Risk factors and characteristics of ischemic stroke in patients with immune thrombocytopenia: A retrospective cohort study.

OBJECTIVES: Previous research has found that patients with immune thrombocytopenia (ITP) have an increased risk of thrombosis, such as venous thromboembolism (VT), ischemic stroke (IS)/transient ischemic attack (TIA), and cardiovascular disease (CVD), but the risk factors for stroke in patients with ITP have yet to be determined. This study aims to determine the risk factors and characteristics of ischemic stroke in patients with ITP. MATERIALS AND METHODS: This study included adults with incident primary ITP diagnosed in a tertiary medical center between 2010 and 2020. The t-test and Mann-Whitney U test were used to compare the variables between IS and non-IS groups, and the multivariate logistic regression model was employed to evaluate correlations. RESULTS: The study enrolled 1824 individuals, of whom 17 (0.93%) had IS, and 138 (1:8) were randomly chosen from 1807 non-IS patients. Age was found to be substantially associated with stroke in the multivariate analysis (OR 1.07, 95% CI: 1.026-1.116; p = 0.001). We found no correlation between platelet counts (PLT) (OR 1.013, 95% CI: 0.995-1.033; p = 0.164), mean platelet volume (MPV), platelet larger cell ratio (P-LCR), prothrombin time (PT) (OR 1.455, 95% CI 0.979-2.164; p = 0.064), activated partial thromboplastin time (APTT), D-dimer, fibrinogen or antinuclear antibody (ANA) and stroke. Of 17 ITP-IS patients, 7 (53.8%) were cryptogenic, greater than the general IS population. Three (23.1%) of them had an embolic pattern. CONCLUSION: For ITP patients, age was a significant predictor of stroke. ITP-IS patients had a more cryptogenic origin, with some showing an embolic pattern.

MicroRNA-126-3p/-5p Overexpression Attenuates Blood-Brain Barrier Disruption in a Mouse Model of Middle Cerebral Artery Occlusion.

Background and Purpose- Blood-brain barrier (BBB) disruption is a critical pathological feature after stroke. MicroRNA-126 (miR-126) maintains BBB integrity by regulating endothelial cell function during development. However, the role of miR-126-3p and -5p in BBB integrity after stroke is unclear. Here, we investigated whether miR-126-3p and -5p overexpression regulates BBB integrity after cerebral ischemia. Methods- A lentivirus carrying genes encoding miR-126-3p or -5p was stereotactically injected into adult male Institute of Cancer Research mouse brains (n=36). Permanent middle cerebral artery occlusion was performed 2 weeks after virus injection. Brain infarct volume, edema volume, and modified neurological severity score were assessed at 1 and 3 days after ischemia. Immunostaining of ZO-1 (zonula occludens-1) and occludin was used to evaluate BBB integrity. IL-1ß (interleukin-1ß), TNF-α (tumor necrosis factor-α), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin expression levels were determined by real-time polymerase chain reaction and Western blot analysis. Results- The expression of miR-126-3p and -5p decreased at 1 and 3 days after ischemia (P<0.05). Injection of lentiviral miR-126-3p or -5p reduced brain infarct volume and edema volume (P<0.05) and attenuated the decrease in ZO-1/occludin protein levels and IgG leakage at 3 days after stroke (P<0.05). Injection of lentiviral miR-126-5p improved behavioral outcomes at 3 days after stroke (P<0.05). miR-126-3p and -5p overexpression downregulated the expression of proinflammatory cytokines IL-1ß and TNF-α and adhesion molecules VCAM-1 and E-selectin, as well as decreased MPO+ (myeloperoxidase positive) cell numbers at 3 days after ischemia (P<0.05). Conclusions- miR-126-3p and -5p overexpression reduced the expression of proinflammatory cytokines and adhesion molecules, and attenuated BBB disruption after ischemic stroke, suggesting that miR-126-3p and -5p are new therapeutic targets in the acute stage of stroke.

cxcl12 gene engineered endothelial progenitor cells further improve the functions of oligodendrocyte precursor cells.

Oligodendrocyte precursor cells (OPCs) are needed for white matter repair after various brain injury. Means that promote OPC functions could benefit white matter recovery after injury. Chemokine CXCL12 and endothelial progenitor cells (EPCs) both have been shown to promote remyelination. We hypothesize that the beneficial effects of EPCs and CXCL12 can be harnessed by genetically modifying EPCs with cxcl12 to synergistically improve the functions of OPCs. In this work, CXCL12-EPC was generated using virus-mediated gene transfer. OPCs were cultured with CXCL12-EPC conditioned media (CM) to analyze its impact on the proliferation, migration, differentiation and survival properties of OPCs. We blocked or knocked-down the receptors of CXCL12, namely CXCR4 and CXCR7, respectively to investigate their functions in regulating OPCs properties. Results revealed that CXCL12-EPC CM further promoted OPCs behavioral properties and upregulated the expression of PDGFR-α, bFGF, CXCR4 and CXCR7 in OPCs, albeit following different time course. Blocking CXCR4 diminished the beneficial effects of CXCL12 on OPCs proliferation and migration, while knocking down CXCR7 inhibited OPCs differentiation. Our results supported that cxcl12 gene modification of EPCs further promoted EPCs' ability in augmenting the remyelination properties of OPCs, suggesting that CXCL12-EPC hold great potential in white matter repair.

Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice.

BACKGROUND: Ischemic stroke induced matrixmetallo-proteinase-9 (MMP-9) upregulation, which increased blood-brain barrier permeability. Studies demonstrated that mesenchymal stem cell therapy protected blood-brain barrier disruption from several cerebrovascular diseases. However, the underlying mechanism was largely unknown. We therefore hypothesized that mesenchymal stem cells reduced blood-brain barrier destruction by inhibiting matrixmetallo-proteinase-9 and it was related to intercellular adhesion molecule-1 (ICAM-1). METHODS: Adult ICR male mice (n = 118) underwent 90-min middle cerebral artery occlusion and received 2 × 105 mesenchymal stem cell transplantation. Neurobehavioral outcome, infarct volume, and blood-brain barrier permeability were measured after ischemia. The relationship between myeloperoxidase (MPO) activity and ICAM-1 release was further determined. RESULTS: We found that intracranial injection of mesenchymal stem cells reduced infarct volume and improved behavioral function in experimental stroke models (p < 0.05). IgG leakage, tight junction protein loss, and inflammatory cytokines IL-1ß, IL-6, and TNF-α reduced in mesenchymal stem cell-treated mice compared to the control group following ischemia (p < 0.05). After transplantation, MMP-9 was decreased in protein and activity levels as compared with controls (p < 0.05). Furthermore, myeloperoxidase-positive cells and myeloperoxidase activity were decreased in mesenchymal stem cell-treated mice (p < 0.05). CONCLUSION: The results showed that mesenchymal stem cell therapy attenuated blood-brain barrier disruption in mice after ischemia. Mesenchymal stem cells attenuated the upward trend of MMP-9 and potentially via downregulating ICAM-1 in endothelial cells. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway may influence MMP-9 expression of neutrophils and resident cells, and ICAM-1 acted as a key factor in the paracrine actions of mesenchymal stem cell.

MicroRNA-137 and microRNA-195* inhibit vasculogenesis in brain arteriovenous malformations.

OBJECTIVE: Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs. METHODS: We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics. RESULTS: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development. INTERPRETATION: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. Ann Neurol 2017;82:371-384.

Optogenetic Inhibition of Striatal GABAergic Neuronal Activity Improves Outcomes After Ischemic Brain Injury.

BACKGROUND AND PURPOSE: Striatal GABAergic neuron is known as a key regulator in adult neurogenesis. However, the specific role of striatal GABAergic neuronal activity in the promotion of neurological recovery after ischemic stroke remains unknown. Here, we used optogenetic approach to investigate these effects and mechanism. METHODS: Laser stimulation was delivered via an implanted optical fiber to inhibit or activate the striatal GABAergic neurons in Gad2-Arch-GFP or Gad2-ChR2-tdTomato mice (n=80) 1 week after 60-minute transient middle cerebral artery occlusion. Neurological severity score, brain atrophy volume, microvessel density, and cell morphological changes were examined using immunohistochemistry. Gene expression and protein levels of related growth factors were further examined using real-time polymerase chain reaction and Western blotting. RESULTS: Inhibiting striatal GABAergic neuronal activity improved functional recovery, reduced brain atrophy volume, and prohibited cell death compared with the control (P<0.05). Microvessel density and bFGF (basic fibroblast growth factor) expression in the inhibition group were also increased (P<0.05). In contrast, activation of striatal GABAergic neurons resulted in adverse effects compared with the control (P<0.05). Using cocultures of GABAergic neurons, astrocytes, and endothelial cells, we further demonstrated that the photoinhibition of GABAergic neuronal activity could upregulate bFGF expression in endothelial cells, depending on the presence of astrocytes. The conditioned medium from the aforementioned photoinhibited 3-cell coculture system protected cells from oxygen glucose deprivation injury. CONCLUSIONS: After ischemic stroke, optogenetic inhibition of GABAergic neurons upregulated bFGF expression by endothelial cells and promoted neurobehavioral recovery, possibly orchestrated by astrocytes. Optogenetically inhibiting neuronal activity provides a novel approach to promote neurological recovery.

Adiponectin modulates the function of endothelial progenitor cells via AMPK/eNOS signaling pathway.

Endothelial progenitor cells have been shown to differentiate into endothelial cells and to play a pivotal role in vascular homeostasis. Adiponectin has anti-atherogenic and anti-inflammatory properties via directly acting on vascular cells. The aim of the present study is to explore the effect of adiponectin on major functions involved in survival, migration, and tube formation of endothelial progenitor cells and to explore the underlying mechanism. In this study, we transferred adiponectin gene into endothelial progenitor cells via lentiviral vectors and investigated the proliferation, migration and tube formation of these transfected cells. We found that adiponectin is highly expressed in endothelial progenitor cells and promotes their proliferation, migration and tube formation. Western blot data showed that the former two processes were mediated through the AMPK/Akt/eNOS pathway, the latter via the AMPK/eNOS pathway. Use of the AMPK inhibitor (Compound C) or Akt inhibitor (MK-2206) reduced eNOS phosphorylation and attenuated adiponectin-induced endothelial progenitor cell proliferation, migration and tube formation compared to the controls (p < 0.05). Taken together, these data indicated that adiponectin promotes endothelial progenitor cell proliferation and migration via AMPK/Akt/eNOS signaling pathway and promotes tube formation through AMPK/eNOS, suggesting that adiponectin-transduced endothelial progenitor cell transplantation is a potential therapeutic target for vascular disease.

Monomeric CXCL12 outperforms its dimeric and wild type variants in the promotion of human endothelial progenitor cells' function.

CXCL12 overexpression improves neurobehavioral recovery during post-ischemic stroke through multiple mechanisms including promoting endothelial progenitor cells function in animal models. It has been proposed that the monomer and dimer forms possess differential chemotactic and regulatory function. The aim of present study is to explore whether a monomeric or dimeric CXCL12 plays a different role in the endothelial progenitor cells proliferation, migration, and tube-formation in vitro. In this study, we transferred monomeric, dimeric and wild type CXCL12 gene into endothelial progenitor cells via lentiviral vectors. We investigated endothelial progenitor cells function following the interaction of CXCL12/CXCR4 or CXCL12/CXCR7 and downstream signaling pathways. Our results showed that the monomeric CXCL12 transfected endothelial progenitor cells had enhanced ability in cell proliferation, migration, and tube-formation compared to that in dimeric or wild type controls (p < 0.05). Both CXCR4 and CXCR7 were significantly overexpressed in the monomeric CXCL12 transfected endothelial progenitor cells compared to that in the dimeric or wide type controls (p < 0.05). The function of migration, but not proliferation or tube-formation, was significantly reduced in the monomeric CXCL12 transfected endothelial progenitor cells when the cells were pre-treated with either CXCR4 inhibitor AMD3100 or siCXCR7 (p < 0.05), suggesting this cell function was partially regulated by CXCL12/CXCR4 and CXCL12/CXCR7 signal pathways. Our study demonstrated that monomeric CXCL12 was the fundamental form, which played important roles in endothelial progenitor cells' proliferation, migration, and tube-formation.

A patient treated with ofatumumab for myasthenia gravis in conjunction with systemic lupus erythematosus and thyroid carcinoma.

Myasthenia gravis (MG) is an autoimmune disease mediated by B cells and is associated with acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK) antibodies in the postsynaptic membrane at the neuromuscular junction. Anti-CD20 monoclonal antibodies, such as ofatumumab demonstrated promising disease control in MG patients. We presented the rare case of a 34-year-old female with acetylcholine receptor-positive myasthenia gravis (AChR-MG), concomitant with systemic lupus erythematosus (SLE) and metastatic thyroid carcinoma, who was treated with ofatumumab and exhibited improvements during follow-up.

Highly sensitive humidity sensor based on composite film of partially reduced graphene oxide and bacterial cellulose.

Breathing is an important physiological activity of human body, which not only reflects the state of human movement, but also is one of the important health indicators. Breathing can change the concentration of water molecules, so monitoring humidity has gradually become a hot topic in modern research. In this study, a humidity sensing composite film with high sensitivity and short response time was made by using the mixture of graphene oxide (GO) and bacterial cellulose (BC) with simple dry film-forming method. L-ascorbic acid was used as reducing agent to reduce GO and improve the conductivity of GO/BC composite film (BG). The influence of different BC contents and the different reduction degree on the resistance change rate of composite film was investigated in details. The maximum resistance change rate of partially reduced BG humidity sensitive composite film reached up to 94%, and the response and recovery time were 13 s and 47 s respectively. Furthermore, the sensor shows obvious resistance change in noncontact sensing test and different breathing states. This kind of humidity sensitive film with fast response and high sensitivity has great potential in human health monitoring and noncontact sensing, and is of great significance in promoting health detection and intelligent life.

Endorepellin downregulation promotes angiogenesis after experimental traumatic brain injury.

Endorepellin plays a key role in the regulation of angiogenesis, but its effects on angiogenesis after traumatic brain injury are unclear. This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice. Mice were randomly divided into four groups: sham, controlled cortical impact only, adeno-associated virus (AAV)-green fluorescent protein, and AAV-shEndorepellin-green fluorescent protein groups. In the controlled cortical impact model, the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+ proliferating endothelial cells and the functional microvessel density in mouse brain. These changes resulted in improved neurological function compared with controlled cortical impact mice. Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein. Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization, which may further improve neurobehavioral outcomes. Furthermore, an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control. Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor- and angiopoietin-1-related signaling pathways.

Natural-Wood-Inspired Ultrastrong Anisotropic Hybrid Hydrogels Targeting Artificial Tendons or Ligaments.

Hydrogels are able to mimic the flexibility of biological tissues or skin, but they still cannot achieve satisfactory strength and toughness, greatly limiting their scope of application. Natural wood can offer inspiration for designing high-strength hydrogels attributed to its anisotropic structure. Herein, we propose an integrated strategy for efficient preparation of ultrastrong hydrogels using a salting-assisted prestretching treatment. The as-prepared poly(vinyl alcohol)/cellulose nanofiber hybrid hydrogels show distinct wood-like anisotropy, including oriented molecular fiber bundles and extended grain size, which endows materials with extraordinarily comprehensive mechanical properties of ultimate breaking strength exceeding 40 MPa, strain approaching 250%, and toughness exceeding 60 MJ·m-3, and outstanding tear resistance. Impressively, the breaking strength and toughness of the reswollen preoriented hydrogels approach 10 MPa and 25 MJ·m-3, respectively. In vitro and in vivo tests demonstrate that the reswollen hydrogels do not affect the growth and viability of the cells, nor do they cause the inflammation or rejection of the mouse tissue, implying extremely low biotoxicity and perfect histocompatibility, showcasing bright prospects for application in artificial ligaments or tendons. The strategy provided in this study can be generalized to a variety of biocompatible polymers for the fabrication of high-performance hydrogels with anisotropic structures.

Chitosan-based thermal insulation compressible foam enhanced with high performance of piezoelectric generation and sensing.

A series of chitosan (CS)-konjac glucomannan (KGM) foams with excellent thermal insulation property has been prepared using a directional freezing method, which exhibit high strain recovery, excellent piezoelectric generation and sensing properties. Layered lamellar or honeycomb morphologies in CS-KGM foams attributes a low thermal conductivity coefficient of ca. 0.03 W/(m·K). Bridge-like structure that mainly observed in CS-KGM foams from horizontal freezing endows them with excellent compression recovery performance even after 200 compression cycles. This along with piezoelectricity of CS contributes a long-lasting piezoelectric generation performance, ranging from 0.809 to 2.460 V during compression cycle process. Piezoelectric signals generated from pressing with certain strain and rate, finger taping and hand grasping can be sensed profoundly by CS-KGM. As thus, fully renewable source-based CS-KGM foams with outstanding thermal insulation and piezoelectric performance shows great potential in application as wearable thermal insulation and piezoelectric devices.

Enhancing Therapeutic Efficacy of Donepezil by Combined Therapy: A Comprehensive Review.

Combination therapy involving different therapeutic strategies mostly provides more rapid and effective results as compared to monotherapy in diverse areas of clinical practice. The most worldwide famous acetylcholinesterase inhibitor (AChEIs) donepezil for its dominant role in Alzheimer's disease (AD) has also attracted the attention of many pharmaceuticals due to its promising pharmacological potencies such as neuroprotective, muscle relaxant, and sleep inducer. Recently, a combination of donepezil with other agents has displayed better desirable results in managing several disorders, including the most common Alzheimer's disease (AD). This study involves all the data regarding the therapeutic effect of donepezil in its combination with other agents and explains its therapeutic targets and mode of action. Furthermore, this review also puts light on the current status of donepezil with other agents in clinical trials. The combination therapy of donepezil with symptomatic relief drugs and disease-modifying agents opens a new road for treating multiple pathological disorders. To the best of our knowledge, this is the first report encircling all the pharmacologic effects of donepezil in its combination therapy with other agents and their current status in clinical trials.

Self-healing and anti-freezing graphene-hydrogel-graphene sandwich strain sensor with ultrahigh sensitivity.

Hydrogels with specially designed structures and adjustable properties have been considered as smart materials with multi-purpose application prospects, especially in the field of flexible sensors. However, most hydrogel-based sensors have low sensitivity, which inevitably affects their promotion in the market. Herein, a strain sensor comprising a poly(vinyl alcohol)/poly(acrylic acid) (PVA/PAA) hybrid hydrogel sandwiched between two graphene layers was successfully constructed in a facile way, and it exhibited many excellent properties including extremely high sensitivity. The incorporation of glycerol ensured the good flexibility and anti-freezing performance of the hydrogel-based sensor even at -15 °C. The dynamic coordination bonds in the hydrogel-based sensor endowed it with excellent self-healing properties. In particular, the sandwich-structured hydrogel sensor showed a very high gauge factor (GF) value of 39 at the strain of 50%, which is much higher than those of most ordinary hydrogel-based strain sensors. A super stable signal value after 5000 strain cycles and a very short response time of 274 ms guaranteed the long-term usability and sensitivity of the hydrogel-based sandwich sensor. More importantly, the hydrogel-based sandwich sensor could detect both large and tiny human motions accurately and instantly in a series of real-time monitoring experiments, showing great potential for intelligent wearable electronic devices.

Development and Validation of a Plasma FAM19A5 and MRI-Based Radiomics Model for Prediction of Parkinson's Disease and Parkinson's Disease With Depression.

Background: Prediction and early diagnosis of Parkinson's disease (PD) and Parkinson's disease with depression (PDD) are essential for the clinical management of PD. Objectives: The present study aimed to develop a plasma Family with sequence similarity 19, member A5 (FAM19A5) and MRI-based radiomics nomogram to predict PD and PDD. Methods: The study involved 176 PD patients and 181 healthy controls (HC). Sandwich enzyme-linked immunosorbent assay (ELISA) was used to measure FAM19A5 concentration in the plasma samples collected from all participants. For enrolled subjects, MRI data were collected from 164 individuals (82 in the PD group and 82 in the HC group). The bilateral amygdala, head of the caudate nucleus, putamen, and substantia nigra, and red nucleus were manually labeled on the MR images. Radiomics features of the labeled regions were extracted. Further, machine learning methods were applied to shrink the feature size and build a predictive radiomics signature. The resulting radiomics signature was combined with plasma FAM19A5 concentration and other risk factors to establish logistic regression models for the prediction of PD and PDD. Results: The plasma FAM19A5 levels (2.456 ± 0.517) were recorded to be significantly higher in the PD group as compared to the HC group (2.23 ± 0.457) (P < 0.001). Importantly, the plasma FAM19A5 levels were also significantly higher in the PDD subgroup (2.577 ± 0.408) as compared to the non-depressive subgroup (2.406 ± 0.549) (P = 0.045 < 0.05). The model based on the combination of plasma FAM19A5 and radiomics signature showed excellent predictive validity for PD and PDD, with AUCs of 0.913 (95% CI: 0.861-0.955) and 0.937 (95% CI: 0.845-0.970), respectively. Conclusion: Altogether, the present study reported the development of nomograms incorporating radiomics signature, plasma FAM19A5, and clinical risk factors, which might serve as potential tools for early prediction of PD and PDD in clinical settings.

Oligodendrocyte precursor cells transplantation protects blood-brain barrier in a mouse model of brain ischemia via Wnt/ß-catenin signaling.

Blood-brain barrier damage is a critical pathological feature of ischemic stroke. Oligodendrocyte precursor cells are involved in maintaining blood-brain barrier integrity during the development. However, whether oligodendrocyte precursor cell could sustain blood-brain barrier permeability during ischemic brain injury is unknown. Here, we investigate whether oligodendrocyte precursor cell transplantation protects blood-brain barrier integrity and promotes ischemic stroke recovery. Adult male ICR mice (n = 68) underwent 90 min transient middle cerebral artery occlusion. After ischemic assault, these mice received stereotactic injection of oligodendrocyte precursor cells (6 × 105). Oligodendrocyte precursor cells transplantation alleviated edema and infarct volume, and promoted neurological recovery after ischemic stroke. Oligodendrocyte precursor cells reduced blood-brain barrier leakage via increasing claudin-5, occludin and ß-catenin expression. Administration of ß-catenin inhibitor blocked the beneficial effects of oligodendrocyte precursor cells. Wnt7a protein treatment increased ß-catenin and claudin-5 expression in endothelial cells after oxygen-glucose deprivation, which was similar to the results of the conditioned medium treatment of oligodendrocyte precursor cells on endothelial cells. We demonstrated that oligodendrocyte precursor cells transplantation protected blood-brain barrier in the acute phase of ischemic stroke via activating Wnt/ß-catenin pathway. Our results indicated that oligodendrocyte precursor cells transplantation was a novel approach to the ischemic stroke therapy.

Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice.

Endothelial progenitor cell transplantation is a potential therapeutic approach in brain ischemia. However, whether the therapeutic effect of endothelial progenitor cells is via affecting complement activation is unknown. We established a mouse focal ischemia model (n = 111) and transplanted endothelial progenitor cells into the peri-infarct region immediately after brain ischemia. Neurological outcomes and brain infarct/atrophy volume were examined after ischemia. Expression of C3, C3aR and pro-inflammatory factors were further examined to explore the role of endothelial progenitor cells in ischemic brain. We found that endothelial progenitor cells improved neurological outcomes and reduced brain infarct/atrophy volume after 1 to 14 days of ischemia compared to the control (p < 0.05). C3 and C3aR expression in the brain was up-regulated at 1 day up to 14 days (p < 0.05). Endothelial progenitor cells reduced astrocyte-derived C3 (p < 0.05) and C3aR expression (p < 0.05) after ischemia. Endothelial progenitor cells also reduced inflammatory response after ischemia (p < 0.05). Endothelial progenitor cell transplantation reduced astrocyte-derived C3 expression in the brain after ischemic stroke, together with decreased C3aR and inflammatory response contributing to neurological function recovery. Our results indicate that modulating complement C3/C3aR pathway is a novel therapeutic target for the ischemic stroke.

MicroRNA-126 Regulates Angiogenesis and Neurogenesis in a Mouse Model of Focal Cerebral Ischemia.

Studies demonstrate that microRNA-126 plays a critical role in promoting angiogenesis. However, its effects on angiogenesis following ischemic stroke are unclear. Here, we explored the effect of microRNA-126-3p and microRNA-126-5p on angiogenesis and neurogenesis after brain ischemia. We demonstrated that both microRNA (miRNA)-126-3p and microRNA-126-5p increased the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) compared with the scrambled miRNA control (p < 0.05). Transferring microRNA-126 into a mouse middle cerebral artery occlusion model via lentivirus, we found that microRNA-126 overexpression increased the number of CD31+/BrdU+ (5-bromo-2'-deoxyuridine-positive) proliferating endothelial cells and DCX+/BrdU+ neuroblasts in the ischemic mouse brain, improved neurobehavioral outcomes (p < 0.05), and reduced brain atrophy volume (p < 0.05) compared with control mice. Western blot results showed that AKT and ERK signaling pathways were activated in the lentiviral-microRNA-126-treated group (p < 0.05). Both PCR and western blot results demonstrated that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) was decreased in the lentiviral-microRNA-126-treated group (p < 0.05). Dual-luciferase gene reporter assay also showed that PTPN9 was the direct target of microRNA-126-3p and microRNA-126-5p in the ischemic brain. We demonstrated that microRNA-126-3p and microRNA-126-5p promoted angiogenesis and neurogenesis in ischemic mouse brain, and further improved neurobehavioral outcomes. Our mechanistic study further showed that microRNA-126 mediated angiogenesis through directly inhibiting its target PTPN9 and activating AKT and ERK signaling pathways.