Antioxidative polyphenols attenuate pyocyanin-induced ROS production in neuronal HT22 cell lines.

Pyocyanin, a secreted virulence factor, plays an essential role during Pseudomonas aeruginosa infection. Infection of the central nervous system by this bacterium results in high mortality, but the studies on its mechanism are still rather limited. In this study, we first evaluate the neuronal damage caused by pyocyanin exposure in neuronal HT22 cells. Pyocyanin leads to mitochondrial syndrome and antioxidant defense disruption, therefore increasing intercellular reactive oxygen species (ROS) production. Several typical superior antioxidant polyphenols effectively protect against pyocyanin-induced neuronal cell damage. These findings suggest the neuronal protective activity more or less relies on the structure, rather than the residues. Pre-incubation of catechin activates the essential pathway, indicating inverse correlation of ERK and AMPK phosphorylation participates in this process. These data outline a novel strategy to eliminate intracellular generated ROS. The investigated candidates could be potentially used as therapeutic agents against various ROS-related neurological diseases.

Research on Relationship Between Dysphagia and Sudden Death After Medullary Infarction.

BACKGROUND: Medullary infarction (MI) often leads to severe dysphagia and sudden death. We investigated whether dysphagia was associated with sudden death. METHODS: Patients with MI were divided into sudden death group and nonsudden death group. Dysphagia was evaluated in 2 ways: the water-swallowing test (WST) points and the degree of dysphagia. Random undersampling (RUS), random oversampling (ROS), and synthetic minority oversampling technique (SMOTE) techniques were used to process the original data and solve the imbalance problem between 2 classes. Univariate and multivariate logistic regressions were used to analyze the association between the independent variables (WST and degree of dysphagia) and the dependent variable (sudden death or not), while the National Institutes of Health Stroke Scale (NIHSS) score was used as a control. RESULTS: Univariate logistic regression analysis showed that for all resampling methods, both the WST and NIHSS were risk factors for sudden death after MI. For multivariable logistic regression, the fitting effect of RUS logistic regression was satisfactory, which showed the same results. The results of the univariate logistic regression analysis of dysphagia degree showed that for all resampling methods, compared with no dysphagia, both mild to moderate dysphagia degree and severe dysphagia degree were risk factors for sudden death. For multivariable logistic regressions, the logistic regressions of the original data and the RUS resampling method were satisfactory which showed the same results. CONCLUSIONS: Dysphagia is closely related to sudden death after MI. The more severe the dysphagia, the higher is the incidence of sudden death.

Sex Differences in Outcomes After Spontaneous Intracerebral Hemorrhage Among Patients With Low Total Cholesterol Levels.

BACKGROUND: Low total cholesterol (TC) levels were shown to be an independent predictor of intracerebral hemorrhagic stroke in previous studies. However, the role of sex in risk and outcome of patients with ICH and low TC levels is unclear. Therefore, the objective of our study was to assess the sex differences in the risk factors and outcomes after spontaneous intracerebral hemorrhage (ICH) in patients with low TC levels in China. METHODS: This study recruited consecutive patients diagnosed with ICH who were admitted to the Stroke Registry System in Tianjin between May 2005 and May 2018. Patients with low TC levels (defined as TC<200 mg/dl) were analyzed in this study. Sex differences in clinical features, risk factors, and outcomes at hospital discharge, 3 months, and 12 months after ICH were evaluated. RESULTS: Of the 824 patients with low TC levels, 610 men (74%) and 214 women (26%). The mean age at ICH onset was younger in men than in women (60.93±12.54 vs. 64.5±12.28, P<0.001), and men were more likely to have higher educational levels than women. There were higher prevalence rates of hypertension, current smoking status, and alcohol consumption in men. Urinary tract infections were more prevalent in women, and hepatic/renal dysfunctions were more prevalent in men. Women had significantly higher neurological function deficits. With lower Barthel indices (BIs) and higher modified Rankin scale (mRS) scores at admission; but there was no significant difference between men and women in National Institutes of Health Stroke Scale (NIHSS) scores. The study showed that there was no significant difference in mortality and dependency rates at hospital discharge, 3 months, and 12 months after ICH. CONCLUSIONS: Our study showed that there were no sex differences in clinical outcomes of patients with ICH and low TC levels, which suggests that the effect of low cholesterol as a risk factor for cerebral hemorrhage is the same on patients of different sexs. The possible mechanisms need larger, prospective, multicenter studies to further research.

Low Triglyceride Levels are Associated with Unfavorable Outcomes in Patients with Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND AIMS: The relationship between serum lipid level and clinical outcome after spontaneous intracerebral hemorrhage (ICH) remains controversial. We sought to evaluate the association of serum lipid levels with clinical outcomes in patients with ICH. METHODS: Data on consecutive patients hospitalized with spontaneous ICH were prospectively collected from May 2005 to May 2018 and retrospectively analyzed. Following clinical and demographic data, age and gender, risk factors, serum lipid levels [total cholesterol, triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol] and the outcomes were analyzed. RESULTS: A total of 1451 patients with ICH (mean age, 60.41 ± 12.3 years; 32.6% women) was evaluated. Although admission TG levels were associated with the outcomes at hospital discharge and 3 months in initial univariate analyses, the former association did not retain its statistical significance in multivariate logistic regression analyses adjusting for potential confounders. However, lower admission TG levels were independently associated (p = 0.045) with a higher likelihood of 12-month unfavorable outcomes (odds ratio 0.91, 95% confidence interval 0.83-0.99) in multivariate logistic regression models. CONCLUSIONS: Low TG levels at hospital admission were an independent predictor for unfavorable long-term outcomes in patients with spontaneous ICH. The exact mechanisms of the association need further investigations.

MiR-199a-5p inhibition protects cognitive function of ischemic stroke rats by AKT signaling pathway.

To explore the effect of miR-199a-5p and AKT signal pathway on cognitive function and neuronal cells in rats with ischemic stroke. Sprague-Dawley rats were divided into 6 groups: Normal group (normal rats), Sham group (rats received sham operation), Model group (MCAO rats), miR-199a-5p inhibitor group (model rats treated with miR-199a-5p inhibitor), IGF-1 group (model rats treated with AKT signaling pathway activator), miR-199a-5p inhibitor + IGF-1 group (model rats treated by miR-199a-5p inhibitor and AKT signaling pathway activator). Rat behavior and cerebral infarction area were observed. TUNEL fluorescence staining was used to detect neuronal apoptosis in hippocampal CA1 region of rats. The dual luciferase reporter assay validated the targeting relationship between miR-199a-5p and AKT. qRT-PCR and WB were used to detect the expression level of miR-199a-5p, (p)-AKT and (p)-mTOR, apoptosis-related proteins Bax and Bcl-2. Compared with the normal group, the expression of miR-199a-5p was increased in the Model group, and the expression levels of AKT, mTOR, p-AKT, and p-mTOR were decreased (all P < 0.05); the cognitive function of the rats in the Model group was thereby significantly lower (P < 0.05). miR-199a-5p was targeted to inhibit AKT. Compared with the Model group, miR-199a-5p inhibition combined with IGF-1 showed more significant effects on improving cognitive function and protecting neuronal cells of rats. In conclusion, silencing miR-199a-5p can effectively improve cognitive function in ischemic stroke rats and decrease neuronal apoptosis in hippocampus by activating the AKT signaling pathway.

Author Correction: Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Sex differences in outcomes and associated factors among stroke patients with small artery occlusion in China.

BACKGROUND: Sex differences in outcomes after small artery occlusion (SAO) stroke have not been well described, particularly in a Chinese population. We aimed to assess sex differences in outcomes and related risk factors among patients with SAO. METHODS: All consecutive patients with SAO were recruited between May 2005 and September 2014. Clinical features and risk factors were recorded. The mortality, recurrence, and dependency rates at 3 months after stroke were assessed. RESULTS: A total of 2524 patients with SAO were included in this study. There was a higher frequency of mild stroke, current smoking, and alcohol consumption in men than in women. Women were more likely than men to be older, to have diabetes and obesity, and to have higher total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels. There were worse outcomes in men than in women at 3 months after stroke (P < 0.05). There were more independent risk factors of poor outcome in men than in women. Older age was a common predictive factor of outcome both in men and in women. In men, low triglyceride levels and high fasting plasma glucose levels were independent risk factors for mortality; in addition, a high low-density lipoprotein cholesterol level was associated with recurrence. Moreover, in men, moderate and severe stroke, and high total cholesterol and fasting plasma glucose levels were risk factors for dependency. A negative association was found between low-density lipoprotein cholesterol level and risk of mortality and between total cholesterol level and risk of recurrence in women. CONCLUSIONS: These findings suggest that it is crucial to control conventional risk factors and fasting plasma glucose and lipid levels among patients with SAO, especially male patients, to reduce the burden of stroke in China.

Apolipoprotein E mimetic peptide CN-105 improves outcome in a murine model of SAH.

Objective: Subarachnoid haemorrhage (SAH) accounts for 3% of all strokes, and is associated with significant morbidity and mortality. There is growing evidence implicating apolipoprotein E (apoE) in mediating adaptive anti-inflammatory and neuroprotective responses following ischaemic and traumatic brain injury. In the current study, we test the efficacy of a small apoE mimetic peptide, CN-105 in a murine model of SAH. Methods: Mice subjected to SAH received repeated intravenous injections of CN-105 every 12 hours for 3 days, with the first dose given 2 hours after injury. Daily functional outcomes were assessed by rotarod and neurological severity score. Haemorrhage grade and cerebral vascular diameters were measured at 5 days post-SAH. Cerebral microgliosis, neuronal degeneration and survival were analysed at 5 and 35 days post-SAH, respectively. Results: CN-105 reduces histological evidence of inflammation, reduces vasospasm and neuronal injury and is associated with improved long-term behavioural outcomes in a murine model of SAH. Conclusions: Given its favourable pharmacokinetic profile, central nervous system penetration and demonstration of clinical safety, CN-105 represents an attractive therapeutic candidate for treatment of brain injury associated with SAH.

Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model.

At present, there are no proven pharmacological treatments demonstrated to improve long term functional outcomes following traumatic brain injury(TBI). In the setting of non-penetrating TBI, sterile brain inflammatory responses are associated with the development of cerebral edema, intracranial hypertension, and secondary neuronal injury. There is increasing evidence that endogenous apolipoprotein E(apoE) modifies the neuroinflammatory response through its role in downregulating glial activation, however, the intact apoE holoprotein does not cross the blood-brain barrier due to its size. To address this limitation, we developed a small 5 amino acid apoE mimetic peptide(CN-105) that mimics the polar face of the apoE helical domain involved in receptor interactions. The goal of this study was to investigate the therapeutic potential of CN-105 in a murine model of closed head injury. Treatment with CN-105 was associated with a durable improvement in functional outcomes as assessed by Rotarod and Morris Water Maze and a reduction in positive Fluoro-Jade B stained injured neurons and microglial activation. Administration of CN-105 was also associated with reduction in mRNA expression of a subset of inflammatory and immune-related genes.

Sex differences in outcomes after stroke among patients with low total cholesterol levels: a large hospital-based prospective study.

BACKGROUND: Previous studies have shown that total cholesterol (TC) levels are associated with stroke outcomes, but sex differences in the association between TC levels, especially a low TC level, and ischemic stroke outcomes are unknown. We aimed to assess the sex differences in stroke outcomes among patients with atherothrombotic infarctions and low TC levels in China. METHODS: This study recruited patients with atherothrombotic infarctions from Tianjin, China, between May 2005 and September 2014. Patients with low TC levels (defined as TC <4.22 mmol/L) were analyzed in this study. Sex differences in stroke subtypes, severity, risk factors, and outcomes at 3 and 12 months after stroke were compared. RESULTS: Overall, 1587 patients with low TC levels were recruited to this study from among 6407 patients with atherothrombotic infarctions listed in a stroke registry. Women were more likely than men to have posterior circulation infarcts, severe stroke, hypertension, and obesity but less likely to be current smokers or to consume alcohol. There were no sex differences in stroke outcomes. Older age and severe stroke were common risk factors for poor outcomes after stroke in this study. The presence of diabetes mellitus was an independent predictor of low mortality at 12 months after stroke, possibly because a drug commonly used to treat diabetes, metformin, enhances angiogenesis. Obesity was the determinant of the recurrence and dependency rates at 12 months after stroke. CONCLUSIONS: These findings suggest that patients (both men and women) with atherothrombotic infarction who have low TC levels would not benefit from receiving statin treatment. Therefore, it is crucial to explore the impact of statin treatment on outcomes in Asian patients, especially Chinese patients with atherothrombotic and low TC levels, in order to improve outcomes after stroke and reduce the disease burden.

Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

Presently, no pharmacological treatments have been demonstrated to improve long-term functional outcomes following intracerebral hemorrhage (ICH). Clinical evidence associates apolipoprotein E (apoE) genotype with ICH incidence and outcome. While apoE modifies neuroinflammatory responses through its adaptive role in glial downregulation, intact apoE holoprotein is too large to cross the blood-brain barrier (BBB). Therefore, we developed a 5-amino acid peptide - CN-105 - that mimics the polar face of the apoE helical domain involved in receptor interactions. In the current study, we investigated the therapeutic potential of CN-105 in a mouse model of ICH. Three doses of CN-105 (0.05 mg/kg) was administered by tail vein injection within 24 hours after ICH induction. Functional assessment showed durable improvement in vestibulomotor performance after CN-105 treatment, as quantified by increased Rotarod latencies on Days 1-5 post-ICH, and long-term improvement in neurocognitive performance, as quantified by reduced Morris water maze latencies on Days 29-32 post-ICH. Further, brain water content was significantly reduced, neuroinflammation was decreased and hippocampal CA3 neuronal survival was increased, although hemorrhage volume was not affected by CN-105. We concluded, therefore, that pentapeptide CN-105 improved short- and long-term neurobehavioral outcomes in a murine model of ICH, suggesting therapeutic potential for patients with acute ICH.

Low total cholesterol level is the independent predictor of poor outcomes in patients with acute ischemic stroke: a hospital-based prospective study.

BACKGROUND: Total cholesterol is a well-documented risk factor for coronary disease. Previous studies have shown that high total cholesterol level is associated with better stroke outcomes, but the association of low total cholesterol levels and ischemic stroke outcomes is rare. Therefore, we aimed to assess the association of low total cholesterol levels and stroke outcomes among acute ischemic stroke patients in China. METHODS: This study recruited 6407 atherothrombotic infarction patients from Tianjin, China, between May 2005 and September 2014. All patients were categorized into five groups according to TC level quintiles at admission. Differences in subtypes, severity, risk factors, and outcomes at 3, 12, and 36 months after stroke were compared between these groups. RESULTS: In total, 1256 (19.6%) patients had low cholesterol levels, with a higher prevalence in men than in women (23.7% vs. 11.2%, P < 0.001). Compared with higher cholesterol levels, the lowest cholesterol level quintile (TC, <4.07 mmol/L) was associated with older age (64.7 years, P = 0.033), anterior circulation infarct (22.8%), atrial fibrillation (4.9%), current smoking (41.1%), and alcohol consumption (21.1%) and lower frequencies of hypertension (72.9%), diabetes (30.7%), and obesity (9.9%). Dependency and recurrence rates were significantly higher at 36 months in patients in the lowest TC level quintile than in those with higher cholesterol levels (dependency rates, 51.2% vs 45.2%; P = 0.007 and recurrence rates, 46.3% vs 37.3%, P = 0.001). Moreover, these differences remained after adjustment for age, sex, stroke severity, and Oxfordshire Community Stroke Project classification (odds ratios [ORs] for dependency rate, 1.41; 95% confidence interval [CI], 1.11, 1.79; P = 0.005 and recurrence rate, 1.50; 95% CI, 1.19, 1.89; P = 0.001). However, mortality rates after stroke were not significantly different between the groups. CONCLUSIONS: These findings suggest that statin treatment for patients with atherothrombotic infarction and low cholesterol levels increase long-term dependency and recurrence rates, but do not increase mortality rates. It is crucial to highlight the different impact of statin treatment on patients with atherothrombotic infarction and lower cholesterol levels for secondary stroke prevention in China.

Sex differences in long-term outcomes among acute ischemic stroke patients with diabetes in China.

BACKGROUND: Diabetes has been shown to be significantly associated with poor outcome after stroke. However, the sex differences in stroke outcome among patients with diabetes are unknown. Therefore, we aimed to assess the sex differences in long-term prognosis among acute ischemic stroke patients with diabetes. METHODS: The ischemic stroke patients with diabetes were recruited to this study between May 2005 and September 2014 in Tianjin, China. Sex differences in mortality, dependency (modified rank scale > 2), and recurrence at 3, 12, and 36 months after stroke were analyzed. RESULTS: A total of 2360 patients were recruited in this study. The age of stroke onset, National Institute of Health stroke scale (NIHSS), and modified rank scale (mRS) on admission were greater in women than in men (P < 0.05). Women were more likely to have hypertension, obesity, atrial fibrillation, and dyslipidemias. In contrast, men were more likely to have artery stenosis, current smoking, and alcohol consumption (P < 0.001). There was higher mortality in women than in men at 3 months (7.9 % vs 5.2 %), 12 months (12.2 % vs 8.2 %), and 36 months (21.9 % vs 16.1 %) after stroke; but no differences were found in dependency and recurrence. Sex differences were found in associated factors of outcomes by time-point. Trial of Org 10172 in Acute Stroke Treatment (TOAST) of large artery atherothrombosis (LAA), cardioembolism (CE), and smoking were risk factors of outcomes in women at short term and medium term; but atrial fibrillation (AF), obesity, and alcohol were risk factors of outcomes in men at medium term and long term. CONCLUSIONS: These findings suggest that it is crucial to establish the individual scheme of therapy for every patient by different risk factors of stroke, strengthen the rehabilitation of stroke, and carry on the health education early for the secondary prevention of stroke in patients with diabetes mellitus (DM).

Moyamoya syndrome as an unusual presenting manifestation of systemic lupus erythematosus in a young woman.

OBJECTIVE: To describe a rare case of moyamoya syndrome associated with systemic lupus erythematosus (SLE). PRESENTATION AND INTERVENTION: A 22-year-old woman presented with left-sided hemiparesis in addition to fever, fatigue and malar rash. Brain magnetic resonance imaging revealed acute infarction in the right middle cerebral artery territory. Cerebral angiography showed features of moyamoya syndrome. Brain biopsy showed evidence of vasculitis. She responded well to steroid therapy. CONCLUSION: This case represented a rare co-occurrence of SLE-related vasculitis and moyamoya syndrome. Early vascular imaging is critical in patients with SLE and suspected ischemic stroke.