Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury.

Dysregulation of microRNAs (miRNAs) has been found in injured spinal cords after spinal cord injury (SCI). Previous studies have shown that miR-133b plays an important role in the differentiation of neurons and the outgrowth of neurites. Recently, exosomes have been used as novel biological vehicles to transfer miRNAs locally or systemically, but little is known about the effect of the delivery of exosome-mediated miRNAs on the treatment of SCI. In the present study, we observed that mesenchymal stem cells, the most common cell types known to produce exosomes, could package miR-133b into secreted exosomes. After SCI, tail vein injection of miR-133b exosomes into rats significantly improved the recovery of hindlimb function when compared to control groups. Additionally, treatment with miR-133b exosomes reduced the volume of the lesion, preserved neuronal cells, and promoted the regeneration of axons after SCI. We next observed that the expression of RhoA, a direct target of miR-133b, was decreased in the miR-133b exosome group. Moreover, we showed that miR-133b exosomes activated ERK1/2, STAT3, and CREB, which are signaling pathway proteins involved in the survival of neurons and the regeneration of axons. In summary, these findings demonstrated that systemically injecting miR-133b exosomes preserved neurons, promoted the regeneration of axons, and improved the recovery of hindlimb locomotor function following SCI, suggesting that the transfer of exosome-mediated miRNAs represents a novel therapeutic approach for the treatment of SCI.

Higher Serum Fibroblast Growth Factor-23 Levels and the Risk of Stroke and Its Subtypes: Evidence From a Meta-Analysis of Prospective Studies.

BACKGROUND: Epidemiologic studies have indicated conflicting associations of fibroblast growth factor-23 (FGF23) with the risk of stroke. To this end, a meta-analysis of prospective studies was conducted to assess the association. METHODS: Relevant studies were identified by searching PubMed and Embase databases to March 23, 2018. Relative risks (RRs) with 95% confidence intervals (CIs) were combined with the fixed-effects model or random-effects model according to the degree of heterogeneity. Moreover, stratified analyses and sensitivity analysis were carried out for further analysis. RESULTS: Seven prospective studies involving 1988 stroke events among 18048 participants were eligible for our meta-analysis. The combined RRs for total stroke were 1.29 (95% CI: 1.10, 1.52) for the highest versus lowest category of FGF23, with low heterogeneity among studies (Pheterogeneity = 0.38, I2 = 6.1%). Stratified analyses showed that the combined RRs for ischemic stroke (IS) and hemorrhagic stroke (HS) risk were 1.12 (95% CI: 0.92, 1.37) and 2.63 (95% CI: 1.61, 4.30), respectively. In the stratification by geographic areas, the association between higher FGF23 and stroke was similar with studies performed in the United States (RR = 1.24, 95%CI: 1.03, 1.49) and Europe (RR = 1.88, 95%CI: 0.77, 4.55); however, only the results in the United States were statistically significant. Sensitivity analysis indicated the combined results were robust. CONCLUSIONS: Our meta-analysis showed that higher FGF23 levels were associated with an increased risk of stroke. The positive association consistently existed in HS rather than in IS. Further studies are required to confirm these causal associations and to investigate the mechanisms.

Transcranial Near-infrared Laser Therapy in Improving Cognitive Recovery of Function Following Traumatic Brain Injury.

Traumatic brain injury (TBI) has turned into a major health and socioeconomic problem affecting young people and military personnel. Numerous TBI patients experienced the sequela of brain injury called cognitive impairment, which reduced functions in attention, working memory, motivation, and execution. In recent years, transcranial near-infrared laser therapy (tNiRLT) as a possible therapy has been gradually applied in treating cognitive impairment post-TBI. In the present review, the biological mechanisms of transcranial tNiRLT for TBI are synthesized mainly based on the photonic impact of chronic mild TBI. Various exciting molecular events possibly occur during the procedure, such as stimulation of ATP production, regional cerebral blood flow, acupoint, neurogenesis and synaptogenesis, as well as a reduction in anti-inflammatory effect. Some animal experiments and clinical studies of tNiRLT for TBI are outlined. Several labs have displayed that tNiRLT is effective not only in improving neurological functions but also in increasing memory and learning capacity in rodent animals' model of TBI. In a 2 patients case report and a 11-case series, cognitive functions were ameliorated. Efficacy on cognitive and emotional effects was also observed in a double-blind, controlled clinical study. Several Randomized, parallel, double blind, sham-controlled trials are underway, aiming to evaluate the efficacy of tLED on cognitive functions and neuropsychiatric status in participants post-TBI. Therefore, tNiRLT is a promising method applied to cognitive impairment following TBI.

Role of Exosomes Derived from miR-133b Modified MSCs in an Experimental Rat Model of Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) has poor outcomes due to high mortality and morbidity, but until now, the effective treatments remain limited. MicroRNAs (miRNAs) are vital regulators of gene expression and demonstrated to be linked to the pathogenesis of various central nervous system (CNS) diseases. Exosomes are considered as cell-to-cell communication vectors and secreted largely by mesenchymal stromal cells (MSCs). The present study investigated the role of miR-133b delivered by exosomes secreted from MSCs to brain tissues in rats after ICH. An autologous arterial blood ICH model in adult male Sprague-Dawley (SD) rats was used in this study. At 72 h after transfection with miR-133b mimics in MSCs, miR-133b-modified MSC-derived exosomes were collected from medium of MSCs and then injected to rats via tail vein. The levels of miR-133b in secreted exosomes and brain tissues of rats in various groups and the levels of RhoA, phosphorylations of extracellular signal regulating kinase (ERK1/2), and cAMP response element-binding protein (CREB) were detected by real-time PCR and western blot analysis, respectively. The effects of miR-133b on neuronal apoptosis and degeneration were respectively evaluated by TUNEL and fluoro-jade B staining. The miR-133b levels were reduced in brain tissues of rats at 24 h and peaked at 72 h after ICH. At 24 h after miR-133b-modified exosome administration, the level of miR-133b was significantly increased, while the apoptotic and neurodegenerative neurons were obviously reduced in brain tissues after ICH. The results of western blot analysis showed that miR-133b modified exosomes treatment remarkably suppressed RhoA expression and activated ERK1/2/CREB in brain tissues after ICH. Collectively, our investigation suggested that exosomes derived from miR-133b modified MSCs exhibited neuroprotective role for anti-apoptotic effect of miR-133b mediating RhoA and ERK1/2/CREB in rats after ICH.

Autophagy in hemorrhagic stroke: Mechanisms and clinical implications.

Accumulating evidence advances the critical role of autophagy in brain pathology after stroke. Investigations employing autophagy induction or inhibition using pharmacological tools or autophagy-related gene knockout mice have recently revealed the biological significance of intact and functional autophagy in stroke. Most of the reported cases attest to a pro-survival role for autophagy in stroke, by facilitating removal of damaged proteins and organelles, which can be recycled for energy generation and cellular defenses. However, these observations are difficult to reconcile with equally compelling evidence demonstrating stroke-induced upregulation of brain cell death index that parallels enhanced autophagy. This begs the question of whether drug-induced autophagy during stroke culminates in improved or worsened pathological outcomes. A corollary fascinating hypothesis, but presents as a tricky conundrum, involves the effects of autophagy on cell death and inflammation, which are two main culprits in the disease progression of stroke-induced brain injury. Evidence has extended the roles of autophagy in inflammation via cytokine regulation in an unconventional secretion manner or by targeting inflammasomes for degradation. Moreover, in the recently concluded Vancouver Autophagy Symposium (VAS) held in 2014, the potential of selective autophagy for clinical treatment has been recognized. The role of autophagy in ischemic stroke has been reviewed previously in detail. Here, we evaluate the strength of laboratory and clinical evidence by providing a comprehensive summary of the literature on autophagy, and thereafter we offer our perspectives on exploiting autophagy as a drug target for cerebral ischemia, especially in hemorrhagic stroke.

Necroptosis: A novel manner of cell death, associated with stroke (Review).

Cell death is indispensable in the physiology, pathology, growth, development, senility and death of an organism. In recent years, the identification of a highly regulated form of necrosis, known as necroptosis, has challenged the traditional concept of necrosis and apoptosis, which are two major modes of cell death. This novel manner of cell death is similar in form to necrosis in terms of morphological features, and it can also be regulated in a caspase­independent manner. Therefore, necroptosis can be understood initially as a combination of necrosis and apoptosis. The mechanism of its regulation, induction and inhibition is complicated, and involves a range of molecular expression and regulation. According to the recent literature, necroptosis takes place in the physiological regulatory processes of an organism and is involved in the occurrence, development and prognosis of a variety of diseases that have a necrosis phenotype, including neurodegenerative diseases, ischemic disease, hemorrhagic disease, inflammation and viral infectious diseases. In the present review, the features, molecular mechanism and identification of necroptosis under pathological conditions are discussed, with particular emphasis on its association with stroke.

Phosphorylation at S153 as a Functional Switch of Phosphatidylethanolamine Binding Protein 1 in Cerebral Ischemia-Reperfusion Injury in Rats.

This study aimed to estimate the role of phosphatidylethanolamine binding protein 1 (PEBP1) in cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in adult male Sprague Dawley rats (250-280 g) were established and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Expression vectors encoding wild-type PEBP1 and PEBP1 with Ser153Ala mutation (S153A), PEBP1 specific siRNAs, and human recombinant PEBP1 (rhPEBP1) were administered intracerebroventricularly. Endogenous PEBP1 level and its phosphorylation at Ser153 were increased within penumbra tissue and cultured neurons after I/R, accompanied by decreased interaction between PEBP1 and Raf-1. There was a trend toward increased Raf-1/MEK/ERK/NF-κB signaling pathway and phosphatidylcholine-phospholipase C (PC-PLC) activity after I/R, which was enhanced by wild-type PEBP1overexpression and rhPEBP1 treatment and inhibited by PEBP1 (S153A) overexpression. And PEBP1 (S153A) overexpression increased its interaction with Raf-1, reduced infarct size, neuronal death and inflammation, and improved neurological function after I/R, while wild-type PEBP1overexpression exerted opposite effects, suggesting that phosphorylation at Ser153 may exert as a functional switch of PEBP1 by switching PEBP1 from Raf-1 inhibition to PC-PLC activation following I/R. Compared with PEBP1 knockdown, PEBP1 (S153A) overexpression exerted a better rescue effect on I/R injury, which further proved that PEBP1 may be a good protein gone bad with phosphorylation at S153 as a functional switch following I/R. Collectively, our findings suggest that PEBP1 contributed to neuronal death and inflammation after I/R. Selective inhibition of PEBP1 phosphorylation may be a novel approach to ameliorate I/R injury.

Role for RIP1 in mediating necroptosis in experimental intracerebral hemorrhage model both in vivo and in vitro.

Cell death is a hallmark of second brain injury after intracerebral hemorrhage (ICH); however, the mechanism still has not been fully illustrated. In this study, we explored whether necroptosis, a type of regulated necrosis, has an essential role in brain injury after ICH. We found that inhibiting receptor-interacting protein 1 (RIP1) - a core element of the necroptotic pathway - by a specific chemical inhibitor or genetic knockdown attenuated brain injury in a rat model of ICH. Furthermore, necroptosis of cultured neurons could be induced by conditioned medium from microglia stimulated with oxygen hemoglobin, and this effect could be inhibited by TNF-α inhibitor, indicating that TNF-α secreted from activated microglia is an important factor in inducing necroptosis of neurons. Undoubtedly, overexpression of RIP1 increased conditioned medium-induced necroptosis in vitro, but this effect was partially diminished in mutation of serine kinase phosphorylation site of RIP1, showing that phosphorylation of RIP1 is the essential molecular mechanism of necroptosis, which was activated in the in vitro model of ICH. Collectively, our investigation identified that necroptosis is an important mechanism of cell death in brain injury after ICH, and inhibition of necroptosis may be a potential therapeutic intervention of ICH.

Safety and efficiency of flow diverters for treating small intracranial aneurysms: A systematic review and meta-analysis.

Background We evaluated the safety and efficiency of flow diverters (FDs) in treating small intracranial aneurysms (IAs). Materials and Methods We reviewed the literature published in PubMed and EMBASE. R for Project software was used to calculate the complete aneurysm occlusion rates, procedure-related neurologic mortality, procedure-related neurologic morbidity and procedure-related permanent morbidity. Results Ten observational studies were included in this analysis. The complete aneurysm occlusion rate was 84.23% (80.34%-87.76%), the procedure-related neurologic mortality was 0.87% (0.29%-1.74%), the procedure-related neurologic morbidity rate was 5.22% (3.62%-7.1%), the intracerebral haemorrhage rate was 1.42% (0.64%-2.49%), the ischemic rate was 2.35% (1.31%-3.68%), the subarachnoid haemorrhage rate was 0.03% (0%-0.32%) and the procedure-related permanent morbidity was 2.41% (0.81%-4.83%). Conclusions Treatment of small IAs with FDs may be correlated with high complete occlusion rates and low complication rates. Future long-term follow-up randomized trials will determine the optimal treatment for small IAs.

Erythropoietin Treatment in Patients with Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Erythropoietin (EPO) for treating acute ischemic stroke (AIS) has been investigated in many studies. However, the evidence was inconsistent. Thus, a systematic review and metaanalysis were performed to elucidate the role of EPO in treating patients with AIS. METHODS: Two electronic databases (PubMed and EMBASE) were used. 30-day NIHSS measures primary outcome while all-cause mortality in the follow up and 90-day Barthel Index were regarded as secondary outcome. Results are presented as relative risk (RR), standardized mean difference (SMD) and 95% confidence intervals (CI). We employed Stata software to perform the meta-analysis. RESULTS: Four randomized controlled trials (RCTs) involving 784 patients were contained in this metaanalysis. The total combined results on 30-day NIHSS were (SMD = -0.52, 95% CI: -1.39, 0.34) with random-effects model and sensitivity analysis showed a significant difference after excluding the Ehrenreich 2009 trial. The total combined secondary measured results were (RR=1.72, 95% CI: 1.10, 2.70) and (SMD = 0.01, 95% CI: -0.14, 0.16) for all-cause mortality and 90-day Barthel Index. In the subgroup analysis by using recombinant tissue plasminogen activator (rtPA) earlier, the rtPA group showed increased all-cause mortality with the result of (RR = 1.92, 95% CI: 1.04, 3.52), but not in non-rtPA group. CONCLUSION: To our systematic review and meta-analysis, we didn't recommend EPO administration for patients with AIS, especially with the combination of rtPA. Large RCTs are warranted to examine EPO efficacy in AIS patients in the future.

Alcohol consumption and risk of subarachnoid hemorrhage: A meta-analysis of 14 observational studies.

The association between alcohol consumption and the risk of subarachnoid hemorrhage (SAH) is inconsistent. Thus, meta- and a dose-response analyses are presented with the purpose of assessing their associations. A systematic literature search was performed using Pubmed and Embase electronic databases for pertinent observational studies. Random-effects or fixed-effect models were employed to combine the estimates of the relative risks (RRs) with corresponding 95% confidence intervals (CIs). A dose-response pattern was conducted for further analysis. The current meta-analysis includes 14 observational studies reporting data on 483,553 individuals and 2,556 patients. The combined RRs of light alcohol consumption (<15 g/day) and moderate alcohol consumption (15-30 g/day) compared with teetotal individuals were 1.27 (95% CI: 0.95, 1.68) and 1.33 (95% CI: 0.84, 2.09), respectively, which indicated no significant association between light-to-moderate alcohol consumption and SAH. An increased risk of SAH was noted in heavy alcohol consumption (>30 g/day) when compared with no alcohol consumption, as demonstrated by a result of 1.78 (95% CI: 1.46, 2.17). Dose-response analysis showed evidence of a linear association (P=0.0125) between alcohol consumption and SAH. The risk of SAH increased by 12.1% when alcohol consumption was increased by 10 g/day. Therefore, heavy alcohol consumption was found to be associated with an increased risk of SAH. Furthermore, the association between SAH and alcohol consumption has clinical relevance with regard to risk factor modification and the primary and secondary prevention of SAH.

Diabetes mellitus and the risk of aneurysmal subarachnoid haemorrhage: A systematic review and meta-analysis of current evidence.

Objective This systematic review aimed to define the relationship between diabetes mellitus (DM) and the risk of aneurysmal subarachnoid haemorrhage (aSAH). Methods Studies associated with DM and aSAH published until March 2016 were retrieved from Pubmed, Embase, Web of Science, and Cochrane Library databases. A random-effects model was used to calculate the relative risks (RRs) with 95% confidence intervals (CIs). Results Eighteen observational studies were retrieved. The overall RRs for DM and aSAH were RRs = 0.59 (0.44, 0.79), with moderate heterogeneity ( I2 = 55.7%, Pheterogeneity = 0.000). Subgroup analysis by study quality revealed a reduced association between DM and aSAH risk in high quality studies only (RRs = 0.40, 95% CI: 0.29, 0.56; I2 = 0.0%, Pheterogeneity = 0.549), therefore study quality may be a source of heterogeneity. Conclusion A potential decreased risk of aSAH in DM patients was found in high quality studies. Further studies are required to confirm this causal relationship and to investigate the biological mechanisms.