Regulation and molecular mechanism of adiponectin on the proliferation, apoptosis, autophagy, and chemosensitivity of LN18 Glioma cell line.

This study aimed to explore the regulatory effects and associated mechanisms of adiponectin on apoptosis and proliferation in the LN18 glioma cell line through the AMPK and Akt signaling pathways. Additionally, we sought to elucidate the impact of adiponectin on the chemosensitivity of the LN18 glioma cell line to temozolomide (TMZ). The proliferation rate of glioma cells treated with adiponectin was assessed using the cholecystokinin (CCK8) assay. The Western blot analysis was employed to assess the expression of p-Akt, p-AMPK, p-mTOR, cleaved caspase3, Bax, Cyclin D1, and Cyclin B1 following adiponectin treatment. Cell apoptosis was quantified using AnnexinV/PI flow cytometry, while changes in the cell cycle were detected using PI staining flow cytometry. The findings revealed that adiponectin upregulates p-AMPK expression and downregulates p-mTOR expression in the PTEN wild-type glioma cell line LN18, with no discernible effect on p-Akt expression. Moreover, adiponectin inhibits the proliferation rate of the PTEN wild-type glioma cell line LN18, enhances the expression of cleaved caspase3 and Bax, and significantly elevates the apoptosis rate, as evidenced by AnnexinV/PI flow cytometry. Adiponectin was observed to suppress the expression of Cyclin D1 and Cyclin B1, increase the number of cells in the G1 phase, and promote autophagy. Additionally, adiponectin augments the expression of Beclin1 and the ratio of LC3II/I in the PTEN wild-type glioma cell line LN18, while decreasing p62 expression. In conclusion, this study posits that adiponectin holds therapeutic promise for glioma treatment. Furthermore, adiponectin enhances the inhibitory effect of TMZ on the proliferation rate of LN18 cells when treated with 0.1 mM and 1 mM TMZ. These results collectively suggest that adiponectin impedes proliferation, encourages apoptosis and autophagy in the LN18 glioma cell line, and heightens its sensitivity to the chemotherapeutic drug TMZ.

Enlarged perivascular spaces predict malignant cerebral edema after acute large hemispheric infarction.

INTRODUCTION: Enlarged perivascular spaces (EPVS) are considered early manifestations of impaired clearance mechanisms in the brain; however, it is unclear whether EPVS they are associated with the development of malignant cerebral edema (MCE) after large hemispheric infarction (LHI). Therefore, we investigated the predictive value of EPVS in predicting MCE in LHI. METHODS: Patients suffering from acute LHI were consecutively enrolled. EPVS were rated after the stroke with validated rating scales from magnetic resonance imagess. Patients were divided into two groups according to the occurrence of MCE. Logistic regression was used to analyze the relationship between EPVS and MCE in the basal ganglia (BG) and centrum semiovale (CS) regions. Receiver operating characteristic (ROC) curves assessed the ability of EPVS individually and with other factors in predicting MCE. RESULTS: We included a total of 255 patients, of whom 98 were MCE patients (58 [59.2%] males, aged 70 [range=61.75-78] years) and found that atrial fibrillation, National Institutes of Health Stroke Scale score, infarct volume, neutrophil-lymphocyte ratio, and moderate-to-severe CS-EPVS were positively associated with MCE. After adjusting for confounds, moderate-to-severe CS-EPVS remained independent risk factor of MCE (odds ratio=16.212, p＜0.001). According to the ROC analysis, MCE was highly suspected when CS-EPVS > 14 (sensitivity=0.82, specificity=0.48), and the guiding value were higher when CS-EPVS combined with other MCE predictors (area under the curve=0.90, sensitivity=0.74, specificity=0.90). CONCLUSION: CS-EPVS were important risk factor for MEC in patients with acute LHI and can help identify patients at risk for MCE.

Solasonine ameliorates cerebral ischemia-reperfusion injury via suppressing TLR4/MyD88/NF-κB pathway and activating AMPK/Nrf2/HO-1 pathway.

Solasonine (SS), the main active ingredient of Solanum nigrum L., has been reported to possess a variety of pharmacological properties. A recent study demonstrated a neuroprotective effect of SS in a mouse nerve injury model. However, its protective effects on cerebral ischemia/reperfusion injury (CIRI) remain to be elucidated. We investigated herein the in vitro and in vivo neuroprotective effects of SS. Primary hippocampal neurons were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to construct an in vitro model while rats were treated with middle cerebral artery occlusion/reperfusion (MCAO/R) to establish an in vivo CIRI model. The results showed that SS reduced OGD/R-induced inflammatory responses of neurons by blocking secretion of TNF-α, IL-1ß and IL-6. Moreover, SS ameliorated OGD/R-induced oxidative stress in neurons by decreasing the level of ROS and MDA and increasing the activity of SOD and GPx. We also found that SS protected neurons from OGD/R-induced apoptosis by down-regulating bax and cleaved caspase-3 and up-regulating bcl-2. The in vivo results revealed that SS administration reduced the infarct volume and alleviated the neurological deficit of MCAO/R rats as well as diminished neuronal damages in these rats. Our investigation on the underlying mechanisms indicated that the neuroprotective effect of SS on CIRI may be associated with the TLR4/MyD88/NF-κB and AMPK/Nrf2/HO-1 pathways. Taken together, these findings demonstrate that SS ameliorates CIRI via suppressing TLR4/MyD88/NF-κB pathway and activating AMPK/Nrf2/HO-1 pathway.

Post-dural puncture headache combined with pneumocephalus secondary to vaginal delivery following epidural anesthesia: a case report.

BACKGROUND: Pneumocephalus is rare in vaginal deliveries. Pneumocephalus may be asymptomatic or present with signs of increased intracranial pressure. However, parturients who received epidural anesthesia with air in their brains may experience low intracranial pressure headaches after giving birth, causing the diagnosis of pneumocephalus to be delayed. We report a case of a parturient who developed post-dural puncture headache combined with pneumocephalus secondary to vaginal delivery following epidural anesthesia. CASE PRESENTATION: A 24-year-old G1P0 Chinese woman at 38 weeks gestation was in labor and received epidural anesthesia using the loss of resistance to air technique and had a negative prior medical history. She presented with postural headache, neck stiffness and auditory changes 2 h after vaginal delivery. The head non-contrast computed tomography revealed distributed gas density shadows in the brain, indicating pneumocephalus. Her headache was relieved by bed rest, rehydration, analgesia, and oxygen therapy and completely disappeared after 2 weeks of postpartum bed rest. CONCLUSIONS: This is the first report that positional headaches after epidural anesthesia may not indicate low intracranial pressure alone; it may combine with pneumocephalus, particularly when using the loss of resistance to air technique. At this moment, head computed tomography is essential to discover other conditions like pneumocephalus.

Loganin attenuates neuroinflammation after ischemic stroke and fracture by regulating α7nAChR-mediated microglial polarization.

Fracture in acute stage of ischemic stroke can increase inflammatory response and enhance stroke injury. Loganin alleviates the symptoms of many inflammatory diseases through its anti-inflammatory effect, but its role in ischemic stroke and fracture remains to be explored. Here, mice were handled with permanent middle cerebral artery occlusion (pMCAO) followed by tibial fracture 1 day later to establish a pMCAO+fracture model. Loganin or Methyllycaconitine (MLA, a specific a7nAchR inhibitor) were intragastrically administered 2 or 0.5 h before pMCAO, respectively. And mouse motor function and infarct volume were evaluated 3 days after pMCAO. We found that loganin alleviated the neurological deficit, cerebral infarction volume, and neuronal apoptosis (NeuN+ TUNEL+ ) in mice with pMCAO+fracture. And loganin suppressed pMCAO+fracture-induced neuroinflammation by promoting M2 microglia polarization (Iba1+ CD206+ ) and inhibiting M1 microglia polarization (Iba1+ CD11b+ ). While administration with MLA reversed the protective effect of loganin on pMCAO+fracture-induced neurological deficit and neuroinflammation. Next, LPS was used to stimulate BV2 microglia to simulate pMCAO+fracture-induced inflammatory microenvironment in vitro. Loganin facilitated the transformation of LPS-stimulated BV2 cells from M1 pro-inflammatory state (CD11b+ ) to M2 anti-inflammatory state (CD206+ ), which was antagonized by treatment with MLA. And loganin induced autophagy activation in LPS-stimulated BV2 cells by activating a7nAchR. Moreover, treatment with rapamycin (an autophagy activator) neutralized the inhibitory effect of MLA on loganin induced transformation of BV2 cells to M2 phenotype. Furthermore, BV2 cells were treated with LPS, LPS + loganin, LPS + loganin+MLA, or LPS + loganin+MLA+ rapamycin to obtain conditioned medium (CM) for stimulating primary neurons. Loganin reduced the damage of primary neurons caused by LPS-stimulated BV2 microglia through activating a7nAchR and inducing autophagy activation. In conclusion, loganin played anti-inflammatory and neuroprotective roles in pMCAO + fracture mice by activating a7nAchR, enhancing autophagy and promoting M2 polarization of microglia.

Sleep disturbance is associated with mild cognitive impairment: a community population-based cross-sectional study.

BACKGROUND: Sleep is conducive to the elimination of brain metabolites and the recovery of brain function. However, the relationship between sleep disturbance and Mild Cognitive Impairment is not fully been determined. METHODS: This was a community population-based cross-sectional study. A total of 1,443 participants from a village in the suburbs of Xi'an, China were enrolled in 2017. Sleep quality was evaluated using the Pittsburgh sleep quality index (PSQI), and sleep disturbance was defined as a PSQI score > 5. Mini-Mental State Examination (MMSE) was used to assess cognitive function and Mild Cognitive Impairment(MCI) was defined as the MMSE score less than cutoff values and meets the diagnostic criteria. Univariate and multivariate analyses were used to analyze the relationships between sleep disturbance and MCI. RESULTS: Among 1,443 subjects, 69(4.78%) had MCI, and 830 (57.52%) had sleep disturbance. In bivariate analysis, MCI was associated with sleep disturbance (ρ = 0.094, P<0.001). In the binary logistic regression, MCI was positively associated with the sleep disturbance (OR = 2.027, 95%CI = 1.112-3.698, P = 0.021). In the internal constitution of PSQI, MCI was negatively associated with the habitual sleep efficiency (OR = 0.447, 95%CI = 0.299-0.669, P < 0.001). Compared with waking up before or at 7 am, waking up after 7 am (OR = 0.555, 95%CI = 0.309-0.995, P = 0.048), or 8 am (OR = 0.296, 95%CI = 0.097-0.902, P = 0.032) was probably more likely to have normal cognition. However, people who slept more than 8 h a day might be more likely to suffer from MCI (OR = 5.560, 95%CI = 1.419-21.789, P = 0.014). CONCLUSION: Sleep disturbance is associated with Mild Cognitive Impairment. However, the causal relationship between them is not clear. It needs to be further studied.

Protocol of End-PSCI trial: a multicenter, randomized controlled trial to evaluate the effects of DL-3-n-butylphthalide on delayed-onset post stroke cognitive impairment.

BACKGROUND: Delayed-onset post stroke cognitive impairment (PSCI) results from secondary neurodegeneration induced by stroke. Whereas targeted prevention or treatment strategies are still missing due to lack of evidences. This trial aims to evaluate the preventive effects of DL-3-n-butylphthalide (NBP) on delayed-onset PSCI. METHODS: Effects of NBP on Delayed-onset Post Stroke Cognitive Impairment (End-PSCI) is a prospective, parallel-group, open-label, multicenter, randomized controlled trial with blinded outcome assessment. Hospital patients with acute cerebral infarction (within 2 weeks of onset) will be randomized into either standard medical therapy group or standard medical therapy combined NBP treatment group (NBP 200 mg, three times per day for 24 weeks). The primary outcome is the difference of incidence of delayed-onset PSCI between two groups. The secondary outcomes include difference of white matter degeneration, cognitive scores and prevalence of early-onset PSCI between two groups. DISCUSSION: End-PSCI trial will provide evidences for NBP preventing delayed-onset PSCI. The secondary outcomes will also provide valuable insights into the pathogenesis of delayed-onset PSCI and mechanism of NBP's actions. TRIAL REGISTRATION: Trialsearch.who.int , ChiCTR2000032555, 2020/5/2, prospectively registered.

A tool for predicting overall survival in patients with Ewing sarcoma: a multicenter retrospective study.

OBJECTIVE: The aim of this study was to establish and validate a clinical prediction model for assessing the risk of metastasis and patient survival in Ewing's sarcoma (ES). METHODS: Patients diagnosed with ES from the Surveillance, Epidemiology and End Results (SEER) database for the period 2010-2016 were extracted, and the data after exclusion of vacant terms was used as the training set (n=767). Prediction models predicting patients' overall survival (OS) at 1 and 3 years were created by cox regression analysis and visualized using Nomogram and web calculator. Multicenter data from four medical institutions were used as the validation set (n=51), and the model consistency was verified using calibration plots, and receiver operating characteristic (ROC) verified the predictive ability of the model. Finally, a clinical decision curve was used to demonstrate the clinical utility of the model. RESULTS: The results of multivariate cox regression showed that age, , bone metastasis, tumor size, and chemotherapy were independent prognostic factors of ES patients. Internal and external validation results: calibration plots showed that the model had a good agreement for patient survival at 1 and 3 years; ROC showed that it possessed a good predictive ability and clinical decision curve proved that it possessed good clinical utility. CONCLUSIONS: The tool built in this paper to predict 1- and 3-year survival in ES patients ( https://drwenleli0910.shinyapps.io/EwingApp/ ) has a good identification and predictive power.

Resting heart rate is associated with novel plasma atherosclerosis biomarkers.

BACKGROUND: Resting heart rate (RHR) is a strong predictor of adverse cardiovascular outcomes. Both soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor for advanced glycation end products (sRAGE) are novel plasma biomarkers for atherosclerosis. In this study, we examined the potential associations between RHR and plasma sLRP1 and sRAGE levels and whether any associations might be modified by apolipoprotein E (APOE) ε4 carrier status. METHODS: This cross-sectional study included 941 apparently healthy adults aged 40 years or older. Plasma sLRP1 and sRAGE levels were measured by a commercial enzyme-linked immunosorbent assay. APOE gene polymorphisms were analyzed by a polymerase chain reaction and Sanger sequencing. RESULTS: RHR was a significant determinant of log-transformed sLRP1 (ß = 0.004; 95% confidence interval [CI], 0.002-0.007; P = 0.001) and log-transformed sRAGE (ß = 0.005; 95% CI, 0.002-0.007; P <0.001) independently of age, sex, body mass index, blood pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, APOE ε4 carrier status was inversely associated with log-transformed plasma sLRP1 level (ß = -0.072; 95% CI, -0.130 to -0.015; P = 0.01) and did not modify the relationship between RHR and plasma sLRP1 level. CONCLUSIONS: An elevated RHR was associated with increased sLRP1 and sRAGE values, which was not modified by APOE genotype. The underlying mechanism of this effect may be relevant to the progression of atherosclerosis.

The Association of Plasma Amyloid-ß and Cognitive Decline in Cognitively Unimpaired Population.

Purpose: This study investigates the relationship between baseline plasma Aß and cognitive decline during follow-up in cognitively unimpaired population. Materials and Methods: Cognitively unimpaired population was selected from people who lived in the suburbs of Xi'an, China. The levels of plasma Aß1-42 and Aß1-40 were tested using commercial enzyme-linked immunosorbent assay (ELISA). The mini-mental state examination (MMSE) and neuropsychological battery were used to assess cognition. Two years later, MMSE was tested again, and significant cognitive decline was defined as a decrease in MMSE scores ≥5 points. Logistic regression analysis was performed to analyze the relationship between baseline plasma Aß and cognitive change during the two-year follow-up. Results: A total of 1144 participants completed the study, among whom 59 subjects (5.2%) presented significant cognitive decline. The high plasma Aß1-42 level group had more significant cognitive decline (P = 0.023). Multivariable logistic regression analysis showed that significant cognitive decline was associated with the high levels of baseline plasma Aß1-42 (OR = 1.043, 95% CI: 1.005-1.083, P = 0.026). However, significant cognitive decline was not associated with baseline plasma Aß1-40 levels and Aß1-42 /Aß1-40 ratio. Conclusion: Population with high level of baseline plasma Aß1-42 manifested significant cognitive decline over 2 years; however, further investigation on the dynamics of plasma Aß and long-term follow-up are needed.

Perilipin 5 protects against oxygen-glucose deprivation/reoxygenation-elicited neuronal damage by inhibiting oxidative stress and inflammatory injury via the Akt-GSK-3ß-Nrf2 pathway.

BACKGROUND: Perilipin 5 (Plin5) acts as a pivotal mediator of oxidative stress and inflammation and is associated with the progression of relevant diseases. Cerebral ischemic stroke is a severe pathological condition that involves excess oxidative stress and inflammation. However, whether Plin5 plays a role in the progression of cerebral ischemic stroke remains unaddressed. This work focused on the investigation of Plin5 in oxygen-glucose deprivation/reoxygenation (OGD/R)-injured neurons, an in vitro model for studying cerebral ischemic stroke. METHODS: The primary neuronal cells were isolated from the hippocampus of newborn mice. Neurons were subjected to OGD/R treatment to establish an in vitro model for studying cerebral ischemic stroke. Neurons were infected with recombinant adenovirus expressing Plin5 to upregulate Plin5 expression. The mRNA levels were measured by real-time quantitative PCR (RT-qPCR). Protein levels were determined by immunoblotting. Cell viability was assessed via cell counting kit-8 (CCK-8) assay. Cell apoptosis was evaluated via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Annexin V-Allophycocyanin/7-Amino Actinomycin D (Annexin V-APC/7-AAD) apoptotic assays. Oxidative stress was monitored by dichlorofluorescein diacetate (DCFH-DA) probe. Inflammatory cytokine release was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: A decreased level of Plin5 was observed in neurons challenged with OGD/R. Plin5 overexpression remarkably subdued OGD/R-elicited apoptosis, oxidative stress and proinflammatory response. Plin5 overexpression led to an enhancement of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway associated with regulation of the Akt-glycogen synthase kinase-3ß (GSK-3ß). The blocking of Akt was able to reverse the enhancing effect of Plin5 on Nrf2 activation. The restraining of Akt or silencing of Nrf2 diminished the protective effects of Plin5 in OGD/R-injured neurons. CONCLUSIONS: Plin5 confers neuroprotection for neurons against OGD/R damage via effects on the Nrf2-Akt-GSK-3ß pathway. This work indicates a possible role of Plin5 in cerebral ischemic stroke and the up-regulation of Plin5 is a sort of survival strategy for neurons suffering from ischemic injury.

Peripheral Transport Proteins Were Associated with 4-Year Cognitive Decline in APOE ɛ4 Non-Carriers: A Longitudinal, Population-Based Study.

BACKGROUND: Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE) play major roles in peripheral clearance of amyloid-ß (Aß). OBJECTIVE: To determine the relationship between baseline sLRP1/sRAGE and early cognitive decline in a longitudinal study and explore the possible effect of apolipoprotein E (APOE) on their association. METHODS: Cognitively normal subjects were followed-up for 4 years. The baseline plasma levels of sLRP1 and sRAGE were measured using commercial ELISA kits. Global cognition was evaluated by Mini-Mental State Examination (MMSE), and cognitive decline was defined as a ≥2-point decrease of MMSE after 4 years. The association between baseline sLRP1/sRAGE and 4-year cognitive decline were analyzed using logistic regression analysis. Interaction analysis was performed to discover the potential effect of APOE genotype on the relationship. RESULTS: 769 participants were included in the final analysis, with 122 subjects (15.86%) were cognitive decline. Baseline sLRP1/sRAGE levels were not associated with 4-year cognitive decline after multivariable adjustments in the total cohort. However, there was significant interaction effect between sRAGE and APOE genotype on cognitive decline (adjusted odds ratio [OR] = 2.09, 95% confidence interval [CI]: 1.13-3.86, p = 0.019). Lower levels of sRAGE were associated with increased risk of cognitive decline among APOE ɛ4 non-carriers (adjusted OR = 1.60, 95% CI: 1.04-2.48, p = 0.034). CONCLUSION: Individuals with lower levels of sRAGE had an increased risk of 4-year cognitive decline in APOE ɛ4 non-carriers, indicating that the association between sRAGE and cognitive decline might depend on the APOE genotype. However, the specific mechanisms need to be further elucidated.

The Relationships Between Lipid Accumulation Product Levels and Cognitive Decline Over 4 Years in a Rural Area of Xi'an, China.

Background and Aims: The relationships between blood lipid levels and obesity and cognitive impairment have not been fully determined. Considering that the lipid accumulation product (LAP) is a composite index of blood lipid levels and obesity, we investigated the relationships between LAP levels at baseline and cognitive decline over 4 years. Methods: A total of 983 subjects (≥40 years) from a longitudinal cohort in a village of Xi'an, China, who completed the baseline survey were followed-up for 4 years. All participants underwent face-to-face interviews and cognitive assessments at baseline and at the 4-year follow-up. The Mini-Mental State Examination (MMSE) was used to assess cognitive function, and an MMSE score dropping ≥ 2 points from baseline was defined as cognitive decline. The relationships between LAP and cognitive decline were analyzed by linear regression models. Results: During the 4-year follow-up, 172 patients exhibited cognitive decline (17.5%). Univariate analysis showed that the rate of change in MMSE score was significantly different between the low-LAP group and the high-LAP group (t = -2.26, p = 0.024). Multiple linear regression indicated that a high LAP was positively associated with cognitive decline (ß = 0.564, p = 0.012). Stratified multivariate analysis showed that LAP was positively associated with cognitive decline in the normal blood pressure female subgroup (ß = 1.29, p = 0.002) but not in the high blood pressure group or the male group. Conclusions: High LAP is associated with cognitive decline in females with normal blood pressure but not in those with high blood pressure or males. This indicates that the relationships between blood lipid levels and obesity and cognitive impairment may be affected by blood pressure and sex.

Blood Triglyceride and High-Density Lipoprotein Levels Are Associated with Plasma Amyloid-ß Transport: A Population-Based Cross-Sectional Study.

BACKGROUND: Studies have found that blood lipids are associated with plasma amyloid-ß (Aß) levels, but the underlying mechanism is still unclear. Two Aß transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aß transport. OBJECTIVE: The aim was to investigate the effects of lipids on the relationships between plasma Aß and transporter levels. METHODS: This study included 1,436 adults aged 40 to 88 years old. Blood Aß, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze the relationships between lipids and plasma Aß, sLRP1, and sRAGE. RESULTS: After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aß42 and sRAGE (ß= 6.158, p = 0.049; ß= 121.156, p < 0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aß40, Aß42, and sRAGE (ß= -48.389, p = 0.017; ß= -11.142, p = 0.020; ß= -147.937, p = 0.003, respectively). Additionally, positive correlations were found between plasma Aß and sRAGE in the normal TG (Aß40: ß= 0.034, p = 0.005; Aß42: ß= 0.010, p = 0.001) and HDL-c groups (Aß40: ß= 0.023, p = 0.033; Aß42: ß= 0.008, p = 0.002) but not in the high TG and low HDL-c groups. CONCLUSION: Abnormal levels of TG and HDL-c are associated with decreased Aß and sRAGE levels. Positive correlations between plasma Aß and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aß levels might also be involved in peripheral Aß clearance.

Hypertension management in elderly with severe intracerebral hemorrhage.

OBJECTIVE: To explore the effect of individualized blood pressure (BP)-lowering treatment on the outcomes of elderly patients with severe intracerebral hemorrhage (ICH). METHODS: We performed an exploratory analysis of Controlling Hypertension After Severe Cerebrovascular Event (CHASE) trial, which was a multicenter, randomized, controlled clinical trial. Patients with severe ischemic or hemorrhagic stroke (defined as GCS ≤ 12 or NIHSS ≥ 11) were randomized into individualized versus standard BP-lowering treatment in CHASE trial. In this exploratory analysis, patients with severe ICH were included. The primary outcome was the percentage of patients with 90-day functional independence defined as modified Rankin Scale (mRS) ≤2. RESULTS: We included 242 patients with severe ICH in the present analysis, consisting of 142 patients aged <65 years and 100 patients aged ≥65 years. There were significant differences between patients aged ≥65 years and <65 years in the proportion of functional independence (47.9% vs. 15.0%, P < 0.001) and good outcome (73.9% vs. 50.0%, P < 0.001) at day 90. In patients aged ≥65 years, the adjusted individualized BP-lowering treatment had an unequivocal effect on the functional independence at day 90 (21.6% vs. 8.2%, odds ratio [OR]: 4.309, 95% confidence interval [CI]: 1.040-17.859, P = 0.044) and improved the neurological deficits at discharge (∆ NIHSS ≥ 4: 64.7% vs. 34.7%, OR: 4.300, 95% CI: 1.599-11.563, P = 0.004). INTERPRETATION: Compared with the younger counterparts, the elderly patients (≥65 years) with acute severe ICH might benefit more from individualized BP-lowering treatment.

Blood Pressure Level Is Associated With Changes in Plasma Aß1 -40 and Aß1-42 Levels: A Cross-sectional Study Conducted in the Suburbs of Xi'an, China.

Objectives: Amyloid-ß (Aß) deposition in the brain is the hallmark of Alzheimer's disease (AD) pathology. Hypertension is a risk factor for AD, but the effects of hypertension on Aß deposition are not fully determined. Considering peripheral Aß closely relates to Aß deposition in the brain, we investigated the relationships between blood pressure (BP) level and plasma Aß concentrations. Methods: One-thousand and sixty-nine participants (age above 45) from a village in the suburbs of Xi'an, China were enrolled. Questionnaires and validated Chinese versions of the Mini-Mental State Examination (MMSE) were used to collect information about vascular risk factors and assess cognition function. The apolipoprotein E (ApoE) genotype was detected using PCR and sequencing. Plasma Aß levels were measured using ELISA. The associations between BP and plasma Aß levels were analyzed by using multivariate linear regression. Results: Plasma Aß1-40 level was higher in high BP group than that in normal BP group (53.34 ± 8.50 pg/ml vs. 51.98 ± 8.96 pg/ml, P = 0.013), in high SBP group than that in normal SBP group (53.68 ± 8.69 pg/ml vs. 51.88 ± 8.80 pg/ml, P = 0.001) and in high MABP group than that in normal MABP group (54.05 ± 8.78 pg/ml vs. 52.04 ± 8.75 pg/ml, P = 0.001). After controlling for the confounding factors, SBP (b = 0.078, P < 0.001), DBP (b = 0.090, P = 0.008) and MABP (b = 0.104, P < 0.001) correlated with plasma Aß1-40 level positively in ApoE ε4 non-carriers, but not ApoE ε4 carriers. Conclusions: Elevated BP levels were associated with increased plasma Aß1-40 levels in middle-aged and elderly ApoE ε4 non-carriers.

Reduction of neuroinflammation alleviated mouse post bone fracture and stroke memory dysfunction.

Tibia fracture (BF) enhances stroke injury and post-stroke memory dysfunction in mouse. Reduction of neuroinflammation by activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced acute neuronal injury and sensorimotor dysfunction in mice with BF 1-day after stroke. We hypothesize that reduction of neuroinflammation by activation of α-7 nAchR improves long-term memory function of mice with BF 6-h before stroke. The mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and methyllycaconitine (antagonist) treatment groups. The sensorimotor function was tested by adhesive removal and corner tests at 3 days, the memory function was tested by Y-maze test weekly for 8 weeks and novel objective recognition test at 8 weeks post-injuries. We found PHA-568487 treatment reduced, methyllycaconitine increased the number of CD68+ cells in the peri-infarct and hippocampal regions, neuronal injury in the infarct region, sensorimotor and long-term memory dysfunctions. PHA-568487 treatment also reduced, while methyllycaconitine treatment increased atrophy of hippocampal granule cell layer and white matter damage in the striatum. In addition, PHA-568487 treatment increased neuron proliferation in granule cell layer. Our data indicated that reduction of neuroinflammation through activation of α-7 nAchR decreased neuronal damage, sensorimotor and long-term memory dysfunction of mice with BF shortly before stroke.

JZL184 protects hippocampal neurons from oxygen-glucose deprivation-induced injury via activating Nrf2/ARE signaling pathway.

JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL) that has neuroprotective effect. However, the role of JZL184 in cerebral ischemia/reperfusion (I/R) injury and the exact mechanism have not been fully understood. This study was designed to elucidate the role of JZL184 in cerebral I/R injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons. Hippocampal neurons were pretreated with various concentrations of JZL184 for 2 h, followed by OGD for 3 h and reoxygen for 24 h. Our results showed that JZL184 improved cell viability in hippocampal neurons in response to OGD/R. JZL184 treatment significantly inhibited the production of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in OGD/R-induced hippocampal neurons. The increased TNF-α, IL-1ß, and IL-6 productions in OGD/R-induced hippocampal neurons were decreased after treatment with JZL184. Moreover, the OGD/R-caused intense TUNEL staining in hippocampal neurons was attenuated by JZL184. JZL184 treatment prevented OGD/R-caused increases in bax and cleaved caspase-3 expression and a decrease in bcl-2 expression. Furthermore, JZL184 treatment significantly promoted the activation of Nrf2/ARE signaling pathway in OGD/R-induced hippocampal neurons. Additionally, silencing of Nrf2 reversed the protective effect of JZL184 on hippocampal neurons under OGD/R condition. Taken together, these findings suggested that JZL184 exerted protective effect against OGD/R-induced injury in hippocampal neurons via activating Nrf2/ARE signaling pathway, which provided in vitro experimental support for the therapeutic benefit of JZL184 in cerebral ischemia.

Controlling Hypertension After Severe Cerebrovascular Event (CHASE): A randomized, multicenter, controlled study.

BACKGROUND: The optimal blood pressure lowering target in the acute phase of severe stroke is uncertain. Our aim was to compare the efficacy and safety of individualized blood pressure lowering with standard blood pressure lowering in severe stroke. METHODS: Five-hundred consecutive patients with acute severe stroke and elevated BP were recruited from 26 Chinese hospitals. Eligible patients were randomized into an individualized blood pressure lowering group (with 10-15% reduction in systolic blood pressure from admission level or standard blood pressure lowering group (with a target SBP of <200 mm Hg in acute ischemic stroke and <180 mm Hg in intracerebral hemorrhage). The primary outcome was the proportion of patients with a poor functional outcome at day 90 of enrolment. RESULTS: Of 483 participants included in the analysis, 242 received individualized blood pressure lowering treatment and 241 received standard treatment. The primary outcome event was observed in 71.1% of the participants in the individualized treatment group and in 73.4% of the standard treatment group (odds ratio with individualized treatment for primary outcome, 0.75; 95% confidence interval, 0.47 to 1.19; p = 0.222). The rates of serious adverse events in the two groups were similar (27.7% vs. 28.2%). CONCLUSIONS: In patients with acute severe stoke, individualized blood pressure lowering treatment did not significantly reduce the rate of three-month death or dependence. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02982655. Registered in 5 December 2016, https://clinicaltrials.gov/ct2/show/NCT02982655.

Blood pressure variability and outcome in acute severe stroke: A post hoc analysis of CHASE-A randomized controlled trial.

The influence of blood pressure variability (BPV) on outcomes in patients with severe stroke is still largely unsettled. Using the data of CHASE trial, the authors calculated the BPV during the acute phase and subacute phase of severe stroke, respectively. The primary outcome was to investigate the relationship between BPV and 90-day modified Rankin scale (mRS) ≥ 3. The BPV was assessed by eight measurements including standard deviation (SD), mean, maximum, minimum, coefficient of variation (CV), successive variation (SV), functional successive variation (FSV), and average real variability (ARV). Then, the SD of SBP was divided into quintiles and compared the quintile using logistic regression in three models. The acute phase included 442 patients, and the subacute phase included 390 patients. After adjustment, six measurements of BPV during the subacute phase rather than acute phase were strongly correlated with outcomes including minimum (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.69-0.99, p = .037), SD (OR: 1.10, 95% CI: 1.03-1.17, p = .007), CV (OR: 1.12, 95% CI: 1.03-1.23, p = .012), ARV (OR: 1.13, 95% CI: 1.05-1.20, p < .001), SV (OR: 1.09, 95% CI: 1.04-1.15, p = .001), and FSV (OR: 1.12, 95% CI: 1.05-1.19, p = .001). In the logistic regression, the highest fifth of SD of SBP predicted poor outcome in all three models. In conclusion, the increased BPV was strongly correlated with poor outcomes in the subacute phase of severe stroke, and the magnitude of association was progressively increased when the SD of BP was above 12.