scholarly journals Mesenchymal stem cell-derived exosome miR-542-3p suppresses inflammation and prevents cerebral infarction

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guofeng Cai ◽  
Guoliang Cai ◽  
Haichun Zhou ◽  
Zhe Zhuang ◽  
Kai Liu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cerebral Infarction ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Cerebral Injury ◽  
Inflammatory Factors ◽  
Toll Like Receptor 4 ◽  
Cerebral Disease ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion

Abstract Background Cerebral infarction ranks as the second leading cause of disability and death globally, and inflammatory response of glial cells is the main cause of brain damage during cerebral infarction. Methods Studies have shown that mesenchymal stem cells (MSCs) can secrete exosomes and contribute to cerebral disease. Here, we would explore the function of MSC-derived exosome in cerebral infarction. Results Microarray indicated a decrease of miR-542-3p and an increase of Toll-Like Receptor 4 (TLR4) in middle cerebral artery occlusion (MCAO) mice comparing with sham mice. And luciferase and RIP analysis indicated a binding of miR-542-3p and TLR4. Then, we injected AAV9-miR-542-3p into paracele of sham or MCAO mice. Functional analysis showed that AAV9-miR-542-3p inhibited infarction area and the number of degenerating neurons and suppressed inflammatory factors’ expression and inflammatory cell infiltration. As well, transfection of miR-542-3p mimics into HA1800 cells underwent oxygen and glucose deprivation (OGD). Similarly, overexpression of miR-542-3p alleviated OGD induced cell apoptosis, ROS, and activation of inflammation response. Moreover, miR-542-3p could be packaged into MSCs and secreted into HA1800 cells. The extractive exosome-miR-21-3p treatment relieved MCAO- or OGD-induced cerebral injury and inflammation through targeting TLR4. Conclusion These results confirmed that MSC-derived exosome miR-542-3p prevented ischemia-induced glial cell inflammatory response via inhibiting TLR4. These results suggest possible therapeutic strategies for using exosome delivery of miR-542-3p to cure cerebral ischemic injury.

Berberine Preconditioning Protects Neurons Against Ischemia via Sphingosine-1-Phosphate and Hypoxia-Inducible Factor-1α

2016 ◽  
Vol 44 (05) ◽  
pp. 927-941 ◽  
Author(s):  
Qichun Zhang ◽  
Huimin Bian ◽  
Liwei Guo ◽  
Huaxu Zhu
Keyword(s):  
Cortical Neurons ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Cerebral Injury ◽  
Male Rats ◽  
Neuroprotective Effects ◽  
Sphingosine 1 Phosphate ◽  
Cerebral Ischemic

Berberine exerts neuroprotective and modulates hypoxia inducible factor-1-alpha (HIF-1[Formula: see text]. Based on the role of HIF-1[Formula: see text] in hypoxia preconditioning and association between HIF-1[Formula: see text] and sphingosine-1-phosphate (S1P), we hypothesized that berberine preconditioning (BP) would ameliorate the cerebral injury induced by ischemia through activating the system of HIF-1[Formula: see text] and S1P. Adult male rats with middle cerebral artery occlusion (MCAO) and rat primary cortical neurons treated with oxygen and glucose deprivation (OGD) with BP at 24[Formula: see text]h (40[Formula: see text]mg/kg) and 2[Formula: see text]h (10[Formula: see text][Formula: see text]mol/L), respectively, were used to determine the neuroprotective effects. The HIF-1[Formula: see text] accumulation, and S1P metabolism were assayed in the berberine-preconditioned neurons, and the HIF-1[Formula: see text]-mediated transcriptional modulation of sphingosine kinases (Sphk) 1 and 2 was analyzed using chromatin immunoprecipitation and real-time polymerase chain reaction. BP significantly prevented cerebral ischemic injury in the MCAO rats at 24[Formula: see text]h and 72[Formula: see text]h following ischemia/reperfusion. In OGD-treated neurons, BP enhanced HIF-1[Formula: see text] accumulation with activation of PI3K/Akt, and induced S1P production by activating Sphk2 via the promotion of HIF-1[Formula: see text]-mediated Sphk2 transcription. In conclusion, BP activated endogenous neuroprotective mechanisms associated with the S1P/HIF-1 pathway and helped protect neuronal cells against hypoxia/ischemia.

cGAS-STING signaling regulates control of microglia polarization in cerebral ischemic stroke

2020 ◽  
Author(s):  
Guoliang Jiang ◽  
Xinglong Yang ◽  
Houjun Zhou ◽  
Jiang Long ◽  
Linming Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Response ◽  
Cell Model ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Ht22 Cells ◽  
Bv2 Microglia ◽  
Cerebral Ischemic Stroke ◽  
Sting Pathway ◽  
Cerebral Ischemic

Abstract Background Cerebral ischemic stroke is a highly debilitating disease, in which inflammation is well document to play a pivotal role in its pathophysiology. Microglia are the the major immuncompetent cells of the brain involved in different neuropathologies. Recent discovery of cyclic GMP-AMP synthase(cGAS) activation and its induction of the downstream signaling protein stimulator of interferon genes (STING) is increasingly recognized as a crucial determinant of neuropathophysiology. Although cGAS-STING pathway has been reported to play an important role in inflammatory response in myocardial infarction (MI), its mechanism in inflammatory response in ischemic stroke (IS) has remained to be fully explored.Methods In light of the above, this study sought to explore the roles of cGAS-STING pathway in inflammatory reaction in IS. It is hoped that the results would provide new insights for designing of therapeutic strategies targeting at IS. We used HT22 cells to establish an oxygen-glucose deprivation (OGD) cell model. The supernatant derived from this and which contained OGD-induced DAMPs(OIDs) was used to stimulate the BV2 microglia. Additionally, we used siRNA technology to interfere with cGAS gene expression to observe changes in downstream cytokines. Furthermore, we established middle cerebral artery occlusion (MCAO) mouse model and performed cGAS-siRNA lentivirus infection to further elucidate the mechanism of cGAS-STING pathway in vivo.Results We show here that OIDs strongly activated the cGAS-STING pathway and triggered accumulation of a plethora of proinflammatory factors in activated Microglia. Of note, the cascade reaction was successfully inhibited by cGAS-siRNA. Furthermore, we extended the study of cGAS-STING in a mouse MCAO model, which showed that inhibiting cGAS-STING pathway can effectively diminish MIDs(MCAO-induced DAMPs)-induced neuronal apoptosis and ultimately functional improvement.Conclusion The present results have shown GAS-STING signaling pathway controls the polarity transformation of microglia. The underlying mechanisms of cGAS-STING triggering microglial inflammatory response is now better clarified which made the pathway a potential therapeutic target of IS.

scholarly journals Apocynin promotes neural function recovery and suppresses neuronal apoptosis by inhibiting Tlr4/NF-κB signaling pathway in a rat model of cerebral infarction

2018 ◽  
Vol 32 ◽  
pp. 205873841881770
Author(s):  
Lemen Pan ◽  
Shuxia Qian
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Cerebral Infarction ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neuronal Apoptosis ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
And Oxidative Stress

Occlusion of arteries in the brain is a common cause of cerebral infarction which induces inflammatory response and oxidative stress resulting in neuronal apoptosis and disruption of neurological function. The present study investigated the protective roles of an nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, against cerebral infarction. Rat went through a surgery of middle cerebral artery occlusion and a subset of rats was treated with apocynin by intraperitoneal injection. The volume of cerebral infarction and water content were measured. Neuronal apoptosis, inflammatory response, and oxidative stress were assessed following middle cerebral artery occlusion and apocynin treatment. We found that apocynin significantly improved neurological function, increased forelimb placement test scores, and suppressed balance beam walk latency in rats with cerebral infarction. Histological and biochemistry analysis revealed that apocynin lead to a significant reduction in the volume of cerebral infarction as well as cerebral water content, suppressed neuronal apoptosis, oxidative stress, and inflammatory response induced by middle cerebral artery occlusion. Finally, we found that apocynin suppressed Tlr4/nuclear factor-k-gene binding signaling pathway that was upregulated in rats with cerebral infarction. Our results indicate that apocynin may represent a potent therapeutic strategy in alleviating neurological dysfunctions in patients with cerebral infarction.

scholarly journals The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke

2021 ◽  
Author(s):  
Yong-Ming Zhu ◽  
Liang Lin ◽  
Chao Wei ◽  
Yi Guo ◽  
Yuan Qin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Glial Scar ◽  
Scar Formation ◽  
Reactive Astrocytes ◽  
Interacting Protein ◽  
Protein Levels ◽  
Endothelial Growth Factor ◽  
Cerebral Artery Occlusion

AbstractNecroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar. Graphical Abstract

Activation of astroglial CB1R mediates cerebral ischemic tolerance induced by electroacupuncture

2021 ◽  
pp. 0271678X2199439
Author(s):  
Cen Yang ◽  
Jingjing Liu ◽  
Jingyi Wang ◽  
Anqi Yin ◽  
Zhenhua Jiang ◽  
...  
Keyword(s):  
Endocannabinoid System ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Protective Mechanisms ◽  
Promising Therapeutic Approach ◽  
Subsequent Activation ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion ◽  
The Brain

There are no effective treatments for stroke. The activation of endogenous protective mechanisms is a promising therapeutic approach, which evokes the intrinsic ability of the brain to protect itself. Accumulated evidence strongly suggests that electroacupuncture (EA) pretreatment induces rapid tolerance to cerebral ischemia. With regard to mechanisms underlying ischemic tolerance induced by EA, many molecules and signaling pathways are involved, such as the endocannabinoid system, although the exact mechanisms have not been fully elucidated. In the current study, we employed mutant mice, neuropharmacology, microdialysis, and virus transfection techniques in a middle cerebral artery occlusion (MCAO) model to explore the cell-specific and brain region-specific mechanisms of EA-induced neuroprotection. EA pretreatment resulted in increased ambient endocannabinoid (eCB) levels and subsequent activation of ischemic penumbral astroglial cannabinoid type 1 receptors (CB1R) which led to moderate upregulation of extracellular glutamate that protected neurons from cerebral ischemic injury. These findings provide a novel cellular mechanism of EA and a potential therapeutic target for ischemic stroke.

scholarly journals Eye Opener in Stroke

Stroke ◽  
2019 ◽  
Vol 50 (8) ◽  
pp. 2197-2206 ◽  
Author(s):  
Hung Nguyen ◽  
Jea Young Lee ◽  
Paul R. Sanberg ◽  
Eleonora Napoli ◽  
Cesar V. Borlongan
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Glucose Deprivation ◽  
Retinal Ischemia ◽  
Artery Occlusion ◽  
Oxygen Glucose Deprivation ◽  
Retinal Pigmented Epithelium ◽  
Pigmented Epithelium ◽  
Cerebral Artery Occlusion ◽  
Epithelium Cells

Background and Purpose— Retinal ischemia is a major cause of visual impairment in stroke patients, but our incomplete understanding of its pathology may contribute to a lack of effective treatment. Here, we investigated the role of mitochondrial dysfunction in retinal ischemia and probed the potential of mesenchymal stem cells (MSCs) in mitochondrial repair under such pathological condition. Methods— In vivo, rats were subjected to middle cerebral artery occlusion then randomly treated with intravenous MSCs or vehicle. Laser Doppler was used to evaluate the blood flow in the brain and the eye, while immunohistochemical staining assessed cellular degeneration at days 3 and 14 poststroke. In vitro, retinal pigmented epithelium cells were exposed to either oxygen-glucose deprivation or oxygen-glucose deprivation and coculture with MSCs, and subsequently, cell death and mitochondrial function were examined immunocytochemically and with Seahorse analyzer, respectively. Results— Middle cerebral artery occlusion significantly reduced blood flow in the brain and the eye accompanied by mitochondrial dysfunction and ganglion cell death at days 3 and 14 poststroke. Intravenous MSCs elicited mitochondrial repair and improved ganglion cell survival at day 14 poststroke. Oxygen-glucose deprivation similarly induced mitochondrial dysfunction and cell death in retinal pigmented epithelium cells; coculture with MSCs restored mitochondrial respiration, mitochondrial network morphology, and mitochondrial dynamics, which likely attenuated oxygen-glucose deprivation-mediated retinal pigmented epithelium cell death. Conclusions— Retinal ischemia is closely associated with mitochondrial dysfunction, which can be remedied by stem cell-mediated mitochondrial repair.

scholarly journals Alleviation of Cerebral Infarction of Rats With Middle Cerebral Artery Occlusion by Inhibition of Aquaporin 4 in the Supraoptic Nucleus

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142096055 ◽  
Author(s):  
Dan Cui ◽  
Shuwei Jia ◽  
Jiawei Yu ◽  
Dongyang Li ◽  
Tong Li ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Infarction ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Supraoptic Nucleus ◽  
Artery Occlusion ◽  
Aquaporin 4 ◽  
Vasopressin Neurons ◽  
Cerebral Artery Occlusion

In ischemic stroke, vasopressin hypersecretion is a critical factor of cerebral swelling and brain injury. To clarify neural mechanisms underlying ischemic stroke-evoked vasopressin hypersecretion, we observed the effect of unilateral permanent middle cerebral artery occlusion (MCAO) in rats on astrocytic plasticity and vasopressin neuronal activity in the supraoptic nucleus (SON) as well as their associated cerebral injuries. MCAO for 8 hr caused cerebral infarction in the MCAO side where water contents also increased. Immunohistochemical examination revealed that the percentage of phosphorylated extracellular signal-regulated protein kinase 1/2 (pERK1/2)-positive vasopressin neurons in the SON of MCAO side was significantly higher than that in non-MCAO side and in sham group. In the cortex, pERK1/2 and aquaporin 4 expressions increased significantly in the infarction area, while glial fibrillary acidic protein (GFAP) reduced significantly compared with the noninfarction side in brain cortex. Microinjection of N-(1,3,4-Thiadiazolyl)nicotinamide-020 [TGN-020, a specific blocker of aquaporin 4] into the SON blocked MCAO-evoked increases in pERK1/2 in the SON as well as the reduction of GFAP and the increase in pERK1/2 and aquaporin 4 in the infarction area of the cortex. Finally, oxygen and glucose deprivation reduced GFAP expression and the colocalization and molecular association of GFAP with aquaporin 4 in the SON in brain slices. These effects were blocked by TGN-020 and/or phloretin, a blocker of astrocytic volume-regulated anion channels. These findings indicate that blocking aquaporin 4 in the SON may reduce the activation of vasopressin neurons and brain injuries elicited by vasopressin during ischemic stroke.

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