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Sestrin2 Aggravates Oxidative Stress of Neurons by Decreasing the Expression of Nrf2

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Sestrin2 Aggravates Oxidative Stress of Neurons by Decreasing the Expression of Nrf2 European Review for Medical and Pharmacological Sciences 2018; 22: 3493-3501 Sestrin2 aggravates oxidative stress of neurons by decreasing the expression of Nrf2 L.-L. ZHANG, Z.-J. ZHANG Department of Neurology, Hangzhou Fuyang Hospital of Traditional Chinese Medicine, Zhejiang, China Abstract. – OBJECTIVE: Oxidative injury is an Introduction essential part of the pathological changes of ce- rebral ischemia-reperfusion. Sestrin2 (Sesn2), a conserved antioxidant protein, is activated Stroke is a neurological deficit syndrome under stress to protect cells against oxidative caused by acute vascular or blood abnormalities stress. This study mainly explored the function leading to disorders of blood circulation in the and mechanism of Sesn2 during cerebral isch- brain. It is one of the diseases that severely affects emia-reperfusion injury in rats. human health and cause deaths worldwide1-3. Pre- MATERIALS AND METHODS: Oxygen-glu- vention and treatment of ischemic stroke research cose deprivation/reoxygenation (OGD/R) mod- have received more and more attention. Cerebral el of primary neurons was established. MTS and LDH (lactate dehydrogenase) kit were used to ischemia-reperfusion injury is a very complex detect cell viability and cell damage by colori- pathophysiological process, showing a rapid cas- metric method. The superoxide dismutase (SOD) cade reaction. The mechanism mainly includes kit and malondialdehyde (MDA) kit were used to overload of intracellular calcium (Ca), lipid per- access the level of SOD and MDA in neurons. oxidation, oxygen free radical damage, apoptosis To establish a model of middle cerebral artery gene activation, excitement (EAA) cytotoxicity, occlusion (MCAO) in adult male Sprague-Daw- 4-7 ley (SD) rats, the process of cerebral isch- inflammatory cytokine damage, etc. Among emia-reperfusion injury in animals was simulat- them, oxygen free radicals are mainly responsible ed. Western blot and immunofluorescence were for cerebral ischemia-reperfusion injury. There- utilized to further examine the relationship be- fore, it is urgent to explore the inhibitory method tween the expression of Sesn2 and Nrf2 (nuclear in the production of oxygen free radicals, so as to factor E2 related factor 2). provide efficient treatment. RESULTS: Sesn2 aggravated neuronal dam- Sesn2 (Sestrin2), a highly conserved protein, is age and enhanced cell viability in OGD/R mod- el. Intraventricular injection of Sesn2 siRNA len- the essential member of the Sestrin family. Under tivirus aggravated nerve function damage in stress conditions, such as DNA damage, oxidative MCAO model, increased cerebral infarction ar- stress, hypoxia and other circumstances, Sesn2 ea and water content. Sesn2 overexpression re- is activated8-10. Researches11 have shown that af- sulted in the increase of total, nuclear levels of ter silencing Sesn2, intracellular reactive oxygen Nrf2, as well as the downstream proteins of Nrf2, species were significantly upregulated and their sulfiredoxin1 (Srx1) and thioredoxin1 (Trx1). On sensitivity to ionizing radiation was enhanced. the contrary, after knockdown of Sesn2, we ob- 12,13 tained the opposite result. Knockdown of Sesn2 Scholars have also shown that Sesn2 had some reduced Nrf2, Srx1 and Trx1 levels in rat cere- neuroprotective effects in neurodegenerative bral cortex in MCAO model. diseases; however, the exact mechanism has not CONCLUSIONS: Sesn2 promoted the transfer been clearly illustrated. So far, cellular function of nuclear Nrf2 to the cytoplasm, it decreased of Sesn2 has been well recognized; however, the the expressions of Nrf2 and its downstream pro- effect on cerebrovascular has not been fully elu- teins, Srx1 and Trx1. Meanwhile, it increased the cerebral ischemia-reperfusion injury by chang- cidated. ing the distribution of Nrf2. As an important endogenous antioxidant fac- tor, NF-E2-related factor 2 (Nrf2) is an essen- Key Words: tial part of the oxidative stress response14,15. In Sestrin2, Nrf2, Ischemia-reperfusion, Oxygen-glu- the oxidative stress injury, Nrf2 separated from cose deprivation/reoxygenation, Oxidative stress. Keap1 (Kelch-like ECH-associated protein 1) and Corresponding Author: Lingling Zhang, BM; e-mail: [email protected] 3493 L.-L. Zhang, Z.-J. Zhang entered into the nucleus16. When combined with 1 method) and MDA kit were purchased from antioxidant response elements (AREs), the ex- Shanghai GeneChem Biotechnology Co., Ltd. pressions of Phase II detoxification enzymes and (Shanghai, China). Curcumin was obtained from antioxidants were regulated by multiple signaling Sigma-Aldrich (St. Louis, MO, USA). pathways, such as sulfiredoxin1 (Srx1)17 and thi- oredoxin1 (Trx1)18. Protective effect has been ex- Neuronal Survival Rate and Cell Viability erted during the pathological process of resisting Cell viability was determined by cell count- tumors and oxidation19. Studies20 indicated that ing kit-8 (CCK-8) assay (Dojindo, Kumamoto, Nrf2 was mainly regulated by Keap1. Numerous Japan). Neurons were cultured in 96-well plates, researches21,22 have found that Sesn2 could both and 10 μL of CCK8 were added in each well. Af- directly and indirectly participate in the regulation ter incubation for 2 h, the absorbance of each well of Nrf2 in the process of metabolism. However, was measured at 450 nm. The displayed value Nrf2 was proved to be involved in many signal represented the cell viability. Activity value in the pathways, but the specific mechanism and func- negative control group was set to 100% of sur- tional effect were not completely understood. vival rate. Ratio of activity value in other groups We suggested that Sesn2 was one of the key to the one in the negative control group was the regulators of Nrf2 during cerebral ischemia-reper- survival. Lactate dehydrogenase (LDH) leakage fusion and neuronal OGD/R. In this work, we rate assay was based on the instructions provided constructed Sesn2 siRNA lentivirus vector and by Shanghai GeneChem Biotechnology Co., Ltd. transfected primary cultured cortical neurons of (Shanghai, China). Blank wells, standard wells, neonatal SD rats, and established OGD/R model. determination wells and control wells were pre- The effect of Sesn2 on neurons was observed. The pared according to the requirements. Cells were expressions of Sesn2 and Nrf2 were accessed. placed at room temperature for 3 min. Superna- The MCAO rat model with interference of Sesn2 tant in each well was extracted, absorbance value siRNA was conducted. The relationship between of each well at 450 nm was detected by a micro- Sesn2 and neural function, morphological chang- plate reader (Bio-Rad, Hercules, CA, USA). The es, neuronal damage, Nrf2 expression was ex- experiment was repeated three times. plored. The mechanism of Sesn2 was explored through in vivo and in vitro experiments. SOD and MDA Detection Superoxide dismutase (SOD): SOD was ac- Materials and Methods cessed using WST-1 method. Blank wells, stan- dard wells, determination wells and control wells Animals and Groups were prepared according to the requirements. Male SD rats weighing 200-250 g were pro- Cells were incubated at 37°C for 20 min. Absor- vided by Beijing Vital River Laboratory Animal bance value of each well at 450 nm was detected Technology Co., Ltd. (Beijing, China) and were by a microplate reader. randomly divided into groups according to Sesn2 Malondialdehyde (MDA): MDA was deter- interference and OGD/R establishment. Control mined by thiobarbituric acid method. According to group, vector group (blank plasmid transfected the instructions provided by Shanghai GeneChem group), Sesn2 overexpression group, curcum- Biotechnology Co., Ltd. (Shanghai, China), blank in-treated group, vector + OGD/R group, Sesn2 wells, standard wells, determination wells and overexpression + OGD/R group, curcumin treat- control wells were prepared. Absorbance value of ment + OGD/R group. This study was approved each well at 532 nm was detected by a microplate by the Animal Ethics Committee of Hangzhou reader (1 cm of optical path, set zero by distilled Fuyang Hospital of Traditional Chinese Medicine water). Animal Center. Establishment of OGD/R Model Reagents After neurons were cultured in vitro for 6 days Sesn2 gene interference and over-expression or lentiviral transfection for 3 days, 0.01 M PBS of lentivirus were constructed by Shanghai Ge- was used to wash for three times. Sugar-free Dul- nePharm Biotechnology Co., Ltd. (Shanghai, becco’s Modified Eagle Medium (DMEM) was China). 2,3,5-triphenyltetrazolium chloride (TTC replaced and placed in a three-gas incubator for stain) was purchased from Sigma Company (St. 1.5 h. After 1.5 h of OGD, Neurobasal/B27 medi- Louis, MO, USA). LDH kit, SOD kit (WST- um (Gibco, Grand Island, NY, USA) was washed 3494 Sestrin2 aggravates oxidative stress of neurons by decreasing the expression of Nrf2 once, changed to Neurobasal/B27 medium again rica, MA, USA) and phosphatase inhibitor homo- and placed in a normal incubator for reoxygen- genate in the proportion of 100:1:1. Nucleoprotein ation for 24 h. extraction was using a nuclear protein kit. The sample volume was determined and the primary Establishment of Middle Cerebral Artery antibodies of Sesn2, Srx1, Trx1 and Nrf2 (purcha- Infarction Model sed from CST, 1:1000, Danvers, MA, USA) were Establishment of the rat model of middle ce- added after conventional electrophoresis and in- rebral artery occlusion was made according cubated overnight at 4°C. The membrane was wa- to the Longa method. The model of middle ce- shed and then labeled
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