scholarly journals Ubiquitin-Specific Protease 29 Exacerbates Cerebral Ischemia-Reperfusion Injury in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Jia-Bao Hou ◽  
Qian-Ni Shen ◽  
Xing Wan ◽  
Xu-Ke Liu ◽  
Yuan Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion ◽  
Primary Cortical Neurons ◽  
Cerebral Ischemia Reperfusion ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
The Brain

Oxidative stress and apoptosis contribute to the progression of cerebral ischemia/reperfusion (I/R) injury. Ubiquitin-specific protease 29 (USP29) is abundantly expressed in the brain and plays critical roles in regulating oxidative stress and cell apoptosis. The purpose of the present study is to investigate the role and underlying mechanisms of USP29 in cerebral I/R injury. Neuron-specific USP29 knockout mice were generated and subjected to cerebral I/R surgery. For USP29 overexpression, mice were stereotactically injected with the adenoassociated virus serotype 9 vectors carrying USP29 for 4 weeks before cerebral I/R. And primary cortical neurons were isolated and exposed to oxygen glucose deprivation/reperfusion (OGD/R) stimulation to imitate cerebral I/R injury in vitro. USP29 expression was elevated in the brain and primary cortical neurons upon I/R injury. Neuron-specific USP29 knockout significantly diminished, whereas USP29 overexpression aggravated cerebral I/R-induced oxidative stress, apoptosis, and neurological dysfunction in mice. In addition, OGD/R-induced oxidative stress and neuronal apoptosis were also attenuated by USP29 silence but exacerbated by USP29 overexpression in vitro. Mechanistically, neuronal USP29 enhanced p53/miR-34a-mediated silent information regulator 1 downregulation and then promoted the acetylation and suppression of brain and muscle ARNT-like protein, thereby aggravating oxidative stress and apoptosis upon cerebral I/R injury. Our findings for the first time identify that USP29 upregulation during cerebral I/R may contribute to oxidative stress, neuronal apoptosis, and the progression of cerebral I/R injury and that inhibition of USP29 may help to develop novel therapeutic strategies to treat cerebral I/R injury.

Abstract TP286: The Study of the Role and Mechanism of TRPM7 in Acute Cerebral Ischemia-Reperfusion Injury

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Jie Xu ◽  
Li Chen ◽  
Li Zeng ◽  
Chunrong Li ◽  
Xiangyu Yang ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion ◽  
Primary Cortical Neurons ◽  
Cerebral Ischemia Reperfusion ◽  
Normal Rat ◽  
A Cell ◽  
Rat Forebrain ◽  
Ion Channel Inhibitors ◽  
Cell Membrane Protein

Although the NMDA receptor was identified to mediate excitotoxicity for ischemia-reperfusion (IR) injury, its antagonists have not shown clinical efficacy. Unrelated to NMDA, the transient receptor potential cation channel, subfamily M, member 7 (TRPM7) has been reported to cause intracellular Ca 2+ overloading, oxidative stress and neuronal apoptosis. We postulated that TRPM7 could be a target for treatment of IR injury. To investigate the potential neuroprotective role of TRPM7 in IR injury, 1) qRT-PCR, Western blot and immuno-staining were used to identify the expression and localization of TRPM7 in normal rat forebrain cortex and cultured primary cortical neurons; 2) the oxygen glucose deprivation and reperfusion (OGD/R) model of primary cortical neurons was used to detect changes in TRPM7 expression and study the effect of two TRPM7 ion channel inhibitors, carvacrol and 2-Aminoethoxydiphenyl borate (2-APB), on neurons in OGD/R; 3) the rat middle cerebral artery (MCAO/R) model was used to study TRPM7 involvement and the effect of its inhibitor during the course of IR. Our results showed that: 1) TRPM7 was expressed in normal neurons and astrocytes mainly as a cell membrane protein in the rat cortex; 2) TRPM7 expression was enhanced in OGD/R treated neurons; treatment with carvacrol or 2-APB reversed the overexpression of TRPM7 in OGD/R neurons and reduced the level of Ca 2+ overload in neuronal IR injury and neuronal apoptosis; 3) TRPM7 expression was also augmented in rat cortical tissues during MCAO/R and peaked between 24-48 hours during the reperfusion stage; 4) treatment with TRPM7 inhibitors reversed TRPM7 overexpression, alleviated neuronal apoptosis, and improved neurobehavioral scores in MCAO/R rats. Our conclusions are: 1) TRPM7 is expressed in normal rat forebrain cortex and functions mainly as a cell membrane protein in neurons and astrocytes; 2) TRPM7 is overexpressed during cerebral ischemia-reperfusion in rats; 3) TRPM7 ion channel inhibitors carvacrol and 2-APB can alleviate OGD/R injury in neurons in vitro as well as cortical damage by MCAO/R in rat forebrain; 4) the mechanism of TRPM7 on neuronal injury in OGD/R and MCAO/R can contribute to its role in neuronal apoptosis and Ca 2+ influx toxicity.

scholarly journals Calycosin-7-O-β-D-glucoside Attenuates OGD/R-Induced Damage by Preventing Oxidative Stress and Neuronal Apoptosis via the SIRT1/FOXO1/PGC-1α Pathway in HT22 Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Xiangli Yan ◽  
Aiming Yu ◽  
Haozhen Zheng ◽  
Shengxin Wang ◽  
Yingying He ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Pathological Process ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
Positive Effects ◽  
Antioxidant Stress

Neuronal apoptosis induced by oxidative stress is a major pathological process that occurs after cerebral ischemia-reperfusion. Calycosin-7-O-β-D-glucoside (CG) is a representative component of isoflavones in Radix Astragali (RA). Previous studies have shown that CG has potential neuroprotective effects. However, whether CG alleviates neuronal apoptosis through antioxidant stress after ischemia-reperfusion remains unknown. To investigate the positive effects of CG on oxidative stress and apoptosis of neurons, we simulated the ischemia-reperfusion process in vitro using an immortalized hippocampal neuron cell line (HT22) and oxygen-glucose deprivation/reperfusion (OGD/R) model. CG significantly improved cell viability and reduced oxidative stress and neuronal apoptosis. In addition, CG treatment upregulated the expression of SIRT1, FOXO1, PGC-1α, and Bcl-2 and downregulated the expression of Bax. In summary, our findings indicate that CG alleviates OGD/R-induced damage via the SIRT1/FOXO1/PGC-1α signaling pathway. Thus, CG maybe a promising therapeutic candidate for brain injury associated with ischemic stroke.

scholarly journals Targeted Delivery of Intranasally Administered Cyclovirobuxine D Liposomes to Brain for Treatment Cerebral Ischemia-Reperfusion Injury via Anti-oxidative Stress and Activating Autophagy

2022 ◽  
Author(s):  
Tuo Liu ◽  
Fang Yang ◽  
Xiangyi Lu ◽  
Chang Liu ◽  
Yang Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Protein Expressions ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Ht22 Cell

Abstract The lack of effective therapy mandates development of treatment for cerebral ischemia-reperfusion injury (CIRI. The previous study suggested that Cyclovirobuxine D (CVBD) encapsulated in Angiopep-conjugated Polysorbate 80-Coated Liposomes showed a better brain targeting by intranasal administration. Therefore, this study focused on the protection and mechanism of CVBD brain-targeted liposomes in treating CIRI. In order to evaluate these, the CIRI rat model was induced by middle cerebral artery occlusion (MCAO)-reperfusion. Pharmacological evaluation was assessed in vivo by general indexs, neurobehavioral scores, triphenyl tetrazolium chloride (TTC) staining, histopathological staining (HE staining and Nissl staining), small animal magnetic resonance imaging, biochemical assay and Western blot. The results show that CVBD liposomes alleviated pathological damage of brain. Futhermore, the protective effect of CVBD liposomes on OGD/R-injured HT22 cell was investigated by cell fusion degree, cell proliferation curve and cell viability. OGD/R-injured HT22 cell was infected by mRFP-GFP-LC3 adenovirus. The autophagosome and autophagy flow were observed by laser confocal microscopy, and autophagy-related protein expressions (LC3, p62 and Beclin 1) were analyzed by Western blot. Meanwhile, the classic autophagy inhibitor, chloroquine, was used to explore the autophagy-regulated mechanism of CVBD brain-targeted liposomes in treating CIRI. In cell model of oxygen and glucose deprivation/re-oxygenation, CVBD liposomes increased cell viability and decreased ROS level. CVBD liposomes improved oxidative stress protein expressions and activated autophagy in vitro. Furthermore, CVBD liposomes reversed the decrease of cell viability, increase of ROS level, and reduction of protein expressions associated to anti-oxidative stress and autophagy induced by chloroquine. Collectively, CVBD liposomes inhibited CIRI via regulating oxidative stress and enhancing autophagy level in vivo and in vitro, showing a great potential in treating CIRI in clinic.

scholarly journals Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Bo Zhao ◽  
Quan Yuan ◽  
Jia-bao Hou ◽  
Zhong-yuan Xia ◽  
Li-ying Zhan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
High Glucose ◽  
Ischemia Reperfusion ◽  
Pathological Process ◽  
Diabetic Mice ◽  
Diabetic State ◽  
Cerebral Ischemia Reperfusion

Background. A substantial increase in histone deacetylase 3 (HDAC3) expression is implicated in the pathological process of diabetes and stroke. However, it is unclear whether HDAC3 plays an important role in diabetes complicated with stroke. We aimed to explore the role and the potential mechanisms of HDAC3 in cerebral ischemia/reperfusion (I/R) injury in diabetic state. Methods. Diabetic mice were subjected to 1 h ischemia, followed by 24 h reperfusion. PC12 cells were exposed to high glucose for 24 h, followed by 3 h of hypoxia and 6 h of reoxygenation (H/R). Diabetic mice received RGFP966 (the specific HDAC3 inhibitor) or vehicle 30 minutes before the middle cerebral artery occlusion (MCAO), and high glucose-incubated PC12 cells were pretreated with RGFP966 or vehicle 6 h before H/R. Results. HDAC3 inhibition reduced the cerebral infarct volume, ameliorated pathological changes, improved the cell viability and cytotoxicity, alleviated apoptosis, attenuated oxidative stress, and enhanced autophagy in cerebral I/R injury model in diabetic state in vivo and in vitro. Furthermore, we found that the expression of HDAC3 was remarkably amplified, and the Bmal1 expression was notably decreased in diabetic mice with cerebral I/R, whereas this phenomenon was obviously reversed by RGFP966 pretreatment. Conclusions. These results suggested that the HDAC3 was involved in the pathological process of the complex disease of diabetic stroke. Suppression of HDAC3 exerted protective effects against cerebral I/R injury in diabetic state in vivo and in vitro via the modulation of oxidative stress, apoptosis, and autophagy, which might be mediated by the upregulation of Bmal1.

scholarly journals Inhibition of miR-34a ameliorates cerebral ischemia/reperfusion injury by targeting brain-derived neurotrophic factor

2021 ◽  
Author(s):  
Shilin Zhu ◽  
Jianghong Tang ◽  
Lan Lan ◽  
Feng Su
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Neurotrophic Factor ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neurological Deficits ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

IntroductionOxidative stress and neuronal apoptosis are strongly associated with the pathogenesis of ischemic stroke. In this study, we aimed to determine whether miR-34a was involved in ischemia/reperfusion (I/R) injury, oxidative stress, and neuronal apoptosis by targeting brain-derived neurotrophic factor (BDNF).Material and methodsRats received middle cerebral artery occlusion (MCAO) surgery to simulate I/R injury. At 24 h after MCAO surgery, neurological deficits and infarct volumes were evaluated according to Longa’s scale and 2,3,5-triphenyltetrazolium (TTC) chloride staining. Neuronal apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and the expression of miR-34a and associated proteins were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and western blotting. Several markers of oxidative stress were detected using commercial kits, and the interaction between miR-34a and BDNF was measured by RNA immunoprecipitation (RIP).ResultsThe results showed that miR-34a was upregulated (p < 0.05), whereas BDNF was downregulated (p < 0.05) in the MCAO rats, and this negative correlation was accompanied by clear oxidative stress and neuronal apoptosis. RIP demonstrated a clear interaction between miR-34a and BDNF. Furthermore, miR-34a was also found to inhibit oxidative stress and neuronal apoptosis, increase BDNF expression, and ameliorate neurological deficits and infarct volumes (p < 0.05) seen in the MCAO rats.ConclusionsThese data suggested that inhibition of miR-34a ameliorated cerebral ischemia/reperfusion injury by targeting BDNF. This mechanism represents a novel and promising target for the treatment of strokes.

scholarly journals Low-level laser therapy (LLLT) reduces oxidative stress in primary cortical neurons in vitro

2012 ◽  
pp. n/a-n/a ◽  
Author(s):  
Ying-Ying Huang ◽  
Kazuya Nagata ◽  
Clark E. Tedford ◽  
Thomas McCarthy ◽  
Michael R. Hamblin
Keyword(s):  
Oxidative Stress ◽  
Laser Therapy ◽  
Cortical Neurons ◽  
Low Level Laser Therapy ◽  
Primary Cortical Neurons ◽  
Low Level ◽  
Low Level Laser ◽  
Level Laser
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