scholarly journals Restoration of HDAC1 Enzymatic Activity after Stroke Protects Neurons from Ischemia/Reperfusion Damage and Attenuates Behavioral Deficits in Rats

2021 ◽  
Vol 22 (19) ◽  
pp. 10654
Author(s):  
Jui-Sheng Chen ◽  
Hao-Kuang Wang ◽  
Yu-Ting Su ◽  
Chien-Yu Hsu ◽  
Jia-Shing Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cerebral Ischemia ◽  
Enzymatic Activity ◽  
Histone Deacetylase ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Stroke Therapy ◽  
Dna Breaks ◽  
Histone Deacetylase 1 ◽  
Enzymatic Function

A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.

scholarly journals Surface-modified engineered exosomes attenuated cerebral ischemia/reperfusion injury by targeting the delivery of quercetin towards impaired neurons

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lin Guo ◽  
Zhixuan Huang ◽  
Lijuan Huang ◽  
Jia Liang ◽  
Peng Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Targeted Delivery ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Therapeutic Drug ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

Abstract Background The incidence of ischemic stroke in the context of vascular disease is high, and the expression of growth-associated protein-43 (GAP43) increases when neurons are damaged or stimulated, especially in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Experimental design We bioengineered neuron-targeting exosomes (Exo) conjugated to a monoclonal antibody against GAP43 (mAb GAP43) to promote the targeted delivery of quercetin (Que) to ischemic neurons with high GAP43 expression and investigated the ability of Exo to treat cerebral ischemia by scavenging reactive oxygen species (ROS). Results Our results suggested that Que loaded mAb GAP43 conjugated exosomes (Que/mAb GAP43-Exo) can specifically target damaged neurons through the interaction between Exo-delivered mAb GAP43 and GAP43 expressed in damaged neurons and improve survival of neurons by inhibiting ROS production through the activation of the Nrf2/HO-1 pathway. The brain infarct volume is smaller, and neurological recovery is more markedly improved following Que/mAb GAP43-Exo treatment than following free Que or Que-carrying exosome (Que-Exo) treatment in a rat induced by MCAO/R. Conclusions Que/mAb GAP43-Exo may serve a promising dual targeting and therapeutic drug delivery system for alleviating cerebral ischemia/reperfusion injury.

scholarly journals PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Nan Huang ◽  
Chang Xu ◽  
Liang Deng ◽  
Xue Li ◽  
Zhixuan Bian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
De Novo ◽  
Dna Damage Repair ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

Poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling

2020 ◽  
Author(s):  
Peng-Fei Wang ◽  
Wei-Bin Zhong ◽  
Xiao-Hua Ju ◽  
Zhen-Guang LI ◽  
Fa-Xiang Wang
Keyword(s):  
Cerebral Ischemia ◽  
Cognitive Dysfunction ◽  
Sham Group ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Poly I:C ◽  
Model Group ◽  
Vector Group ◽  
Aav Vector ◽  
Cerebral Ischemia Reperfusion

Abstract Objective: Toll-like receptor (TLR) activation plays an important role in cerebral ischemia-reperfusion injury. In addition, increasing evidence suggests that TLRs may affect cognitive behavior through TLR-mediated signaling. Here, we explored the protective effects of TLR3 on cognitive dysfunction after ischemia in the context of poly(I:C) preconditioning.Materials and Methods : Mice (n=84) were randomly divided into the sham group, AAV (vector) group, middle cerebral artery occlusion (MCAO) model group, poly(I:C) (pre) + MCAO model group, and AAV (TRAF6) + poly(I:C) (pre) + MCAO model group. The mice were injected i.p. with poly(I:C) (1.25 mg/g) 24 h prior to cerebral ischemia. Then, neurological scores were assessed, and the infarct volume was measured after cerebral ischemia-reperfusion. We evaluated the poly(I:C) preconditioning-induced attenuation of neuronal damage using Nissl and TUNEL staining. We assessed the poly(I:C) preconditioning-mediated inhibition of I/R-induced glial activation, inflammatory factor levels and TRAF6 expression. We also assessed whether TRAF6 affects poly(I:C) preconditioning to improve cognitive dysfunction and neuroprotection.Results: The results showed that compared with those of the sham group and AAV (vector) group, the functional neurological scores and focal infarct volume of the MCAO group and poly(I:C) preconditioning group were significantly increased. The results also showed that compared with those of the MCAO group, the functional neurological scores and focal infarct volume of the poly(I:C) preconditioning group were significantly reduced. Our results indicated that poly(I:C) preconditioning significantly attenuated neuronal apoptosis and cell loss. Poly(I:C) preconditioning also inhibited I/R-induced glial cell activation and reduced NF-κB, TNF-α and IL-β levels. Our findings showed that poly(I:C) preconditioning affected cognitive dysfunction following cerebral I/R. Here, we observed that poly(I:C) preconditioning affected the expression and distribution of TRAF6 following cerebral I/R. TRAF6 overexpression abolished poly(I:C)-induced neuroprotection and worsened cognitive dysfunction in cerebral I/R injury.Significance: Our findings suggested that poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling, which is a potential therapeutic target for the treatment of cognitive dysfunction after stroke.

scholarly journals Protective effect of extract of the Camellia japonica L. on cerebral ischemia-reperfusion injury in rats

2019 ◽  
Vol 77 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Weizhuo Lu ◽  
Ling Xv ◽  
Jiyue Wen
Keyword(s):  
Cerebral Ischemia ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Camellia Japonica ◽  
Lactate Dehydrogenase Activity ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

ABSTRACT Objective: We investigated the protective effect of the extract of the Camellia japonica L. flower on cerebral ischemia-reperfusion injury in rats. Methods: The rat ischemia-reperfusion injury was induced by middle cerebral artery occlusion for 90 minutes and reperfusion for 48 hours. The animals received an intravenous injection once a day of 20, 40, 80 mg/kg extract of C. japonica for three consecutive days before the ischemia reperfusion. The learning and memory function, the infarct volume, serum malondialdehyde (MDA) level and lactate dehydrogenase activity, and extravasation of immunoglobulin G (IgG) into cerebral parenchyma were assessed as the cell damage index. Results: Pretreatment with extract of C. japonica markedly reduced the infarct volume, serum malondialdehyde level and lactate dehydrogenase activity, and markedly inhibited the extravasation of IgG. Moreover, pretreatment with extract of C. japonica may also inhibit the learning and memory deficits induced by an ischemia-reperfusion injury. Conclusion: It was concluded that pretreatment with extract of C. japonica has a protective effect on cerebral ischemia-reperfusion injury in rats.

NADPH oxidase inhibitor improves outcome of mechanical reperfusion by suppressing hemorrhagic transformation

2016 ◽  
Vol 9 (5) ◽  
pp. 492-498 ◽  
Author(s):  
Yong-Hua Tuo ◽  
Zhong Liu ◽  
Jian-Wen Chen ◽  
Qing-Yuan Wang ◽  
Song-Lin Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nadph Oxidase ◽  
Acute Stroke ◽  
Neuronal Apoptosis ◽  
Mechanical Thrombectomy ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hemorrhagic Transformation ◽  
Stroke Treatment

BackgroundSevere hemorrhagic transformation (HT) after mechanical thrombectomy predicts a poor clinical outcome in acute ischemic stroke. To better understand the mechanism of HT, we investigated the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in HT after reperfusion during acute stroke and whether NOX2/4 inhibitor VAS2870 reduces reperfusion-induced HT after mechanical recanalization.MethodsA model of reperfusion-induced HT was established in rats (n=182) with hyperglycemic challenge and 5 h middle cerebral artery occlusion followed by 19 h reperfusion. NOX inhibitor VAS2870 was delivered intravenously 30 min before reperfusion. Infarct volume, brain water content, HT, neurological score, mortality rate, blood–brain barrier (BBB) damage, neuronal apoptosis, and reactive oxygen species were determined at 24 h after cerebral ischemia. The expressions of NOX1, NOX2, NOX4, and BBB-associated proteins were measured.ResultsNOX2 and NOX4 upregulation and severe HT were observed in hyperglycemic rats after cerebral ischemia/reperfusion. VAS2870 suppressed oxidative stress, neuronal apoptosis, and NOX2/4 upregulation in the ischemic hemisphere. VAS2870 reduced infarct volume (17.2±5.3% vs 37.4±9.2%, p<0.01) and the frequency of reperfusion-induced parenchymal hematoma (29.7% vs 59.5%, p<0.05) at 24 h after ischemia compared with the ischemia/reperfusion group. VAS2870 attenuated brain edema and reduced reperfusion-induced BBB breakdown, resulting in improved neurological outcome (neurological deficit score 1.43±0.50 vs 2.43±0.93, p<0.001) and reduced mortality (11.9% vs 64.1%, p<0.001).ConclusionsNOX2 and NOX4 may mediate HT in rats with large vessel stroke after mechanical reperfusion. Infusion of NOX inhibitor VAS2870 before mechanical thrombectomy represents a novel adjunctive therapeutic strategy to prevent reperfusion-induced HT and improve outcome of acute stroke treatment.

scholarly journals Neuroprotective and Anti-Inflammatory Effect of Pterostilbene Against Cerebral Ischemia/Reperfusion Injury via Suppression of COX-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjun Yan ◽  
Dongqing Ren ◽  
Xiaoxue Feng ◽  
Jinwen Huang ◽  
Dabin Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Inflammatory Cytokines ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Polymorphonuclear Leucocyte ◽  
The Body ◽  
Cox 2 ◽  
Anti Inflammatory

Background: The incidence of cerebral ischemia disease leading cause of death in human population worldwide. Treatment of cerebral ischemia remains a clinical challenge for researchers and mechanisms of cerebral ischemia remain unknown. During the cerebral ischemia, inflammatory reaction and oxidative stress plays an important role. The current investigation scrutinized the neuroprotective and anti-inflammatory role of pterostilbene against cerebral ischemia in middle cerebral artery occlusion (MCAO) rodent model and explore the underlying mechanism.Methods: The rats were divided into following groups viz., normal, sham, MCAO and MCAO + pterostilbene (25 mg/kg) group, respectively. The groups received the oral administration of pterostilbene for 30 days followed by MCAO induction. The neurological score, brain water content, infarct volume and Evan blue leakage were estimated. Hepatic, renal, heart, inflammatory cytokines and inflammatory mediators were estimated.Results: Pterostilbene treatment significantly (p &lt; 0.001) improved the body weight and suppressed the glucose level and brain weight. Pterostilbene significantly (p &lt; 0.001) reduced the hepatic, renal and heart parameters. Pterostilbene significantly (p &lt; 0.001) decreased the level of glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and decreased the level of malonaldehyde (MDA), 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Pterostilbene significantly (p &lt; 0.001) inflammatory cytokines and inflammatory parameters such as cyclooxygenase-2 (COX-2), inducible nitric oxidase synthase (iNOS) and prostaglandin (PGE2). Pterostilbene significantly (p &lt; 0.001) down-regulated the level of metalloproteinases (MMP) such as MMP-2 and MMP-9. Pterostilbene suppressed the cellular swelling, cellular disintegration, macrophage infiltration, monocyte infiltration and polymorphonuclear leucocyte degranulation in the brain.Conclusion: In conclusion, Pterostilbene exhibited the neuroprotective effect against cerebral ischemia in rats via anti-inflammatory mechanism.

scholarly journals Tetrandrine alleviates cerebral ischemia/reperfusion injury by suppressing NLRP3 inflammasome activation via Sirt-1

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9042
Author(s):  
Jun Wang ◽  
Ming Guo ◽  
Ruojia Ma ◽  
Maolin Wu ◽  
Yamei Zhang
Keyword(s):  
Cerebral Ischemia ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Sirtuin 1 ◽  
Neurological Deficits ◽  
Inflammasome Activation ◽  
Cerebral Ischemia Reperfusion ◽  
Nlrp3 Inflammasome Activation

Background & Aims Tetrandrine (Tet) has been reported to have anti-inflammatory effects and protect from the ischemic strokes. The NLRP3 inflammasome plays a key role in cerebral ischemia/reperfusion (I/R)-induced inflammatory lesions. However, the molecular mechanisms of Tet related to the progression of cerebral ischemia are still unclear. Therefore, the aim of this study was to investigate the possible effects of Tet on cerebral ischemia and the related mechanisms involved in NLRP3 inflammasome. Methods C57BL/6J mice used as a cerebral I/R injury model underwent middle cerebral artery occlusion (MCAO) for 2 h following reperfusion for 24 h. Tet (30 mg/kg/day, i.p.) was administered for seven days and 30 min before and after MCAO. Their brain tissues were evaluated for NLRP3 inflammasome and Sirtuin-1 (Sirt-1) expression. An intracerebroventricular injection of Sirt-1 siRNA was administered to assess the activation of the NLRP3 inflammasome. Results Tet significantly reduced the neurological deficits, infarction volume, and cerebral water content in MCAO mice. Moreover, it inhibited I/R-induced over expression of NLRP3, cleaved caspase-1, interleukin (IL)-1β, IL-18, and Sirt-1. Sirt-1 knockdown with siRNA greatly blocked the Tet-induced reduction of neurological severity score and infarct volume, and reversed the inhibition of NLRP3 inflammasome activation. Conclusion Our results demonstrate that Tet has benefits for cerebral I/R injury, which are partially related to the suppression of NLRP3 inflammasome activation via upregulating Sirt-1.

scholarly journals Preparation of Borneol Angelica Polysaccharide Liposomes and Study Evaluation of Its Anti-Cerebral Ischemia-Reperfusion Inflammatory Reaction

2021 ◽  
Author(s):  
Ke Wang ◽  
Lin Qin He ◽  
Xiao Yu Yang ◽  
Hai Hong Huang ◽  
Wen Long Liu ◽  
...  
Keyword(s):  
Particle Size ◽  
Cerebral Ischemia ◽  
Inflammatory Reaction ◽  
Encapsulation Efficiency ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Inflammatory Reactions ◽  
Expression Levels ◽  
Cerebral Ischemia Reperfusion ◽  
Ultrasonication Time

Abstract Objective To prepare borneol angelica polysaccharide liposomes (BAPLs) with distinct characteristics in Chinese and Western medicine, to explore their effects on anti-cerebral ischemia-reperfusion inflammatory reactions and to explain their mechanism. Methods Under the guidance of the basic theory of traditional Chinese medicine, a new dosage form of nanoliposomes was selected to prepare BAPL by the thin film dispersion ultrasonic method. The effects of angelica polysaccharide (AP), lecithin, cholesterol and ultrasonication time on encapsulation efficiency were investigated. Triphenyltetrazolium chloride (TTC) staining was used to detect the volume of cerebral infarction. Western blotting was used to detect the expression levels of TLR-4, NF-κBp65, ZO-1, ZO-2, IL-1β, IL-6, IL-8 and IL-10. Results As the mass ratio of lecithin to cholesterol (X1), the mass of angelica polysaccharide (X2) and the interaction between X1 and X2 (X1X2) were used as investigation factors, the fitting equation between encapsulation efficiency Y and X was Y=0.307-0.153X1+0.026 X2+0.006X12-0.000301 X22+0.002X1X2 (P＜0.05). The best ultrasonication time was 15 min, the highest encapsulation efficiency was 80.4%, the particle size was 179.1 nm, and the surface zeta potential was -17.2 mV. In BAPL group, the infarct volume of TTC staining was significantly decreased (P＜0.05), and the expression levels of NF-κBp65, TLR-4, IL-8, IL-6, IL-1β in brain tissue were significantly decreased (P＜0.05), while the expression levels of ZO-1, ZO-2, IL-10 were significantly increased (P＜0.05). Conclusion BAPL has high encapsulation efficiency, small particle size and stable properties and can alleviate cerebral ischemia-reperfusion injury. Its mechanism may be related to inhibiting inflammatory reactions, downregulating inflammatory reaction signaling pathways and protecting the blood–brain barrier (BBB).

scholarly journals Electroacupuncture Pretreatment Elicits Tolerance to Cerebral Ischemia/Reperfusion through Inhibition of the GluN2B/m-Calpain/p38 MAPK Proapoptotic Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Bao-yu Zhang ◽  
Guan-ran Wang ◽  
Wen-hua Ning ◽  
Jian Liu ◽  
Sha Yang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
P38 Mapk ◽  
Cellular Localization ◽  
Mapk Pathway ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Neurological Deficits ◽  
Inhibition Mechanism ◽  
Tunel Staining ◽  
Model Preparation

Background. As one of the first steps in the pathology of cerebral ischemia, glutamate-induced excitotoxicity progresses too fast to be the target of postischemic intervention. However, ischemic preconditioning including electroacupuncture (EA) might elicit cerebral ischemic tolerance through ameliorating excitotoxicity. Objective. To investigate whether EA pretreatment based on TCM theory could elicit cerebral tolerance against ischemia/reperfusion (I/R) injury, and explore its potential excitotoxicity inhibition mechanism from regulating proapoptotic pathway of the NMDA subtype of glutamate receptor (GluN2B). Methods. The experimental procedure included 5 consecutive days of pretreatment stage and the subsequent modeling stage for one day. All rats were evenly randomized into three groups: sham MCAO/R, MCAO/R, and EA+MCAO/R. During pretreatment procedure, only rats in the EA+MCAO/R group received EA intervention on GV20, SP6, and PC6 once a day for 5 days. Model preparation for MCAO/R or sham MCAO/R started 2 hours after the last pretreatment. 24 hours after model preparation, the Garcia neurobehavioral scoring criteria was used for the evaluation of neurological deficits, TTC for the measurement of infarct volume, TUNEL staining for determination of neural cell apoptosis at hippocampal CA1 area, and WB and double immunofluorescence staining for expression and the cellular localization of GluN2B and m-calpain and p38 MAPK. Results. This EA pretreatment regime could improve neurofunction, decrease cerebral infarction volume, and reduce neuronal apoptosis 24 hours after cerebral I/R injury. And EA pretreatment might inhibit the excessive activation of GluN2B receptor, the GluN2B downstream proapoptotic mediator m-calpain, and the phosphorylation of its transcription factor p38 MAPK in the hippocampal neurons after cerebral I/R injury. Conclusion. The EA regime might induce tolerance against I/R injury partially through the regulation of the proapoptotic GluN2B/m-calpain/p38 MAPK pathway of glutamate.

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