Ischemic Cerebral Vascular Disease Research Articles

Disección carotídea espontánea: Presentación de un caso clínico con revisión de la literatura

Introduction: Carotid dissection consists of a tear in the vessel wall. It is a rare pathology, but it is the most common cause of ischemic cerebral vascular disease (CVD) in people under 45 years of age. The clinical manifestations are very variable. Method: We used CARE recommendations for reporting clinical cases. Clinical case: Previously, a healthy 45-year-old man with acute weakness of the right thoracic extremity without apparent cause. The simple skull tomography did not show any alterations. MRI showed complete occlusion of the internal carotid artery in all its segments and decreased flow of the left middle cerebral artery. The clinical evolution was unfavorable. Conclusion: Carotid dissection should be suspected in people with CVD without cardiovascular risk factors. Keywords: Carotid artery; spontaneous carotid dissection; acute ischemic stroke; emergency medicine; interventional radiology

Atherogenic lipid profile in patients with acute coronary syndrome

Abstract Background Adverse atherogenic lipid profile is associated with an increased risk of major adverse cardiac events in patients with acute coronary syndrome (ACS). Objective To evaluate the control status of atherogenic lipid profile among ACS patients within 12 months after discharge. Methods We retrospectively analyzed the data from the multi-center iHeart program. Twenty tertiary hospitals in China were included. Natural language processing technique was used to extract real-world data from electronic health records (EHRs). Patients with a diagnosis of ACS from January 2014 to December 2021 during index hospitalization and having at least one medical record after discharge within 12 months were enrolled. Measurements of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), triglycerides (TGs), apolipoprotein B (ApoB), lipoprotein (a) (Lp[a]) at baseline and follow-up were collected and analyzed. Remnant cholesterol (RC) was calculated as TC minus HDL-C minus LDL-C. The treatment goal of LDL-C was defined as <1.8 mmol/L according to the guideline. An even lower LDL-C goal of <1.4 mmol/L was recommended in specific patients at extremely high risk with concomitant diabetes or ischemic cerebral vascular diseases. Results Among the 3956 patients, the mean age was 72 (12) years, and 64.8% were men. Diabetes was common (22.7%). There were 1612 (40.7%) patients with unstable angina, 391(9.9%) patients with non-ST-elevation myocardial infarction, 1146 (29.0%) patients with ST-elevation myocardial infarction, and 807 (20.4%) patients with undetermined ACS category. At baseline, the mean values for TC, LDL-C, HDL-C, non-HDL-C, ApoB, and RC were 4.61 (1.26) mmol/L, 2.83 (0.98) mmol/L, 1.12 (0.30) mmol/L, 3.38 (0.75) mmol/L, 96 (34) mg/dL, and 0.65 (0.56) mmol/L, respectively. The median values for TGs and Lp(a) were 1.44 mmol/L [1.06, 2.00] and 27.22 mg/dL [12.34, 39.2], respectively. The rate of lipid-lowering treatment was 94.8% (statins 93.1%, PCSK9 inhibitors 0.4%). The levels of TC, TGs, LDL-C, HDL-C, non-HDL-C, and ApoB were significantly decreased (P < 0.001) within 12 months. Median Lp(a) was 19.52 mg/dL [8.73, 39.08] (P = 0.117). Mean RC was 0.69 (1.10) mmol/L (P < 0.001). Overall, the proportion of patients achieving the LDL-C level of <1.8 mmol/L at baseline increased from 13.42% to 36.6% during follow-up. In patients with concomitant diabetes or ischemic cerebral vascular diseases, the rate of LDL-C <1.4 mmol/L was 17.79% and 17.52%, respectively. Conclusion Only 1/3 of patients had LDL-C <1.8mmol/L within 12 months after ACS. Despite the high treatment rate of statins, Lp(a) level had no change beyond the reduction in LDL-C. Elevated remnant cholesterol may be a critical contributor to residual risk. Novel therapeutics targeting the whole atherogenic lipid profile will be warranted to improve cardiovascular outcomes.LDL-C control rate within 12 months

Neurological manifestations in COVID-19 survivors: Observations in one of the largest only COVID-19 centers in México. (P5-10.003)

<h3>Objective:</h3> To describe the neurological complications in COVID-19 survivors 3 months after hospital discharge <h3>Background:</h3> Since the beginning of the pandemic in 2019 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing human coronavirus disease 2019 (COVID-19) persistent symptoms are being reported among COVID-19 survivors, our objective is to report neurological manifestations in hospitalized COVID-19 survivors. <h3>Design/Methods:</h3> We report the neurological sequelae observed in a cohort of 238 patients who were admitted in a single center with acute respiratory distress syndrome (ARDS) due to COVID-19, 3 months after their hospital discharge, a complete neurological examination and MOCA cognitive screening test was performed by 2 neurologists in Mexico City from August 31, 2020 to January 8, 2021. <h3>Results:</h3> In all patients, reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of nasopharyngeal samples were positive for SARSCoV-2. The mean age of the patients was 51 years, 97 patients (68.3%) needed mechanical ventilatory support, 52% with a periphery oxygen saturation at admission of less than 60%, 10.6% were health care workers, 8 patients has had previous neurologic disorders. The main sequels observed were sensory motor neuropathy (66.4%), myopathic pain (43. 9%), cognitive complains (59.7%) with an average MOCA of 25.5 (46.6%). 5 patients had ischemic cerebral vascular disease, 5 patients had seizures, 108 (45.6%) affective symptoms, 52.2% patients with a RANKIN less than 2. <h3>Conclusions:</h3> It is crucial a multidisciplinary long term follow up of the patients who survived the COVID-19 to recognize the different range of neurological sequelae; this in order to provide better clinical prognoses and to optimize the algorithms of treatment <b>Disclosure:</b> Dr. Santos has nothing to disclose. Dr. Rodríguez has nothing to disclose. Dr. Lopez Gonzalez has nothing to disclose.

Cryptogenic ischemic cerebral vascular disease with patent foramen ovale: analysis of the long-term efficacy of treatments and prognostic factors

Objective: To evaluate the long-term efficacy of treatments on cryptogenic ischemic cerebral vascular disease (CICVD) with patent foramen ovale (PFO) and analyze prognostic factors, so as to provide the references for the treatment and secondary prevention of PFO related cerebral vascular disease. Methods: Consecutive patients with CICVD and PFO related right-to-left shunting confirmed by transesophageal echocardiography or transcranial doppler bubble test, who admitted to the Department of Neurology in Xuanwu Hospital from May 1, 2012 to December 31 2021 were enrolled. All the patients underwent hypercoagulability screening, and the degree of hypercoagulability was evaluated by a scoring scale. Each PFO was classified as either high-risk or low-risk according to its anatomic features. Patients were divided into the drug treatment group (including antiplatelet and anticoagulation therapies) and transcatheter PFO closure group. After follow-up, the recurrence of cerebral ischemic events were compared between the two groups by Kaplan-Meier method, the prognostic factors were analyzed by multifactorial Cox's regression model. Results: A total of 117 patients were recruited, 10 patients were lost to follow-up, and 107 patients were included in the final analysis, consisting of 66 males and 41 females, with age ranging from 14 to 67 years and the follow-up period of 1 229 (45, 3 508) d. The recurrence rate of cerebral ischemic events was 6% (4/66) and 7% (3/41) for the drug treatment group (66 cases) and closure group (41 cases), respectively, and residual shunting was detected in all patients with recurrent events in the closure group. Cumulative hazard curve indicated that there was no significant difference of recurrence risk of cerebral ischemic events between the two groups (cumulative recurrence rate: 17.9% in the closure group vs 7.1% in the drug treatment group, χ2=0.368, P=0.544), and the insignificance persisted even in subgroup analysis of CICVD patients with either high-risk (χ2=0.685, P=0.408) or low-risk PFO (χ2=0.072, P=0.789). Cox's regression model indicated that hypercoagulability related factor score was an independent predictor of recurrent cerebral ischemic events (HR=2.079, 95%CI 1.069-4.045, P=0.031) after adjusting for high-risk PFO, PFO closure and other confounding factors. Moreover, a rising trend of cumulative recurrence rate was observed as the score got higher (P=0.046). Conclusions: For CICVD patients with either high-risk or low-risk PFO, the significant value of drug treatment as the first-line therapy for PFO related CICVD should not be ignored, which awaits further discussion. The abnormality of hypercoagulability related factors might increase the recurrent risk of cerebral ischemic events, which calls for more attention and should be screened and treated with corresponding medication.

MiRNA: Involvement of the MAPK Pathway in Ischemic Stroke. A Promising Therapeutic Target.

Ischemic stroke (IS) is a cerebrovascular disease with a high rate of disability and mortality. It is classified as the second leading cause of death that arises from the sudden occlusion of small vessels in the brain with consequent lack of oxygen and nutrients in the brain tissue. Following an acute ischemic event, the cascade of events promotes the activation of multiple signaling pathways responsible for irreversible neuronal damage. The mitogen-activated protein kinase (MAPK) signaling pathway transmits signals from the cell membrane to the nucleus in response to different stimuli, regulating proliferation, differentiation, inflammation, and apoptosis. Several lines of evidence showed that MAPK is an important regulator of ischemic and hemorrhagic cerebral vascular disease; indeed, it can impair blood–brain barrier (BBB) integrity and exacerbate neuroinflammation through the release of pro-inflammatory mediators implementing neurovascular damage after ischemic stroke. This review aims to illustrate the miRNAs involved in the regulation of MAPK in IS, in order to highlight possible targets for potential neuroprotective treatments. We also discuss some miRNAs (miR), including miR-145, miR-137, miR-493, and miR-126, that are important as they modulate processes such as apoptosis, neuroinflammation, neurogenesis, and angiogenesis through the regulation of the MAPK pathway in cerebral IS. To date, limited drug therapies are available for the treatment of IS; therefore, it is necessary to implement preclinical and clinical studies aimed at discovering novel therapeutic approaches to minimize post-stroke neurological damage.

Network pharmacology-based prediction of the active compounds and mechanism of Buyang Huanwu Decoction for ischemic stroke.

Buyang Huanwu Decoction (BYHWD) is used to promote blood circulation and is widely used in Chinese clinical practice for the treatment and prevention of ischemic cerebral vascular diseases. However, the mechanism and active compounds of BYHWD used to treat ischemic stroke are not well understood. The current study aimed to identify the potential active components of BYHWD and explore its mechanism using network pharmacology and bioinformatics analyses. The compounds of BYHWD were obtained from public databases. Oral bioavailability and drug-likeness were screened using the absorption, distribution, metabolism and excretion (ADME) criteria. Components of BYHWD, alongside the candidate targets of each component and the known therapeutic targets of ischemic stroke were collected. A network of target gene compounds and cerebral ischemia compounds was established using network pharmacology data sources. The enrichment of key targets and pathways was analyzed using STRING and DAVID databases. Moreover, three of key targets [IL6, VEGFA and hypoxia-inducible-factor-1α (HIF-1α)] were verified using western blot analysis. Network analysis determined 102 compounds in seven herbal medicines that were subjected to ADME screening. A total of 42 compounds as well as 79 genes formed the principal pathways associated with ischemic stroke. The 16 key compounds identified were baicalein, beta-carotene, baicalin, kaempferol, luteolin, quercetin, hydroxysafflor yellow A, isorhamnetin, bifendate, formononetin, calycosin, astragaloside IV, stigmasterol, sitosterol, Z-ligustilide, and dihydrocapsaicin. The core genes in this network were IL6, TNF, VEGFA, HIF-1α, MAPK1, MAPK3, JUN, STAT3, IL1B and IL10. Furthermore, the TNF, IL17, apoptosis, PI3K-Akt, toll-like receptor, MAPK, NF-κB and HIF-1 signaling pathways were identified to be associated with ischemic stroke. Compared with the control group (no treatment), BYHWD significantly inhibited the expression of IL6 and increase the expression of HIF-1α and VEGFA. Network pharmacology analyses can help to reveal close interactions between multi-components and multi-targets and enhance understanding of the potential effects of BYHWD on ischemic stroke.

Anti-IL-23 exerted protective effects on cerebral ischemia-reperfusion injury through JAK2/STAT3 signaling pathway.

Ischemia-reperfusion frequently occurs in ischemic cerebral vascular disease, during which the inflammatory signaling plays essential roles. The aim of this study was to discover the efficacy of the antibody to a key immune cytokine IL-23 (anti-IL-23) for the therapy of cerebral ischemia-reperfusion injury. We established the cerebral ischemia-reperfusion injury model by middle cerebral artery occlusion (MCAO). Anti-IL-23 injection attenuated lesions indicated by histology study. RT-PCR and Western blot were employed to detect the mRNA and protein expression of JAK2 and STAT3 after anti-IL-23 treatment. ELISA was utilized to measure the levels of MDA (malondialdehyde) and superoxide dismutase (SOD). Moreover, curcumin and IL-6 were implicated in the endogenous intervention of IL-23 signaling in vivo. Our data demonstrated that the treatment of anti-IL-23 might transcriptionally activate the classic immune pathway in the brain. Anti-IL-23 augmented phosphorylation levels of both JAK2 and STAT3, suggesting the amplification signaling of JAK/STAT after exogenous IL-23 intervention. Anti-IL-23 reduced ROS molecules of STAT downstream in the serum and brain. It also alleviated the injury by bringing down levels of MDA and SOD in the serum. JAK2 inhibitor could abolish the effect of anti-IL-23 whereas JAK3 ameliorated the injury. The combination of anti-IL-23 and JAK3i could reduce infarct volume more effectively. In summary, this study indicated that anti-IL-23 had protective effects against cerebral ischemia-reperfusion injury by targeting the immune specific JAK2-STAT3 in JAK/STAT pathway.

Effects of Antithrombotic Treatment on Bleeding Complications of EBUS-TBNA.

Background and Objectives: The application of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been markedly increased over the past decade. EBUS-TBNA is known to be a very safe and accurate procedure; however, the incidence of bleeding complications in patients who are taking antithrombotic agents (ATAs) is not well established. Materials and Methods: We conducted a retrospective analysis of a prospectively registered EBUS-TBNA cohort in a single tertiary hospital from May 2009 to December 2016. The patients were divided into two groups: an insufficient discontinuation group, defined as having a prescription for ATAs on the procedure day or only interrupting them for a short period of time, and a sufficient discontinuation group, defined as having prescription for ATAs during 30 days prior to the procedure and interrupting them for a sufficient period of time. Results: During the study period, a total of 4271 patients, after excluding 3773 patients who did not take ATAs at all, 498 patients were classified into the insufficient discontinuation group (n = 102) and the sufficient discontinuation group (n = 396). The baseline characteristics of patients and examined lesions between two groups were not significantly different, except insufficient discontinuation group had longer prothrombin times than the sufficient discontinuation group. In the insufficient discontinuation group, the most common reasons for prescriptions of ATAs were ischemic heart disease (48.0%) and cerebral vascular disease (28.4%), and half of the patients were taking two or more ATAs. Eventually, only one bleeding complication in the insufficient discontinuation group (1/102, 1.0%) and one event in the sufficient discontinuation group (1/396, 0.3%) occurred (p = 0.368). Conclusions: EBUS-TBNA is considered a safe procedure in terms of bleeding complications, even in patients with insufficient stopping of ATAs.

Clinical characteristics and risk factors of cardiovascular disease in patients with elderly-onset rheumatoid arthritis: A large cross-sectional clinical study

OBJECTIVE To investigate the clinical characteristics of patients with elderly-onset rheumatoid arthritis (EORA), and the risk factors of EORA complicated with cardiovascular disease (CVD). METHODS A cross-sectional study was conducted in Peking University People's Hospital from July 2009 to December 2014 and 1 116 patients were recruited. The patients' characteristics and CVD, including ischemic heart disease, cerebral and peripheral vascular disease, were recorded. The patients were divided into EORA group (n=212) and younger-onset rheumatoid arthritis (YORA) group (n=904) according to the age of onset ≥60 years and < 60 years. Then, the differences between the groups were analyzed by Student's t test, Mann-Whitney U test or χ2test, and risk influencing CVD were analyzed using Logistic regression. RESULTS There was no significant difference in the disease activity between the EORA and YORA groups. The proportion of male, pulmonary interstitial disease (ILD), and numbers of deformity joint count (DJC) were significantly higher in the EORA group compared with the YORA group [32.1% vs. 18.5%, χ2=19.11, P < 0.001; 23.6% vs. 13.6%, χ2=16.50, P < 0.001; 6 (2, 12) vs. 3 (2, 7), Z=-3.60, P < 0.001], while the prevalence of Sjogren's syndrome was lower than that of the YORA group (13.5% vs. 5.2%, χ2=11.29, P=0.001). Moreover, there were lower prevalences in the patients treated with disease-modifying antirheumatic drugs (DMARDs) in EORA group (35.4%) than in YORA group (26.7%) (χ2=6.43, P=0.011), especially in methotrexate (MTX), hydroxychloroquine (HCQ) and sulfasalazine (SSZ). In addition, the patients with EORA had a higher prevalence of CVD (27.8%) than the YORA group (11.6%, χ2=40.46, P < 0.001), accompanied with higher prevalence of smoking, hypertension, and hyperlipidemia. Multivariate Logistic regression analysis showed that elder age (OR=1.10, 95%CI: 1.00-1.20), DJC (OR=3.17, 95%CI: 1.04-9.68), rheumatoid nodules (OR=3.56, 95%CI: 1.03-12.23), hypertension (OR=2.37, 95%CI: 1.09-5.13) and hyperlipidemia (OR=8.85, 95%CI: 2.50-31.27) were independent risk factors, while HCQ (OR=0.22, 95%CI: 0.07-0.70) and MTX (OR=0.32, 95%CI: 0.14-0.73) were protective factors of EORA complicated with CVD. CONCLUSION Compared with YORA, patients with EORA have higher ratio of male, ILD and DJC, which may be attributed to inappropriate therapies. EORA is more likely to be complicated with CVD than YORA. Elder age, DJC, rheumatoid nodules, hypertension, and hyperlipidemia are independent risk factors, while HCQ and MTX are protective factors of EORA complicated with CVD.

Drug delivery for intracerebral of flunarizine hydrochloride after intraocular administration in rats.

Intraocular administration was a commonly route of administration in clinic, but most of the intraocular administration was only used to treat local ocular diseases. Based on the particularity of the ocular structure, this article mainly explored the feasibility of flunarizine hydrochloride in the treatment of ischemic cerebral vascular diseases (ICVD) by intraocular administration. A total of 150 SD rats were randomly divided into 3 groups with intraocular, intragastric, and intravenous administration, respectively. The doses were 14 mg/kg for intraocular and intragastric groups and 5 mg/kg for intravenous group. The plasma and brain concentration of flunarizine hydrochloride were analyzed by high performance liquid chromatography (HPLC). Main pharmacokinetic parameters and absolute bioavailability were evaluated. Brain targeting of flunarizine hydrochloride through intraocular administration was studied by drug targeting index of brain (DTIbrain). Maximum contentration (Cmax) and area under the time-concentration curve from o to t (AUC0-t) of plasma after intraocular administration were significantly higher than those of plasma after intragastric administration (both P<0.05). Cmax and AUC0-t of brain after intraocular administration were significantly higher than those of brain after intragastric administration (both P<0.05). The bioavailability of plasma and brain after intraocular administration was 18.67% and 34.67%, respectively, which was higher than 14.32% and 21.56% of plasma and brain after intragastric administration. The DTIbrain of intraocular administration was 1.84, and the DTIbrain of intragastric administration was 1.48. Flunarizine hydrochloride could be absorbed into the systemic circulation after intraocular administration. Not only the absolute bioavailability but also the brain targeting index of intraocular administration is higher than that of intragastric administration.

The comparative study between thromboelastography and conventional coagulation tests in ischemic cerebral vascular disease

Objective To explore the correlation and consistency between thromboelastography (TEG) and traditional coagulation tests (CCTs) in ischemic cerebral vascular disease (ICVD). Methods Totally 108 ICVD patients admitted to Nanyang Central Hospital from May 1 to October 31 2018 were enrolled. Patients’ TEG parameters (R value, K value, Angle value, MA value, CI value and G value) and CCTs parameters (PT, APTT, TT, and FIB) were collected and analyzed retrospectively. The Spearman correlation coefficient was used to explore the correlation between TEG and CCTs parameters, and Kappa (κ) to explore the consistency in determining the coagulation status of the patients. The ROC curve was used to analyze the predictive value of TEG parameters for abnormal results of CCTs, and the results of TEG and CCTs were comprehensively analyzed to evaluate the ability to predict the coagulation status of patients. Results (1) PLT was positively correlated with MA value and G value; PT and APTT were positively correlated with K value; TT was positively correlated with R value and K value; FIB was positively correlated with Angle value, MA value and G value. TT was negatively correlated with Angle value and CI value; FIB was negatively correlated with K value. (2) PT and MA values, PT and G values, FIB and MA values, FIB and G values were accordant in valuing the hypoxic state of ICVD patients. (3) PLT and Angle values, PLT and MA values, PLT and CI values, PLT and G values were accordant in assessing hypercoagulable status of ICVD patients; FIB and Angle values, FIB and MA values, FIB and CI value, and FIB and G value were consistent in evaluating the hypercoagulable state of ICVD patients. (4) For detecting TT>20 s, the AUC of K value and Angle value were 0.648, 0.651, respectively; For detecting FIB>4 g/L, the AUC of Angle value and MA value were 0.717 and 0.747, respectively; For detecting PLT>300×109/L, the AUC of MA value was 0.808 (all P<0.05). Conclusions There is weak correlation and consistency between TEG and CCTs parameters in ICVD patients. The TEG parameters have good predictive value in evaluating the abnormal results of CCTs, but cannot replace the CCTs. Combination of these two methods can better reflect the coagulation status of patients, so as to afford assistance. Key words: Thromboelastography; Conventional coagulation tests; Ischemic cerebral vascular disease; Ischemic stroke; Comparation

Study on the association between ambient air pollution and daily cardiovascular death in Hefei, China.

Cardiovascular disease has always been the most serious public health problem in China. Although many studies have found that the risk of death caused by cardiovascular disease is related to air pollutants, the existing results are still inconsistent. The aim of this study was to investigate the effects of air pollutants on the risk of daily cardiovascular deaths in Hefei, China. Daily data on cardiovascular deaths, daily air pollutants, and meteorological factors from 2007 to 2016 were collected in this study. A time-series study design using a distributed lag nonlinear model was employed to evaluate the association between air pollutants and cardiovascular deaths. First, a single air pollutant model was established based on the minimum value of Akaike information criterion (AIC), and the single day lag effects and multi-day lag effects were discussed separately. Then, two-pollutant models were fitted. Subgroup analyses were conducted by gender (male and female), age (< 65 age and ≥ 65 age), and disease type (ischemic heart disease and cerebral vascular disease). There were 34,500 cases of cardiovascular deaths during the period 2007-2016, and the average concentrations of air pollutants (PM10, SO2, NO2, PM2.5, CO, O3) were 106.11, 20.34, 30.49, 72.59, 958.7, and 67.88 μg/m3, respectively. An increase of interquartile range (IQR) in PM10, SO2, NO2, PM2.5, CO, and O3 were associated with an increase of 4.34% (95%CI 1.54~7.23%) at lag 0-6, 5.79% (95%CI 2.43~9.27%) at lag 0-5, 4.47% (95%CI 1.64~7.37%) at lag 0-5, 3.14% (95%CI 0.03~6.36%) at lag 0-4, 3.11% (95%CI 0.21~6.10%) at lag 0-3, and 8.17% (95%CI 1.89~14.84%) at lag 0-5 in cardiovascular deaths, respectively. Females, older group (≥ 65 years) and deaths from cerebral vascular disease were more vulnerable to air pollution than males, younger individuals (< 65 years) and deaths from ischemic heart disease. Our results suggest that air pollution increased the risk of cardiovascular deaths in Hefei. These findings can provide evidence for effective air quality interventions in Hefei.

Herbal Formula Fo Shou San Attenuates Alzheimer's Disease-Related Pathologies via the Gut-Liver-Brain Axis in APP/PS1 Mouse Model of Alzheimer's Disease.

Fo Shou San (FSS) is an ancient paired-herb decoction, used in China to treat blood deficiency, blood stasis, stroke, and ischemic cerebral vascular disease for about one thousand years. The mechanisms associated with these properties, however, are not completely understood. Gut bacteria, gut bacterial lipopolysaccharides (LPS), alkaline phosphatase (AP), and lipid peroxidation are common biochemical signaling that takes place on gut-liver-brain axis. Growing evidences have revealed that gut bacterial lipopolysaccharides (LPS) enter the systemic circulation via the portal vein, and finally entering the brain tissue is an important cause of inflammatory degeneration of Alzheimer's disease (AD). Alkaline phosphatase (AP) dephosphorylates LPS forming a nontoxic LPS and reduces systemic inflammation via gut-liver-brain axis. In this study, to identify the differentially gut-liver-brain axis among APP/PS1 mice, FSS-treated APP/PS1 mice, and control mice, behavioral tests were performed to assess the cognitive ability and hematoxylin-eosin staining was used to assess neuronal damage in the hippocampus; immunohistochemistry, western blotting, a quantitative chromogenic end-point Tachypleus amebocyte lysate (TAL) assay kit, Malondialdehyde (MDA) assay kit, AP Assay Kit, and real-time quantitative PCR (qPCR) were used to assess the level of LPS, MDA, AP, and gut bacteria. We found that FSS regulates gut-liver-brain axis to regulate AP and gut bacteria and attenuate the LPS-related systemic inflammation, oxidative stress (MDA), and thereby AD-related pathology in APP/PS1 mice. This is the first study to provide a reference for FSS-treated AD mice to aid in understanding the underlying mechanisms of FSS. FSS may also improve gastrointestinal tract barrier and blood-brain barrier and thus ameliorates the symptoms of AD; this is subject to our further study.

Relevance research on carotid atherosclerosis and levels of serum cathepsin K and cystatin C on patients with ischemic cerebral vascular disease

The relationship between carotid atherosclerosis (AS) and levels of serum cathepsin K (CatK) and cystatin C (CysC) on patients with ischemic cerebral vascular disease (ICVD) was explored. In total, 266 patients with ICVD who were admitted in our hospital were enrolled. According to the results of carotid ultrasound, they were randomly divided into plaque group (n = 133) and control group (n = 133). According to atherosclerotic plaque type distribution, the plaque group was divided into stable plaque group and unstable group. The relationship between levels of serum CatK and CysC of two groups and carotid AS indicator (such as intima-media thickness (IMT)) were analyzed with Spearman’s correlation. Spearman’s correlation analysis showed that IMT level was positively correlated with stability of carotid atherosclerotic plaque ( P &lt; 0.05). The level of serum CatK in plaque group was significantly higher than control group, and the level of serum CysC in plaque group was significantly lower than control group ( P &lt; 0.05); the level of serum CatK in unstable plaque group was significantly higher than stable plaque group, and the level of serum CysC in unstable plaque group was significantly lower than stable plaque group ( P &lt; 0.05). Serum CatK and IMT levels were positively correlated, and serum CysC and CatK levels were negatively correlated ( P &lt; 0.05). CatK and CysC levels may be used as serum markers for predicting carotid AS plaque instability, providing a new observational index for prevention and treatment of ICVD caused by carotid AS plaque.

Association between Airborne Fine Particulate Matter and Residents' Cardiovascular Diseases, Ischemic Heart Disease and Cerebral Vascular Disease Mortality in Areas with Lighter Air Pollution in China.

Background: China began to carry out fine particulate matter (PM2.5) monitoring in 2013 and the amount of related research is low, especially in areas with lighter air pollution. This study aims to explore the association between PM2.5 and cardiovascular disease (CVD), ischemic heart disease (IHD) and cerebral vascular disease (EVD) mortality in areas with lighter air pollution. Methods: Data on resident mortality, air pollution and meteorology in Shenzhen during 2013–2015 were collected and analyzed using semi-parametric generalized additive models (GAM) with Poisson distribution of time series analysis. Results: Six pollutants were measured at seven air quality monitoring sites, including PM2.5, PM10, SO2, NO2, CO and O3. The PM2.5 daily average concentration was 35.0 ± 21.9 μg/m3; the daily average concentration range was from 7.1 μg/m3 to 137.1 μg/m3. PM2.5 concentration had significant effects on CVD, IHD and EVD mortality. While PM2.5 concentration of lag5 and lag02 rose by 10 μg/m3, the excess risk (ER) of CVD mortality were 1.50% (95% CI: 0.51–2.50%) and 2.09% (95% CI: 0.79–3.41%), respectively. While PM2.5 concentration of lag2 and lag02 rose by 10 μg/m3, the ER of IHD mortality were 2.87% (95% CI: 0.71–5.07%) and 3.86% (95% CI: 1.17–6.63%), respectively. While PM2.5 concentration of lag4 and lag04 rose by 10 μg/m3, the ER of EVD mortality were 2.09% (95% CI: 2.28–3.92%) and 3.08% (95% CI: 0.68–5.53%), respectively. Conclusions: PM2.5 increased CVD mortality. The government needs to strengthen the governance of air pollution in areas with a slight pollution.

Progress of Experimental Researches on Mechanisms of Acupuncture Underlying Improvement of Ischemic Cerebral Vascular Disease by Regulating Different Intracellular Signaling Pathways

China is in the "high death zone" of the world cerebrovascular disease (CVD) map. The prevention and treatment of ischemic CVD (ICVD) have become the top priority in clinical practice. It has been demonstrated that acupuncture therapy has a positive role in bettering clinical symptoms of ICVD patients. Findings of recent experimental studies displayed that electroacupuncture (EA) intervention is effective in reducing the cerebral infarcted volume and cellular injury, promoting proliferation, migration and differentiation of nerve stem cells, facilitating the regeneration of nerve tissue, bettering dysneuria and limb locomotor ability, etc. in ICVD rats, which are closely associated with its effects in regulating different intracellular signaling pathways. In the present study, we review the progress of recent experimental studies on the underlying mechanisms of EA in improving ICVD from six major signaling pathways including Notch, mitogen-activated protein kinases (MAPK)/ extracellular signal regulated protein kinases (ERK), phosphatidy linositol-3-kinase (PI 3 K)/ protein kinase B (Akt), Janus kinase-signal transducer and activator of transcription (JAK-STAT), erythropoietin-producing hepatocyte receptor (Eph)/Ephrin, nuclear factor of kappa B (NF-κB) and their compositions, which may provide new therapeutic targets for acupuncture treatment of ICVD. More attention should be paid to the comparison of the efficacy of acupuncture of different acupoint combinations (traditional acupoint formulas) in relieving ICVD.

MRI Features and Site-specific Factors of Ischemic Changes in White Matter: A Retrospective Study.

Brain magnetic resonance imaging (MRI) of the elderly often reveals white matter changes (WMCs) with substantial variability across individuals. Our study was designed to explore MRI features and site-specific factors of ischemic WMCs. Clinical data of consecutive patients diagnosed with ischemic cerebral vascular disease who had undergone brain MRI were collected and analyzed. Multi-logistic regression analysis comparing patients with mild versus severe WMCs was performed to detect independent associations. Analyses of variance (ANOVAs) were used to detect regionally specific differences in lesions. We found that lesion distribution differed significantly across five cerebral areas, with lesions being predominant in the frontal lobe and parieto-occipital area. To explore WMCs risk factors, after adjusting for gender, diabetes mellitus, and hypertension, only age (P<0.01), creatinine (P=0.01), alkaline phosphatase (ALP) (P=0.01) and low-density lipoprotein cholesterol (LDL-C) (P=0.03) were found to be independently associated with severe WMCs. Age (P<0.001) was strongly associated with WMCs in the frontal lobe while hypertension was independently related to lesions in the basal ganglia (P=0.048) or infratentorial area (P=0.016). In conclusion, MRI of WMCs showed that ischemic WMCs occurred mostly in the frontal lobe and parieto-occipital area. The infratentorial area was least affected by WMCs. Typically, age-related WMCs were observed in the frontal lobes, while hypertension-related WMCs tended to occur in the basal ganglia and infratentorial area.

Cilostazol Use Is Associated with Reduced Risk of Dementia: A Nationwide Cohort Study.

Whether antiplatelet agents have a preventive effect on cognitive function remains unknown. We examined the potential association between the use of cilostazol, an antiplatelet agent and cyclic adenosine monophosphate phosphodiesterase 3 inhibitor, and the risk of dementia in an Asian population. Patients initiating cilostazol therapy between 1 January 2004 and 31 December 2009 without a prior history of dementia were identified from Taiwan's National Health Insurance database. Participants were stratified by age, sex, comorbidities, and comedication. The outcome of interest was all-cause dementia (ICD-9-CM codes 290.0, 290.4, 294.1, 331.0). Cox regression models were used to estimate the hazard ratio (HR) of dementia. The cumulative cilostazol dosage was stratified by quartile of defined daily doses using no cilostazol use as a reference. A total of 9148 participants 40years of age or older and free of dementia at baseline were analyzed. Patients using cilostazol (n = 2287) had a significantly decreased risk of incident dementia compared with patients not using the drug [n = 6861; adjusted HR (aHR) 0.75; 95% confidence interval (CI) 0.61-0.92]. Notably, cilostazol use was found to have a dose-dependent association with reduced rate of dementia emergence (p for trend = 0.001). Subgroup analysis identified a decline of dementia in cilostazol users with diagnosed ischemic heart disease (aHR 0.44, 95% CI 0.24-0.83) and cerebral vascular disease (aHR 0.34, 95% CI 0.21-0.54). These observations suggest that cilostazol use may reduce the risk to develop dementia, and a high cumulative dose further decreases the risk of dementia. These findings should be examined further in randomized clinical trials.

MiR-30s Family Inhibit the Proliferation and Apoptosis in Human Coronary Artery Endothelial Cells Through Targeting the 3'UTR Region of ITGA4 and PLCG1.

Atherosclerosis (As) is a common disease, which is serious hazard to human health. As the main pathological basis of ischemic cardiac and cerebral vascular disease, including coronary heart disease, cerebrovascular disease, and thromboembolic disease, it is a chronic inflammatory lesion of the arterial vessel wall. So far the pathogenesis of As has not been fully understood. Therefore, it is still lack of effective clinical prevention and treatment of drugs. More and more evidence indicate that miRNA plays an important role in the pathophysiology of many diseases, especially the occurrence and development of cardiovascular diseases. MiRNAs are widely detected in human coronary artery endothelial cells, which might participate in diverse biological functions through targeting different As associated genes. The aim of this study was to investigate the molecular mechanisms underlying miR-30s roles in As. Our study found the high expression of miR-30b and miR-30e in As clinical samples, identified the regulatory relationship of miR-30b and miR-30e to ITGA4 and PLCG1, respectively, and initially explored the effects of miR-30b and miR-30e on cell cycle and apoptosis through targeting ITGA4 and PLCG1. These data may provide a theoretical basis for clarifying the mechanism of miR-30s in As.

RLj-RGD3, a Novel Recombinant Toxin Protein from Lampetra japonica, Protects against Cerebral Reperfusion Injury Following Middle Cerebral Artery Occlusion Involving the Integrin-PI3K/Akt Pathway in Rats.

BackgroundThe RGD-toxin protein Lj-RGD3 is a naturally occurring 118 amino acid peptide that can be obtained from the salivary gland of the Lampetra japonica fish. This unique peptide contains 3 RGD (Arg-Gly-Asp) motifs in its primary structure. Lj-RGD3 is available in recombinant form (rLj-RGD3) and can be produced in large quantities using DNA recombination techniques. The pharmacology of the three RGD motif-containing peptides has not been studied. This study investigated the protective effects of rLj-RGD3, a novel polypeptide, against ischemia/reperfusion-induced damage to the brain caused by middle cerebral artery occlusion (MCAO) in a rat stroke model. We also explored the mechanism by which rLj-RGD3 acts by measuring protein and mRNA expression levels, with an emphasis on the FAK and integrin-PI3K/Akt anti-apoptosis pathways.MethodsrLj-RGD3 was obtained from the buccal secretions of Lampetra japonica using gene recombination technology. Sprague Dawley (SD) rats were randomly divided into the following seven groups: a sham group; a vehicle-treated (VT) group; 100.0 μg·kg-1, 50.0 μg·kg-1 and 25.0 μg·kg-1 dose rLj-RGD3 groups; and two positive controls, including 1.5 mg·kg-1 Edaravone (ED) and 100.0 μg·kg-1 Eptifibatide (EP). MCAO was induced using a model consisting of 2 h of ischemia and 24 h of reperfusion. Behavioral changes were observed in the normal and operation groups after focal cerebral ischemia/reperfusion was applied. In addition, behavioral scores were evaluated at 4 and 24 h after reperfusion. Brain infarct volumes were determined based on 2,3,5-triphenyltetrazolium chloride (TTC) staining. Pathological changes in brain tissues were observed using hematoxylin and eosin (H&E) staining. Moreover, neuronal apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assays. We determined the expression levels of focal adhesion kinase (FAK), phosphatidyl inositol 3-kinase (PI3K), protein kinase B (Akt, PKB), caspase-3 and Bcl-2 in the brain using western blot analysis and RT-PCR assays. The research protocol was approved by the Institutional Ethics Committee of Dalian Medical University.ResultsThe behavioral scores and cerebral infarct volumes of the rLj-RGD3 groups were markedly lower at 4 and 24 h/RF. The rLj-RGD3 protein significantly ameliorated pathological changes in the brain and reduced the number of apoptotic neurons. Furthermore, the FAK and PI3K/Akt pathways were activated. rLj-RGD3 significantly increased the expression of FAK, p-FAK and Bcl-2 proteins. In contrast, caspase-3 expression was inhibited.Conclusion/SignificanceWe conclude that recombinant Lampetra japonica RGD-peptide (rLj-RGD3) exerts a protective effect against cerebral ischemia/reperfusion injury in the brain. In addition, the mechanism of this protection is associated with the activation of the integrin-PI3K/Akt pathway. These results provide a theoretical foundation and an experimental basis for using RGD peptides as novel drugs for treating ischemic cerebral vascular diseases in addition to promoting the research and development of marine biotechnology drugs.