Relationship between carotid atherosclerosis and lipoprotein (a) in patients with acute ischemic stroke.

Objective: This study aimed to examine the relationship between lipoprotein (a) (Lp[a]) and other blood lipid indexes and carotid artery atherosclerosis in patients with acute ischemic stroke (AIS). Methods: A total of 2,018 patients were selected from the hospital "acute stroke intervention and secondary prevention registration database" by identifying blood fat indexes (cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and Lp[a]). Based on the results of carotid artery ultrasound examinations, the patients were divided into a "no plaque" group, comprising 400 patients, a "plaque and no stenosis" group, comprising 1,122 patients and a "carotid stenosis" group, comprising 496 patients. The relationship between Lp(a) and blood lipid indexes and carotid artery atherosclerosis was then investigated using multi-factor logistics regression analysis. Results: There were 400 patients (19.8%) with no carotid plaque, 1,122 patients (55.6%) with plaque and no carotid stenosis and 496 patients (24.6%) with carotid stenosis. As the degree of carotid artery atherosclerosis increased, the Lp(a) level gradually increased; Lp(a) and cholesterol were identified as independent risk factors for carotid atherosclerosis. Conclusion: Lipoprotein (a) and cholesterol are independent risk factors for patients with AIS with carotid atherosclerosis, and their levels increase with the degree of carotid artery atherosclerosis; therefore, attention should focus on levels of cholesterol and Lp(a) in acute stroke patients to control atherosclerosis effectively.

Nrf2 attenuates methamphetamine-induced myocardial injury by regulating oxidative stress and apoptosis in mice.

OBJECTIVES: Methamphetamine (MA) abuse is a serious social problem worldwide. Cardiovascular complications were the second leading cause of death among MA abusers. We aimed to clarify the effects of MA on myocardial injury, oxidative stress, and apoptosis in myocardial cells and to explore the potential mechanism of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) in MA-induced oxidative stress and apoptosis. METHODS: An acute cardiac toxicity model of MA was established by intraperitoneal injection of MA (2 mg/kg) for 5 days. Nrf2 activation (by sulforaphane (SFN) 1 h before MA injection) and Nrf2 gene knockout were performed to explore the regulatory effects of Nrf2 on cardiac toxicity. RESULTS: The protein expressions of Nrf2 (p < .001) and heme oxygenase-1 (HO-1) were increased (p < .01), suggesting that MA activated the Nrf2/HO-1 pathway. In the MA group, cardiac injury score (p < .001) and cardiac troponin I (cTnI) protein expression increased (p < .01). Malondialdehyde (MDA) content increased (p < .001), superoxide dismutase (SOD) activity decreased (p < .05). Protein expressions of Caspase-3 (p < .001) and Bax (p < .001) increased, and Bcl-2 decreased (p < .001) as well. These changes were reversed by activation of Nrf2 but became more pronounced after Nrf2 knockout, suggested that the activation and knockout of Nrf2 attenuated and aggravated MA-induced myocardial injury, oxidative stress and apoptosis in myocardial cells, respectively. CONCLUSIONS: MA administration induced myocardial injury, oxidative stress, and apoptosis in mice. Nrf2 attenuated MA-induced myocardial injury by regulating oxidative stress and apoptosis, thus playing a protective role.

The Potential Role of PKA/CREB Signaling Pathway Concerned with Gastrodin Administration on Methamphetamine-Induced Conditioned Place Preference Rats and SH-SY5Y Cell Line.

To investigate the effects of gastrodin (GAS) on methamphetamine (MA)-induced conditioned place preference (CPP) in rats and explore its potential mechanisms. MA (10 mg/kg) was initially injected intraperitoneally (i.p.) in rats, after which they were administered either MA or saline alternately from day 4 to 13 (D4-13) for 10 days, followed by treatment with GAS (10 or 20 mg/kg, i.p.) on D15-21 for 7 days. The rats underwent CPP testing after MA and GAS treatment. In vitro, SH-SY5Y cells were exposed to MA (2.0 mM) for 24 h, followed by treatment with GAS (2.0 or 4.0 mM) for 24 h. The expression levels of PKA, P-PKA, CREB, and P-CREB proteins in the prefrontal cortex, nucleus accumbens, and ventral tegmental area of MA-induced CPP rats and in SH-SY5Y cells were detected by Western blot analysis. The MA-induced CPP rat model was successfully established. The administration of MA stimulated a significant alteration in behavior, as measured by the CPP protocol. After treatment with GAS, the amount of time rats spent in the MA-paired chamber was significantly reduced. Results also showed that MA increased the expression levels of PKA, P-PKA, CREB, and p-CREB proteins in the prefrontal cortex, nucleus accumbens, and ventral tegmental area of CPP rats and in SH-SY5Y cells (p < 0.05). GAS attenuated the effect of MA-induced CPP in rats and decreased the expression levels of proteins in vivo and in vitro. Our study suggests that GAS can attenuate the effects of MA-induced CPP in rats by regulating the PKA/CREB signaling pathway.

ECAS progression score: a web-based model to predict progression of extracranial carotid artery stenosis.

BACKGROUND AND PURPOSE: To develop and validate a risk model (Extracranial Carotid Artery Stenosis progression score, ECAS-PS) and to predict risk of ECAS progression. METHODS: The ECAS-PS was developed based on the Renqiu Stroke Screening Study (RSSS), in which eligible participants were randomly divided into derivation (60%) and validation (40%) cohorts. ECAS at baseline and follow-up was diagosed by carotid duplex ultrasound according to the published criteria. ECAS progression was defined as an increase in ECAS to≥50% for those with a baseline of <50% or as an increase to a higher category of stenosis if the baseline stenosis was ≥50%. Independent predictors of ECAS progression were obtained using multivariable logistic regression. The area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow test were used to assess model discrimination and calibration. RESULTS: A total of 4111 participants were included and the mean age was 64.3. A total number of 29 (0.7%), 24 (0.6%) and 48 (1.2%) patients progressed during 2-year follow-up for left, right and bilateral (either left or right) carotid artery, respectively. The ECAS-PS was developed from a set of predictors of ECAS progression. The ECAS-PS demonstrated good discrimination in both the derivation and validation cohorts (AUROC range: 0.824-0.917). The Hosmer-Lemeshow tests of ECAS progression score were not significant in the derivation and validation cohorts (all P > 0.05). CONCLUSION: The ECAS progression score is a valid model for predicting the risk of ECAS progression. Further validation of the ECAS-PS in different populations and larger samples is warranted.

ECAS score: a web-based risk model to predict moderate and severe extracranial carotid artery stenosis.

Background and purpose To develop and validate a risk model (Extracranial Carotid Artery Stenosis score, ECAS score) to predict moderate and severe ECAS. Furthermore, we compared discrimination of the ECAS score and three existing models with regard to both moderate and severe ECAS. Methods The ECAS score was developed based on the Renqiu Stroke Screening Study (RSSS), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. ECAS was diagnosed by carotid duplex ultrasound according to the published criteria. Independent predictors of moderate (≥50%) and severe (≥70%) ECAS were obtained using multivariable logistic regression. The area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow test were used to assess model discrimination and calibration. Results A total of 5010 participants were included and the mean age was 64.3. The proportion of ECAS of < 50%, 50-69%, 70-99% and occlusion was 4.4, 0.5, 0.4, and 0.4%, respectively. The ECAS score was developed from sets of predictors of moderate and severe ECAS. The ECAS score demonstrated good discrimination in the derivation and validation cohorts (AUROC range: 0.785-0.846). The Hosmer-Lemeshow tests of ECAS score for moderate and severe ECAS were not significant in the derivation and validation cohorts (all P > 0.05). When compared to the three existing models, the ECAS score showed significantly better discrimination for both moderate and severe ECAS (all P < 0.001). Conclusion The ECAS score is a valid model for predicting moderate and severe ECAS. Further validation of the ECAS score in different populations and larger samples is warranted.

Maged1 co-interacting with CREB through a hexapeptide repeat domain regulates learning and memory in mice.

Maged1 is a member of the type II melanoma antigen (MAGE) family of proteins, which is highly conserved in the brain between mouse and human. Recently, Maged1 has been reported to be involved in depression and impaired sexual behavior. However, the role of Maged1 in learning and memory remains unknown. The aim of the present study was therefore to investigate whether Maged1 deficiency can impair learning and memory formation. By behavioral tests and electrophysiological recording, we observed that 5-6-month-old Maged1 knockout mice displayed the reduced basal synaptic transmission, pronounced hippocampal dysfunction, impaired spatial learning, and a deficit in long-term potentiation induction. Data from immunohistochemical and Western blot showed the reduced dendritic spine density and the number of synapses in the hippocampus of the Maged1 knockout mice, and Maged1 deficiency prevented the interaction of Maged1 with cAMP response element-binding protein (CREB). Furthermore, by chromatin immunoprecipitation and luciferase assay, we observed the downregulated activity of CREB and the suppressed CREB-dependent transcription after deficiency of Maged1, which lead to the decreased levels of brain-derived neurotrophic factor. Taken together, our results provide the evidence that Maged1 is involved in synaptic transmission and hippocampus-dependent learning and memory formation.

Molecular and cellular basis of the regulation of lymphatic contractility and lymphatic absorption.

Lymphatic absorption is a highly regulated process driven by both an extrinsic mechanism (external force) and an intrinsic mechanism (lymphatic vessel contractility). The lymphatic muscle is a specialized smooth muscle with unique mechanical properties. To understand the molecular mechanism and relative contribution of smooth muscle contraction in lymphatic absorption, we analyzed mice with a smooth muscle-specific deletion of Mylk, a critical gene for smooth muscle contraction. Interestingly, the knockout mice were significantly resistant to anesthesia reagents. Upon injection in the feet with FITC-dextran, the mutant mice displayed a 2-fold delay of the absorption peak in the peripheral circulation. Examining the ear lymphatic vessels of the mutant mice revealed a reduction in the amount of fluid in the lumens of the lymphangions, suggesting an impairment of lymph formation. The Mylk-deficient lymphatic muscle exhibited a significant reduction of peristalsis and of myosin light chain phosphorylation in response to depolarization. We thus concluded that MLCK and myosin light chain phosphorylation are required for lymphatic vessel contraction. Lymphatic contractility is not an exclusive requirement for lymphatic absorption, and external force appears to be necessary for absorption.

Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway.

Resveratrol (RSV) is a natural compound found in grapes and red wine. It has been well known for its beneficial effects as a dietary supplement in prevention of cardiovascular diseases and cancer. Recently, in vitro studies have reported the neuroprotective role of RSV in neurodegenerative process in Alzheimer's disease (AD). However, in vivo effects of RSV on the decline of brain function accompanying the aging process, especially those on cognitive loss, have not been not investigated. Here we report that, after intraventricular injection of RSV for one week in 8-9 month-old mice, the long-term memory formation and the LTP induction from hippocampus CA1 were improved. The RSV enhancement effects were blocked in SIRT1 mutant mice. Additional experiments suggest that RSV effects are likely to be mediated through reduced expressions of miR-134 and miR-124, which may in turn up-regulate CREB levels to subsequently promote BDNF synthesis. These findings demonstrate a role for RSV in cognition and a microRNA-CREB-BDNF mechanism by which RSV regulates these processes, demonstrating its value as a potential therapeutic target against CNS disorders in aging.