206438 PMCID: PMC8871533 DOI: 10.3390/ijerph19042254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 11/16/2022]
Abstract
The objective of this study was to assess the value of serum leptin, adiponectin, apelin, and ghrelin as biomarkers for the prediction and diagnosis of intra-hepatic cholestasis (ICP). This prospective study included pregnant women in the third trimester of pregnancy: 63 with ICP, 48 and 15 of whom had mild and severe disease, respectively, and 32 as controls. ICP women had increased median levels of serum leptin, adiponectin, apelin, and ghrelin compared to the controls (p < 0.05). These biomarkers meaningfully changed regarding the severity of ICP: While leptin was reduced, apelin and ghrelin were increased, and adiponectin was increased somewhat. To predict and diagnose ICP, the predictive values of serum leptin, adiponectin, and apelin need to be accepted as comparable, with moderate to high sensitivity and specificity; however, the predictive value of serum ghrelin was somewhat lower. More research is needed to clarify the potential properties of adipokines to gain acceptance as a predictive or diagnostic biomarker for ICP.
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Affiliation(s)
- Nazan Yurtcu
- Department of Obstetrics and Gynecology, Sivas Cumhuriyet University Faculty of Medicine, Sivas 58140, Turkey
- Correspondence:
| | - Canan Soyer Caliskan
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Health Sciences University, Samsun 55270, Turkey; (C.S.C.); (S.C.)
| | - Huri Guvey
- Department of Obstetrics and Gynecology, Private Kütahya Parkhayat Hospital, Kütahya 43100, Turkey;
| | - Samettin Celik
- Department of Obstetrics and Gynecology, Samsun Training and Research Hospital, Health Sciences University, Samsun 55270, Turkey; (C.S.C.); (S.C.)
| | - Safak Hatirnaz
- In Vitro Fertilization Unit, Medicana International Hospital, Samsun 55080, Turkey;
| | - Andrea Tinelli
- Department of Obstetrics and Gynecology, Veris delli Ponti Hospital, 73020 Lecce, Italy;
- Department of Obstetrics and Gynecology, Division of Experimental Endoscopic Surgery, Imaging, Technology and Minimally Invasive Therapy, Vito Fazzi Hospital, 73100 Lecce, Italy
- Phystech BioMed School, Faculty of Biological & Medical Physics, Moscow Institute of Physics and Technology, State University, 141701 Moscow, Russia
- Xi’an Jiaotong University, Xi’an 710049, China
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Chen L, Zhou T, White T, O’Brien A, Chakraborty S, Liangpunsakul S, Yang Z, Kennedy L, Saxena R, Wu C, Meng F, Huang Q, Francis H, Alpini G, Glaser S. The Apelin-Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis. Hepatology 2021; 73:2411-2428. [PMID: 32964473 PMCID: PMC9288669 DOI: 10.1002/hep.31545] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 07/28/2020] [Accepted: 08/11/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Apelin (APLN) is the endogenous ligand of its G protein-coupled receptor, apelin receptor (APJ). APLN serum levels are increased in human liver diseases. We evaluated whether the APLN-APJ axis regulates ductular reaction and liver fibrosis during cholestasis. APPROACH AND RESULTS We measured the expression of APLN and APJ and serum APLN levels in human primary sclerosing cholangitis (PSC) samples. Following bile duct ligation (BDL) or sham surgery, male wild-type (WT) mice were treated with ML221 (APJ antagonist) or saline for 1 week. WT and APLN-/- mice underwent BDL or sham surgery for 1 week. Multidrug resistance gene 2 knockout (Mdr2-/- ) mice were treated with ML221 for 1 week. APLN levels were measured in serum and cholangiocyte supernatants, and cholangiocyte proliferation/senescence and liver inflammation, fibrosis, and angiogenesis were measured in liver tissues. The regulatory mechanisms of APLN-APJ in (1) biliary damage and liver fibrosis were examined in human intrahepatic biliary epithelial cells (HIBEpiCs) treated with APLN and (2) hepatic stellate cell (HSC) activation in APLN-treated human HSC lines (HHSteCs). APLN serum levels and biliary expression of APLN and APJ increased in PSC samples. APLN levels were higher in serum and cholangiocyte supernatants from BDL and Mdr2-/- mice. ML221 treatment or APLN-/- reduced BDL-induced and Mdr2-/- -induced cholangiocyte proliferation/senescence, liver inflammation, fibrosis, and angiogenesis. In vitro, APLN induced HIBEpiC proliferation, increased nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expression, reactive oxygen species (ROS) generation, and extracellular signal-regulated kinase (ERK) phosphorylation. Pretreatment of HIBEpiCs with ML221, diphenyleneiodonium chloride (Nox4 inhibitor), N-acetyl-cysteine (NAC, ROS inhibitor), or PD98059 (ERK inhibitor) reduced APLN-induced cholangiocyte proliferation. Activation of HHSteCs was induced by APLN but reduced by NAC. CONCLUSIONS The APLN-APJ axis induces cholangiocyte proliferation through Nox4/ROS/ERK-dependent signaling and HSC activation through intracellular ROS. Modulation of the APLN-APJ axis may be important for managing cholangiopathies.
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Affiliation(s)
- Lixian Chen
- Department of Medical Physiology, Texas A&M University College of Medicine; Bryan, TX,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Tianhao Zhou
- Department of Medical Physiology, Texas A&M University College of Medicine; Bryan, TX
| | - Tori White
- Department of Medical Physiology, Texas A&M University College of Medicine; Bryan, TX
| | - April O’Brien
- Department of Medical Physiology, Texas A&M University College of Medicine; Bryan, TX
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University College of Medicine; Bryan, TX
| | - Suthat Liangpunsakul
- Research, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Chaodong Wu
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX
| | - Fanyin Meng
- Research, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Qiaobing Huang
- Department of Pathophysiology, Guangdong Provincial Key Lab of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Heather Francis
- Research, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Gianfranco Alpini
- Research, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine; Bryan, TX
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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13
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Owen NE, Nyimanu D, Kuc RE, Upton PD, Morrell NW, Alexander GJ, Maguire JJ, Davenport AP. Plasma levels of apelin are reduced in patients with liver fibrosis and cirrhosis but are not correlated with circulating levels of bone morphogenetic protein 9 and 10. Peptides 2021; 136:170440. [PMID: 33171278 PMCID: PMC7883214 DOI: 10.1016/j.peptides.2020.170440] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/06/2020] [Accepted: 11/01/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND The peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver. However, it is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis. METHODS Plasma from patients with liver fibrosis (n = 14), cirrhosis (n = 56), and healthy controls (n = 25) was solid-phase extracted using a method optimised for recovery of apelin, which was measured by ELISA. RESULTS Plasma apelin was significantly reduced in liver fibrosis (8.3 ± 1.2 pg/ml) and cirrhosis (6.5 ± 0.6 pg/ml) patients compared with controls (15.4 ± 2.0 pg/ml). There was no obvious relationship between apelin and BMP 9 or BMP10 previously measured in these patients. Within the cirrhotic group, there was no significant correlation between apelin levels and disease severity scores, age, sex, or treatment with β-blockers. CONCLUSIONS Apelin was significantly reduced in plasma of patients with both early (fibrosis) and late-stage (cirrhosis) liver disease. Fibrosis is more easily reversible and may represent a potential target for new therapeutic interventions. However, it remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and therefore, whether an apelin antagonist or agonist have clinical use.
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Affiliation(s)
- Nicola E Owen
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Duuamene Nyimanu
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Rhoda E Kuc
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Paul D Upton
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Nicholas W Morrell
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Graeme J Alexander
- Institute for Liver and Digestive Health, Upper 3rd Floor, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Janet J Maguire
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Anthony P Davenport
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
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Mashimo K, Ohno Y. Cultured Neonatal Rat Cardiomyocytes Continue Beating Through Upregulation of CTGF Gene Expression. J NIPPON MED SCH 2020; 87:268-276. [PMID: 33311008 DOI: 10.1272/jnms.jnms.2020_87-505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Some cultured neonatal rat cardiomyocytes continue spontaneous beating even in serum-free medium. The present study explored the cause and genes responsible for this phenomenon. METHODS Ingenuity Pathway Analysis (IPA) software was used to analyze fold changes in gene expression in beating neonatal rat cardiomyocytes, as compared with non-beating cardiomyocytes, which were obtained from DNA microarray data of total RNA extracts of cardiomyocytes. To confirm the involvement of the 8 genes selected by IPA prediction, cellular protein abundances were determined by Western blot. The gene expression of connective tissue growth factor (CTGF) was substantially higher in beating cardiomyocytes than in non-beating cardiomyocytes; thus, CTGF protein content released from cardiomyocytes into the culture medium was examined. RESULTS IPA showed that the "Apelin Cardiac Fibroblast Signaling Pathway" was significantly inhibited and that microtubule dynamics and cytoskeleton organization were significantly activated. Each fluctuation in the cellular abundances of the 8 proteins in beating cardiomyocytes, as compared with non-beating cardiomyocytes, was primarily in the same direction as that of gene expression. However, the cellular CTGF protein abundance as well as CTGF content released into the medium did not substantially differ between beating and non-beating cardiomyocytes. CONCLUSIONS The present results suggest that the large increase in CTGF gene expression in beating cardiomyocytes is not a cause but a result of beating, which may provide a putative pathway for controlling beating. Beating is sustained by developed cardiomyofibrils and directly upregulates CTGF gene expression, which is not followed by CTGF protein synthesis.
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Bayraktar B, Tekce E, Aksakal V, Gül M, Takma Ç, Bayraktar S, Bayraktar FG, Eser G. Effect of the addition of essential fatty acid mixture to the drinking water of the heat stress broilers on adipokine (Apelin, BDNF) response, histopathologic findings in liver and intestines, and some blood parameters. ITALIAN JOURNAL OF ANIMAL SCIENCE 2020. [DOI: 10.1080/1828051x.2020.1778548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Bülent Bayraktar
- Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Bayburt University, Bayburt, Turkey
| | - Emre Tekce
- Faculty of Applied Sciences, Department of Organic Agriculture Management, Bayburt University, Bayburt, Turkey
| | - Vecihi Aksakal
- Faculty of Applied Sciences, Department of Organic Agriculture Management, Bayburt University, Bayburt, Turkey
| | - Mehmet Gül
- Faculty of Veterinary Medicine, Animal Nutrition and Nutrition Disease, Atatürk University, Erzurum, Turkey
| | - Çiğdem Takma
- Faculty of Agriculture, Department of Animal Science, Biometry and Genetics Unit, Ege University, İzmir, Turkey
| | - Sevil Bayraktar
- Faculty of Veterinary Medicine, Department of physiology, Ondokuz Mayıs University, Samsun, Turkey
| | - Fatma Gülten Bayraktar
- Faculty of Veterinary Medicine, Department of pathology, Atatürk University, Erzurum, Turkey
| | - Gizem Eser
- Faculty of Veterinary Medicine, Department of pathology, Atatürk University, Erzurum, Turkey
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Vitamin D(3) regulates hepatic VEGF-A and apelin expression in experimental type 1 diabetes. UKRAINIAN BIOCHEMICAL JOURNAL 2020. [DOI: 10.15407/ubj92.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Lv S, Zhang X, Zhou Y, Feng Y, Yang Y, Wang X. Intrathecally Administered Apelin-13 Alleviated Complete Freund's Adjuvant-Induced Inflammatory Pain in Mice. Front Pharmacol 2020; 11:1335. [PMID: 32982745 PMCID: PMC7485460 DOI: 10.3389/fphar.2020.01335] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 08/11/2020] [Indexed: 12/25/2022] Open
Abstract
Apelin is the endogenous ligand for APJ, a G-protein-coupled receptor. Apelin gene and protein are widely distributed in the central nervous system and peripheral tissues. The role of apelin in chronic inflammatory pain is still unclear. In the present study, a mouse model of complete Freund’s adjuvant (CFA)-induced inflammatory pain was utilized, and the paw withdrawal latency/threshold in response to thermal stimulation and Von Frey filament stimulation were recorded after intrathecal (i.t.) injection of apelin-13 (0.1, 1, and 10 nmol/mouse). The mRNA and protein expression, concentration of glutamic acid (Glu), and number of c-Fos immunol staining in lumbar spinal cord (L4/5) were determined. The results demonstrated that Apln gene expression in the lumbar spinal cord was down-regulated in the CFA pain model. Apelin-13 (10 nmol/mouse, i.t.) alleviated CFA-induced inflammatory pain, and it exhibited a more potent antinociceptive effect than apelin-36 and (pyr)apelin-13. The antinociception of apelin-13 could be blocked by APJ antagonist apelin-13(F13A). I.T. apelin-13 attenuated the increased levels of Aplnr, Grin2b, Camk2d, and c-Fos genes expression, Glu concentration, and NMDA receptor 2B (GluN2B) protein expression caused by CFA. Apelin-13 significantly reduced the number of Fos-positive cells in laminae III and IV/V of the dorsal horn. This study indicated that i.t. apelin-13 exerted an analgesic effect against inflammatory pain, which was mediated by activation of APJ, and inhibition of Glu/GluN2B function and neural activity of the spinal dorsal horn.
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Affiliation(s)
- Shuangyu Lv
- Institute of Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Xiaomei Zhang
- Institute of Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Yuchen Zhou
- Institute of Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Yu Feng
- Institute of Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Yanjie Yang
- Institute of Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Xinchun Wang
- Key Laboratory of Clinical Resources Translation, The First Affiliated Hospital of Henan University, Kaifeng, China
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Mannelli M, Gamberi T, Magherini F, Fiaschi T. The Adipokines in Cancer Cachexia. Int J Mol Sci 2020; 21:ijms21144860. [PMID: 32660156 PMCID: PMC7402301 DOI: 10.3390/ijms21144860] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/01/2020] [Accepted: 07/07/2020] [Indexed: 12/19/2022] Open
Abstract
Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies.
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Méndez-Sánchez N, Valencia-Rodríguez A, Coronel-Castillo C, Vera-Barajas A, Contreras-Carmona J, Ponciano-Rodríguez G, Zamora-Valdés D. The cellular pathways of liver fibrosis in non-alcoholic steatohepatitis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:400. [PMID: 32355844 PMCID: PMC7186641 DOI: 10.21037/atm.2020.02.184] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is considered the advanced stage of non-alcoholic fatty liver disease (NAFLD). It is characterized by liver steatosis, inflammation and different degrees of fibrosis. Although the exact mechanisms by which fatty liver progresses to NASH are still not well understood, innate and adaptive immune responses seem to be essential key regulators in the establishment, progression, and chronicity of these disease. Diet-induced lipid overload of parenchymal and non-parenchymal liver cells is considered the first step for the development of fatty liver with the consequent organelle dysfunction, cellular stress and liver injury. These will generate the production of pro-inflammatory cytokines, chemokines and damage-associated molecular patterns (DAMPs) that will upregulate the activation of Kupffer cells (KCs) and monocyte-derived macrophages (MMs) favoring the polarization of the tolerogenic environment of the liver to an immunogenic phenotype with the resulting transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts developing fibrosis. In the long run, dendritic cells (DCs) will activate CD4+ T cells polarizing into the pro-inflammatory lymphocytes Th1 and Th17 worsening the liver damage and inflammation. Therefore, the objective of this review is to discuss in a systematic way the mechanisms known so far of the immune and non-proper immune liver cells in the development and progression of NASH.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico.,Faculty of Medicine. National Autonomous University of Mexico, Mexico City, Mexico
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Ibrahim SM, Bastawy AA. The Relevance of Single-nucleotide Polymorphism +62 G>A to the Expression of Resistin Gene Affecting Serum Resistin Levels in Metabolic Syndrome in the Egyptian Population. Curr Pharm Biotechnol 2019; 21:626-634. [PMID: 31820685 DOI: 10.2174/1389201021666191210122851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/30/2019] [Accepted: 11/05/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Metabolic Syndrome (MS) is a clinical condition consisting of risk factors associated with type two diabetes and developing cardiovascular disease. It has been suggested that resistin is a linkage between obesity, inflammation and type two diabetes. This study aims to investigate whether Resistin Gene (RETN) polymorphism (+62G>A) is linked to MS and resistin levels among the Egyptian population. METHODS This study was performed with 310 Egyptian volunteers: 160 MS subjects and 150 controls. Anthropometric parameters and biochemical variables were determined. The RETN +62G>A polymorphism was genotyped by PCR-RFLP technique. RESULTS The resistin levels of the MS group were significantly higher than those of the control group. Resistin levels were positively correlated with anthropometric parameters and liver biomarkers in the MS group. According to RETN +62G>A polymorphism, carriers with the A allele (GA/AA) had significantly increased resistin levels than subjects with the GG genotype, consequently, the RETN +62G >A polymorphism was found to be related to MS, biochemical parameters and anthropometric variables. CONCLUSION These findings propose that the RETN +62G>A polymorphism has a great impact on the circulating resistin concentrations, and that resistin levels are strongly related to MS. Therefore, this RETN polymorphism is related to the risk of the prevalence of MS in the Egyptians.
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Affiliation(s)
- Sherine M Ibrahim
- Biochemistry Department, Faculty of Pharmacy, Modern Sciences and Arts University, Postal Code: 202, Cairo, Egypt
| | - Afaf A Bastawy
- Biochemistry Department, Faculty of Pharmacy, Modern Sciences and Arts University, Postal Code: 202, Cairo, Egypt
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Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis. Cells 2019; 8:cells8111311. [PMID: 31653030 PMCID: PMC6912778 DOI: 10.3390/cells8111311] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/17/2019] [Accepted: 10/23/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology-both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB1 and CB2 receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.
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Mechanism of KLF4 Protection against Acute Liver Injury via Inhibition of Apelin Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6140360. [PMID: 31687083 PMCID: PMC6811788 DOI: 10.1155/2019/6140360] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/22/2019] [Accepted: 09/07/2019] [Indexed: 12/31/2022]
Abstract
Krüppel-like factor 4 (KLF4) is a key transcription factor that regulates genes involved in the proliferation or differentiation in different tissues. Apelin plays roles in cardiovascular functions, metabolic disease, and homeostatic disorder. However, the biological function of apelin in liver disease is still ongoing. In this study, we investigated the mechanism of KLF4-mediated protection against acute liver injury via the inhibition of the apelin signaling pathway. Mice were intraperitoneally injected with carbon tetrachloride (CCl4; 0.2 mL dissolved in 100 mL olive oil, 10 mL/kg) to establish an acute liver injury model. A KLF4 expression plasmid was injected through the tail vein 48 h before CCl4 treatment. In cultured LX-2 cells, pAd-KLF4 or siRNA KLF4 was overexpressed or knockdown, and the mRNA and protein levels of apelin were determined. The results showed that the apelin serum level in the CCl4-injected group was higher than that of control group, and the expression of apelin in the liver tissues was elevated while KLF4 expression was decreased in the CCl4-injected group compared to the KLF4-plasmid-injected group. HE staining revealed serious hepatocellular steatosis in the CCl4-injected mice, and KLF4 alleviated this steatosis in the mice injected with KLF4 plasmid. In vitro experiments showed that tumor necrosis factor-alpha (TNF-α) could downregulate the transcription and translation levels of apelin in LX-2 cells and also upregulate KLF4 mRNA and protein expression. RT-PCR and Western blotting showed that the overexpression of KLF4 markedly decreased basal apelin expression, but knockdown of KLF4 restored apelin expression in TNF-α-treated LX-2 cells. These in vivo and in vitro experiments suggest that KLF4 plays a key role in inhibiting hepatocellular steatosis in acute liver injury, and that its mechanism might be the inhibition of the apelin signaling pathway.
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Read C, Nyimanu D, Williams TL, Huggins DJ, Sulentic P, Macrae RGC, Yang P, Glen RC, Maguire JJ, Davenport AP. International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand. Pharmacol Rev 2019; 71:467-502. [PMID: 31492821 PMCID: PMC6731456 DOI: 10.1124/pr.119.017533] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The predicted protein encoded by the APJ gene discovered in 1993 was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, apelin-36 in 1998. Substantial research identified a family of shorter peptides activating the apelin receptor, including apelin-17, apelin-13, and [Pyr1]apelin-13, with the latter peptide predominating in human plasma and cardiovascular system. A range of pharmacological tools have been developed, including radiolabeled ligands, analogs with improved plasma stability, peptides, and small molecules including biased agonists and antagonists, leading to the recommendation that the APJ gene be renamed APLNR and encode the apelin receptor protein. Recently, a second endogenous ligand has been identified and called Elabela/Toddler, a 54-amino acid peptide originally identified in the genomes of fish and humans but misclassified as noncoding. This precursor is also able to be cleaved to shorter sequences (32, 21, and 11 amino acids), and all are able to activate the apelin receptor and are blocked by apelin receptor antagonists. This review summarizes the pharmacology of these ligands and the apelin receptor, highlights the emerging physiologic and pathophysiological roles in a number of diseases, and recommends that Elabela/Toddler is a second endogenous peptide ligand of the apelin receptor protein.
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Affiliation(s)
- Cai Read
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Duuamene Nyimanu
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Thomas L Williams
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - David J Huggins
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Petra Sulentic
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Robyn G C Macrae
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Peiran Yang
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Robert C Glen
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Janet J Maguire
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
| | - Anthony P Davenport
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
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Apelin promotes hepatic fibrosis through ERK signaling in LX-2 cells. Mol Cell Biochem 2019; 460:205-215. [PMID: 31270645 PMCID: PMC6745032 DOI: 10.1007/s11010-019-03581-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 05/27/2019] [Indexed: 02/08/2023]
Abstract
Apelin participates in cardiovascular functions, metabolic disease, and homeostasis disorder. However, the biological function of apelin in liver diseases, especially liver fibrosis is still under investigation. The present study aimed to investigate the expression of apelin in nonalcoholic fatty liver disease (NAFLD) and the mechanism of apelin promoting hepatic fibrosis through ERK signaling in hepatic stellate LX-2 cells. The results showed that the ALT and AST levels in serum were increased in the mice fed HFC. The histological staining revealed that hepatocellular steatosis and ballooning degeneration was severe, and fibrogenesis appeared as increased pericellular collagen deposition along with pericentral (lobular) collagen deposition in the mice fed HFC. Immunochemistry and qRT-PCR results showed that the expression of apelin and profibrotic genes was higher as compared to the control group. The in vitro experiments demonstrated that apelin-13 upregulated the transcription and translation levels of collagen type I (collagen-I) and α-smooth muscle actin (α-SMA) in LX-2 cells. The immunofluorescent staining, qRT-PCR, and Western blot results showed that the overexpression of apelin markedly increased the expression of α-SMA and cyclinD1. The LX-2 cells treated with apelin-13 displayed an increased expression of pERK1/2 in a time-dependent manner, while the pretreatment with PD98059 abolished the apelin-induced expression of α-SMA and cyclinD1. Furthermore, the in vivo and in vitro assays suggested a key role of apelin in promoting liver fibrosis, and the underlying mechanism might be ascribed to the apelin expression of profibrotic genes via ERK signaling pathway.
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Adipose Tissue-Derived Signatures for Obesity and Type 2 Diabetes: Adipokines, Batokines and MicroRNAs. J Clin Med 2019; 8:jcm8060854. [PMID: 31208019 PMCID: PMC6617388 DOI: 10.3390/jcm8060854] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 12/13/2022] Open
Abstract
: Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues-the white adipose tissue (WAT) and brown adipose tissue (BAT)-secrete bioactive peptides and proteins, known as "adipokines" and "batokines," respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, "exosomal microRNAs (miRNAs)" were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors-adipokines, batokines, and exosomal miRNA-in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.
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26
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Emam MN, Abo El gheit RE. Promoting effect of adipocytokine, apelin, on hepatic injury in caerulein-induced acute pancreatitis in rats. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2015.11.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Marwa N. Emam
- Physiology Department, Faculty of Medicine, Tanta University, Egypt
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27
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Plasma apelin levels in overweight/obese adults following a single bout of exhaustive exercise: A preliminary cross-sectional study. ENDOCRINOL DIAB NUTR 2019; 66:278-290. [DOI: 10.1016/j.endinu.2018.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 11/23/2018] [Accepted: 12/04/2018] [Indexed: 12/11/2022]
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Sato T, Kuba K. [The functional role of endogenous APJ agonists; Apelin and Elabela/Toddler in cardiovascular diseases]. Nihon Yakurigaku Zasshi 2019; 153:172-178. [PMID: 30971657 DOI: 10.1254/fpj.153.172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Apelin is an endogenous peptide ligand for APJ receptor, which is widely expressed in human body, and exerts various physiological effects such as vasodilation, inotropic effect, water balance, heart development, angiogenesis and energy metabolism. The beneficial effects of Apelin in cardiovascular diseases have been elucidated, and the roles of Apelin in aging-associated diseases are recently implicated. The mechanisms for therapeutic effects of Aplein include an antagonistic action to renin-angiotensin system (RAS) in addition to inotropic and vasodilatory actions. We have revealed that endogenous Apelin negatively regulates RAS via upregulation of Angiotensin converting enzyme 2 (ACE2). In addition, a second ligand for APJ receptor, Elabela/Toddler, was identified as an essential hormone for heart development, and it has been reported to have physiological effects similar to Apelin. We and others have shown that Elabela exerts inotropic and protective effects in the heart. Although the number of heart failure patients is rapidly increasing, the pathophysiology of heart failure remains elusive and further development of new therapeutic option is awaited. Apelin is a unique bifunctional molecule, which has both inotropic and cardioprotective effects in heart failure, and thus further elucidation of the mechanisms for Apelin/Elabela-APJ signaling would contribute to development of a novel therapeutics for heart failure patients.
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Affiliation(s)
- Teruki Sato
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine
- Department of Cardiology, Akita University Graduate School of Medicine
| | - Keiji Kuba
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine
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29
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Huang Z, Luo X, Liu M, Chen L. Function and regulation of apelin/APJ system in digestive physiology and pathology. J Cell Physiol 2018; 234:7796-7810. [PMID: 30390294 DOI: 10.1002/jcp.27720] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 10/16/2018] [Indexed: 12/11/2022]
Abstract
Apelin is an endogenous ligand of seven-transmembrane G-protein-coupled receptor APJ. Apelin and APJ are distributed in various tissues, including the heart, lung, liver, kidney, and gastrointestinal tract and even in tumor tissues. Studies show that apelin messenger RNA is widely expressed in gastrointestinal (GI) tissues, including stomach and small intestine, which is closely correlated with GI function. Thus, the apelin/APJ system may exert a broad range of activities in the digestive system. In this paper, we review the role of the apelin/APJ system in the digestive system in physiological conditions, such as gastric acid secretion, control of appetite and food intake, cell proliferation, cholecystokinin secretion and histamine release, gut-brain axis, GI motility, and others. In pathological conditions, the apelin/APJ system plays an important role in the healing process of stress gastric injury, the clinical features and prognosis of patients with gastric cancers, the reduction of inflammatory response to enteritis and pancreatitis, the mediation of liver fibrogenesis, the promotion of liver damage, the inhibition of liver regeneration, the contribution of splanchnic neovascularization in portal hypertension, the treatment of colon cancer, and GI oxidative damage. Overall, the apelin/APJ system plays diversified functions and regulatory roles in digestive physiology and pathology. Further exploration of the relationship between the apelin/APJ system and the digestive system will help to find new and effective drugs for treating and alleviating the pain of digestive diseases.
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Affiliation(s)
- Zhen Huang
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China.,Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Xuling Luo
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China
| | - Meiqing Liu
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang, China
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30
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Affiliation(s)
- Saverio Cinti
- Professor of Human Anatomy, Director, Center of Obesity, University of Ancona (Politecnica delle Marche), Ancona, Italy
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31
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El Wakeel MA, El-Kassas GM, Kamhawy AH, Galal EM, Nassar MS, Hammad EM, El-Zayat SR. Serum Apelin and Obesity-Related Complications in Egyptian Children. Open Access Maced J Med Sci 2018; 6:1354-1358. [PMID: 30159056 PMCID: PMC6108807 DOI: 10.3889/oamjms.2018.312] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/23/2018] [Accepted: 07/27/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The rapidly increasing prevalence of childhood obesity became a major burden on health worldwide, giving an alarm to clinicians and researchers. Adipocytes act as an active endocrine organ by releasing plenty of bioactive mediators (adipokines) that play a major role in regulating metabolic processes. Apelin is a recently identified adipokine that is expressed in adipocytes. AIM The current work aimed to uncover the relation between serum apelin and childhood obesity and its related complications as hypertension and hyperglycemia. METHOD A group of 50 obese and 31 non-obese; sex- and age-matched children were enrolled in our study with a mean age of (9.5 ± 2.1) and (8.7 ± 1.3) respectively. Anthropometric measurements, blood pressure, were assessed in all studied participants, we also determined the lipid profile, serum insulin, fasting blood glucose (FBG) level, HOMA-IR and serum apelin. RESULTS Obese children had higher levels of HbA1c, FBG, serum insulin, HOMA-IR, total cholesterol, triglycerides, low-density lipoprotein (LDL) and diastolic blood pressure (DBP Z-score); compared to controls (all P < 0.05). Apelin was significantly higher in obese children versus controls and correlated positively with BMI Z-Score (P = 0.008), DBP Z-Score (P = 0.02), cholesterol, TG (both P = 0.02), serum insulin (P = 0.003), FBG and HOMA-IR (both P = 0.001). Linear regression analysis showed that FBG was the most effective factor in predicting the level of serum apelin (P = 0.04). CONCLUSION This work supports the hypothesis that apelin may have a crucial role in the pathogenesis of health hazards related to obesity in children including insulin resistance, hypertension and a higher risk of occurrence of metabolic syndrome.
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Affiliation(s)
- Maged A. El Wakeel
- Child Health Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Ghada M. El-Kassas
- Child Health Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Alyaa H. Kamhawy
- Child Health Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Essam M. Galal
- Child Health Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Maysa S. Nassar
- Child Health Department, Medical Division, National Research Centre, Cairo, Egypt
| | | | - Salwa Refat El-Zayat
- Department of Medical Physiology, Medical Division, National Research Centre, Cairo, Egypt
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32
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Rai R, Ghosh AK, Eren M, Mackie AR, Levine DC, Kim SY, Cedernaes J, Ramirez V, Procissi D, Smith LH, Woodruff TK, Bass J, Vaughan DE. Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan. Cell Rep 2018; 21:1471-1480. [PMID: 29117554 DOI: 10.1016/j.celrep.2017.10.057] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 07/24/2017] [Accepted: 10/13/2017] [Indexed: 11/29/2022] Open
Abstract
Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age-associated pathologies. However, the "anti-aging" factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging. Genetic or pharmacological abrogation of apln signaling also induces cellular senescence mediated, in part, by the activation of senescence-promoting transcription factors. Conversely, restoration of apln in 15-month-old wild-type mice reduces cardiac hypertrophy and exercise-induced hypertensive response. Additionally, apln-restored mice exhibit enhanced vigor and rejuvenated behavioral and circadian phenotypes. Hence, a declining apelinergic axis promotes aging, whereas its restoration extends the murine healthspan.
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Affiliation(s)
- Rahul Rai
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Asish K Ghosh
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Mesut Eren
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Alexander R Mackie
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Daniel C Levine
- Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA; Department of Medicine, Division of Endocrinology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - So-Youn Kim
- Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Jonathan Cedernaes
- Department of Medicine, Division of Endocrinology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Veronica Ramirez
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Daniele Procissi
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Layton H Smith
- Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA
| | - Teresa K Woodruff
- Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Joseph Bass
- Department of Medicine, Division of Endocrinology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Douglas E Vaughan
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Bertrand C, Pradère JP, Geoffre N, Deleruyelle S, Masri B, Personnaz J, Le Gonidec S, Batut A, Louche K, Moro C, Valet P, Castan-Laurell I. Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism. Endocrine 2018; 60:112-121. [PMID: 29392617 DOI: 10.1007/s12020-018-1536-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 01/15/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies. METHODS Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 µmol/kg) or PBS during 28 days. RESULTS Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin-treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS-treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect. CONCLUSIONS Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes.
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Affiliation(s)
- Chantal Bertrand
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Jean-Philippe Pradère
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Nancy Geoffre
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Simon Deleruyelle
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Bernard Masri
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Jean Personnaz
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Sophie Le Gonidec
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Aurélie Batut
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Katie Louche
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Cédric Moro
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Philippe Valet
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France
- Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Isabelle Castan-Laurell
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France.
- Université de Toulouse, Université Paul Sabatier, Toulouse, France.
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Dala AG, Ebied OM, Abo-Raia GY. Is serum apelin related to portal hemodynamics in patients with liver cirrhosis? THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2018. [DOI: 10.4103/ejim.ejim_61_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Babaei P, Dastras A, Tehrani BS, Pourali Roudbaneh S. The Effect of Estrogen Replacement Therapy on Visceral Fat, Serum Glucose, Lipid Profiles and Apelin Level in Ovariectomized Rats. J Menopausal Med 2017; 23:182-189. [PMID: 29354618 PMCID: PMC5770528 DOI: 10.6118/jmm.2017.23.3.182] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 05/30/2017] [Accepted: 06/14/2017] [Indexed: 12/27/2022] Open
Abstract
Objectives Ovarian hormones have been shown to regulate body weight, intra-abdominal fat accumulation and plasma level of cytokines. The aim of this study was to investigate the effect of estrogen replacement therapy on visceral adipose tissue, plasma level of apelin, lipid profiles, and glucose in ovariectomized (OVX) rats. Methods Thirty female Wistar rats were divided into OVX (n = 20) and sham (n = 10) groups. OVX rats were subdivided into estrogen replacement therapy (OVX+est; n = 10) receiving 17 β-estradiol valerates (30 µg/kg, s.c., 5 day/week, for eight weeks), and vehicle control group receiving sesame oil same as experiment group (OVX+ses oil; n = 10). After the treatments, all groups were sacrificed and blood samples were collected, visceral fats were taken from the abdominal cavity and weighed immediately. Apelin were measured using enzyme-linked immunosorbent assay kits. Lipid profiles and glucose were measured using the enzymatic colorimetric method. Data were analyzed with one-way analysis of variance and (P < 0.05) determined as the statistical significance level. Results After eight weeks, body weight, body mass index (BMI), visceral fat, apelin and lipid profiles (P < 0.01) were increased significantly in OVX rats compared to sham group. Treatment with estrogen leads to significant reduction in body weight and BMI (P < 0.05), there was no significant change in serum apelin level in OVX+est rats compared to OVX+ses. Conclusions These results suggest that estradiol replacement therapy successfully attenuated some of the metabolic syndrome components, and apelin does not probably stand as a mediator of these physiological functions.
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Affiliation(s)
- Parvin Babaei
- Cellular & Molecular Research Center, Guilan University of Medical Sciences, Rasht, Iran.,Neuroscience Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Adele Dastras
- Cellular & Molecular Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Bahram Soltani Tehrani
- Cellular & Molecular Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Shiva Pourali Roudbaneh
- Department of Midwifery, School of Nursing, Midwifery and Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
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Abstract
Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein-coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand-AR interactions have been implicated in regulation of the adipoinsular axis, cardiovascular system, and central nervous system alongside pathological processes. Each ligand may be processed into a variety of bioactive isoforms endogenously, with apelin ranging from 13 to 55 amino acids and apela from 11 to 32, typically being cleaved C-terminal to dibasic proprotein convertase cleavage sites. The C-terminal region of the respective precursor protein is retained and is responsible for receptor binding and subsequent activation. Interestingly, both apelin and apela exhibit isoform-dependent variability in potency and efficacy under various physiological and pathological conditions, but most studies focus on a single isoform. Biophysical behavior and structural properties of apelin and apela isoforms show strong correlations with functional studies, with key motifs now well determined for apelin. Unlike its ligands, the AR has been relatively difficult to characterize by biophysical techniques, with most characterization to date being focused on effects of mutagenesis. This situation may improve following a recently reported AR crystal structure, but there are still barriers to overcome in terms of comprehensive biophysical study. In this review, we summarize the three components of the apelinergic system in terms of structure-function correlation, with a particular focus on isoform-dependent properties, underlining the potential for regulation of the system through multiple endogenous ligands and isoforms, isoform-dependent pharmacological properties, and biological membrane-mediated receptor interaction. © 2018 American Physiological Society. Compr Physiol 8:407-450, 2018.
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Affiliation(s)
- Kyungsoo Shin
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Calem Kenward
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Jan K Rainey
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
- Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada
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Lv SY, Cui B, Chen WD, Wang YD. Apelin/APJ system: A key therapeutic target for liver disease. Oncotarget 2017; 8:112145-112151. [PMID: 29340118 PMCID: PMC5762386 DOI: 10.18632/oncotarget.22841] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 11/11/2017] [Indexed: 12/12/2022] Open
Abstract
Apelin, a new bioactive peptide, was identified as an endogenous ligand for APJ (Angiotensin II receptor-like 1). Apelin and its receptor have an abundant distribution in central nervous system and peripheral tissues, including liver. Apelin/APJ has diverse physiological and pathological effects, including regulation of cardiovascular function, angiogenesis, fluid homeostasis and so on. Apelin/APJ system may act as a novel potential therapeutic target for liver disease. In this article, we review the role of apelin/APJ system in liver fibrosis, hepatitis, hepatic cirrhosis, liver injury and metabolic liver disease.
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Affiliation(s)
- Shuang-Yu Lv
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, Henan, P. R. China
| | - Binbin Cui
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, Henan, P. R. China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, Henan, P. R. China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia, P. R. China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, P. R. China
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Apelin protects against liver X receptor-mediated steatosis through AMPK and PPARα in human and mouse hepatocytes. Cell Signal 2017; 39:84-94. [DOI: 10.1016/j.cellsig.2017.08.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 07/04/2017] [Accepted: 08/14/2017] [Indexed: 12/19/2022]
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Lv X, Kong J, Chen WD, Wang YD. The Role of the Apelin/APJ System in the Regulation of Liver Disease. Front Pharmacol 2017; 8:221. [PMID: 28484393 PMCID: PMC5401884 DOI: 10.3389/fphar.2017.00221] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 04/10/2017] [Indexed: 12/29/2022] Open
Abstract
Apelin is an endogenous peptide that is a ligand for the APJ receptor (angiotensin II receptor like-1, AT-1). The apelin/APJ system is distributed in diverse periphery organ tissues. It has been shown that the apelin/APJ system plays various roles in physiology and pathophysiology of many organs. It regulates cardiovascular development or cardiac disease, glycometabolism and fat metabolism as well as metabolic disease. The apelin/APJ system participates in various cell activities such as proliferation, migration, apoptosis or inflammation. However, apelin/APJ function in the liver is still under investigation. In the liver, the apelin-APJ system could play an inhibitory role in liver regeneration and promote Fas-induced apoptosis. It may participate in the formation of hepatic fibrosis or cirrhosis, and even cancer. In this review, we summarize the role of the apelin/APJ system in liver disease.
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Affiliation(s)
- Xinrui Lv
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan UniversityKaifeng, China
| | - Jing Kong
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan UniversityKaifeng, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan UniversityKaifeng, China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical UniversityHohhot, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical TechnologyBeijing, China
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Son JS, Kim HJ, Son Y, Lee H, Chae SA, Seong JK, Song W. Effects of exercise-induced apelin levels on skeletal muscle and their capillarization in type 2 diabetic rats. Muscle Nerve 2017; 56:1155-1163. [PMID: 28164323 DOI: 10.1002/mus.25596] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 01/24/2017] [Accepted: 01/28/2017] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Exercise-induced apelin as a myokine is believed to play a role in the improvement of type 2 diabetes mellitus (T2DM) and capillarization. In this study, we evaluated the association between exercise-induced apelin and muscle capillarization. METHODS Zucker rats underwent a treadmill exercise program. Body composition, muscle strength, muscle size, muscle capillarization, and insulin resistance (homeostatic model assessment [HOMA-IR]) were measured. Apelin levels of skeletal muscle and plasma were then analyzed. RESULTS Exercise improved body composition (P < 0.05), HOMA-IR (P < 0.05), and grip strength (P < 0.001). In the soleus, the fiber size of T2DM was decreased (P < 0.001), but it increased in fiber size and capillarization after exercise (P < 0.001) occurred. We identified an increase in plasma apelin (P < 0.05) and a decrease in soleus apelin (P < 0.01), as well as an association between soleus apelin and angiogenesis (P < 0.01). DISCUSSION A role for exercise-induced apelin in improving metabolism indicates the possibility of a new drug target for the treatment of metabolic diseases and repairing skeletal muscle damage. Muscle Nerve 56: 1155-1163, 2017.
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Affiliation(s)
- Jun Seok Son
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.,Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea
| | - Hee-Jae Kim
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.,Physical Activity & Performance Institute, Konkuk University, Seoul, Republic of Korea
| | - Yeri Son
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Development Biology and Genomics, BK21 Program for Veterinary Science, Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea
| | - Hojun Lee
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Development Biology and Genomics, BK21 Program for Veterinary Science, Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea
| | - Song Ah Chae
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Laboratory of Development Biology and Genomics, BK21 Program for Veterinary Science, Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea
| | - Wook Song
- Health and Exercise Science Laboratory, Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.,Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea.,Institute on Aging, Seoul National University, Seoul, Republic of Korea
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Hall C, Ehrlich L, Venter J, O'Brien A, White T, Zhou T, Dang T, Meng F, Invernizzi P, Bernuzzi F, Alpini G, Lairmore TC, Glaser S. Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth. Cancer Lett 2017; 386:179-188. [PMID: 27894959 PMCID: PMC5510601 DOI: 10.1016/j.canlet.2016.11.025] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/21/2016] [Accepted: 11/22/2016] [Indexed: 12/16/2022]
Abstract
PURPOSE Cholangiocarcinoma (CCA) is a malignancy of the biliary epithelium that is associated with low five-year survival. The apelin receptor (APLNR), which is activated by the apelin peptide, has not been studied in CCA. The purpose of this study is to determine if inhibition of the apelin/APLNR axis can inhibit CCA growth. METHODS Immunohistochemistry, rtPCR, immunofluorescence, flow cytometry, and ELISA was used to measure APLNR expression in human CCA cells and tissues. Mz-ChA-1 cells were treated with increasing concentrations of apelin and ML221, an APLNR antagonist. Expression of proliferative and angiogenic genes were measured via rtPCR. In vivo, Mz-ChA-1 cells were injected into the flanks of nu/nu mice, which were treated with ML221 (150 μg/kg) via tail vein injection. RESULTS Expression of the apelin/APLNR axis was increased in CCA. In vitro, CCA proliferation and angiogenesis was inhibited by ML221 treatment. ML221 treatment significantly decreased tumor growth in nu/nu mice. CONCLUSION The apelin/APLNR axis regulates CCA proliferation and angiogenesis. Inhibition of the apelin/APLNR axis decreases tumor growth in our xenograft model. Targeting APLNR signaling has the potential to serve as a novel, tumor directed therapy for CCA.
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Affiliation(s)
- Chad Hall
- Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA
| | - Laurent Ehrlich
- Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA
| | - Julie Venter
- Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA
| | - April O'Brien
- Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA
| | - Tori White
- Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA
| | - Tianhao Zhou
- Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Texas A&M University Health Science Center, Temple, TX 76504, USA
| | - Tien Dang
- Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA
| | - Fanyin Meng
- Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Francesca Bernuzzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA; Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA; Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA
| | - Terry C Lairmore
- Scott & White Medical Center, Department of Surgery, Temple, TX 76508, USA
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, TX 76504, USA; Scott & White Medical Center, Department of Medicine, Temple, TX 76508, USA.
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Abstract
In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.
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Affiliation(s)
- Juan Cristóbal Gana
- Department of Pediatric Gastroenterology & Nutrition, Division of Pediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile. Chile
| | - Carolina A Serrano
- Department of Pediatric Gastroenterology & Nutrition, Division of Pediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile. Chile
| | - Simon C Ling
- Division of Gastroenterology, Hepatology & Nutrition, Department of Paediatrics, University of Toronto, and The Hospital for Sick Children, Toronto, Canada
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Apelin/APJ system: A novel promising therapy target for pathological angiogenesis. Clin Chim Acta 2016; 466:78-84. [PMID: 28025030 DOI: 10.1016/j.cca.2016.12.023] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 12/19/2016] [Accepted: 12/22/2016] [Indexed: 12/21/2022]
Abstract
Apelin is the endogenous ligand of the G protein-coupled receptor APJ. Both Apelin and APJ receptor are widely distributed in various tissues such as heart, brain, limbs, retina and liver. Recent research indicates that the Apelin/APJ system plays an important role in pathological angiogenesis which is a progress of new blood branches developing from preexisting vessels via sprouting. In this paper, we review the important role of the Apelin/APJ system in pathological angiogenesis. The Apelin/APJ system promotes angiogenesis in myocardial infarction, ischemic stroke, critical limb ischemia, tumor, retinal angiogenesis diseases, cirrhosis, obesity, diabetes and other related diseases. Furthermore, we illustrate the detailed mechanism of pathological angiogenesis induced by the Apelin/APJ system. In conclusion, the Apelin/APJ system would be a promising therapeutic target for angiogenesis-related diseases.
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Lim YL, Choi E, Jang YO, Cho YZ, Kang YS, Baik SK, Kwon SO, Kim MY. Clinical Implications of the Serum Apelin Level on Portal Hypertension and Prognosis of Liver Cirrhosis. Gut Liver 2016; 10:109-16. [PMID: 25963087 PMCID: PMC4694742 DOI: 10.5009/gnl14345] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Levels of serum apelin (s-apelin), an endogenous ligand for angiotensin-like receptor 1, have been shown to be related to hepatic fibrosis and hemodynamic abnormalities in preclinical studies. We investigated the clinical implications of s-apelin as a noninvasive prognostic biomarker for chronic liver disease (CLD). METHODS From January 2009 to December 2012, 215 CLD patients were enrolled and underwent clinical data collection, hepatic venous pressure gradient (HVPG) measurement, and liver biopsy. s-apelin was detected with a human total apelin enzyme-linked immunosorbent assay kit. All patients were prospectively observed during the median follow-up period of 23.0±12.9 months for decompensation and mortality. RESULTS A total of 42 patients (19.5%) died during the follow-up period. s-apelin was significantly correlated with measurements of liver stiffness (R2=0.263, p<0.001) and collagen proportional area (R2=0.213, p<0.001) measured from liver biopsy tissue and HVPG (R2=0.356, p<0.001). In a multivariate analysis using a Cox regression hazard model, s-apelin was a weakly significant predictor of decompensation (hazard ratio [HR], 1.002; p<0.001) and mortality (HR, 1.003; p<0.001). CONCLUSIONS s-apelin showed a significant relationship with CLD severity. However, its significance as a noninvasive biomarker for disease severity and prognosis was weak.
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Affiliation(s)
- Yoo Li Lim
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Cell Therapy and Tissue Engineering, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Eunhee Choi
- Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Yoon Ok Jang
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Cell Therapy and Tissue Engineering, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Youn Zoo Cho
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Cell Therapy and Tissue Engineering, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Yong Seok Kang
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Cell Therapy and Tissue Engineering, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Cell Therapy and Tissue Engineering, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Sang Ok Kwon
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Cell Therapy and Tissue Engineering, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
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Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism 2016; 65:1062-79. [PMID: 26725002 DOI: 10.1016/j.metabol.2015.11.006] [Citation(s) in RCA: 252] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 11/19/2015] [Accepted: 11/20/2015] [Indexed: 12/13/2022]
Abstract
Since the discovery of adipose tissue as a higly active endocrine tissue, adipokines, peptides produced by adipose tissue and exerting autocrine, paracrine and endocrine function, have gained increasing interest in various obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD). Data regarding the association between NAFLD and circulating leptin and adiponectin levels are generally well documented: leptin levels increase, whereas adiponectin levels decrease, by increasing the severity of NAFLD. Data regarding other adipokines in histologically confirmed NAFLD populations are inconclusive (e.g., resistin, visfatin, retinol-binding protein-4, chemerin) or limited (e.g., adipsin, obestatin, omentin, vaspin etc.). This review summarizes evidence on the association between adipokines and NAFLD. The first part of the review provides general consideration on the interplay between adipokines and NAFLD, and the second part provides evidence on specific adipokines possibly involved in NAFLD pathogenesis. A thorough insight into the pathophysiologic mechanisms linking adipokines with NAFLD may result in the design of studies investigating the combined adipokine use as noninvasive diagnostic markers of NAFLD and new clinical trials targeting the treatment of NAFLD.
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Affiliation(s)
- Stergios A Polyzos
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece.
| | - Jannis Kountouras
- Second Medical Clinic, Department of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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Huang S, Chen L, Lu L, Li L. The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis. Clin Chim Acta 2016; 456:81-88. [PMID: 26944568 DOI: 10.1016/j.cca.2016.02.025] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 02/25/2016] [Accepted: 02/28/2016] [Indexed: 12/16/2022]
Abstract
Apelin, an endogenous ligand of the G-protein-coupled receptor APJ, is expressed in a diverse number of organs. The apelin-APJ axis helps to control the processes of pathological and physiological fibrosis, including renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. However, the role of apelin-APJ in organ fibrosis remains controversial due to conflicting study results. The apelin-APJ axis is a detrimental mechanism which promotes liver fibrosis mainly via up-regulation the expression of collagen-II and platelet-derived growth factor receptor β (PDGFRβ). On the contrary, the apelin-APJ axis is beneficial for renal fibrosis, cardiac fibrosis and pulmonary fibrosis. The apelin-APJ axis alleviates renal fibrosis by restraining the expression of transforming growth factor-β1 (TGF-β1). In addition, the apelin-APJ axis attenuates cardiac fibrosis through multiple pathways. Furthermore, the apelin-APJ axis has beneficial effects on experimental bronchopulmonary dysplasia (BPD) and acute respiratory distress syndrome (ARDS) which suggest the apelin-APJ axis potentially alleviates pulmonary fibrosis. In this article, we review the controversies associated with apelin-APJ in organ fibrosis and introduce the drugs that target apelin-APJ. We conclude that future studies should place more emphasis on the relationship among apelin isoforms, APJ receptor subtypes and organ fibrosis. The apelin-APJ axis will be a potential therapeutic target and those drugs targeted for apelin-APJ may constitute a novel therapeutic strategy for renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis.
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Affiliation(s)
- Shifang Huang
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, China
| | - Linxi Chen
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, China
| | - Liqun Lu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, China
| | - Lanfang Li
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, Learning Key Laboratory for Pharmacoproteomics, University of South China, Hengyang 421001, China.
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Fernández-Varo G, Oró D, Cable EE, Reichenbach V, Carvajal S, de la Presa BG, Wiśniewski K, Ginés P, Harris G, Jiménez W. Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats. Hepatology 2016; 63:207-16. [PMID: 26403564 DOI: 10.1002/hep.28250] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 09/20/2015] [Indexed: 12/30/2022]
Abstract
UNLABELLED Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1 a -AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites. The hemodynamic effects of cumulative intravenous doses of FE 204038, terlipressin, or vehicle were investigated. Mean arterial pressure and PP were continuously recorded and cardiac output and systemic vascular resistance (SVR) assessed at 30-minute intervals for 90 minutes. Urine volume, urine osmolality, and urinary excretion of sodium and creatinine were measured in basal conditions and following twice-daily subcutaneous doses of FE 204038 or vehicle. PP, mean arterial pressure, cardiac output, SVR, and ascites volume were also measured after 6 days. The expression of an array of vasoactive genes was assessed in the thoracic aorta and the mesenteric circulation of control rats and rats with cirrhosis and ascites. FE 204038 dose-dependently decreased PP, did not modify mean arterial pressure, and increased SVR. The effect of the V1a -AVP receptor partial agonist on PP was associated with an improvement in urine volume and urinary excretion of sodium during the first day of treatment. SVR was higher and cardiac output and ascites volume were lower in rats with cirrhosis and ascites treated with FE 204038. V1a -AVP receptor expression in rats with cirrhosis and ascites was markedly enhanced in the mesenteric circulation compared to the thoracic aorta. CONCLUSION FE 204038 increases sodium excretion and reduces portal hypertension and ascites in experimental cirrhosis. V1a -AVP receptor partial agonism could be a useful pharmacological treatment in decompensated patients with cirrhosis.
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Affiliation(s)
- Guillermo Fernández-Varo
- Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.,Department Ciencies Fisiologiques I, University of Barcelona, Barcelona, Spain
| | - Denise Oró
- Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | | | - Vedrana Reichenbach
- Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Silvia Carvajal
- Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Bernardino González de la Presa
- Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | | | - Pere Ginés
- Liver Unit, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | | | - Wladimiro Jiménez
- Biochemistry and Molecular Genetics Service, Hospital Clínic i Provincial de Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.,Department Ciencies Fisiologiques I, University of Barcelona, Barcelona, Spain
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Bocca C, Novo E, Miglietta A, Parola M. Angiogenesis and Fibrogenesis in Chronic Liver Diseases. Cell Mol Gastroenterol Hepatol 2015; 1:477-488. [PMID: 28210697 PMCID: PMC5301407 DOI: 10.1016/j.jcmgh.2015.06.011] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 06/02/2015] [Indexed: 12/12/2022]
Abstract
Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles.
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Key Words
- ANGPTL3, angiopoietin-like-3 peptide
- Akt, protein kinase B
- Ang-1, angiopoietin-1
- CCL2, chemokine ligand 2
- CCR, chemokine receptor
- CLD, chronic liver disease
- ET-1, endothelin 1
- HCC, hepatocellular carcinoma
- HIF, hypoxia-inducible factor
- HSC, hepatic stellate cell
- HSC/MFs, myofibroblast-like cells from activated hepatic stellate cells
- Hh, Hedgehog
- Hypoxia
- LSEC, liver sinusoidal endothelial cell
- Liver Angiogenesis
- Liver Fibrogenesis
- MF, myofibroblast
- MP, microparticle
- Myofibroblasts
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NO, nitric oxide
- PDGF, platelet-derived growth factor
- ROS, reactive oxygen species
- VEGF, vascular endothelial growth factor
- VEGF-R2, vascular endothelial growth factor receptor type 2
- eNOS, endothelial nitric oxide synthase
- α-SMA, α-smooth muscle actin
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Affiliation(s)
| | | | | | - Maurizio Parola
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, School of Medicine, University of Torino, Torino, Italy
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Abd-Elbaky AE, Abo-ElMatty DM, Mesbah NM, Ibrahim SM. Omentin and apelin concentrations in relation to obesity, diabetes mellitus type two, and cardiovascular diseases in Egyptian population. Int J Diabetes Dev Ctries 2015. [DOI: 10.1007/s13410-015-0416-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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Taveau C, Chollet C, Waeckel L, Desposito D, Bichet DG, Arthus MF, Magnan C, Philippe E, Paradis V, Foufelle F, Hainault I, Enhorning S, Velho G, Roussel R, Bankir L, Melander O, Bouby N. Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats. Diabetologia 2015; 58:1081-90. [PMID: 25622862 DOI: 10.1007/s00125-015-3496-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/22/2014] [Indexed: 12/11/2022]
Abstract
AIMS/HYPOTHESIS High plasma copeptin, a marker of vasopressin (VP) secretion, has been shown to be associated with the metabolic syndrome and development of type 2 diabetes in humans. The present study was designed to determine the long-term influence of plasma VP concentration in a rodent model prone to metabolic dysfunction. METHODS Obese Zucker rats and their lean counterparts were submitted for 4 weeks to one of three protocols inducing different levels of VP. Circulating VP was either reduced by increasing the daily water intake (low-VP), or increased by a chronic i.p. infusion of VP (high-VP). The control rats had normal VP levels that depended on their own regulation of water intake and VP secretion. RESULTS Compared with controls with normal VP, lean rats with high-VP had a higher fasting glycaemia after 4 weeks. In obese rats, high-VP promoted hyperinsulinaemia, glucose intolerance, assessed by glucose and insulin tolerance tests, and an impaired response to a pyruvate challenge. Conversely, treatment with a selective arginine vasopressin receptor 1A (V1aR) antagonist reduced glucose intolerance. Low-VP obese rats had unchanged glucose tolerance but exhibited a drastic decrease in liver steatosis compared with control obese rats, associated with low hepatic triacylglycerol and cholesterol content, and reduced expression of hepatic lipogenic genes. These effects were independent of changes in body adiposity, and plasma sodium and osmolality did not differ among groups. CONCLUSION/INTERPRETATION These findings show a causal relationship between the VP-hydration axis and the metabolic risk. Therapeutic perspectives include diet recommendations regarding hydration, but also potential pharmacological interventions targeting the VP V1aR.
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Affiliation(s)
- Christopher Taveau
- Inserm U1138, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Medecine, 75006, Paris, France
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