Inflammation In Ischemic Stroke Research Articles

Bibliometric insights into the inflammation and mitochondrial stress in ischemic stroke

BackgroundResearch in the areas of inflammation and mitochondrial stress in ischemic stroke is rapidly expanding, but a comprehensive overview that integrates bibliometric trends with an in-depth review of molecular mechanisms is lacking. ObjectiveTo map the evolving landscape of research using bibliometric analysis and to detail the molecular mechanisms that underpin these trends, emphasizing their implications in ischemic stroke. MethodsWe conducted a bibliometric analysis to identify key trends, top contributors, and focal research themes. In addition, we review recent research advances in mitochondrial stress and inflammation in ischemic stroke to gain a detailed understanding of the pathophysiological processes involved. ConclusionOur integrative approach not only highlights the growing research interest and collaborations but also provides a detailed exploration of the molecular mechanisms that are central to the pathology of ischemic stroke. This synthesis offers valuable insights for researchers and paves the way for targeted therapeutic interventions.

The role of SUMO specific peptidase 3 in secondary inflammation of ischemic stroke in mice

Ischemic stroke is the main cause of death and disability, and microglia play a crucial role in the pathophysiology of hypoxic ischemic brain injury. We found that SENP3 is highly expressed in the early stages of ischemic stroke in both in vivo and in vitro mouse models, and may be related to the deSUMOylation of the key kinase MKK7 in the TLR4/p-JNK signaling pathway. Knocking down SENP3 can inhibit the deSUMOylation of MKK7, thereby inhibiting the activation of the TLR4/p-JNK signaling pathway in an in vitro stroke model. Proteomic analysis showed that SENP3 undergoes phosphorylation at the T429 site after ischemic stroke. Computer simulation predictions show a significant enhancement of the interaction between pT429-SENP3 and MKK7, which has been confirmed through experiments on the interaction of biological macromolecules (SPR). The mitochondrial metabolic abnormalities caused by energy abnormalities in the early stages of stroke provide a good explanation for the phosphorylation of SENP3. Therefore, we used the mitochondrial complex inhibitor TTFA to reverse demonstrate that the phosphorylation of SENP3 comes from the large amount of adenosine triphosphate produced by mitochondrial abnormal metabolism caused by early oxygen glucose deficiency. Finally, proteomic analysis indicates that a significant amount of oxidative phosphorylation does occur in the early stages of stroke. In summary, targeted regulation of SENP3 phosphorylation to affect the deSUMOylation of MKK7 may inhibit secondary inflammation in ischemic stroke.

Current status and prospects for development of therapy targeting post-ischemic inflammation in ischemic stroke

Current status and prospects for development of therapy targeting post-ischemic inflammation in ischemic stroke

Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke.

Ischemic-induced neuronal injury arises due to low oxygen/nutrient levels and an inflammatory response that exacerbates neuronal loss. NOD-like receptor family pyrin domain-containing 3 (NLRP3) is an important regulator of inflammation after ischemic stroke, with its inhibition being involved in nerve regeneration. Curcumin, a main active ingredient in Chinese herbs, plays a positive role in neuronal repair and neuroprotection by regulating the NLRP3 signaling pathway. Nevertheless, the signaling mechanisms relating to how curcumin regulates NLRP3 inflammasome in inflammation and neural restoration following ischemic stroke are unknown. In this report, we summarize the main biological functions of the NLRP3 inflammasome along with the neuroprotective effects and underlying mechanisms of curcumin via impairment of the NLRP3 pathway in ischemic brain injury. We also discuss the role of medicinal interventions that target the NLRP3 and potential pathways, as well as possible directions for curcumin therapy to penetrate the blood-brain barrier (BBB) and hinder inflammation in ischemic stroke. This report conclusively demonstrates that curcumin has neuroprotective properties that inhibit inflammation and prevent nerve cell loss, thereby delaying the progression of ischemic brain damage.

Elastin-like polypeptide delivery of anti-inflammatory peptides to the brain following ischemic stroke.

Inflammatory processes are activated following ischemic stroke that lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to the drug carrier elastin-like polypeptide (ELP), decreases NF-κB induced inflammatory cytokine production in cultured macrophages, crosses the plasma membrane and accumulates in the cytoplasm of both neurons and microglia in vitro, and accumulates at the infarct site where the blood-brain barrier (BBB) is compromised following middle cerebral artery occlusion (MCAO) in rats. Additionally, SynB1-ELP-p50i treatment reduces infarct volume by 11.86% compared to saline-treated controls 24 h following MCAO. Longitudinally, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP-delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.

The mechanism of microglia-mediated immune inflammation in ischemic stroke and the role of natural botanical components in regulating microglia: A review.

Ischemic stroke (IS) is one of the most fatal diseases. Neuroimmunity, inflammation, and oxidative stress play important roles in various complex mechanisms of IS. In particular, the early proinflammatory response resulting from the overactivation of resident microglia and the infiltration of circulating monocytes and macrophages in the brain after cerebral ischemia leads to secondary brain injury. Microglia are innate immune cells in the brain that constantly monitor the brain microenvironment under normal conditions. Once ischemia occurs, microglia are activated to produce dual effects of neurotoxicity and neuroprotection, and the balance of the two effects determines the fate of damaged neurons. The activation of microglia is defined as the classical activation (M1 type) or alternative activation (M2 type). M1 type microglia secrete pro-inflammatory cytokines and neurotoxic mediators to exacerbate neuronal damage, while M2 type microglia promote a repairing anti-inflammatory response. Fine regulation of M1/M2 microglial activation to minimize damage and maximize protection has important therapeutic value. This review focuses on the interaction between M1/M2 microglia and other immune cells involved in the regulation of IS phenotypic characteristics, and the mechanism of natural plant components regulating microglia after IS, providing novel candidate drugs for regulating microglial balance and IS drug development.

OIP5-AS1 Inhibits Oxidative Stress and Inflammation in Ischemic Stroke Through miR-155-5p/IRF2BP2 Axis.

Ischemic stroke is a very dangerous disease with high incidence, fatality and disability rate in human beings. Massive evidence has indicated that oxidative stress and inflammation are intimately correlated with progression of ischemic stroke. Additionally, LncRNAs were reported to be involved in ischemic stroke. Here, we aim to explore the effects and molecular mechanism of lncRNA OIP5-AS1 on oxidative stress and inflammation in ischemic stroke. HMC3 and SH-SY5Y cells were under the condition of oxygen-glucose deprivation/reoxygenation (OGD/R) treatment to establish cell models of ischemic stroke. Commercial kits were employed to detect the indicators of oxidative stress including ROS, MDA and SOD. The expression of OIP5-AS1, miR-155-5p and IRF2BP2 mRNA was determined using RT-qPCR. The protein levels of inflammatory factors including TNF-α, IL-1β and IL-6 and IRF2BP2 were assessed by western blot and/or ELISA. Luciferase activity assay was employed to validate their correlations among OIP5-AS1, miR-155-5p and IRF2BP2. In OGD/R-induced HMC3 and SH-SY5Y cells, the expression of OIP5-AS1 and IRF2BP2 was reduced while miR-155-5p was elevated. OGD/R induction promoted oxidative stress and inflammatory response in HMC3 and SH-SY5Y cells, while OIP5-AS1 or IRF2BP2 sufficiency as well as miR-155-5p inhibitor attenuated OGD/R-induced these influences. In addition, IRF2BP2 knockdown abolished the suppressive impacts of OIP5-AS1 overexpression on oxidative stress and inflammatory response in OGD/R-induced HMC3 and SH-SY5Y cells. Mechanistically, OIP5-AS1 enhanced IRF2BP2 expression via sponging miR-155-5p. OIP5-AS1 suppressed oxidative stress and inflammatory response to alleviate cell injury caused by OGD/R induction in HMC3 and SH-SY5Y cells through regulating miR-155-5p/IRF2BP2 axis, which might offer novel targeted molecules for ischemic stroke therapy.

Bone marrow mesenchymal stem cell-derived exosomes carrying long noncoding RNA ZFAS1 alleviate oxidative stress and inflammation in ischemic stroke by inhibiting microRNA-15a-5p.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes can prevent oxidative stress and inflammation in cerebral ischemia-reperfusion injury. This study intended to assess influences of BMSC-released exosomes on oxidative stress and inflammation following ischemic stroke. In vitro and in vivo models were developed using oxygen-glucose deprivation/reperfusion (OGD/R) and middle cerebral artery occlusion (MCAO), respectively. After exosome isolation, co-culture experiments of BMSCs or BMSC-derived exosomes and OGD/R-treated BV-2 cells were implemented to evaluate the impacts of BMSCs or BMSC-secreted exosomes on proliferation, inflammation, oxidative stress, and apoptosis. The gain-of-function experiments of ZFAS1 or microRNA (miR)-15a-5p were conducted to investigate the associated mechanisms. Besides, MCAO mice were injected with exosomes from BMSCs overexpressing ZFAS1 for in vivo verification. The binding of ZFAS1 to miR-15a-5p was assessed through dual-luciferase reporter gene assay. Co-culture with BMSCs accelerated proliferation and downregulated IL-1β, IL-6, and TNF-α in OGD/R-exposed BV-2 cells, accompanied by increased SOD level and decreased MDA level and apoptosis, all of which were nullified by inhibiting exosome secretion. Mechanistically, ZFAS1 bound to miR-15a-5p to negatively orchestrate its expression. In addition, BMSC-released exosomes or BMSC-secreted exosomal ZFAS1 augmented proliferation but reduced oxidative stress, apoptosis, and inflammation in OGD/R-exposed BV-2 cells, whereas these impacts of BMSC-released exosomal ZFAS1 were nullified by overexpressing miR-15a-5p. Moreover, BMSC-derived exosomal ZFAS1 diminished MCAO-induced oxidative stress, cerebral infarction, and inflammation in mice. Conclusively, BMSC-released exosomes might carry long noncoding RNA ZFAS1 to curb oxidative stress and inflammation related to ischemic stroke, which was possibly realized through miR-15a-5p inhibition.

Thrombo-Inflammation and Immunological Response in Ischemic Stroke: Focusing on Platelet-Tregs Interaction.

Strokes are mainly caused by thromboembolic obstruction of a major cerebral artery. Major clinical manifestations include paralysis hemiplegia, aphasia, memory, and learning disorders. In the case of ischemic stroke (IS), hyperactive platelets contribute to advancing an acute thrombotic event progression. Therefore, the principal goal of treatment is to recanalize the occluded vessel and restore cerebral blood flow by thrombolysis or mechanical thrombectomy. However, antiplatelets or thrombolytic therapy may increase the risk of bleeding. Beyond the involvement in thrombosis, platelets also contribute to the inflammatory process induced by cerebral ischemia. Platelet-mediated thrombosis and inflammation in IS lie primarily in the interaction of platelet receptors with endothelial cells and immune cells, including T-cells, monocytes/macrophages, and neutrophils. Following revascularization, intervention with conventional antiplatelet medicines such as aspirin or clopidogrel does not substantially diminish infarct development, most likely due to the limited effects on the thrombo-inflammation process. Emerging evidence has shown that T cells, especially regulatory T cells (Tregs), maintain immune homeostasis and suppress immune responses, playing a critical immunomodulatory role in ischemia-reperfusion injury. Hence, considering the deleterious effects of inflammatory and immune responses, there is an urgent need for more targeted agents to limit the thrombotic-inflammatory activity of platelets and minimize the risk of a cerebral hemorrhage. This review highlights the involvement of platelets in neuroinflammation and the evolving role of Tregs and platelets in IS. In response to all issues, preclinical and clinical strategies should generate more viable therapeutics for preventing and managing IS with immunotherapy targeting platelets and Tregs.

Long non-coding RNA H19 promotes leukocyte inflammation in ischemic stroke by targeting the miR-29b/C1QTNF6 axis.

AimsInflammatory processes induced by leukocytes are crucially involved in the pathophysiology of acute ischemic stroke. This study aimed to elucidate the inflammatory mechanism of long non‐coding RNA (lncRNA) H19‐mediated regulation of C1q and tumor necrosis factor 6 (C1QTNF6) by sponging miR‐29b in leukocytes during ischemic stroke.MethodsH19 and miR‐29b expression in leukocytes of patients with ischemic stroke and rats with middle cerebral artery occlusion were measured by real‐time polymerase chain reaction. H19 siRNA and miR‐29b antagomir were used to knock down H19 and miR‐29b, respectively. We performed in vivo and in vitro experiments to determine the impact of H19 and miR‐29b on C1QTNF6 expression in leukocytes after ischemic injury.ResultsH19 and C1QTNF6 upregulation, as well as miR‐29b downregulation, was detected in leukocytes of patients with stroke. Moreover, miR‐29b could bind C1QTNF6 mRNA and repress its expression, while H19 could sponge miR‐29b to maintain C1QTNF6 expression. C1QTNF6 overexpression promoted the release of IL‐1β and TNF‐α in leukocytes, further exacerbated blood‐brain barrier disruption, and aggravated the cerebral ischemic injury.ConclusionsOur findings confirm that H19 promotes leukocyte inflammation by targeting the miR‐29b/C1QTNF6 axis in cerebral ischemic injury.

Guhong Injection Prevents Ischemic Stroke-Induced Neuro-Inflammation and Neuron Loss Through Regulation of C5ar1.

C5ar1 (CD88) has been identified as an important potential therapeutic target for regulating inflammation in ischemic stroke. In this study, the neuroprotective effect of Guhong injection (GHI) on middle cerebral artery occlusion (MCAO)-induced reperfusion injury was assessed and the mechanism was explored by RNA-seq technology. GHI administered for 6 consecutive days significantly decreased body weight loss, infarction rate, neurological deficient scores, and neuron loss but improved rat survival percentage and regional cerebral blood flow after MCAO surgery. Furthermore, we identified inflammation as a vital process and C5AR1 as a vital target in GHI-mediated protection by using RNA-seq analysis. Further experiments confirmed that GHI decreased C5AR1, C5A, CASP3, 8-OHdG, and inflammatory factors such as IL-1β, TNF, IL6, ICAM-1, MMP9, and MCP-1, and enhanced the expression of TIMP1, JAM-A, and laminin. Furthermore, GHI and its major components hydroxysafflower yellow A (HSYA) and aceglutamide (AG) enhanced cell viability and reduced LDH level and C5AR1 expression in a C5A-induced Neuro-2a cell damage model. In general, this study elucidated the mechanism of GHI against ischemic stroke by inhibiting inflammation and highlighted the potential important role of C5AR1 in ischemic stroke. This research provided new insights into the mechanism of GHI in resisting ischemic stroke and benefits of its clinical application.

Evaluation of anti-inflammatory diphenyldihaloketone EF24 in transient ischemic stroke model

ABSTRACT Objectives Revascularization is necessary in patients with ischemic stroke, however it does not address inflammation that contribute to reperfusion injury and the early growth of ischemic core. We investigated EF24, an anti-inflammatory agent, in a stroke model. Methods Ischemic stroke was induced in mice by occluding middle cerebral artery for 1 h followed by reperfusion. EF24 was given either 10 min post-reperfusion (EF24Post) or 10 min before occlusion (prophylactic, EF24Pro). Survival, ipsilateral uptake of radioactive infarct marker 18F-fluoroglucaric acid (FGA), inflammatory cytokines, and tetrazolium chloride (TTC) staining were assessed. Results Survival was increased in both EF24-treated groups compared to the stroke+vehicle group. Ipsilateral 18F-FGA uptake increased 2.6-fold in stroke+vehicle group compared to sham group (p < 0.05); the uptake in EF24-treated groups and sham group was not significantly different. TTC-staining also showed reduction in infarct size by EF24 treatment. Plasma IL-6, TNF-α, and corticosterone did not show significant changes among groups. However, ipsilateral tissue in stroke+vehicle mice showed increased IL-6 (>90-fold) and TNF-α (3-fold); the tissue IL-6 and TNF-α were significantly reduced in stroke+EF24Pro and stroke+EF24Post groups. 18F-FGA uptake significantly correlated with tissue IL-6 levels. Conclusions EF24 controls infarct growth and suppresses tissue inflammation in ischemic stroke, which can be monitored by 18F-FGA uptake.

NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in vitro and protects blood\u2013brain barrier integrity in murine stroke

In ischemic stroke (IS) impairment of the blood–brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and—in good agreement with the in vitro results—MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC.

Platelet-Mediated NET Formation Exacerbates Ischemic Stroke Brain Injury

▪Background: Ischemic stroke provokes a strong inflammatory response which has been shown to exacerbate ischemic stroke brain injury in mice and is associated with worse outcomes in ischemic stroke patients. Classic anti-inflammatory strategies have been unsuccessful in clinical trials for ischemic stroke, implying other mechanisms contribute to injurious inflammation in ischemic stroke. Immunothrombosis is the interplay between coagulation, platelet activation and the innate immune system leading to thrombosis. A critical component of immunothrombosis is the formation of neutrophil extracellular traps (NETs). In this study, we investigated mechanistic regulators of NET formation in stroke and if they contribute to ischemic stroke outcomes.Methods: Markers of immunothrombosis were assessed in plasma from ischemic stroke patients and healthy matched donors. Flow cytometry was used to characterize platelet and neutrophil function. For murine studies, we used male and female C57Bl/6 mice that were subjected to transient middle cerebral artery occlusion. Stroke outcomes were assessed 24 hours or 7 days after stroke using neurological and motor function testing as well as brain infarct size analysis.Results: Ischemic stroke patients had significantly increased plasma biomarkers of immunothrombosis including D-Dimers (coagulation), platelet factor 4 (platelet activation) and calprotectin (neutrophil activation). Moreover, specific markers of NET formation including citrullinated histone H3 (H3cit) and MPO-DNA complexes were significantly elevated in ischemic stroke patients. Interestingly, H3cit and MPO-DNA complexes positively correlated with worse stroke outcomes at discharge while they did not correlate with stroke severity at admission.Next, we observed increased plasma and platelet surface expressed high mobility group box 1 (HMGB1) in ischemic stroke patients compared to matched healthy controls. NETs were found in platelet-rich areas in ischemic stroke thrombi, and HMGB1 colocalized with platelets in ischemic stroke thrombi. Blocking platelet-derived HMGB1 in vitro prevented platelet-induced NET formation. Mechanistically, depleting platelets in mice reduced plasma HMGB1 levels as well as NET formation and improved outcomes after ischemic stroke. In contrast, depleting neutrophils did not affect plasma HMGB1 levels, but reduced plasma NETs and improved stroke outcomes. Treatment of mice with a competitive HMGB1 inhibitor (BoxA) reduced NET formation and improved stroke outcomes. Combined, these results imply a causative role for platelet-derived HMGB1 in mediating detrimental NET formation after ischemic stroke.Finally, as NETs appeared injurious in ischemic stroke, we investigated the therapeutic potential of a recently discovered neonatal NET inhibitory factor (nNIF). nNIF is a cleavage fragment of alpha-1-antitrypsin and specifically blocks NET formation in human and murine neutrophils without affecting other critical neutrophil functions such as chemotaxis or phagocytosis. Mice treated with nNIF had reduced brain and plasma NETs after stroke while cerebral neutrophil recruitment remained unaffected. The reduction in NET formation after stroke was associated with reduced neuronal apoptosis and smaller brain infarcts. Furthermore, nNIF treated mice had improved neurological and motor function and enhanced 7-day survival after ischemic stroke.Conclusions: These results support a pathological role for NETs in acute ischemic stroke and warrant further investigation into nNIF as a therapeutic to improve stroke outcomes. DisclosuresNeal: Instrumentation Laboratories: Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Haima Therapeutics: Membership on an entity's Board of Directors or advisory committees; Haemonetics: Honoraria, Research Funding.

MiR-499a prevents astrocytes mediated inflammation in ischemic stroke by targeting PTEN.

IntroductionIschemic stroke (IS) is a common and severe neurological disorder and is associated with high rates of mortality and morbidity. Inflammatory reaction in astrocytes is one of the important pathological factors of stroke. Improved understanding of the underlying molecular mechanisms should aid better treatment of the disease. This study aimed to test our hypothesis that a miR-499a played an important role in the inflammatory response in astrocytes induced by IS targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN).MethodsThis study was comprised of two models: oxygen-glucose deprivation (OGD) and reoxygenation model. Quantitative real-time PCR (qRT-PCR) and Western blot were used to examine gene expression levels, and MTT assay analysis were used to examine cell states. The relationships between miR-499a and PTEN were confirmed by luciferase reporter assay.ResultsMiR-499a was robustly downregulated with OGD induced injury in astrocytes. Forced transient expression of miR-499a in OGD astrocytes nearly completely reversed the inflammatory response. Knockdown of miR-499a by its specific inhibitor in healthy astrocytes induced the inflammatory response resembling those produced by OGD. On the other hand, PTEN was markedly upregulated in OGD astrocytes, which was reciprocal to the expression of miR-499a. PTEN was experimentally validated as a direct target gene for miR-499a. Overexpression of PTEN was able to induce an inflammatory response of astrocytes. Moreover, PTEN siRNA counteracted the inflammatory response induced by OGD.ConclusionsTaken together, our findings indicate miR-499a as an important factor to prevent inflammatory response and suggest miR-499a as a new molecule for the treatment of IS. The present study also demonstrated the relationship between miR-499a and PTEN, with PTEN as a downstream signaling mediator of miR-499a in the inflammatory response of astrocytes induced by IS.

Lipid mediators and sterile inflammation in ischemic stroke

Stroke is one of the major causes of lethality and disability, yet few effective therapies have been established for ischemic stroke. Inflammation in the ischemic brain is induced by the infiltration and subsequent activation of immune cells. Loss of cerebral blood flow and ischemic brain-cell death trigger the activation of infiltrating immune cells and drastic changes in the lipid content of the ischemic brain. In particular, polyunsaturated fatty acids and their metabolites regulate cerebral post-ischemic inflammation and ischemic stroke pathologies. In this review, we discuss the relationships between the lipid mediators and cerebral post-ischemic inflammation and their relevance to possible future therapeutic strategies targeting lipid mediators for ischemic stroke.

CD99 mediates neutrophil transmigration through the bEnd.3 monolayer via the induction of oxygen-glucose deprivation

Aim/backgroundCD99 participate in neutrophil infiltration after inflammatory events; however, despite the important role of inflammation in ischemic stroke, the role of CD99 in ischemic stroke remains unclear. MethodIn the present study, we detected the protein expression of CD99, ICAM-1, and CD31 (PECAM-1) in oxygen-glucose deprivation (OGD)-induced bEnd.3 cells and neutrophils and explored the influence of HIF-1α and IL-1β on their expression. We also explored the role of CD99 in the OGD-induced transmigration of neutrophils. ResultsOur results showed that OGD induction upregulated CD99 in bEnd.3 cells and that this effect could be abolished by the preadministration of IL-1β and was not mediated by HIF-1α. However, the activation of ICAM-1 by OGD remained activated with IL-1β treatment. No significant influence of IL-1β on OGD-induced CD31. Finally, we found a significant increase in infiltrated neutrophils after OGD induction compared with the control and OGD + anti-CD99 groups. ConclusionOur results indicated that CD99 mediates neutrophil infiltration and transmigration via OGD induction and thus constitutes a potential therapeutic target for anti-inflammatory treatment after ischemic stroke.

Hypothermia treatment reduced cyclin-dependent kinase 5-mediated inflammation in ischemic stroke and improved outcomes in ischemic stroke patients

Dear Editor, We read with interest the article by Sun et al. concerning the reduction of inflammation with therapeutic hypothermia in acute ischemic stroke (). In this study, the authors demonstrated the improvement of inflammatory biomarkers after hypothermia treatment in both animal cerebral infarct models and patients with ischemic stroke. […] Hypothermia treatment reduced cyclin-dependent kinase 5-mediated inflammation in ischemic stroke and improved outcomes in ischemic stroke patients

Neutrophil Membrane-Derived Nanovesicles Alleviate Inflammation To Protect Mouse Brain Injury from Ischemic Stroke.

Ischemic stroke is an acute and severe neurological disease, resulting in disability and death. Reperfusion to an ischemic brain is a means to reverse brain damage after stroke; however, this causes secondary tissue damage induced by inflammation responses, called ischemia/reperfusion (I/R) injury. Adhesion of neutrophils to endothelial cells underlies the initiation of inflammation in I/R. Inspired by this interaction, we report a drug delivery system comprised of neutrophil membrane-derived nanovesicles loaded with Resolvin D2 (RvD2) that can enhance resolution of inflammation, thus protecting brain damage during ischemic stroke. In the study, the middle cerebral artery occlusion (MCAO) mouse model was developed to mimic ischemic stroke. Using intravital microscopy of a live mouse brain, we visualized the binding of nanovesicles to inflamed brain vasculature for delivery of therapeutics to ischemic stroke lesionsin real-time. We also observed that RvD2-loaded nanovesicles dramatically decreased inflammation in ischemic stroke and improved mouse neurological functions. Our study provides a strategy to inhibit neuroinflammation using neutrophil-derived nanovesicles for ischemic stroke therapy.

Hypothermia treatment ameliorated cyclin-dependent kinase 5-mediated inflammation in ischemic stroke and improved outcomes in ischemic stroke patients

OBJECTIVES:The inflammatory response is a key mechanism of neuronal damage and loss during acute ischemic stroke. Hypothermia has shown promise as a treatment for ischemic stroke. In this study, we investigated the molecular signaling pathways in ischemic stroke after hypothermia treatment.METHODS:Cyclin-dependent kinase 5 (CDK5) was overexpressed or silenced in cultured cells. Nuclear transcription factor-κB (NF-κB) activity was assessed by measurement of the luciferase reporter gene. An ischemic stroke model was established in Sprague-Dawley (SD) rats using the suture-occluded method. Animals were assigned to three groups: sham operation control, ischemic stroke, and ischemic stroke + hypothermia treatment groups. Interleukin 1β (IL-1β) levels in the culture supernatant and blood samples were assessed by ELISA. Protein expression was measured by Western blotting.RESULTS:In HEK293 cells and primary cortical neuronal cultures exposed to hypothermia, CDK5 overexpression was associated with increased IL-1β, caspase 1, and NF-κB levels. In both a murine model of stroke and in patients, increased IL-1β levels were observed after stroke, and hypothermia treatment was associated with lower IL-1β levels. Furthermore, hypothermia-treated patients showed significant improvement in neurophysiological functional outcome.CONCLUSIONS:Overall, hypothermia offers clinical benefit, most likely through its effects on the inflammatory response.