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      SIRT1: A Novel Protective Molecule in Pre-eclampsia

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          Abstract

          Pre-eclampsia is a severe pregnant complication, mainly characterized by insufficient trophoblast invasion, impaired uterine spiral artery remodeling, placental hypoxia and ischemia, and endothelial dysfunction. However, the potential mechanisms of pre-eclampsia remain unclear. SIRT1 is a NAD+-dependent deacetylase, involving in multiple biological processes, including energy metabolism, oxidative stress, inflammatory response, and cellular autophagy. Several studies showed that SIRT1 might play a vital role in the pathogenesis of pre-eclampsia. In this review, we aim to integrate the latest research on SIRT1 and pre-eclampsia to explore the comprehensive mechanisms of SIRT1 in pre-eclampsia. More specifically, SIRT1 might affect placental development and trophoblast invasion through autophagy and senescence in pre-eclampsia, and SIRT1 protects vascular endothelial cells from oxidative stress, inflammatory response, autophagy, and senescence. Furthermore, SIRT1 deficiency mice showed typical pre-eclampsia-like performances, which can be reversed via direct SIRT1 supplement or SIRT1 agonist treatment. Additionally, resveratrol, a SIRT1 agonist, attenuates vascular endothelial injury and placental dysfunction, and exerts protective effect on decreasing blood pressure. In this review, we provide new insights into the development of pre-eclampsia, which can establish a theoretical basis for prevention and treatment for pre-eclampsia. Besides, we also propose questions that still need to be further addressed in order to elucidate the comprehensive molecular mechanisms of pre-eclampsia in the future.

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          Most cited references129

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          Autophagy fights disease through cellular self-digestion.

          Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.
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            Nitric oxide synthases: regulation and function.

            Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.
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              The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis.

              The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exogenous and endogenous origins. KEAP1 acts as a cysteine thiol-rich sensor of redox insults, whereas NRF2 is a transcription factor that robustly transduces chemical signals to regulate a battery of cytoprotective genes. KEAP1 represses NRF2 activity under quiescent conditions, whereas NRF2 is liberated from KEAP1-mediated repression on exposure to stresses. The rapid inducibility of a response based on a derepression mechanism is an important feature of the KEAP1-NRF2 system. Recent studies have unveiled the complexities of the functional contributions of the KEAP1-NRF2 system and defined its broader involvement in biological processes, including cell proliferation and differentiation, as well as cytoprotection. In this review, we describe historical milestones in the initial characterization of the KEAP1-NRF2 system and provide a comprehensive overview of the molecular mechanisms governing the functions of KEAP1 and NRF2, as well as their roles in physiology and pathology. We also refer to the clinical significance of the KEAP1-NRF2 system as an important prophylactic and therapeutic target for various diseases, particularly aging-related disorders. We believe that controlled harnessing of the KEAP1-NRF2 system is a key to healthy aging and well-being in humans.
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                Author and article information

                Journal
                Int J Med Sci
                Int J Med Sci
                ijms
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                1449-1907
                2022
                29 May 2022
                : 19
                : 6
                : 993-1002
                Affiliations
                [1 ]Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
                [2 ]Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
                Author notes
                ✉ Corresponding authors: Dr. Weirong Gu, The Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, No. 419 Fangxie Road, Shanghai 200011, China. E-mail: guweirong@ 123456fudan.edu.cn . Prof. Mingqing Li, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, No. 413 Zhaozhou Road, Shanghai 200011, China. E-mail: mqli@ 123456fudan.edu.cn .

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijmsv19p0993
                10.7150/ijms.73012
                9254375
                35813294
                8ad20b46-53b0-45de-9e95-29a3a51b6181
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 18 March 2022
                : 20 May 2022
                Categories
                Review

                Medicine
                pre-eclampsia (pe),sirt1,trophoblasts,endothelial cells (ecs),resveratrol
                Medicine
                pre-eclampsia (pe), sirt1, trophoblasts, endothelial cells (ecs), resveratrol

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