Microglial repopulation induced by PLX3397 protects against ischemic brain injury by suppressing neuroinflammation in aged mice.

As the resident immune cells in the central nervous system, microglia exhibit a 'sensitized' or 'primed' phenotype with dystrophic morphology and dysregulated functions in aged brains. Although studies have demonstrated the inflammatory profile of aged microglia in several neurological diseases, this issue is largely uncertain in stroke. Consequently, this study investigated the effects of primed and repopulated microglia on post-ischemic brain injury in aged mice. We replaced primed microglia with newly repopulated microglia through pharmacological administration and withdrawal of the colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397. Further, we performed a series of behavioral tests and flow cytometry in mouse models of middle cerebral artery occlusion (MCAO) to study the effects of microglial replacement on ischemic injury in the aged brain. With depletion and subsequent repopulation of microglia in MCAO mice, microglial replacement in aged mice improved neurological function and decreased brain infarction. This protective effect was accompanied by the reduction of peripheral immune cells infiltrating into brains. We showed that the repopulated microglia expressed elevated neuroprotective factors (including Cluster of Differentiation 206, transforming growth factor-ß, and interleukin-10) and diminished expression of inflammatory markers (including Cluster of Differentiation 86, interleukin-6, and tumor necrosis factor α). Moreover, microglial replacement protected the blood-brain barrier and relieved neuronal death in aged mice subjected to 60 min of MCAO. These results imply that the replacement of microglia in the aged brain may alleviate brain damage and neuroinflammation, and therefore, ischemic brain damage. Thus, targeting microglia could be a promising therapeutic strategy for ischemic stroke.

Dietary Flavonoid Intake and Carotid Calcification in Patients with Ischemic Stroke.

INTRODUCTION: Owing to the antioxidant and anti-inflammatory effects, flavonoids can influence the initiation and development of atherosclerosis, but the underlying mechanisms remain largely undetermined. This study aimed to evaluate the associations between dietary flavonoids and carotid calcification in patients with ischemic stroke. METHODS: This study screened consecutive patients with ischemic stroke via Nanjing Stroke Registry Program from February 2016 to April 2021. A semiquantitative food frequency questionnaire was used to evaluate dietary consumption of flavonoids and other nutritional components. Presence and degree of carotid calcification were determined according to Agatston scores on computer tomography angiography. Logistic regression was performed to evaluate the association between dietary flavonoids (total flavonoids, flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and isoflavones) and carotid calcification. RESULTS: Of the 601 enrolled patients, 368 (61.2%) were detected with carotid calcification. Patients with high intake of total flavonoids (the fifth quintile) had a 52% lower carotid calcification risk than those with low intake (the first quintile; odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.26-0.90; p = 0.007 for trends) after adjusting for major confounders. Patients with high intake of flavan-3-ols (the fifth quintile) had a 51% lower carotid calcification risk than those with low intake (the first quintile; OR = 0.49; 95% CI, 0.25-0.97; p = 0.016 for trends). CONCLUSION: Dietary flavonoid intake is associated with carotid calcification, and, therefore, may influence the risk of stroke occurrence and recurrence.

Association between dietary antioxidant capacity and atherosclerotic carotid stenosis in patients with ischemic stroke.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the relationship between dietary total antioxidant capacity (DTAC) and atherosclerotic carotid stenosis in patients with ischemic stroke. METHODS: Patients with acute ischemic stroke were consecutively enrolled. Daily food consumption was estimated by a semi-quantitative food frequency questionnaire (FFQ). DTAC was calculated based on classified food intake. Antioxidant potential value was measured by ferric-reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) methods. Evaluation of carotid artery stenosis was based on computed tomography angiography (CTA). Logistic regression was used to assess the relationship between DTAC and degree of carotid stenosis. RESULTS: Of the 608 enrolled, 232 patients (38.2%) had moderate or severe carotid stenosis. After adjusting for major confounding factors, FRAP (OR =0.640; 95% CI: 0.410-0.998; P =0.049) and ORAC (OR =0.625; 95% CI: 0.400-0.976; P =0.039) were associated with lower degree of carotid artery stenosis (third vs first tertile). Spearman analysis indicated that FRAP (r =-0.121, P =0.003) and ORAC (r =-0.147, P <0.001) were correlated with degree of carotid stenosis. CONCLUSIONS: DTAC may influence the initiation and development of atherosclerosis, and, therefore, the risk of ischemic stroke.

The Association between Migraine and Fetal-Type Posterior Cerebral Artery in Patients with Ischemic Stroke.

OBJECTIVE: The aim of the study was to determine if migraine is associated with fetal-type posterior cerebral artery (PCA) in patients with ischemic stroke. METHOD: In this cross-sectional study, patients with acute ischemic stroke were enrolled from two hospitals. The history of migraine headache was evaluated during a face-to-face interview. The variants of fetal-type PCA were assessed with MRA, CTA, or DSA. Patients with and without migraine were compared in terms of fetal-type PCA status and other clinic characteristics. Multivariate logistic regression analyses were performed to adjust for confounders and provide risk estimates for observed associations. RESULT: In 750 patients qualified for analysis, 85 (11.3%) were determined with migraine. Patients with migraine had a higher proportion of female gender (51.8% vs. 31.0%, p < 0.001), hypertension (72.9% vs. 57.7%, p = 0.007), and fetal-type PCA (36.5% vs. 20.1%, p = 0.001), while lower proportion of current smoking (25.9% vs. 38.3%, p = 0.025) than patients without migraine. National Institutes of Health Stroke Scale (NIHSS) score (3 vs. 2, p = 0.016) was also higher in migraineurs than in non-migraineurs. After adjustment for confounders, fetal-type PCA status was independently associated with migraine (odds ratio [OR] = 2.06; 95% confidence interval [CI], 1.25-3.38; p = 0.005). Other factors associated to migraine included female gender (OR = 2.03; 95% CI, 1.13-3.62; p = 0.017), hypertension (OR = 1.97; 95% CI, 1.17-3.34; p = 0.011), and NIHSS score (OR = 1.08; 95% CI, 1.01-1.16; p = 0.018). CONCLUSION: Migraine was associated with fetal-type PCA in patients with ischemic stroke. This finding supported the hypothesis that vascular mechanisms get involved in the migraine-stroke association.

Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury.

BACKGROUND: Thrombo-inflammation is an important checkpoint that orchestrates infarct development in ischemic stroke. However, the underlying mechanism remains largely unknown. Here, we explored the role of endothelial Caveolin-1 (Cav-1) in cerebral thrombo-inflammation. METHODS: The correlation between serum Cav-1 level and clinical outcome was analyzed in acute ischemic stroke patients with successful recanalization. Genetic manipulations by endothelial-specific adeno-associated virus (AAV) and siRNA were applied to investigate the effects of Cav-1 in thrombo-inflammation in a transient middle cerebral artery occlusion (tMCAO) model. Thrombo-inflammation was analyzed by microthrombosis formation, myeloid cell infiltration, and endothelial expression of adhesion molecules as well as inflammatory factors. FINDINGS: Reduced circulating Cav-1, with the potential to predict microembolic signals, was more frequently detected in recanalized stroke patients without early neurological improvement. At 24 h after tMCAO, serum Cav-1 was consistently reduced in mice. Endothelial Cav-1 was decreased in the peri-infarct region. Cav-1-/- endothelium, with prominent barrier disruption, displayed extensive microthrombosis, accompanied by increased myeloid cell inflammatory infiltration after tMCAO. Specific enhanced expression of endothelial Cav-1 by AAV-Tie1-Cav-1 remarkably reduced infarct volume, attenuated vascular hyper-permeability and alleviated thrombo-inflammation in both wild-type and Cav-1-/- tMCAO mice. Transcriptome analysis after tMCAO further designated Rxrg as the most significantly changed molecule resulting from the knockdown of Cav-1. Supplementation of RXR-γ siRNA reversed AAV-Tie1-Cav-1-induced amelioration of thrombo-inflammation without affecting endothelial tight junction. INTERPRETATION: Endothelial Cav-1/RXR-γ may regulate infarct volume and neurological impairment, possibly through selectively controlling thrombo-inflammation coupling, in cerebral ischemia/reperfusion. FUNDING: This work was supported by National Natural Science Foundation of China.

High-frequency repetitive transcranial magnetic stimulation (rTMS) protects against ischemic stroke by inhibiting M1 microglia polarization through let-7b-5p/HMGA2/NF-κB signaling pathway.

BACKGROUND: Microglia assume opposite phenotypes in response to ischemic brain injury, exerting neurotoxic and neuroprotective effects under different ischemic stages. Modulating M1/M2 polarization is a potential therapy for treating ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) held the capacity to regulate neuroinflammation and astrocytic polarization, but little is known about rTMS effects on microglia. Therefore, the present study aimed to examine the rTMS influence on microglia polarization and the underlying possible molecular mechanisms in ischemic stroke models. METHODS: Previously reported 10 Hz rTMS protocol that regulated astrocytic polarization was used to stimulate transient middle cerebral artery occlusion (MCAO) rats and oxygen and glucose deprivation/reoxygenation (OGD/R) injured BV2 cells. Specific expression levels of M1 marker iNOS and M2 marker CD206 were measured by western blotting and immunofluorescence. MicroRNA expression changes detected by high-throughput second-generation sequencing were validated by RT-PCR and fluorescence in situ hybridization (FISH) analysis. Dual-luciferase report assay and miRNA knock-down were applied to verify the possible mechanisms regulated by rTMS. Microglia culture medium (MCM) from different groups were collected to measure the TNF-α and IL-10 concentrations, and detect the influence on neuronal survival. Finally, TTC staining and modified Neurological Severity Score (mNSS) were used to determine the effects of MCM on ischemic stroke volume and neurological functions. RESULTS: The 10 Hz rTMS inhibited ischemia/reperfusion induced M1 microglia and significantly increased let-7b-5p level in microglia. HMGA2 was predicted and proved to be the target protein of let-7b-5p. HMGA2 and its downstream NF-κB signaling pathway were inhibited by rTMS. Microglia culture medium (MCM) collected from rTMS treated microglia contained lower TNF-α concentration but higher IL-10 concentration than no rTMS treated MCM, reducing ischemic volumes and neurological deficits of MCAO mice. However, knockdown of let-7b-5p by antagomir reversed rTMS effects on microglia phenotype and associated HMGA/NF-κB activation and neurological recovery. CONCLUSION: High-frequency rTMS could alleviate ischemic stroke injury through inhibiting M1 microglia polarization via regulating let-7b-5p/HMGA2/NF-κB signaling pathway in MCAO models.

Extracellular vesicles carrying proinflammatory factors may spread atherosclerosis to remote locations.

Most cells involved in atherosclerosis release extracellular vesicles (EVs), which can carry bioactive substances to downstream tissues via circulation. We hypothesized that EVs derived from atherosclerotic plaques could promote atherogenesis in remote locations, a mechanism that mimics the blood metastasis of cancer. Ldlr gene knockout (Ldlr KO) rats were fed on a high cholesterol diet and underwent partial carotid ligation to induce local atherosclerosis. EVs were separated from carotid artery tissues and downstream blood of carotid ligation by centrifugation. MiRNA sequencing and qPCR were then performed to detect miRNA differences in EVs from rats with and without induced carotid atherosclerosis. Biochemical analyses demonstrated that EVs derived from atherosclerosis could increase the expression of ICAM-1, VCAM-1, and E-selectin in endothelial cells in vitro. EVs derived from atherosclerosis contained a higher level of miR-23a-3p than those derived from controls. MiR-23a-3p could promote endothelial inflammation by targeting Dusp5 and maintaining ERK1/2 phosphorylation in vitro. Inhibiting EV release could attenuate atherogenesis and reduce macrophage infiltration in vivo. Intravenously administrating atherosclerotic plaque-derived EVs could induce intimal inflammation, arterial wall thickening and lumen narrowing in the carotids of Ldlr KO rats, while simultaneous injection of miR-23a-3p antagomir could reverse this reaction. The results suggested that EVs may transfer atherosclerosis to remote locations by carrying proinflammatory factors, particularly miR-23a-3p.

Cystatin C predicts futile recanalization in patients with acute ischemic stroke after endovascular treatment.

BACKGROUND: A previous study reported that cystatin C was related to acute ischemic stroke. The association between cystatin C and the clinical outcome in acute ischaemic stroke patients with successful recanalization after endovascular thrombectomy has rarely been reported. This study aimed to evaluate the association between cystatin C and futile recanalization in AIS patients who underwent endovascular thrombectomy. METHODS: We carried out a retrospective study of acute ischaemic stroke patients with anterior circulation proximal arterial occlusion who achieved complete arterial recanalization after mechanical thrombectomy from May 2017 to April 2020. The patients with complete recanalization were divided into a useful recanalization group and a futile recanalization group according to their 3-month modified Rankin scale score. FR was defined as a modified mRS score of 3-6 at 3 months. Logistic regression analysis was used to identify the risk factors for FR. Receiver operating characteristic curves were used to assess the predictive value of cystatin C for FR. RESULTS: Of 241 patients, 125 underwent futile recanalization and 116 underwent useful recanalization. Baseline serum cystatin C levels were higher in the futile recanalization group than in the useful recanalization group. After adjustment for potential confounding factors, multivariable adjusted regression models showed that cystatin C was an independent predictor of futile recanalization (odds ratio, 4.111 [95% CI 1.427-11.840], P = 0.009). Receiver operator characteristic (ROC) curve analysis indicated that the model combining cystatin C with other factors model effectively predicted unfavourable outcomes at 3 months (area under the curve = 0.782, p < 0.01). CONCLUSIONS: A higher level of cystatin C is associated with unfavourable outcomes at 3 months in anterior circulation acute ischaemic stroke patients with endovascular thrombectomy.

A Nomogram for Predicting Stroke Recurrence Among Young Adults.

Background and Purpose- This study aimed to develop and validate a nomogram for predicting the risk of stroke recurrence among young adults after ischemic stroke. Methods- Patients aged between 18 and 49 years with first-ever ischemic stroke were selected from the Nanjing Stroke Registry Program. A stepwise Cox proportional hazards regression model was employed to develop the best-fit nomogram. The discrimination and calibration in the training and validation cohorts were used to evaluate the nomogram. All patients were classified into low-, intermediate-, and high-risk groups based on the risk scores generated from the nomogram. Results- A total of 604 patients were enrolled in this study. Hypertension (hazard ratio [HR], 2.038 [95% CI, 1.504-3.942]; P=0.034), diabetes mellitus (HR, 3.224 [95% CI, 1.848-5.624]; P<0.001), smoking status (current smokers versus nonsmokers; HR, 2.491 [95% CI, 1.304-4.759]; P=0.006), and stroke cause (small-vessel occlusion versus large-artery atherosclerosis; HR, 0.325 [95% CI, 0.109-0.976]; P=0.045) were associated with recurrent stroke. Educational years (>12 versus 0-6; HR, 0.070 [95% CI, 0.015-0.319]; P=0.001) were inversely correlated with recurrent stroke. The nomogram was composed of these factors, and successfully stratified patients into low-, intermediate-, and high-risk groups (P<0.001). Conclusions- The nomogram composed of hypertension, diabetes mellitus, smoking status, stroke cause, and education years may predict the risk of stroke recurrence among young adults after ischemic stroke.

Optical coherence tomography evaluation of vertebrobasilar artery stenosis: case series and literature review.

BACKGROUND: Intracranial vertebrobasilar artery stenosis is an important cause of ischemic stroke. With its high resolution, intravascular optical coherence tomography (OCT) provides detailed assessment of vessel wall features. It is widely applied to identify high-risk plaque in the cardiovascular system, but its use in the intracranial artery has been limited. OBJECTIVE: To explore, in this pilot study, the usefulness of OCT in imaging of the intracranial artery wall. METHODS: Between November 2017 and July 2018, four patients with severe intracranial vertebrobasilar artery stenosis were enrolled for preintervention OCT evaluation of the lesion artery. Stenosis was present in the basilar artery in one case and in the intracranial vertebral artery in three cases. RESULTS: OCT images of the lesions showed various features of plaque vulnerability, such as intraluminal thrombus, lipid-rich plaque with plaque rupture, thin fibrous cap, macrophage accumulations, and a mixed lesion with dissecting aneurysm. In view of the OCT findings, all patients received balloon angioplasty and stent implantation. CONCLUSIONS: These cases describe the successful implementation of OCT in intracranial vertebrobasilar artery stenosis. No side effects were seen during the OCT imaging. This technology may help in the diagnosis and treatment of cerebrovascular disease.

Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation.

BACKGROUND: Functions of astrocytes in the rehabilitation after ischemic stroke, especially their impacts on inflammatory processes, remain controversial. This study uncovered two phenotypes of astrocytes, of which one was helpful, and the other harmful to anoxic neurons after brain ischemia. METHODS: We tested the levels of inflammatory factors including TNF-a, IL-6, IL-10, iNOS, IL-1beta, and CXCL10 in primary astrocytes at 0 h, 6 h, 12 h, 24 h, and 48 h after OGD, grouped the hypoxia astrocytes into iNOS-positive (iNOS(+)) and iNOS-negative (iNOS(-)) by magnetic bead sorting, and then co-cultured the two groups of cells with OGD-treated neurons for 24 h. We further verified the polarization of astrocytes in vivo by detecting the co-localization of iNOS, GFAP, and Iba-1 on MCAO brain sections. Lentivirus overexpressing LCN2 and LCN2 knockout mice (#024630. JAX, USA) were used to explore the role of LCN2 in the functional polarization of astrocytes. 7.0-T MRI scanning and the modified Neurological Severity Score (mNSS) were used to evaluate the neurological outcomes of the mice. RESULTS: After oxygen-glucose deprivation (OGD), iNOS mRNA expression increased to the peak at 6 h in primary astrocytes, but keep baseline expression in LCN2-knockout astrocytes. In mice with transient middle cerebral artery occlusion (tMCAO), LCN2 was proved necessary for astrocyte classical activation. In LCN2 knockout mice with MCAO, no classically activated astrocytes were detected, and smaller infarct volumes and better neurological functions were observed. CONCLUSIONS: The results indicated a novel pattern of astrocyte activation after ischemic stroke and lipocalin-2 (LCN2) plays a key role in polarizing and activating astrocytes.

Overexpression of BRCA1 in Neural Stem Cells Enhances Cell Survival and Functional Recovery after Transplantation into Experimental Ischemic Stroke.

Transplantation of neural stem cells (NSCs) is a promising therapy for ischemic stroke. However, the effectiveness of this approach is limited by grafted cell death. Breast cancer susceptibility protein 1 (BRCA1) could suppress apoptosis in neural progenitors and modulate oxidative stress in neurons. In this study, we found that BRCA1 was upregulated by oxygen-glucose deprivation/reoxygenation (OGD/R). Overexpression of BRCA1 in NSCs reduced cell apoptosis and oxidative stress after OGD/R insult. The molecule overexpression also stimulated cellular proliferation in OGD/R NSCs and increased the survival rate of grafted cells. Further, the transplantation of BRCA1-transfected NSCs into mice with ischemic stroke increased brain-derived neurotropic factor and nerve growth factor expression in the brain and elicited neurological function improvement. In addition, we found that RING finger domain and BRCT domain of BRCA1 could physically interact with p53 in NSCs. The cross talk between BRCA1 RING finger domain and p53 was responsible for p53 ubiquitination and degradation. Our findings indicate that modification with BRCA1 could enhance the efficacy of NSCs transplantation in ischemic stroke.

Impact of Smoking Status on Stroke Recurrence.

Background Smoking is a well-established risk factor of stroke and smoking cessation has been recommended for stroke prevention; however, the impact of smoking status on stroke recurrence has not been well studied to date. Methods and Results Patients with first-ever stroke were enrolled and followed in the NSRP (Nanjing Stroke Registry Program). Smoking status was assessed at baseline and reassessed at the first follow-up. The primary end point was defined as fatal or nonfatal recurrent stroke after 3 months of the index stroke. The association between smoking and the risk of stroke recurrence was analyzed with multivariate Cox regression model. At baseline, among 3069 patients included, 1331 (43.4%) were nonsmokers, 263 (8.6%) were former smokers, and 1475 (48.0%) were current smokers. At the first follow-up, 908 (61.6%) patients quit smoking. After a mean follow-up of 2.4±1.2 years, 293 (9.5%) patients had stroke recurrence. With nonsmokers as the reference, the adjusted hazard ratios for stroke recurrence were 1.16 (95% CI , 0.75-1.79) in former smokers, 1.31 (95% CI , 0.99-1.75) in quitters, and 1.93 (95% CI , 1.43-2.61) in persistent smokers. Among persistent smokers, hazard ratios for stroke recurrence ranged from 1.68 (95% CI , 1.14-2.48) in those who smoked 1 to 20 cigarettes daily to 2.72 (95% CI , 1.36-5.43) in those who smoked more than 40 cigarettes daily ( P for trend <0.001). Conclusions After an initial stroke, persistent smoking increases the risk of stroke recurrence. There exists a dose-response relationship between smoking quantity and the risk of stroke recurrence.

Prognosis of asymptomatic intracranial hemorrhage after endovascular treatment.

OBJECTIVE: Asymptomatic intracranial hemorrhage (aSICH) is a common phenomenon after endovascular treatment of acute ischemic stroke, but its prognostic impacts remain unclear. This study evaluated functional outcomes of thrombectomy in patients with and without aSICH. METHODS: Patients with acute ischemic stroke due to large artery occlusion in the anterior circulation who were treated with thrombectomy were enrolled in 21 centers. According to CT scans performed within 72 hours of endovascular procedures, patients with aSICH or without intracranial hemorrhage were included while patients with symptomatic intracranial hemorrhage (SICH) were excluded. Baseline data and functional outcomes were compared between patients with aSICH and those without intracranial hemorrhage. Logistic regression analysis was applied to evaluate the impacts of aSICH on functional outcomes. RESULTS: Of the 632 patients with endovascular treatment, 101 (16.0%) were classified as having SICH, 212 (33.5%) as having aSICH, and 319 (50.5%) as being without intracranial hemorrhage. Patients with aSICH after endovascular treatment had a lower ratio of excellent outcome (mRS 0-1, OR 0.53; 95% CI 0.33 to 0.84, P=0.007) than those without intracranial hemorrhage. There were no significant differences concerning favorable outcome (mRS 0-2, OR 0.76; 95% CI 0.50 to 1.14, P=0.185) or mortality (OR 0.64; 95% CI 0.38 to 1.09, P=0.101) between patients with aSICH and those without intracranial hemorrhage. CONCLUSIONS: In an Asian population, aSICH after thrombectomy may decrease the likelihood of an excellent functional outcome but does not influence a favorable outcome and mortality in patients with ischemic stroke due to large artery occlusion in the anterior circulation.

Neutrophil to Lymphocyte Ratio as a Predictor of Restenosis After Angioplasty and Stenting for Asymptomatic Carotid Stenosis.

The inflammatory response plays a vital role in the development of in-stent restenosis (ISR) after carotid angioplasty and stenting (CAS). The neutrophil to lymphocyte ratio (NLR) has been suggested as a sensitive inflammatory marker. We explored the association between NLR and ISR in CAS patients. A total of 427 patients who underwent CAS were enrolled. Neutrophil to lymphocyte ratio was measured before the procedure. Clinical examination and radiographic evaluation were performed at 6 months and annually after the procedure. In-stent restenosis was defined as ≥50% stenosis in the treated lesion. Cox regression was used to identify predictors of ISR after CAS. Of the 459 arteries (in 427 patients) with CAS, 72 (15.7%) were identified with ISR during a mean follow-up of 14.6 (19.1) months (range, 0.7-120.7 months). Increased NLR (≥2.13) was significantly related to ISR in patients with asymptomatic stenosis ( P = .001). However, significance was not observed in symptomatic stenosis. On multivariate analysis, baseline NLR ≥ 2.13 (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.46-5.14), smoking (HR, 1.99; 95% CI, 1.11-3.58), residual stenosis (HR, 1.12; 95% CI, 1.09-1.15), and baseline glucose level (HR, 1.01; 95% CI, 1.01-1.02) were associated with ISR. Elevated NLR may be a predictor of ISR after CAS for asymptomatic stenosis.

Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway.

Cellular oxidative stress plays a vital role in the pathological process of neural damage in cerebral ischemia/reperfusion (I/R). The breast cancer susceptibility protein 1 (BRCA1), a tumor suppressor, can modulate cellular antioxidant response and DNA repair. Yet the role of BRCA1 in cerebral I/R injury has not been explored. In this study, we observed that BRCA1 was mainly expressed in neurons and was up-regulated in response to I/R insult. Overexpression of BRCA1 attenuated reactive oxygen species production and lipid peroxidation. Enhanced BRCA1 expression promoted DNA double strand break repair through non-homologous end joining pathway. These effects consequently led to neuronal cell survival and neurological recovery. Mechanically, BRCA1 can interact with the nuclear factor (erythroid-derived 2)-like 2 (NRF2) through BRCA1 C-terminal (BRCT) domain. The cross-talk between BRCT and NRF2 activated the NRF2/Antioxidant Response Element signaling pathway and thus protected injured neurons during cerebral I/R. In conclusion, enhanced BRCA1 after cerebral I/R injury may attenuate or prevent neural damage from I/R via NRF2-mediated antioxidant pathway. The finding may provide a potential therapeutic target against ischemic stroke.

Restenosis after carotid artery stenting.

As a common etiology for ischemic stroke, atherosclerotic carotid stenosis has been targeted by vascular surgery since 1950s. Compared with carotid endarterectomy, carotid angioplasty and stenting (CAS) is almost similarly efficacious and less invasive. These advantages make CAS an alternative in treating carotid stenosis. However, accumulative evidences suggested that the long-term benefit-risk ratio of CAS may be decreased or even neutralized by the complications related to in-stent restenosis (ISR). Therefore, investigating the mechanisms and identifying the influential factors of ISR are of vital importance for improving the long-term outcomes of CAS. As responses to intrinsic and extrinsic injuries, intimal hyperplasia and vascular smooth muscle cell proliferation have been regarded as the principle mechanisms for ISR development. Due to the lack of consensus-based definition and consistent follow-up protocol, the reported incidences of ISR after CAS varied widely among studies. These variations made the inter-study comparisons of ISR largely illogical. To eliminate restenosis after CAS, both surgery and endovascular procedures have been attempted with promising results. For preventing ISR, drug-eluting stents and antiplatelets have been proposed as potential solutions.

Dietary fiber intake reduces risk for Barrett's esophagus and esophageal cancer.

BACKGROUND: Observational studies suggest an association between dietary fiber intake and risk of Barrett's esophagus and esophageal cancer. However, the results are inconsistent. OBJECTIVE: To conduct a meta-analysis of observational studies to assess this association. DESIGN: All eligible studies were identified by electronic searches in PubMed and Embase through February 2015. Dose-response, subgroup, sensitivity, and publication bias analyses were performed. RESULTS: A total of 15 studies involving 16,885 subjects were included in the meta-analysis. The pooled odds ratio for the highest compared with the lowest dietary fiber intake was 0.52 (95% CI, 0.43-0.64). Stratified analyses for tumor subtype, study design, geographic location, fiber type, publication year, total sample size, and quality score yielded consistent results. Dose-response analysis indicated that a 10-g/d increment in dietary fiber intake was associated with a 31% reduction in Barrett's esophagus and esophageal cancer risk. Sensitivity analysis restricted to studies with control for conventional risk factors produced similar results, and omission of any single study had little effect on the overall risk estimate. CONCLUSIONS: Our findings indicate that dietary fiber intake is inversely associated with risk of Barrett's esophagus and esophageal cancer. Further large prospective studies are warranted.

Association of GWAS-Supported Variants rs556621 on Chromosome 6p21.1 with Large Artery Atherosclerotic Stroke in a Southern Chinese Han Population.

Recent genome-wide association study associated rs556621 on chromosome 6p21.1 with the risk of large artery atherosclerotic (LAA) stroke in Caucasians. However, subsequent replicate studies showed conflict results in different ethnicities. This study aimed to evaluate whether rs556621 was associated with LAA stroke in Chinese Han population. In this case-control study, 659 patients with LAA stroke and 650 healthy controls were enrolled. Associations between rs556621 genotypes and LAA stroke were analyzed with logistic regression model. Rs556621 variants were associated with increased risks of LAA stroke (codominant model: OR 1.42; 95 % CI 1.01-1.99; P = 0.010; recessive model: OR 1.40; 95 % CI 1.05-1.86; P = 0.003). When subjects were stratified by sex, TT genotype of SNP rs556621 was associated with an increased risk of LAA stroke in female when tested with recessive model (OR 2.36; 95 % CI 1.28-4.36, P = 0.006). In male subjects, however, no significant association was detected. Smoking status, sex did not significantly influence the relationship between genotypes of rs556621 and risk of LAA stroke (P interaction = 0.140, P interaction = 0.076). Rs556621 may play an important role in the development of LAA stroke in female Chinese of Han ethnicity. Larger studies with subjects of different ethnicities are warranted to confirm these findings.