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Ahrens S, Singer D. Placental Adaptation to Hypoxia: The Case of High-Altitude Pregnancies. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2025; 22:214. [PMID: 40003440 PMCID: PMC11855801 DOI: 10.3390/ijerph22020214] [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: 11/18/2024] [Revised: 01/22/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025]
Abstract
Even in the highest inhabited regions of the world, well above 2500 m altitude, women become pregnant and give birth to healthy children. The underlying adaptation to hypobaric hypoxia provides interesting insights into the physio(patho)logy of the human placenta. Although increasing altitude is regularly associated with fetal growth restriction (FGR), oxygen deficiency does not appear to be a direct cause. Rather, placental oxygen consumption is reduced to maintain the oxygen supply to the fetus. This comes at the expense of placental synthesis and transport functions, resulting in inappropriate nutrient supply. The hypoxia-inducible factor (HIF-1α), which modulates the mitochondrial electron transport chain to protect placental tissue from reactive oxygen species, plays a key role here. Reduced oxygen consumption also reflects decreased placental vascularization and perfusion, which is accompanied by an increased risk of maternal pre-eclampsia at high altitude. In native highlanders, the latter seems to be attenuated, partly due to a lower release of HIF-1α. In addition, metabolic peculiarities have been described in indigenous people that enhance glucose availability and thus reduce the extent of FGR. This review attempts to revisit the (albeit incomplete) knowledge in this area to draw the clinical reader's attention to the crucial role of the placenta in defending the fetus against hypoxia.
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Affiliation(s)
- Sofia Ahrens
- Department of Pediatric Surgery, Altona Children’s Hospital, University Medical Center Eppendorf (UKE), 20251 Hamburg, Germany;
- Division of Neonatology and Pediatric Critical Care Medicine, University Medical Center Eppendorf (UKE), 20251 Hamburg, Germany
| | - Dominique Singer
- Division of Neonatology and Pediatric Critical Care Medicine, University Medical Center Eppendorf (UKE), 20251 Hamburg, Germany
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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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Brooker IA, Fisher JJ, Sutherland JM, Pringle KG. Understanding the impact of placental oxidative and nitrative stress in pregnancies complicated by fetal growth restriction. Placenta 2024; 158:318-328. [PMID: 39577026 DOI: 10.1016/j.placenta.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/24/2024]
Abstract
Fetal growth restriction (FGR) impacts approximately 10 % of all pregnancies worldwide and is associated with major adverse effects on fetal health in both the short- and long-term [1]. FGR most commonly arises as a result of impaired placentation, occurring in up to 60 % of cases in developed countries [2]. This narrative review outlines the impact of defective placentation on the placenta, focusing on redox imbalance, how this leads to placental oxidative and nitrative stress, and the implications of these stressors on placental nutrient transfer, premature replicative senescence, and trophoblast cell death. Furthermore, this review highlights the pivotal role of antioxidants in protecting against oxidative and nitrative damage by reducing the burden of reactive species. We explore how targeting antioxidants in pregnancy provides a promising strategy for preventing or treating FGR, to ultimately reduce the devastating burden of FGR on infant health.
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Affiliation(s)
- India A Brooker
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia; Women's Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Joshua J Fisher
- School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia; Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Jessie M Sutherland
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia; Women's Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Kirsty G Pringle
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia; Women's Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
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Ma HZ, Chen Y, Guo HH, Wang J, Xin XL, Li YC, Liu YF. Effect of resveratrol in gestational diabetes mellitus and its complications. World J Diabetes 2023; 14:808-819. [PMID: 37383595 PMCID: PMC10294056 DOI: 10.4239/wjd.v14.i6.808] [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: 12/28/2022] [Revised: 02/23/2023] [Accepted: 04/20/2023] [Indexed: 06/14/2023] Open
Abstract
The incidence rate of diabetes in pregnancy is about 20%, and diabetes in pregnancy will have a long-term impact on the metabolic health of mothers and their offspring. Mothers may have elevated blood glucose, which may lead to blood pressure disease, kidney disease, decreased resistance and secondary infection during pregnancy. The offspring may suffer from abnormal embryonic development, intrauterine growth restriction, obesity, autism, and other adverse consequences. Resveratrol (RSV) is a natural polyphenol compound, which is found in more than 70 plant species and their products, such as Polygonum cuspidatum, seeds of grapes, peanuts, blueberries, bilberries, and cranberries. Previous studies have shown that RSV has a potential beneficial effect on complex pregnancy, including improving the indicators of diabetes and pregnancy diabetes syndrome. This article has reviewed the molecular targets and signaling pathways of RSV, including AMP-activated protein kinase, mitogen-activated protein kinases, silent information regulator sirtuin 1, miR-23a-3p, reactive oxygen species, potassium channels and CX3C chemokine ligand 1, and the effect of RSV on gestational diabetes mellitus (GDM) and its complications. RSV improves the indicators of GDM by improving glucose metabolism and insulin tolerance, regulating blood lipids and plasma adipokines, and modulating embryonic oxidative stress and apoptosis. Furthermore, RSV can ameliorate the GDM complications by reducing oxidative stress, reducing the effects on placentation, reducing the adverse effects on embryonic development, reducing offspring's healthy risk, and so on. Thus, this review is of great significance for providing more options and possibilities for further research on medication of gestational diabetes.
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Affiliation(s)
- Hui-Zhong Ma
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Yuan Chen
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Hao-Hao Guo
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Jing Wang
- School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, Liaoning Province, China
| | - Xiu-Lan Xin
- College of Bioengineering, Beijing Polytechnic, Beijing 100176, China
| | - Yan-Cheng Li
- Department of Epidemiology, University of Florida, Gainesville, FL 32608, United States
| | - Yu-Feng Liu
- School of Pharmaceutical Sciences, Natural Products Pharmaceutical Engineering Technology Research Center of Liaoning Province, Liaoning University, Shenyang 110036, Liaoning Province, China
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Placental Malfunction, Fetal Survival and Development Caused by Sow Metabolic Disorder: The Impact of Maternal Oxidative Stress. Antioxidants (Basel) 2023; 12:antiox12020360. [PMID: 36829919 PMCID: PMC9951909 DOI: 10.3390/antiox12020360] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/24/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
The energy and metabolic state of sows will alter considerably over different phases of gestation. Maternal metabolism increases dramatically, particularly in late pregnancy. This is accompanied by the development of an increase in oxidative stress, which has a considerable negative effect on the maternal and the placenta. As the only link between the maternal and the fetus, the placenta is critical for the maternal to deliver nutrients to the fetus and for the fetus' survival and development. This review aimed to clarify the changes in energy and metabolism in sows during different pregnancy periods, as well as the impact of maternal oxidative stress on the placenta, which affects the fetus' survival and development.
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Wang W, Wang Z, Yang X, Song W, Chen P, Gao Z, Wu J, Huang F. Rhein ameliorates septic lung injury and intervenes in macrophage metabolic reprogramming in the inflammatory state by Sirtuin 1. Life Sci 2022; 310:121115. [DOI: 10.1016/j.lfs.2022.121115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/06/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022]
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Immunohistochemical evaluation of glucose transporter protein-1 density in the placenta in preeclampsia patients and its association with intrauterine growth retardation. JOURNAL OF SURGERY AND MEDICINE 2022. [DOI: 10.28982/josam.7347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Background/Aim: Preeclampsia (PE) complicates 2–8% of all pregnancies worldwide. Placental malperfusion and dysfunction are observed in PE. The supply of glucose, the main energy substrate for the fetus and placenta, is regulated by placental expression and activity of specific glucose transporter proteins (GLUTs), primarily GLUT1. GLUT1 expression is affected by uteroplacental malperfusion and oxidative stress, which are important components of PE. Very few studies have investigated GLUT1 expression in preeclamptic placentas. In this study, we aimed to compare GLUT1 staining intensity in the terminal villi of the placenta in healthy subjects and patients with E-PE or L-PE and determine whether there was a relationship between GLUT1 staining intensity and IUGR.
Methods: This case-control study was carried out in our hospital’s gynecology and obstetrics clinic, a tertiary center for perinatology cases. A total of 94 placentas, 47 of which were preeclamptic and 47 were from uneventful pregnancies (controls), were included in the study. PE was diagnosed according to the American College of Obstetrics and Gynecologists 2019 diagnostic criteria for gestational hypertension and PE. Placentas in the control group were obtained from pregnancies without maternal, placental, or fetal pathology and resulted in spontaneous idiopathic preterm or term delivery. The PE group was divided into two subgroups as early onset PE (E-PE [≤33+6 gestational week]) and late-onset PE (L-PE [≥34+0 gestational week]), according to the gestational week of PE onset. Sections prepared from placental tissues were stained for GLUT-1 by immunohistochemical method. Slides were evaluated by light microscopy, and each slide was scored from 0 to 4 to determine the staining intensity. The results were compared between the control and PE group/PE sub-groups.
Results: GLUT1 scores were significantly higher in both early- and late-onset PE subgroups compared to controls (P < 0.001 for both). In the late-onset PE subgroup, GLUT1 scores were significantly higher in those with severe PE features than those without them (P = 0.039). While intrauterine growth restriction (IUGR) was not found in any cases in the control group, IUGR was present in 11 (23.4%) of 47 pregnant women with PE, including eight (53.3%) of the 15 pregnant women with early-onset PE and 3 (9.38%) of the 32 pregnant women with late-onset PE. GLUT1 scores were similar in placentas obtained from pregnant women who had PE with and without IUGR (P = 0.756). In the late-onset PE subgroup, GLUT1 scores were correlated negatively with maternal body mass index (r = -0.377, P = 0.033) and positively with placental weight-to-fetal weight ratio (r = 0.444, P = 0.011).
Conclusions: Our findings show that GLUT1 expression might be increased due to placental adaptation to new conditions in PE and, thus, is unlikely to be the main factor in PE-related IUGR.
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Sibiak R, Ozegowska K, Wender-Ozegowska E, Gutaj P, Mozdziak P, Kempisty B. Fetomaternal Expression of Glucose Transporters (GLUTs)-Biochemical, Cellular and Clinical Aspects. Nutrients 2022; 14:2025. [PMID: 35631166 PMCID: PMC9146575 DOI: 10.3390/nu14102025] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/28/2022] [Accepted: 05/11/2022] [Indexed: 12/10/2022] Open
Abstract
Several types of specialized glucose transporters (GLUTs) provide constant glucose transport from the maternal circulation to the developing fetus through the placental barrier from the early stages of pregnancy. GLUT1 is a prominent protein isoform that regulates placental glucose transfer via glucose-facilitated diffusion. The GLUT1 membrane protein density and permeability of the syncytial basal membrane (BM) are the main factors limiting the rate of glucose diffusion in the fetomaternal compartment in physiological conditions. Besides GLUT1, the GLUT3 and GLUT4 isoforms are widely expressed across the human placenta. Numerous medical conditions and molecules, such as hormones, adipokines, and xenobiotics, alter the GLUT's mRNA and protein expression. Diabetes upregulates the BM GLUT's density and promotes fetomaternal glucose transport, leading to excessive fetal growth. However, most studies have found no between-group differences in GLUTs' placental expression in macrosomic and normal control pregnancies. The fetomaternal GLUTs expression may also be influenced by several other conditions, such as chronic hypoxia, preeclampsia, and intrahepatic cholestasis of pregnancy.
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Affiliation(s)
- Rafal Sibiak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-701 Poznan, Poland;
- Doctoral School, Poznan University of Medical Sciences, 60-701 Poznan, Poland
| | - Katarzyna Ozegowska
- Department of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
| | - Ewa Wender-Ozegowska
- Department of Reproduction, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (E.W.-O.); (P.G.)
| | - Pawel Gutaj
- Department of Reproduction, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (E.W.-O.); (P.G.)
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartosz Kempisty
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-701 Poznan, Poland;
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Department of Anatomy, Poznan University of Medical Sciences, 60-701 Poznan, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
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Chae SA, Son JS, Du M. Prenatal exercise in fetal development: a placental perspective. FEBS J 2021; 289:3058-3071. [PMID: 34449982 DOI: 10.1111/febs.16173] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/09/2021] [Accepted: 08/26/2021] [Indexed: 02/06/2023]
Abstract
Maternal obesity (MO) and gestational diabetes mellitus (GDM) are common in Western societies, which impair fetal development and predispose offspring to metabolic dysfunction. Placenta is the organ linking the mother to her fetus, and MO suppresses the development of vascular system and expression of nutrient transporters in placenta, thereby affecting fetal development. For maintaining its proper physiological function, placenta is energy demanding, which is met through extensive oxidative phosphorylation. However, the oxidative capacity of placenta is suppressed due to MO and GDM. Recently, several studies showed that physical activity during pregnancy enhances oxidative metabolism and improves placental function, which might be partially mediated by exerkines, referring to cytokines elicited by exercise. In addition, as an endocrine organ, placenta secretes cytokines, termed placentokines, including apelin, superoxide dismutase 3, irisin, and adiponectin, which mediate fetal development and maternal metabolism. Possible molecular mechanisms linking maternal exercise and placentokines to placental and fetal development are further discussed. As an emerging field, up to now, available studies are limited, mostly conducted in rodents. Given the epidemics of obesity and metabolic disorders, as well as the prevalence of maternal sedentary lifestyle, the effects of exercise of pregnant women on placental function and placentokine secretion, as well as their impacts on fetal development, need to be further examined.
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Affiliation(s)
- Song Ah Chae
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, USA
| | - Jun Seok Son
- Laboratory of Perinatal Kinesioepigenetics, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Min Du
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, USA
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Ge Y, Liu X, Huang H. Advances in the role of silence information regulator family in pathological pregnancy. Zhejiang Da Xue Xue Bao Yi Xue Ban 2021; 50:335-344. [PMID: 34402258 PMCID: PMC8710262 DOI: 10.3724/zdxbyxb-2021-0183] [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: 01/29/2021] [Accepted: 04/27/2021] [Indexed: 06/13/2023]
Abstract
Aberrant maternal inflammation and oxidative stress are the two main mechanisms of pathological pregnancy. The silence information regulator (sirtuin) family is a highly conserved family of nicotinamide adenine dinucleotide (NAD)-dependent deacylases. By regulating the post-translational modification of proteins, sirtuin is involved in various biological processes including oxidative stress and inflammation. Nowadays, emerging evidence indicates that sirtuin may be closely related to the occurrence and development of pathological pregnancy. The down-regulation of sirtuin can cause spontaneous preterm delivery by promoting uterine contraction and rupture of fetal membranes, cause gestational diabetes mellitus through promoting oxidative stress and affecting the activity of key enzymes in glucose metabolism, cause preeclampsia by reducing the proliferation and invasion ability of trophoblasts, cause intrahepatic cholestasis of pregnancy by promoting the production of bile acids and T helper 1 cell (Th1) cytokines, and cause intrauterine growth restriction through inducing mitochondrial dysfunction. Moreover, the expression and activation of sirtuin can be modulated through dietary interventions, thus sirtuin is expected to become a new target for the prevention and treatment of pregnancy complications. This article reviews the role of the sirtuin family in the occurrence and development of pathological pregnancy and its influence on the development of the offspring.
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Packer M. Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors: Potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors. Circ Heart Fail 2020; 13:e007197. [PMID: 32894987 DOI: 10.1161/circheartfailure.120.007197] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy-a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX;and Imperial College, London, United Kingdom
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12
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Packer M. Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors. J Card Fail 2020; 26:977-984. [PMID: 32890737 DOI: 10.1016/j.cardfail.2020.08.015] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 12/14/2022]
Abstract
Hyperuricemia increases the risk of heart failure, and higher levels of serum uric acid are seen in patients who have worse ventricular function, functional capacity, and prognosis. Heart failure is also accompanied by an upregulation of xanthine oxidase, the enzyme that catalyzes the formation of uric acid and a purported source of reactive oxygen species. However, the available evidence does not support the premise that either uric acid or the activation of xanthine oxidase has direct injurious effects on the heart in the clinical setting. Xanthine oxidase inhibitors (allopurinol and oxypurinol) have had little benefit and may exert detrimental effects in patients with chronic heart failure in randomized controlled trials, and the more selective and potent inhibitor febuxostat increases the risk of cardiovascular death more than allopurinol. Instead, the available evidence indicates that changes in xanthine oxidase and uric acid are biomarkers of oxidative stress (particularly in heart failure) and that xanthine oxidase may provide an important source of nitric oxide that quenches the injurious effects of reactive oxygen species. A primary determinant of the cellular redox state is nicotinamide adenine dinucleotide, whose levels drive an inverse relationship between xanthine oxidase and sirtuin-1, a nutrient deprivation sensor that exerts important antioxidant and cardioprotective effects. Interestingly, sodium-glucose cotransporter 2 inhibitors induce a state of nutrient deprivation that includes activation of sirtuin-1, suppression of xanthine oxidase, and lowering of serum uric acid. The intermediary role of sirtuin-1 in both uric acid-lowering and cardioprotection may explain why, in mediation analyses of large-scale cardiovascular trials, the effect of sodium-glucose cotransporter 2 inhibitors to decrease serum uric acid is a major predictor of the ability of these drugs to decrease serious heart failure events.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas and Imperial College, London, UK.
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13
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Hu C, Yang Y, Deng M, Yang L, Shu G, Jiang Q, Zhang S, Li X, Yin Y, Tan C, Wu G. Placentae for Low Birth Weight Piglets Are Vulnerable to Oxidative Stress, Mitochondrial Dysfunction, and Impaired Angiogenesis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8715412. [PMID: 32566107 PMCID: PMC7267862 DOI: 10.1155/2020/8715412] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 03/21/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023]
Abstract
Intrauterine growth restriction (IUGR) is associated with fetal mortality and morbidity. One of the most common causes of IUGR is placental insufficiency, including placental vascular defects, and mitochondrial dysfunction. In addition, a high level of oxidative stress induces placental vascular lesions. Here, we evaluated the oxidative stress status, mitochondrial function, angiogenesis, and nutrient transporters in placentae of piglets with different birth weights: <500 g (L), 500-600 g (LM), 600-700 g (M), and >700 g (H). Results showed that placentae from the L group had higher oxidative damage, lower adenosine triphosphate and citrate synthase levels, and lower vascular density, compared to those from the other groups. Protein expression of angiogenic markers, including vascular endothelial cadherin, vascular endothelial growth factor A, and platelet endothelial cell adhesion molecule-1, was the lowest in the L group placentae compared to the other groups. In addition, the protein levels of glucose transporters GLUT1 and GLUT3 were downregulated in the L group, compared to the other groups. Furthermore, oxidative stress induced by H2O2 inhibited tube formation and migration in porcine vascular endothelial cells. Collectively, placentae for lower birth weight neonates are vulnerable to oxidative damage, mitochondrial dysfunction, and impaired angiogenesis.
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Affiliation(s)
- Chengjun Hu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Yunyu Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Ming Deng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Linfang Yang
- Guangdong Yihao Foodstuffs Co., Ltd., Guangzhou, Guangdong 510642, China
| | - Gang Shu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Shuo Zhang
- Yunnan Yin Yulong Academician Workstation, Yunnan Xinan Tianyou Animal Husbandry Technology Co., Ltd., Kunming, Yunnan 650032, China
| | - Xiaozhen Li
- Yunnan Yin Yulong Academician Workstation, Yunnan Xinan Tianyou Animal Husbandry Technology Co., Ltd., Kunming, Yunnan 650032, China
| | - Yulong Yin
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
- National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan 410125, China
| | - Chengquan Tan
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
- Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471, USA
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471, USA
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14
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Packer M. Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs. Cardiovasc Diabetol 2020; 19:62. [PMID: 32404204 PMCID: PMC7222526 DOI: 10.1186/s12933-020-01041-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 05/09/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)—effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall Street, Dallas, TX, 75226, USA. .,Imperial College, London, UK.
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15
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Panda S, Banerjee N, Chatterjee S. Solute carrier proteins and c-Myc: a strong connection in cancer progression. Drug Discov Today 2020; 25:891-900. [DOI: 10.1016/j.drudis.2020.02.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/07/2020] [Accepted: 02/17/2020] [Indexed: 01/06/2023]
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16
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Stanirowski PJ, Lipa M, Bomba-Opoń D, Wielgoś M. Expression of placental glucose transporter proteins in pregnancies complicated by fetal growth disorders. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 123:95-131. [PMID: 33485490 DOI: 10.1016/bs.apcsb.2019.12.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
During pregnancy fetal growth disorders, including fetal macrosomia and fetal growth restriction (FGR) are associated with numerous maternal-fetal complications, as well as due to the adverse effect of the intrauterine environment lead to an increased morbidity in adult life. Accumulating evidence suggests that occurrence of fetal macrosomia or FGR, may be associated with alterations in the transfer of nutrients across the placenta, in particular of glucose. The placental expression and activity of specific GLUT transporters are the main regulatory factors in the process of maternal-fetal glucose exchange. This review article summarizes the results of previous studies on the expression of GLUT transporters in the placenta, concentrating on human pregnancies complicated by intrauterine fetal growth disorders. Characteristics of each transporter protein found in the placenta is presented, alterations in the location and expression of GLUT isoforms observed in individual placental compartments are described, and the factors regulating the expression of selected GLUT proteins are examined. Based on the above data, the potential function of each GLUT isoform in the maternal-fetal glucose transfer is determined. Further on, a detailed analysis of changes in the expression of glucose transporters in pregnancies complicated by fetal growth disorders is given, and significance of these modifications for the pathogenesis of fetal macrosomia and FGR is discussed. In the final part novel interventional approaches that might reduce the risk associated with abnormalities of intrauterine fetal growth through modifications of placental GLUT-mediated glucose transfer are explored.
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Affiliation(s)
- Paweł Jan Stanirowski
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland; Club 35. Polish Society of Gynecologists and Obstetricians, Warsaw, Poland
| | - Michał Lipa
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland; Club 35. Polish Society of Gynecologists and Obstetricians, Warsaw, Poland
| | - Dorota Bomba-Opoń
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
| | - Mirosław Wielgoś
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
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17
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Zambrano A, Molt M, Uribe E, Salas M. Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy. Int J Mol Sci 2019; 20:ijms20133374. [PMID: 31324056 PMCID: PMC6651361 DOI: 10.3390/ijms20133374] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/14/2019] [Accepted: 07/01/2019] [Indexed: 12/13/2022] Open
Abstract
An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways. The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases. There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells. In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process. Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer. Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth.
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Affiliation(s)
- Angara Zambrano
- Instituto de Bioquimica y Microbiologia, Universidad Austral de Chile, Valdivia 0000000, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Concepción, Concepción 4070386, Chile
| | - Matías Molt
- Instituto de Bioquimica y Microbiologia, Universidad Austral de Chile, Valdivia 0000000, Chile
| | - Elena Uribe
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Concepción, Concepción 4070386, Chile
| | - Mónica Salas
- Instituto de Bioquimica y Microbiologia, Universidad Austral de Chile, Valdivia 0000000, Chile.
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18
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SIRT1 promotes GLUT1 expression and bladder cancer progression via regulation of glucose uptake. Hum Cell 2019; 32:193-201. [PMID: 30868406 DOI: 10.1007/s13577-019-00237-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 01/12/2019] [Indexed: 10/27/2022]
Abstract
Bladder cancer (BC) is one of the most common tumors. Metabolic reprogramming is a feature of neoplasia and tumor growth. Understanding the metabolic alterations in bladder cancer may provide new directions for bladder cancer treatment. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators. In pancreatic cancer, the loss of SIRT1 is accompanied by a decreased expression of proteins in the glycolysis pathway, such as GLUT1, and cancer cell proliferation. Thus, we hypothesize that SIRT1 may interact with GLUT1 to modulate the proliferation and glycolysis phenotype in bladder cancer. In the present study, the expression of SIRT1 and GLUT1 was upregulated in BC tissues and cell lines and positively correlated in tissue samples. SIRT1 overexpression or GLUT1 overexpression alone was sufficient to promote cell proliferation and glucose uptake in BC cells. EX527, a specific inhibitor of SIRT1, exerted an opposing effect on bladder cancer proliferation and glucose uptake. The effect of EX527 could be partially reversed by GLUT1 overexpression. More importantly, SIRT1 overexpression significantly promoted the transcriptional activity and expression of GLUT1, indicating that SIRT1 increases the transcription activity and expression of GLUT1, therefore, promoting the cell proliferation and glycolysis in BC cells. Our study first reported that SIRT1/GLUT1 axis promotes bladder cancer progression via regulation of glucose uptake.
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19
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Illsley NP, Baumann MU. Human placental glucose transport in fetoplacental growth and metabolism. Biochim Biophys Acta Mol Basis Dis 2018; 1866:165359. [PMID: 30593896 DOI: 10.1016/j.bbadis.2018.12.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/13/2018] [Accepted: 12/06/2018] [Indexed: 02/07/2023]
Abstract
While efficient glucose transport is essential for all cells, in the case of the human placenta, glucose transport requirements are two-fold; provision of glucose for the growing fetus in addition to the supply of glucose required the changing metabolic needs of the placenta itself. The rapidly evolving environment of placental cells over gestation has significant consequences for the development of glucose transport systems. The two-fold transport requirement of the placenta means also that changes in expression will have effects not only for the placenta but also for fetal growth and metabolism. This review will examine the localization, function and evolution of placental glucose transport systems as they are altered with fetal development and the transport and metabolic changes observed in pregnancy pathologies.
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Affiliation(s)
- Nicholas P Illsley
- Center for Abnormal Placentation, Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ, USA.
| | - Marc U Baumann
- Department of Obstetrics and Gynaecology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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20
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Marcondes JPDC, Andrade PFB, Sávio ALV, Silveira MAD, Rudge MVC, Salvadori DMF. BCL2 and miR-181a transcriptional alterations in umbilical-cord blood cells can be putative biomarkers for obesity. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2018; 836:90-96. [PMID: 30442352 DOI: 10.1016/j.mrgentox.2018.06.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 04/17/2018] [Accepted: 06/01/2018] [Indexed: 10/14/2022]
Abstract
Several findings suggest that in utero stressor stimuli can alter fetal development by promoting transcriptional changes, and predisposing the neonate to diseases later in life. This study aimed to investigate whether a hyperglycemic environment in pregnant women with gestational diabetes mellitus (GDM) is able to cause fetal genetic alterations and predispose neonates to obesity. Transcriptional alteration of SIRT1, TP53 and BCL2 genes, miR-181a (a SIRT1 or BCL2 regulator) and telomere length were evaluated in placental and umbilical-cord blood cells. Healthy (HP; n = 20) and GDM (n = 20) pregnant women and their respective neonates were included in the study. Additionally, obese (n = 20) and eutrophic (n = 20) adults also participated as reference populations. Gene expression data showed down-regulation of BCL2 in umbilical-cord and peripheral blood cells from GDM neonates and obese adults, respectively. The miR-181a was down-regulated only in umbilical-cord blood cells of GDM neonates. Telomere length presented no significant difference. In conclusion, our study demonstrated that the GDM hyperglycemic intrauterine environment promotes transcriptional alterations in BCL2 and miR-181a in neonate umbilical-cord blood cells. Furthermore, both GDM neonates and obese subjects share the same transcriptional alteration in BCL2. Considering the relationship between obesity development and the functions regulated by these two genes, BCL2 and miR-181a could be adopted as potential biomarkers for childhood obesity. However, further study designs are recommended to confirm this hypothesis.
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Affiliation(s)
- João Paulo de Castro Marcondes
- UNESP - São Paulo State University, Medical School, Botucatu, SP, Brazil; UNESP - São Paulo State University, Bioscience Institute, Botucatu, SP, Brazil.
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21
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Perrone S, Santacroce A, Picardi A, Buonocore G. Fetal programming and early identification of newborns at high risk of free radical-mediated diseases. World J Clin Pediatr 2016; 5:172-181. [PMID: 27170927 PMCID: PMC4857230 DOI: 10.5409/wjcp.v5.i2.172] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 10/30/2015] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Nowadays metabolic syndrome represents a real outbreak affecting society. Paradoxically, pediatricians must feel involved in fighting this condition because of the latest evidences of developmental origins of adult diseases. Fetal programming occurs when the normal fetal development is disrupted by an abnormal insult applied to a critical point in intrauterine life. Placenta assumes a pivotal role in programming the fetal experience in utero due to the adaptive changes in structure and function. Pregnancy complications such as diabetes, intrauterine growth restriction, pre-eclampsia, and hypoxia are associated with placental dysfunction and programming. Many experimental studies have been conducted to explain the phenotypic consequences of fetal-placental perturbations that predispose to the genesis of metabolic syndrome, obesity, diabetes, hyperinsulinemia, hypertension, and cardiovascular disease in adulthood. In recent years, elucidating the mechanisms involved in such kind of process has become the challenge of scientific research. Oxidative stress may be the general underlying mechanism that links altered placental function to fetal programming. Maternal diabetes, prenatal hypoxic/ischaemic events, inflammatory/infective insults are specific triggers for an acute increase in free radicals generation. Early identification of fetuses and newborns at high risk of oxidative damage may be crucial to decrease infant and adult morbidity.
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22
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Yao Q, Chen L, Liang Y, Sui L, Guo L, Zhou J, Fan K, Jing J, Zhang Y, Yao B. Blastomere removal from cleavage-stage mouse embryos alters placental function, which is associated with placental oxidative stress and inflammation. Sci Rep 2016; 6:25023. [PMID: 27109212 PMCID: PMC4842963 DOI: 10.1038/srep25023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 04/08/2016] [Indexed: 01/21/2023] Open
Abstract
Blastomere biopsy is an essential technique in preimplantation genetic diagnosis (PGD), a screening test that can detect genetic abnormalities of embryos before their transfer into uterus. Our results showed that the weights of fetuses derived from biopsied embryos were lower than that of non-biopsied counterparts at E12.5, E15.5, and E18.5. The ratio of fetal/placental (F/P) weights in the biopsied group was significantly lower than that in the non-biopsied group at E18.5. At E18.5, the mRNAs for selected glucose transporters, system A amino acid transporters, system L amino acid transporters, and imprinted genes were downregulated in the placentae of biopsied group, and the GLUT1 and CAT3 protein levels were decreased too. More apoptotic cells were detected by TUNEL in the placentae of biopsied group. Placentae from biopsied embryos exhibited lower levels of SOD and GSH. Furthermore, the concentration of MDA increased in the placentae from biopsied group. The levels of IL1B, IL6, and TNFA also significantly increased in the placentae of biopsied group. This study suggested that placental function may be sensitive to blastomere biopsy procedures, and placental oxidative stress and inflammation associated with blastomere biopsy may be critical factors of abnormal placental function and further influence the fetal development.
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Affiliation(s)
- Qi Yao
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Li Chen
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Yuanjiao Liang
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Liucai Sui
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Li Guo
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Jingwei Zhou
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Kai Fan
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Jun Jing
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
| | - Yunhai Zhang
- Anhui Provincial Laboratory for Local Livestock and Poultry, Genetic Resource Conservation and Breeding, College of Animal Sciences and Technology, Anhui Agricultural University, 130 Changjiang West Road, Hefei 230036, PR China
| | - Bing Yao
- Center of Reproductive Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China
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Mezouar D, Merzouk H, Merzouk AS, Merzouk SA, Belarbi B, Narce M. In vitro effects of vitamins C and E, n-3 and n-6 PUFA and n-9 MUFA on placental cell function and redox status in type 1 diabetic pregnant women. Placenta 2016; 42:114-21. [PMID: 27238721 DOI: 10.1016/j.placenta.2016.04.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 03/22/2016] [Accepted: 04/14/2016] [Indexed: 10/21/2022]
Abstract
The aim of this investigation was to determine the in vitro effects of vitamin C and E, n-3 and n-6 PUFA and n-9 MUFA on placental cell proliferation and function in type 1 diabetes. Placenta tissues were collected from 30 control healthy and 30 type 1 diabetic women at delivery. Placental cells were isolated and were cultured in RPMI medium supplemented with vitamin C (50 μM), vitamin E (50 μM), n-3 PUFA (100 μM), n-6 PUFA (100 μM) or n-9 MUFA (100 μM). Cell proliferation, cell glucose uptake and intracellular oxidative status were investigated. Our results showed that basal placental cell proliferation, glucose uptake, malondialdehyde (MDA) and carbonyl proteins were higher while intracellular reduced glutathione (GSH) levels and catalase activities were lower in placentas from diabetic women as compared to controls. Vitamins C and E induced a modulation of placental cell proliferation and glucose consumption without affecting intracellular redox status in both diabetic and control groups. N-3 and n-6 PUFA diminished placental cell proliferation and enhanced intracellular oxidative stress while n-9 MUFA had no effects in the two groups. Co-administration of n-3 or n-6 PUFA and vitamin C or E were capable of reversing back the PUFA-decreased cell proliferation and normalizing placental cell function and redox status especially in diabetes. In conclusion, PUFA and antioxidant vitamin combinations may be beneficial in improving placenta function and in reducing placental oxidative stress in type 1 diabetic pregnancy.
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Affiliation(s)
- Djamila Mezouar
- Laboratory of Physiology, Physiopathology and Biochemistry of Nutrition, Department of Biology, Faculty of Natural and Life Sciences, Earth and Universe, University Abou-Bekr Belkaïd, Tlemcen 13000, Algeria
| | - Hafida Merzouk
- Laboratory of Physiology, Physiopathology and Biochemistry of Nutrition, Department of Biology, Faculty of Natural and Life Sciences, Earth and Universe, University Abou-Bekr Belkaïd, Tlemcen 13000, Algeria.
| | - Amel Saidi Merzouk
- Laboratory of Physiology, Physiopathology and Biochemistry of Nutrition, Department of Biology, Faculty of Natural and Life Sciences, Earth and Universe, University Abou-Bekr Belkaïd, Tlemcen 13000, Algeria
| | - Sid Ahmed Merzouk
- Department of Technical Sciences, Faculty of Engineering, University Abou-Bekr Belkaïd, Tlemcen 13000, Algeria
| | - Boumediene Belarbi
- Gynecology and Obstetrics Department, Mother and Infant Hospital Center, University Abou-Bekr Belkaïd, Tlemcen 13000, Algeria
| | - Michel Narce
- INSERM UMR866, "Lipids Nutrition Cancer," Faculty of Life, Earth and Environment Sciences, University of Burgundy, Dijon 21000, France
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24
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Araújo JR, Keating E, Martel F. Impact of gestational diabetes mellitus in the maternal-to-fetal transport of nutrients. Curr Diab Rep 2015; 15:569. [PMID: 25620402 DOI: 10.1007/s11892-014-0569-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder prevalent among pregnant women. This disease increases the risk of adverse perinatal outcomes and diseases in the offspring later in life. The human placenta, the main interface between the maternal and fetal blood circulations, is responsible for the maternal-to-fetal transfer of nutrients essential for fetal growth and development. In this context, the aim of this article is to review the latest advances in the placental transport of macro and micronutrients and how they are affected by GDM and its associated conditions, such as elevated levels of glucose, insulin, leptin, inflammation, and oxidative stress. Data analyzed in this article suggest that GDM and its associated conditions, particularly high levels of glucose, leptin, and oxidative stress, disturb placental nutrient transport and, consequently, fetal nutrient supply. As a consequence, this disturbance may contribute to the fetal and postnatal adverse health outcomes associated with GDM.
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Affiliation(s)
- João Ricardo Araújo
- Department of Biochemistry, Faculty of Medicine of Porto, University of Porto, 4200-319, Porto, Portugal,
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25
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Abstract
Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies, complicated by gestational diabetes mellitus (GDM). The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor κB (NFκB). The aim of this study was to determine whether levels of NOD1 and NOD2 are increased in adipose tissue of women with GDM. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed. NOD1, but not NOD2, expression was higher in omental and subcutaneous adipose tissues obtained from women with GDM when compared with those from women with normal glucose tolerance (NGT). In both omental and subcutaneous adipose tissues from NGT and GDM women, the NOD1 ligand g-d-glutamyl-meso-diaminopimelic acid (iE-DAP) significantly induced the expression and secretion of the pro-inflammatory cytokine interleukin 6 (IL6) and chemokine IL8; COX2 (PTGS2) gene expression and subsequent prostaglandin production; the expression and secretion of the extracellular matrix remodelling enzyme matrix metalloproteinase 9 (MMP9) and the gene expression and secretion of the adhesion molecules ICAM1 and VCAM1. There was no effect of the NOD2 ligand muramyl dipeptide on any of the endpoints tested. The effects of the NOD1 ligand iE-DAP were mediated via NFκB, as the NFκB inhibitor BAY 11-7082 significantly attenuated iE-DAP-induced expression and secretion of pro-inflammatory cytokines, COX2 gene expression and subsequent prostaglandin production, MMP9 expression and secretion and ICAM1 and VCAM1 gene expression and secretion. In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM.
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Affiliation(s)
- Martha Lappas
- ObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, AustraliaMercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, AustraliaObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, AustraliaMercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, Australia
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26
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Walker SP, Ugoni AM, Lim R, Lappas M. Inverse relationship between gestational weight gain and glucose uptake in human placenta from female foetuses. Pediatr Obes 2014; 9:e73-6. [PMID: 24302682 DOI: 10.1111/j.2047-6310.2013.00206.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 10/14/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND Maternal obesity and gestational weight gain (GWG) have a significant impact on the in utero environment, and thus on foetal development and the health of the offspring later in life. OBJECTIVE The aim of this study was to determine the effect of maternal pre-existing obesity and maternal GWG on glucose uptake from placentas from male and female offspring. METHODS Total glucose uptake was measured in placental explants using radio-labelled glucose. RESULTS In the female placentas (n = 36), GWG and glucose uptake were significantly negatively correlated (r = -0.7, P < 0.0001; n = 36), and customized birthweight centile correlated with placental glucose uptake (r = 0.36, P = 0.03) but not GWG. In the male placentas (n = 45), GWG and glucose uptake were not related, and customized birthweight centile correlated with GWG (r = 0.34, P = 0.02; n = 45), but not placental glucose uptake. CONCLUSIONS The female placenta can adapt glucose uptake in the face of excessive GWG. The male placenta showed no evidence of changing glucose uptake in response to maternal GWG.
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Affiliation(s)
- S P Walker
- Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia
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27
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Lappas M. Activation of inflammasomes in adipose tissue of women with gestational diabetes. Mol Cell Endocrinol 2014; 382:74-83. [PMID: 24055273 DOI: 10.1016/j.mce.2013.09.011] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 09/09/2013] [Accepted: 09/10/2013] [Indexed: 11/16/2022]
Abstract
Gestational diabetes mellitus (GDM) is characterised by maternal peripheral insulin resistance, increased inflammation, and increasing levels of circulating free fatty acids (FFAs) and advanced glycation endproducts (AGEs). Caspase-1 is a key component of the inflammasome, which is activated upon cellular infection or stress to trigger the maturation IL-1β, a pro-inflammatory cytokine that mediated insulin resistance. The aim of this study was to determine whether the inflammasome is activated in adipose tissue from women with gestational diabetes mellitus (GDM) and if it interferes with the insulin signalling pathway leading to the insulin resistance that is evident in GDM. Protein expression of active caspase-1 and mature IL-1β secretion was increased in adipose tissue of women with GDM. Treatment of adipose tissue with IL-1β decreased insulin-stimulated phosphorylation of IRS-1, GLUT-4 expression and glucose uptake. Low-grade inflammation (induced by LPS), the FFA palmitate and AGE conjugated to BSA (AGE-BSA), induced IL-1β secretion via inflammasome activation. In conclusion, the present findings describe an important role for adipose tissue inflammasome activation in the development of insulin resistance associated in pregnancies complicated by GDM.
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Affiliation(s)
- Martha Lappas
- Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
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28
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Araújo JR, Pereira AC, Correia-Branco A, Keating E, Martel F. Oxidative stress induced by tert-butylhydroperoxide interferes with the placental transport of glucose: in vitro studies with BeWo cells. Eur J Pharmacol 2013. [DOI: 10.1016/j.ejphar.2013.10.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Regulation of nutrient transport across the placenta. J Pregnancy 2012; 2012:179827. [PMID: 23304511 PMCID: PMC3523549 DOI: 10.1155/2012/179827] [Citation(s) in RCA: 290] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 09/02/2012] [Indexed: 12/20/2022] Open
Abstract
Abnormal fetal growth, both growth restriction and overgrowth, is associated with perinatal complications and an increased risk of metabolic and cardiovascular disease later in life. Fetal growth is dependent on nutrient availability, which in turn is related to the capacity of the placenta to transport these nutrients. The activity of a range of nutrient transporters has been reported to be decreased in placentas of growth restricted fetuses, whereas at least some studies indicate that placental nutrient transport is upregulated in fetal overgrowth. These findings suggest that changes in placental nutrient transport may directly contribute to the development of abnormal fetal growth. Detailed information on the mechanisms by which placental nutrient transporters are regulated will therefore help us to better understand how important pregnancy complications develop and may provide a foundation for designing novel intervention strategies. In this paper we will focus on recent studies of regulatory mechanisms that modulate placental transport of amino acids, fatty acids, and glucose.
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