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Sarkar S. Pathological role of RAGE underlying progression of various diseases: its potential as biomarker and therapeutic target. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3467-3487. [PMID: 39589529 DOI: 10.1007/s00210-024-03595-6] [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: 08/12/2024] [Accepted: 10/31/2024] [Indexed: 11/27/2024]
Abstract
The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor with several structural types, performing a myriad of molecular mechanisms. The RAGE-ligand interactions play important roles in maintaining latent chronic inflammation, and oxidative damage underlying various pathological conditions like metabolic syndrome (MetS), neurodegenerative diseases, stroke, cardiovascular disorders, pulmonary disorders, cancer and infections. RAGE is thoroughly explored in knockout animals and human trials, targeted by small molecule inhibitors, peptides, diet, and natural compounds. But it is yet to be incorporated in the mainstream management of any ailment. This review performs an appraisal of the pathological mechanisms influenced by RAGE to uncover its prospects as a biomarker while also assessing its power to become a promising therapeutic target.
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Affiliation(s)
- Sinjini Sarkar
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS Deemed-to-be-University, V.L. Mehta Road, Vile Parle (W), Mumbai, 400056, India.
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Zgutka K, Tkacz M, Grabowska M, Mikołajek-Bedner W, Tarnowski M. Sirtuins and Their Implications in the Physiopathology of Gestational Diabetes Mellitus. Pharmaceuticals (Basel) 2025; 18:41. [PMID: 39861104 PMCID: PMC11768332 DOI: 10.3390/ph18010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/23/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Gestational diabetes mellitus (GDM) imposes serious short- and long-term health problems for the mother and her child. An effective therapeutic that can reduce the incidence of GDM and improve long-term outcomes is a major research priority and is very important for public health. Unfortunately, despite numerous studies, the molecular mechanisms underlying GDM are not fully defined and require further study. Chronic low-grade inflammation, oxidative stress, and insulin resistance are central features of pregnancies complicated by GDM. There is evidence of the involvement of sirtuins, which are NAD+-dependent histone deacetylases, in energy metabolism and inflammation. Taking these facts into consideration, the role of sirtuins in the pathomechanism of GDM will be discussed.
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Affiliation(s)
- Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, 70-210 Szczecin, Poland
| | - Marta Tkacz
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, 70-210 Szczecin, Poland
| | - Marta Grabowska
- Department of Histology and Developmental Biology, Faculty of Health Sciences, Pomeranian Medical University, 71-210 Szczecin, Poland
| | - Wioletta Mikołajek-Bedner
- Department of Obstetrics and Gynecology, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland
| | - Maciej Tarnowski
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, 70-210 Szczecin, Poland
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Xue L, Chen R, Liu Y, Niu P, Zhou J, Liu J, Zhang J, Chen H. Association of maternal blood high-mobility group box 1 levels and adverse pregnancy outcomes: A systematic review and meta-analysis. Reprod Biol 2024; 24:100859. [PMID: 38492434 DOI: 10.1016/j.repbio.2024.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/16/2024] [Accepted: 01/24/2024] [Indexed: 03/18/2024]
Abstract
Conflicting findings have emerged regarding the levels of high mobility group box 1 (HMGB1) in individuals experiencing adverse pregnancy outcomes. Here we conducted a meta-analysis to assess the association between maternal blood HMGB1 levels and adverse pregnancy outcomes. Utilizing databases such as PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Embase and China National Knowledge Infrastructure (CNKI), a systematic literature search was conducted in January 2024. Eligible literature was screened according to inclusion and exclusion criteria. Quality assessment was evaluated using the Newcastle-Ottawa Scale (NOS). The extracted data were analyzed using Review Manager 5.4 and STATA 12.0 software. 21 observational studies with a total of 2471 participants were included in this meta-analysis. Significantly higher peripheral blood levels of HMGB1 were associated with preeclampsia (PE) (SMD=1.34; 95% CI: 0.72-1.95; P < 0.0001) and gestational diabetes mellitus (GDM) (SMD=1.20; 95% CI: 0.31-2.09; P = 0.009). Additionally, HMGB1 levels in peripheral blood were significantly elevated in patients with unexplained recurrent spontaneous abortion (URSA) than those in pregnancy controls (SMD=4.22; 95% CI: 1.64-6.80; P = 0.001) or non-pregnancy controls (SMD=3.87; 95% CI: 1.81-5.92; P = 0.0002). Interestingly, higher blood HMGB1 levels were observed in women with preterm birth (PTB), however, the results did not reach a statistical difference (SMD=0.54; 95% CI: -0.36-1.44; P = 0.24). In conclusion, overexpressed maternal blood HMGB1 levels were associated with adverse pregnancy outcomes, including PE, GDM and URSA. Further studies should be conducted to validate the efficacy of HMGB1 as a biomarker for assessing the risk of adverse pregnancy outcomes.
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Affiliation(s)
- Liping Xue
- Department of Pharmacy, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China; School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - Ruolin Chen
- College of Letter and Science, University of California Davis, CA, USA
| | - Ying Liu
- Department of Pharmacy, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Peiguang Niu
- Department of Pharmacy, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Jintuo Zhou
- Department of Pharmacy, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Jinhua Liu
- Department of Pharmacy, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China; School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China
| | - Jinhua Zhang
- Department of Pharmacy, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China; School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China.
| | - Huajiao Chen
- Department of Pharmacy, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China; School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China.
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Ticconi C, Mardente S, Mari E, Barreca F, Montanaro M, Mauriello A, Rizzo G, Zicari A. High mobility group box 1 in women with unexplained recurrent pregnancy loss. J Perinat Med 2023; 51:1139-1146. [PMID: 37246521 DOI: 10.1515/jpm-2023-0109] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/13/2023] [Indexed: 05/30/2023]
Abstract
OBJECTIVES To investigate whether high mobility group box 1 (HMGB1) is involved in unexplained recurrent pregnancy loss (uRPL). METHODS Plasma levels of HMGB1 were measured by ELISA in non-pregnant women with (n=44) and without (n=53 controls) uRPL. Their platelets and plasma-derived microvesicles (MVs) were also assayed for HMGB1. Endometrial biopsies were taken in selected uRPL (n=5) and control women (n=5) and the tissue expression of HMGB1 was determined by western blot and immunohistochemistry (IHC). RESULTS plasma levels of HMGB1 were significantly higher in women with uRPL than in control women. HMGB1 content in platelets and MVs obtained from women with uRPL was significantly higher than that obtained from control women. HMGB1 expression in endometrium was higher in tissues obtained from women with uRPL than in tissues obtained from control women. IHC analysis revealed that HMGB1 is expressed in endometrium with different patterns between uRPL and control women. CONCLUSIONS HMGB1 could be involved in uRPL.
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Affiliation(s)
- Carlo Ticconi
- Department of Surgical Sciences, Section of Gynecology and Obstetrics, University of Rome "Tor Vergata", Rome, Italy
| | - Stefania Mardente
- Department of Surgical Sciences, Section of Gynecology and Obstetrics, University of Rome "Tor Vergata", Rome, Italy
| | - Emanuela Mari
- Department of Experimental Medicine, University of Rome "La Sapienza", Rome, Italy
| | - Federica Barreca
- Department of Experimental Medicine, University of Rome "La Sapienza", Rome, Italy
| | - Manuela Montanaro
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Alessandro Mauriello
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Giuseppe Rizzo
- Department of Biomedicine and Prevention, Section of Gynecology and Obstetrics, University of Rome "Tor Vergata", Rome, Italy
| | - Alessandra Zicari
- Department of Experimental Medicine, University of Rome "La Sapienza", Rome, Italy
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Ren Y, Zhu D, Han X, Zhang Q, Chen B, Zhou P, Wei Z, Zhang Z, Cao Y, Zou H. HMGB1: a double-edged sword and therapeutic target in the female reproductive system. Front Immunol 2023; 14:1238785. [PMID: 37691930 PMCID: PMC10484633 DOI: 10.3389/fimmu.2023.1238785] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/03/2023] [Indexed: 09/12/2023] Open
Abstract
HMGB1 that belongs to the High Mobility Group-box superfamily, is a nonhistone chromatin associated transcription factor. It is present in the nucleus of eukaryotes and can be actively secreted or passively released by kinds of cells. HMGB1 is important for maintaining DNA structure by binding to DNA and histones, protecting it from damage. It also regulates the interaction between histones and DNA, affecting chromatin packaging, and can influence gene expression by promoting nucleosome sliding. And as a DAMP, HMGB1 binding to RAGE and TLRs activates NF-κB, which triggers the expression of downstream genes like IL-18, IL-1β, and TNF-α. HMGB1 is known to be involved in numerous physiological and pathological processes. Recent studies have demonstrated the significance of HMGB1 as DAMPs in the female reproductive system. These findings have shed light on the potential role of HMGB1 in the pathogenesis of diseases in female reproductive system and the possibilities of HMGB1-targeted therapies for treating them. Such therapies can help reduce inflammation and metabolic dysfunction and alleviate the symptoms of reproductive system diseases. Overall, the identification of HMGB1 as a key player in disease of the female reproductive system represents a significant breakthrough in our understanding of these conditions and presents exciting opportunities for the development of novel therapies.
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Affiliation(s)
- Yu Ren
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
| | - Damin Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Xingxing Han
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Qiqi Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Beili Chen
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Ping Zhou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Zhaolian Wei
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, Anhui, China
- Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, Anhui, China
| | - Zhiguo Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
| | - Huijuan Zou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- National Health Commission (NHC) Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
- Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Hefei, Anhui, China
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Garza-Campos A, Prieto-Correa JR, Domínguez-Rosales JA, Hernández-Nazará ZH. Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer. World J Diabetes 2023; 14:977-994. [PMID: 37547586 PMCID: PMC10401444 DOI: 10.4239/wjd.v14.i7.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 04/17/2023] [Indexed: 07/12/2023] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the “cancer hallmarks” of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
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Affiliation(s)
- Andrea Garza-Campos
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Roberto Prieto-Correa
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Alfredo Domínguez-Rosales
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Zamira Helena Hernández-Nazará
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
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Chen LW, Chen PH, Tang CH, Yen JH. Adipose-derived stromal cells reverse insulin resistance through inhibition of M1 expression in a type 2 diabetes mellitus mouse model. Stem Cell Res Ther 2022; 13:357. [PMID: 35883204 PMCID: PMC9327360 DOI: 10.1186/s13287-022-03046-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 07/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Adipose tissue inflammation is considered as one of the major mechanisms underlying the pathogenesis of insulin resistance and complications in diabetes. Here, we aimed to study the effects of adipose-derived stromal cells on diabetes-induced insulin resistance and M1 cytokine expression. METHODS Stromal vascular fractions (SVFs) purified from the inguinal adipose tissue of diabetic mice were treated with plasma from either nondiabetic (Lepr+/+) or diabetic (Leprdb/db) mice and injected into the inguinal white adipose tissue of Leprdb/db mice. RESULTS We found that diabetic plasma treatment induced, whereas nondiabetic plasma suppressed TNF-α, IL-1β, and dipeptidyl peptidase 4 (DPP4) mRNA expression in SVFs in vitro. Importantly, the injection of nondiabetic plasma-treated SVFs significantly decreased TNF-α, IL-6, IL-1β, CCL2, and IL-33 and induced IL-10 mRNA expression in adipose tissue of Leprdb/db mice in vivo. Furthermore, we observed that nondiabetic plasma-treated SVFs increased mRNA expression of Foxp3 in adipose tissue macrophages and Foxp3 in adipose CD4+ T cells, decreased CD11b+CD11c+ cells in adipose tissue, and suppressed mRNA expression of ICAM-1, FCM3, IL-6, IL-1β, iNOS, TNF-α, and DPP4 as well as protein expression of DPP4 and phosphorylated JNK and NF-κB in the liver of Leprdb/db mice. Moreover, we found that nondiabetic plasma-treated SVFs increased Akt activation following insulin administration and attenuated glucose intolerance in Leprdb/db mice. CONCLUSIONS Our results demonstrate that nondiabetic plasma inhibits M1 but increases M2 cytokine expression in adipose tissue of diabetic mice. Most importantly, our findings reveal that nondiabetic plasma-treated SVFs are capable of mitigating diabetes-induced plasma DPP4 activity, liver inflammation, and insulin resistance and that may be mediated through suppressing M1 cytokines but increasing IL-10 and Tregs in adipose tissue. Altogether, our findings suggest that adipose stromal cell-based therapy could potentially be developed as an efficient therapeutic strategy for the treatment of diabetes.
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Affiliation(s)
- Lee-Wei Chen
- Department of Surgery, Kaohsiung Veterans General Hospital, No.386, Ta-Chung 1st Road, Kaohsiung, 813, Taiwan. .,Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan. .,Department of Biological Sciences, National Sun Yat-Sen University, No.70, Lien-Hai Road, Kaohsiung, 804, Taiwan.
| | - Pei-Hsuan Chen
- Department of Surgery, Kaohsiung Veterans General Hospital, No.386, Ta-Chung 1st Road, Kaohsiung, 813, Taiwan
| | - Chia-Hua Tang
- Department of Surgery, Kaohsiung Veterans General Hospital, No.386, Ta-Chung 1st Road, Kaohsiung, 813, Taiwan
| | - Jui-Hung Yen
- Department of Microbiology and Immunology, Indiana University School of Medicine, 2101 E. Coliseum Blvd. Fort Wayne, Indianapolis, IN, 46805, USA.
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Kurashima CK, Ng PK, Kendal-Wright CE. RAGE against the Machine: Can Increasing Our Understanding of RAGE Help Us to Battle SARS-CoV-2 Infection in Pregnancy? Int J Mol Sci 2022; 23:6359. [PMID: 35742804 PMCID: PMC9224312 DOI: 10.3390/ijms23126359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/02/2022] [Accepted: 06/05/2022] [Indexed: 12/05/2022] Open
Abstract
The receptor of advanced glycation end products (RAGE) is a receptor that is thought to be a key driver of inflammation in pregnancy, SARS-CoV-2, and also in the comorbidities that are known to aggravate these afflictions. In addition to this, vulnerable populations are particularly susceptible to the negative health outcomes when these afflictions are experienced in concert. RAGE binds a number of ligands produced by tissue damage and cellular stress, and its activation triggers the proinflammatory transcription factor Nuclear Factor Kappa B (NF-κB), with the subsequent generation of key proinflammatory cytokines. While this is important for fetal membrane weakening, RAGE is also activated at the end of pregnancy in the uterus, placenta, and cervix. The comorbidities of hypertension, cardiovascular disease, diabetes, and obesity are known to lead to poor pregnancy outcomes, and particularly in populations such as Native Hawaiians and Pacific Islanders. They have also been linked to RAGE activation when individuals are infected with SARS-CoV-2. Therefore, we propose that increasing our understanding of this receptor system will help us to understand how these various afflictions converge, how forms of RAGE could be used as a biomarker, and if its manipulation could be used to develop future therapeutic targets to help those at risk.
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Affiliation(s)
- Courtney K. Kurashima
- School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA; (C.K.K.); (P.K.N.)
| | - Po’okela K. Ng
- School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA; (C.K.K.); (P.K.N.)
| | - Claire E. Kendal-Wright
- School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA; (C.K.K.); (P.K.N.)
- Department of Obstetrics, Gynecology and Women’s Health, John A. Burns School of Medicine, University of Hawai’i, Honolulu, HI 96813, USA
- Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai’i, Honolulu, HI 96813, USA
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Filardi T, Catanzaro G, Grieco GE, Splendiani E, Trocchianesi S, Santangelo C, Brunelli R, Guarino E, Sebastiani G, Dotta F, Morano S, Ferretti E. Identification and Validation of miR-222-3p and miR-409-3p as Plasma Biomarkers in Gestational Diabetes Mellitus Sharing Validated Target Genes Involved in Metabolic Homeostasis. Int J Mol Sci 2022; 23:ijms23084276. [PMID: 35457094 PMCID: PMC9028517 DOI: 10.3390/ijms23084276] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/16/2022] Open
Abstract
Gestational diabetes mellitus (GDM) causes both maternal and fetal adverse outcomes. The deregulation of microRNAs (miRNAs) in GDM suggests their involvement in GDM pathogenesis and complications. Exosomes are extracellular vesicles (EVs) of endosomal origin, released via exocytosis into the extracellular compartment. Through EVs, miRNAs are delivered in distant target cells and are able to affect gene expression. In this study, miRNA expression was analyzed to find new miRNAs that could improve GDM classification and molecular characterization. MiRNA were profiled in total plasma and EVs in GDM patients and normal glucose tolerance (NGT) women. Samples were collected at third trimester of gestation from two diabetes centers. MiRNA expression was profiled in a discovery cohort using the multiplexed NanoString nCounter Human v3 miRNA. Validation analysis was performed in a second independent cohort using RT-qPCR. A set of miRNAs resulted to be differentially expressed (DE) in total plasma and EVs in GDM. Among them, total plasma miR-222-3p and miR-409-3p were validated in the independent cohort. MiR-222-3p levels correlated with fasting plasma glucose (FPG) (p < 0.001) and birth weight (p = 0.012), whereas miR-409-3p expression correlated with FPG (p < 0.001) and inversely with gestational age (p = 0.001). The major validated target genes of the deregulated miRNAs were consistently linked to type 2 diabetes and GDM pathophysiology. MiR-222-3p and miR-409-3p are two circulating biomarkers that could improve GDM classification power and act in the context of the molecular events leading to the metabolic alterations observed in GDM.
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Affiliation(s)
- Tiziana Filardi
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
| | - Giuseppina Catanzaro
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
- Correspondence:
| | - Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (G.S.); (F.D.)
- Fondazione Umberto di Mario, Toscana Life Sciences, 53100 Siena, Italy
| | - Elena Splendiani
- Department of Molecular Medicine, “Sapienza” University, 00161 Rome, Italy; (E.S.); (S.T.)
| | - Sofia Trocchianesi
- Department of Molecular Medicine, “Sapienza” University, 00161 Rome, Italy; (E.S.); (S.T.)
| | - Carmela Santangelo
- Center for Gender-Specific Medicine, Gender Specific Prevention and Health Unit, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Roberto Brunelli
- Maternal and Child Health and Urological Sciences, “Sapienza” University, 00161 Rome, Italy;
| | - Elisa Guarino
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (G.S.); (F.D.)
- Fondazione Umberto di Mario, Toscana Life Sciences, 53100 Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (G.E.G.); (G.S.); (F.D.)
- Fondazione Umberto di Mario, Toscana Life Sciences, 53100 Siena, Italy
- UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
- Tuscany Centre for Precision Medicine (CReMeP), 53100 Siena, Italy
| | - Susanna Morano
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
| | - Elisabetta Ferretti
- Department of Experimental Medicine, “Sapienza” University, 00161 Rome, Italy; (T.F.); (S.M.); (E.F.)
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10
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Epigenetic Changes in Gestational Diabetes Mellitus. Int J Mol Sci 2021; 22:ijms22147649. [PMID: 34299269 PMCID: PMC8303885 DOI: 10.3390/ijms22147649] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/30/2021] [Accepted: 07/14/2021] [Indexed: 12/30/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance that appears or is for the first time diagnosed during pregnancy. It can lead to many complications in the mother and in the offspring, so diagnostics and management of GDM are important to avoid adverse pregnancy outcomes. Epigenetic studies revealed the different methylation status of genes in pregnancies with GDM compared to pregnancies without GDM. A growing body of evidence shows that the GDM can affect not only the course of the pregnancy, but also the development of the offspring, thus contributing to long-term effects and adverse health outcomes of the progeny. Epigenetic changes occur through histone modification, DNA methylation, and disrupted function of non-coding ribonucleic acid (ncRNA) including microRNAs (miRNAs). In this review, we focus on the recent knowledge about epigenetic changes in GDM. The analysis of this topic may help us to understand pathophysiological mechanisms in GDM and find a solution to prevent their consequences.
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Scazzocchio B, Filardi T, Varì R, Brunelli R, Galoppi P, Morano S, Masella R, Santangelo C. Protocatechuic acid influences immune-metabolic changes in the adipose tissue of pregnant women with gestational diabetes mellitus. Food Funct 2021; 12:7490-7500. [PMID: 34213517 DOI: 10.1039/d1fo00267h] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gestational diabetes mellitus (GDM) is associated with immune metabolic changes that increase women's risk of developing metabolic disorders later in life. Nutritional intervention is a crucial component in reducing the burden of these pathological features. We examined whether protocatechuic acid (PCA), a major metabolite of anthocyanins abundant in plant food, is able to exert insulin-mimetic activity and modulate inflammation in the visceral adipose tissue (VAT) obtained at delivery, from pregnant women with GDM or normal glucose tolerance (NGT). PCA stimulated glucose uptake in the VAT from both GDM and NGT women. This capability was associated with increased phosphorylation of p38 mitogen-activated protein kinase (p38MAPK), as further demonstrated by the inhibitory effect of SB203580, a p38MAPK inhibitor, on PCA-induced glucose uptake. The GDM-VAT expressed lower adiponectin levels and PCA stimulated adiponectin release in the NGT-VAT and, albeit to a lower extent, in the GDM-VAT. Higher levels of IL6 and TNFα were secreted by the GDM-VAT compared with the NGT one, and PCA had no effects on them. PCA reduced the overexpression of vasoactive intestinal peptide receptor 2 (VPAC2) in the GDM-VAT. Further studies are needed to establish whether and how anthocyanins and food rich in these compounds may contribute to prevent or delay metabolic disorders in women with GDM.
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Affiliation(s)
- Beatrice Scazzocchio
- Center for Gender-Specific Medicine, Gender Specific Prevention and Health Unit, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.
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12
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Merech F, Hauk V, Paparini D, Fernandez L, Naguila Z, Ramhorst R, Waschek J, Pérez Leirós C, Vota D. Growth impairment, increased placental glucose uptake and altered transplacental transport in VIP deficient pregnancies: Maternal vs. placental contributions. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166207. [PMID: 34186168 DOI: 10.1016/j.bbadis.2021.166207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/17/2021] [Accepted: 06/23/2021] [Indexed: 02/02/2023]
Abstract
Glucose uptake by the placenta and its transfer to the fetus is a finely regulated process required for placental and fetal development. Deficient placentation is associated with pregnancy complications such as fetal growth restriction (FGR). The vasoactive intestinal peptide (VIP) has embryotrophic effects in mice and regulates human cytotrophoblast metabolism and function. Here we compared glucose uptake and transplacental transport in vivo by VIP-deficient placentas from normal or VIP-deficient maternal background. The role of endogenous VIP in placental glucose and amino acid uptake was also investigated. Wild type C57BL/6 (WT) or VIP+/- (VIP HT) females were mated with WT, VIP knock-out (VIP KO) or VIP HT males. Glucose uptake and transplacental transport were evaluated by the injection of the fluorescent d-glucose analogue 2-NBDG in pregnant mice at gestational day (gd) 17.5. Glucose and amino acid uptake in vitro by placental explants were measured with 2-NBDG or 14C-MeAIB respectively. In normal VIP maternal background, fetal weight was reduced in association with placental VIP deficiency, whereas placental weight was unaltered. Paradoxically, VIP+/- placentas presented higher glucose uptake and higher gene expression of GLUT1 and mTOR than VIP+/+ placentas. However, in a maternal VIP-deficient environment placental uptake and transplacental transport of glucose increased while fetal weights were unaffected, regardless of feto-placental genotype. Results point to VIP-deficient pregnancy in a normal background as a suitable FGR model with increased placental glucose uptake and transplacental transport. The apparently compensatory actions are unable to sustain normal fetal growth and could result in complications later in life.
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Affiliation(s)
- Fátima Merech
- Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina
| | - Vanesa Hauk
- Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina
| | - Daniel Paparini
- Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina
| | - Laura Fernandez
- Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina
| | - Zaira Naguila
- Bioterio Central, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina
| | - Rosanna Ramhorst
- Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina
| | - James Waschek
- The David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Claudia Pérez Leirós
- Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina.
| | - Daiana Vota
- Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales (FCEN-UBA), Buenos Aires, Argentina.
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13
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Adipose tissue function in healthy pregnancy, gestational diabetes mellitus and pre-eclampsia. Eur J Clin Nutr 2021; 75:1745-1756. [PMID: 34131300 PMCID: PMC8636251 DOI: 10.1038/s41430-021-00948-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 04/30/2021] [Accepted: 05/17/2021] [Indexed: 01/12/2023]
Abstract
Gestational diabetes mellitus (GDM) is a common disorder of pregnancy with short- and long-term consequences for mother and baby. Pre-eclampsia is of major concern to obstetricians due to its sudden onset and increased morbidity and mortality for mother and baby. The incidence of these conditions continues to increase due to widespread maternal obesity. Maternal obesity is a risk factor for GDM and pre-eclampsia, yet our understanding of the role of adipose tissue and adipocyte biology in their aetiology is very limited. In this article, available data on adipose tissue and adipocyte function in healthy and obese pregnancy and how these are altered in GDM and pre-eclampsia are reviewed. Using our understanding of adipose tissue and adipocyte biology in non-pregnant populations, a role for underlying adipocyte dysfunction in the pathological pathways of these conditions is discussed.
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Catanzaro G, Filardi T, Sabato C, Vacca A, Migliaccio S, Morano S, Ferretti E. Tissue and circulating microRNAs as biomarkers of response to obesity treatment strategies. J Endocrinol Invest 2021; 44:1159-1174. [PMID: 33111214 PMCID: PMC8124039 DOI: 10.1007/s40618-020-01453-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Obesity, characterized by an increased amount of adipose tissue, is a metabolic chronic alteration which has reached pandemic proportion. Lifestyle changes are the first line therapy for obesity and a large variety of dietary approaches have demonstrated efficacy in promoting weight loss and improving obesity-related metabolic alterations. Besides diet and physical activity, bariatric surgery might be an effective therapeutic strategy for morbid obese patients. Response to weight-loss interventions is characterised by high inter-individual variability, which might involve epigenetic factors. microRNAs have critical roles in metabolic processes and their dysregulated expression has been reported in obesity. AIM The aim of this review is to provide a comprehensive overview of current studies evaluating changes in microRNA expression in obese patients undergoing lifestyle interventions or bariatric surgery. RESULTS A considerable number of studies have reported a differential expression of circulating microRNAs before and after various dietary and bariatric surgery approaches, identifying several candidate biomarkers of response to weight loss. Significant changes in microRNA expression have been observed at a tissue level as well, with entirely different patterns between visceral and subcutaneous adipose tissue. Interestingly, relevant differences in microRNA expression have emerged between responders and non-responders to dietary or surgical interventions. A wide variety of dysregulated microRNA target pathways have also been identified, helping to understand the pathophysiological mechanisms underlying obesity and obesity-related metabolic diseases. CONCLUSIONS Although further research is needed to draw firm conclusions, there is increasing evidence about microRNAs as potential biomarkers for weight loss and response to intervention strategies in obesity.
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Affiliation(s)
- G Catanzaro
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - T Filardi
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - C Sabato
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - A Vacca
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - S Migliaccio
- Department of Movement, Human and Health Sciences, "Foro Italico" University of Rome, Rome, Italy
| | - S Morano
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - E Ferretti
- Department of Experimental Medicine, Policlinico Umberto I, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
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15
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Chen LW, Chen PH, Yen JH. Inhibiting adipose tissue M1 cytokine expression decreases DPP4 activity and insulin resistance in a type 2 diabetes mellitus mouse model. PLoS One 2021; 16:e0252153. [PMID: 34043673 PMCID: PMC8158933 DOI: 10.1371/journal.pone.0252153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 05/10/2021] [Indexed: 12/25/2022] Open
Abstract
Adipose tissue inflammation is a major cause of the pathogenesis of obesity and comorbidities. To study the involvement of M1/M2 cytokine expression of adipose tissue in the regulatory mechanisms of dipeptidyl peptidase 4 (DPP4) and insulin resistance in diabetes, stromal vascular fractions (SVFs) were purified from inguinal adipose tissue of diabetic (Leprdb/db) and non-diabetic (Lepr+/+) mice followed by analysis of M1/M2 cytokine expression. SVFs of Leprdb/db mice exhibited increased TNF-α, IL-6, IL-1β, CCL2, and DPP4 mRNA expression but decreased IL-10 mRNA expression. Plasma from Leprdb/db mice induced TNF-α, IL-6, IL-1β, CCL2, and DPP4 mRNA expression and plasma from Lepr+/+ mice induced IL-10 mRNA expression in SVFs from Leprdb/db mice. Injection of Lepr+/+ plasma into the adipose tissue of Leprdb/db mice decreased mRNA expression of TNF-α, IL-6, IL-1β, CCL2, and DPP4 and protein expression of pJNK and DPP4 in SVFs, reduced mRNA expression of ICAM, FMO3, IL-1β, iNOS, TNF-α, IL-6, and DPP4 and protein expression of ICAM, FMO3, and DPP4 in liver, and suppressed mRNA expression of TNF-α, IL-6, IL-1β, and DPP4 in Kupffer cells. Plasma from Leprdb/db mice did not induce M1 cytokine expression in SVFs from Leprdb/db-Jnk1-/- mice. Altogether, we demonstrate that diabetes induces M1 but decreases M2 cytokine expression in adipose tissue. Diabetic plasma-induced M1 expression is potentially through pJNK signaling pathways. Non-diabetic plasma reverses M1/M2 cytokine expression, plasma CCL2 levels, DPP4 activity, and Kupffer cell activation in diabetes. Our results suggest M1/M2 cytokine expression in adipose tissue is critical in diabetes-induced DPP4 activity, liver inflammation, and insulin resistance.
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Affiliation(s)
- Lee-Wei Chen
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
- * E-mail: (L-WC); (J-HY)
| | - Pei-Hsuan Chen
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Jui-Hung Yen
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- * E-mail: (L-WC); (J-HY)
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16
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Ali AM, Kunugi H. Intermittent Fasting, Dietary Modifications, and Exercise for the Control of Gestational Diabetes and Maternal Mood Dysregulation: A Review and a Case Report. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E9379. [PMID: 33333828 PMCID: PMC7765295 DOI: 10.3390/ijerph17249379] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 12/13/2022]
Abstract
Gestational diabetes mellitus (GDM) is a common pregnancy-related condition afflicting 5-36% of pregnancies. It is associated with many morbid maternal and fetal outcomes. Mood dysregulations (MDs, e.g., depression, distress, and anxiety) are common among women with GDM, and they exacerbate its prognosis and hinder its treatment. Hence, in addition to early detection and proper management of GDM, treating the associated MDs is crucial. Maternal hyperglycemia and MDs result from a complex network of genetic, behavioral, and environmental factors. This review briefly explores mechanisms that underlie GDM and prenatal MDs. It also describes the effect of exercise, dietary modification, and intermittent fasting (IF) on metabolic and affective dysfunctions exemplified by a case report. In this patient, interventions such as IF considerably reduced maternal body weight, plasma glucose, and psychological distress without any adverse effects. Thus, IF is one measure that can control GDM and maternal MDs; however, more investigations are warranted.
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Affiliation(s)
- Amira Mohammed Ali
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-0031, Japan;
- Department of Psychiatric Nursing and Mental Health, Faculty of Nursing, Alexandria University, Alexandria 21527, Egypt
| | - Hiroshi Kunugi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-0031, Japan;
- Department of Psychiatry, Teikyo University School of Medicine, Tokyo 173-8605, Japan
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17
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Curcumin: Could This Compound Be Useful in Pregnancy and Pregnancy-Related Complications? Nutrients 2020; 12:nu12103179. [PMID: 33080891 PMCID: PMC7603145 DOI: 10.3390/nu12103179] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries. The growing interest in plant-derived substances has led to increased consumption of them also in pregnancy. The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin’s effects on pregnancy and pregnancy-related complications. It is known that immune-metabolic alterations occurring during pregnancy have consequences on both maternal and fetal tissues, leading to short- and long-term complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. The current review summarizes the latest data, mostly obtained from animal models and in vitro studies, on the impact of curcumin on the molecular mechanisms involved in pregnancy pathophysiology, with the aim to shed light on the possible beneficial and/or adverse effects of curcumin on pregnancy outcomes.
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Saito Reis CA, Padron JG, Norman Ing ND, Kendal-Wright CE. High-mobility group box 1 is a driver of inflammation throughout pregnancy. Am J Reprod Immunol 2020; 85:e13328. [PMID: 32851715 DOI: 10.1111/aji.13328] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 08/10/2020] [Accepted: 08/18/2020] [Indexed: 12/15/2022] Open
Abstract
A proinflammatory response driven by high-mobility group box 1 (HMGB1) is important for the success of both the early stages of pregnancy and parturition initiation. However, the tight regulation of HMGB1 within these two stages is critical, as increased HMGB1 can manifest into pregnancy-related pathologies. Although during the early stages of pregnancy HMGB1 is critical for the development and implantation of the embryo, and uterine decidualization, high levels within the uterine cavity have been linked to pregnancy failure. In addition, chronic inflammation, resultant from increased HMGB1 within the maternal circulation and gestational tissues, also increases the risk for preterm labor, preterm birth, or infant mortality. Due to the link between HMGB1 and several pregnancy pathologies, the possibility of leveraging HMGB1 as a biomarker has been assessed. However, data are limited that demonstrate how known HMGB1 inhibitors could reduce inflammation within pregnancy. Thus, further research is warranted to improve our understanding of the potential of HMGB1 as a therapeutic target to reduce inflammation within pregnancy. This review aims to describe what is understood about the role of HMGB1 that drives inflammation throughout pregnancy and highlight its potential as a biomarker and therapeutic target within this context.
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Affiliation(s)
- Chelsea A Saito Reis
- Natural Science and Mathematics, Chaminade University of Honolulu, Honolulu, HI, USA
| | - Justin G Padron
- Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoā, Honolulu, HI, USA
| | - Nainoa D Norman Ing
- Natural Science and Mathematics, Chaminade University of Honolulu, Honolulu, HI, USA
| | - Claire E Kendal-Wright
- Natural Science and Mathematics, Chaminade University of Honolulu, Honolulu, HI, USA.,Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai'i at Manoā, Honolulu, HI, USA.,Obstetrics, Gynecology and Women's Health, John A. Burns School of Medicine, University of Hawai'I at Manoā, Honolulu, HI, USA
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Non-Coding RNA: Role in Gestational Diabetes Pathophysiology and Complications. Int J Mol Sci 2020; 21:ijms21114020. [PMID: 32512799 PMCID: PMC7312670 DOI: 10.3390/ijms21114020] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/30/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
Gestational Diabetes Mellitus (GDM) is defined as glucose intolerance that develops in the second or third trimester of pregnancy. GDM can lead to short-term and long-term complications both in the mother and in the offspring. Diagnosing and treating this condition is therefore of great importance to avoid poor pregnancy outcomes. There is increasing interest in finding new markers with potential diagnostic, prognostic and therapeutic utility in GDM. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs, are critically involved in metabolic processes and their dysregulated expression has been reported in several pathological contexts. The aberrant expression of several circulating or placenta-related ncRNAs has been linked to insulin resistance and β-cell dysfunction, the key pathophysiological features of GDM. Furthermore, significant associations between altered ncRNA profiles and GDM-related complications, such as macrosomia or trophoblast dysfunction, have been observed. Remarkably, the deregulation of ncRNAs, which might be linked to a detrimental intrauterine environment, can lead to changes in the expression of target genes in the offspring, possibly contributing to the development of long-term GDM-related complications, such as metabolic and cardiovascular diseases. In this review, all the recent findings on ncRNAs and GDM are summarized, particularly focusing on the molecular aspects and the pathophysiological implications of this complex relationship.
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20
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Kopylov AT, Kaysheva AL, Papysheva O, Gribova I, Kotaysch G, Kharitonova L, Mayatskaya T, Krasheninnikova A, Morozov SG. Association of Proteins Modulating Immune Response and Insulin Clearance During Gestation with Antenatal Complications in Patients with Gestational or Type 2 Diabetes Mellitus. Cells 2020; 9:cells9041032. [PMID: 32326243 PMCID: PMC7226479 DOI: 10.3390/cells9041032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/16/2020] [Accepted: 04/19/2020] [Indexed: 12/13/2022] Open
Abstract
Background: The purpose of the study is to establish and quantitatively assess protein markers and their combination in association with insulin uptake that may be have value for early prospective recognition of diabetic fetopathy (DF) as a complication in patients with diabetes mellitus during gestation. Methods: Proteomic surveying and accurate quantitative measurement of selected proteins from plasma samples collected from the patients with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) who gave birth of either healthy or affected by maternal diabetes newborns was performed using mass spectrometry. Results: We determined and quantitatively measured several proteins, including CRP, CEACAM1, CNDP1 and Ig-family that were significantly differed in patients that gave birth of newborns with signs of DF. We found that patients with newborns associated with DF are characterized by significantly decreased CEACAM1 (113.18 ± 16.23 ng/mL and 81.09 ± 10.54 ng/mL in GDM and T2DM, p < 0.005) in contrast to control group (515.6 ± 72.14 ng/mL, p < 0.005). On the contrary, the concentration of CNDP1 was increased in DF-associated groups and attained 49.3 ± 5.18 ng/mL and 37.7 ± 3.34 ng/mL (p < 0.005) in GDM and T2DM groups, respectively. Among other proteins, dramatically decreased concentration of IgG4 and IgA2 subclasses of immunoglobulins were noticed. Conclusion: The combination of the measured markers may assist (AUC = 0.893 (CI 95%, 0.785–0.980) in establishing the clinical finding of the developing DF especially in patients with GDM who are at the highest risk of chronic insulin resistance.
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Affiliation(s)
- Arthur T. Kopylov
- Institute of General Pathology and Pathophysiology, Department of Pathology, 125315 Moscow, Russia; (A.K.); (S.G.M.)
- Institute of Biomedical Chemistry, Department of Proteomic Researches, 119121 Moscow, Russia;
- Correspondence: ; Tel.: +7-926-185-4049
| | - Anna L. Kaysheva
- Institute of Biomedical Chemistry, Department of Proteomic Researches, 119121 Moscow, Russia;
| | - Olga Papysheva
- Sergey S. Yudin 7th State Clinical Hospital, Perinatal Center, 115446 Moscow, Russia;
| | - Iveta Gribova
- Nikolay E. Bauman 29th State Clinical Hospital, 110020 Moscow, Russia; (I.G.); (G.K.)
- “Biopharm-Test” Limited Liability Company, 121170 Moscow, Russia
| | - Galina Kotaysch
- Nikolay E. Bauman 29th State Clinical Hospital, 110020 Moscow, Russia; (I.G.); (G.K.)
| | - Lubov Kharitonova
- Nikolay I. Pirogov Medical University, 117997 Moscow, Russia; (L.K.); (T.M.)
| | - Tatiana Mayatskaya
- Nikolay I. Pirogov Medical University, 117997 Moscow, Russia; (L.K.); (T.M.)
| | - Anna Krasheninnikova
- Institute of General Pathology and Pathophysiology, Department of Pathology, 125315 Moscow, Russia; (A.K.); (S.G.M.)
| | - Sergey G. Morozov
- Institute of General Pathology and Pathophysiology, Department of Pathology, 125315 Moscow, Russia; (A.K.); (S.G.M.)
- Nikolay E. Bauman 29th State Clinical Hospital, 110020 Moscow, Russia; (I.G.); (G.K.)
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Ceddia RP, Collins S. A compendium of G-protein-coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure. Clin Sci (Lond) 2020; 134:473-512. [PMID: 32149342 PMCID: PMC9137350 DOI: 10.1042/cs20190579] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/17/2020] [Accepted: 02/24/2020] [Indexed: 12/15/2022]
Abstract
With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand-receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein-coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.
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Affiliation(s)
- Ryan P Ceddia
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, U.S.A
| | - Sheila Collins
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, U.S.A
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22
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Liu Y, Tang ZZ, Zhang YM, Kong L, Xiao WF, Ma TF, Liu YW. Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes. Biochem Pharmacol 2020; 175:113849. [PMID: 32059841 DOI: 10.1016/j.bcp.2020.113849] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/06/2020] [Indexed: 12/14/2022]
Abstract
Gestational diabetes mellitus (GDM) is associated with an increased risk of progressing to type 2 DM and cardiovascular disease; however, the pathogenesis is still poorly understood. This study was to investigate roles of thrombin and its receptor protease-activated receptor 1 (PAR-1) and NLRP1 inflammasome in endothelial injury in GDM condition. Umbilical cord and plasma of GDM patients and high glucose (HG) cultured human umbilical vein endothelial cells (HUVECs) were used to examine the pathological changes of these pathways. Meanwhile, ameliorative effects and potential mechanisms of a natural product sarsasapogenin (Sar) were investigated in HUVECs. Thrombin/PAR-1 pathway, advanced glycation endproducts (AGEs) and their receptor (RAGE) axis, and the nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1) inflammasome were activated in GDM condition and HG-cultured HUVECs, accompanied by endothelial injury (decreased cell viability and increased lactate dehydrogenase release). Nevertheless, thrombin inhibition or PAR-1 antagonism caused decreases in AGEs formation and RAGE expression in HG-cultured HUVECs, while AGEs inhibition or RAGE antagonism declined PAR-1 expression not thrombin activity. Furthermore, thrombin inhibition or PAR-1 antagonism restrained NLRP1 inflammasome activation in HG-cultured HUVECs; meanwhile, NLRP1 expression and interleukin 18 levels were remarkably reduced in HG-cultured HUVECs after PAR-1 knockdown. Interestingly, Sar co-treatment could suppress thrombin/PAR-1 pathway, NLRP1 inflammasome, and AGEs/RAGE axis. Together, endothelial damages in GDM were likely due to enhanced interaction between AGEs/RAGE axis and thrombin/PAR-1 pathway, followed by NLRP1 inflammasome activation. Moreover, Sar may act as a protective agent against endothelial injury in chronic HG condition.
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Affiliation(s)
- Yue Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Zhuang-Zhuang Tang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Yu-Meng Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Li Kong
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Wei-Fen Xiao
- Department of Obstetrics and Gynecology, Xuzhou Medical University Affiliated Hospital, Xuzhou 221006, Jiangsu, China
| | - Teng-Fei Ma
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Yao-Wu Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Department of Pharmacology, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
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23
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Rancourt RC, Ott R, Ziska T, Schellong K, Melchior K, Henrich W, Plagemann A. Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology. Int J Mol Sci 2020; 21:ijms21020479. [PMID: 31940889 PMCID: PMC7014132 DOI: 10.3390/ijms21020479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 12/19/2022] Open
Abstract
Gestational diabetes (GDM) is among the most challenging diseases in westernized countries, affecting mother and child, immediately and in later life. Obesity is a major risk factor for GDM. However, the impact visceral obesity and related epigenetics play for GDM etiopathogenesis have hardly been considered so far. Our recent findings within the prospective ‘EaCH’ cohort study of women with GDM or normal glucose tolerance (NGT), showed the role, critical factors of insulin resistance (i.e., adiponectin, insulin receptor) may have for GDM pathophysiology with epigenetically modified expression in subcutaneous (SAT) and visceral (VAT) adipose tissues. Here we investigated the expression and promoter methylation of key inflammatory candidates, tumor necrosis factor-alpha (TNF-α) and suppressor of cytokine signaling 3 (SOCS3) in maternal adipose tissues collected during caesarian section (GDM, n = 19; NGT, n = 22). The mRNA expression of TNF-α and SOCS3 was significantly increased in VAT, but not in SAT, of GDM patients vs. NGT, accompanied by specific alterations of respective promoter methylation patterns. In conclusion, we propose a critical role of VAT and visceral obesity for the pathogenesis of GDM, with epigenetic alterations of the expression of inflammatory factors as a potential factor.
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Affiliation(s)
- Rebecca C. Rancourt
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
- Correspondence:
| | - Raffael Ott
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Thomas Ziska
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Karen Schellong
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Kerstin Melchior
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Wolfgang Henrich
- Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany;
| | - Andreas Plagemann
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
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24
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McElwain CJ, Tuboly E, McCarthy FP, McCarthy CM. Mechanisms of Endothelial Dysfunction in Pre-eclampsia and Gestational Diabetes Mellitus: Windows Into Future Cardiometabolic Health? Front Endocrinol (Lausanne) 2020; 11:655. [PMID: 33042016 PMCID: PMC7516342 DOI: 10.3389/fendo.2020.00655] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
Placental insufficiency and adipose tissue dysregulation are postulated to play key roles in the pathophysiology of both pre-eclampsia (PE) and gestational diabetes mellitus (GDM). A dysfunctional release of deleterious signaling motifs can offset an increase in circulating oxidative stressors, pro-inflammatory factors and various cytokines. It has been previously postulated that endothelial dysfunction, instigated by signaling from endocrine organs such as the placenta and adipose tissue, may be a key mediator of the vasculopathy that is evident in both adverse obstetric complications. These signaling pathways also have significant effects on long term maternal cardiometabolic health outcomes, specifically cardiovascular disease, hypertension, and type II diabetes. Recent studies have noted that both PE and GDM are strongly associated with lower maternal flow-mediated dilation, however the exact pathways which link endothelial dysfunction to clinical outcomes in these complications remains in question. The current diagnostic regimen for both PE and GDM lacks specificity and consistency in relation to clinical guidelines. Furthermore, current therapeutic options rely largely on clinical symptom control such as antihypertensives and insulin therapy, rather than that of early intervention or prophylaxis. A better understanding of the pathogenic origin of these obstetric complications will allow for more targeted therapeutic interventions. In this review we will explore the complex signaling relationship between the placenta and adipose tissue in PE and GDM and investigate how these intricate pathways affect maternal endothelial function and, hence, play a role in acute pathophysiology and the development of future chronic maternal health outcomes.
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Affiliation(s)
- Colm J. McElwain
- Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland
- *Correspondence: Colm J. McElwain
| | - Eszter Tuboly
- Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland
| | - Fergus P. McCarthy
- Department of Obstetrics and Gynaecology, Cork University Maternity Hospital, Cork, Ireland
| | - Cathal M. McCarthy
- Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland
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