Imperatorin exerts antioxidant effects in vascular dementia via the Nrf2 signaling pathway.

Imperatorin, an active ingredient extracted from Angelica and Qianghuo, has anti-inflammatory, anti-oxidative stress damage, blocking calcium channels, and other properties. Our preliminary findings revealed the protective role of imperatorin in the treatment of vascular dementia, we further explored the underlying mechanisms concerning the neuroprotection function of imperatorin in vascular dementia. The cobalt chloride (COCl2)-induced chemical hypoxia and hypoglycemia of hippocampal neuronal cells was applied as in vitro vascular dementia model. Primary neuronal cells was isolated from the hippocampal tissue of SD suckling rats within 24 h of birth. Hippocampal neurons were identified by immunofluorescence staining of microtubule-associated protein 2. Silencing or overexpression of Nrf2 was conducted by transfection of corresponding plasmids in hippocampal neuronal cells. Cell viability was detected by MTT assay to determine the optimal modeling concentration of CoCl2. Mitochondrial membrane potential, intracellular reactive oxygen species and apoptosis rate was measured by flow cytometry. The expression of anti-oxidative proteins was detected by quantitative real-time PCR and western blot, including Nrf2, NQO-1 and HO-1. Nrf2 nuclear translocation was detected using laser confocal microscopy. The modeling concentration of CoCl2 was 150umol/l, and the best interventional concentration of imperatorin was 7.5umol/l. Significantly, imperatorin facilitated the nuclear localization of Nrf2, promoted the expressions of Nrf2, NQO-1, and HO-1 relative to the model-control group. Moreover, imperatorin reduced the mitochondrial membrane potential and ameliorated CoCl2-induced hypoxic apoptosis in hippocampal neurons. On the contrary, silencing Nrf2 completely abrogated the protective effects of imperatorin. Imperatorin might be an effective drug for preventing and treating vascular dementia.

Effects of imperatorin on apoptosis and synaptic plasticity in vascular dementia rats.

In view of the complicated pathophysiological process of vascular dementia (VD), drugs for the clinical treatment of VD mainly target related risk factors, while drugs with excellent efficacy in cognitive function are still relatively lacking. Imperatorin (IMP), an active constituent extracted from angelica dahuricae and notopterygium Notopterygii, which has anti-inflammatory, vasodilator, anticoagulant, block calcium channel, anticonvulsant, and anti oxygen free radical injury properties. Therefore,the present study examined its effects on VD rats and the underlying molecular mechanisms, in order to provide promising therapeutic methods. VD was established by modified ligation of perpetual two-vessel occlusion (2VO). After 2VO surgery, IMP (2.5, 5, and 10 mg/kg) was administered by intraperitoneal injection for 12 consecutive weeks to evaluate therapeutic effects. Cognitive function was verified by the Morris water maze. The neuronal morphological changes were examined via Hematoxylin-Eosin staining. Real-Time PCR and Western blot were used for detecting pro- and antiapoptotic biomarkers, and the hippocampus synaptic damage was examined by Transmission electron microscope. We revealed that 2VO-induced cognitive impairment, hippocampus CA1 neuron damage, apoptosis and synaptic damage. IMP-treatment significantly improved 2VO-induced cognitive deficits and hippocampus neuron damage. Molecular analysis revealed that IMP inhibited apoptosis through the down regulation of Bax, Caspase-3 and upregulation of Bcl-2. Meanwhile, IMP-treatment markedly improved synaptic ultrastructure morphology, increased the SAZ length, PSD thickness and up-regulated PSD-95 expression. Collectively, our findings demonstrated that IMP was effective in the treatment of 2VO-induced VD via inhibiting apoptosis of hippocampus neurons and reducing the synaptic plasticity destroy.

Expression of circular RNAs in the vascular dementia rats.

PURPOSE: Circular RNAs (circRNAs) are a class of endogenous noncoding RNA molecules that lack free 5' and a 3' end poly(A) tail. CircRNAs are enriched in neural tissues, and have been found to be associated with various diseases of the central nervous system. This study aimed to examine key circRNAs involved in vascular dementia(VD) model rats. METHODS: Total RNA-seq profiles of hippocampus samples from normal and vascular dementia rats were extracted and high throughput sequencing was performed. Quantitative real-time polymerase chain reaction (qPCR) was used to confirm the circRNA expression profiles. Differential expression of circRNA has been used for analysis via the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The circRNA-miRNA-mRNA network was then constructed. RESULTS: The data of high-throughput sequencing showed that there were 425 circRNAs differentially expressed between VD and normal rats (fold change (FC)≥2.0 and p-value< 0.05). In the VD group, a total of 237 were significantly upwardly revised, while the other 188 were downwardly revised. Eleven of these expressed more than 10 times in the VD model rats. The Expression levels of 10 circRNAs (circ_Map2k5, circ_Ulk2, circ_Plekha5, circ_Plcl1, circ_Sntg1, circ_Morc3, circ_Rims1, circ_ Stxbp5l, circ_ Agtpbp1, circ_Lrrc28) were verified by qPCR, which were persistent with RNA-seq data(P < 0.05). GO analysis indicated that majority of predicted target genes were involved in biological processes, such as cellular processes, nervous system development, etc. Cellular component, such as cellular parts, intracellular parts, cytoplasm and molecular function, such as binding, catalytic activity, etc. Moreover, KEGG analysis showed that many genes were enriched in cholinergic synapses, the MAPK signaling pathways, GABAergic synapses, metabolic pathways, the mTOR signaling pathways, and so on. CONCLUSIONS: Our results suggest the involvement of different ncRNA expression patterns in the pathogenesis (are associated with the pathogenesis of VD. Our findings provide a novel perspective for further research into potential mechanisms of VD and might facilitate the development of novel therapeutics targeting ncRNAs.

Factors associated with health-related quality of life among family caregivers of people with Alzheimer's disease.

AIM: Based on the ageing population and the inadequate healthcare system in China, the majority of care for patients with Alzheimer's disease (AD) is provided by family caregivers. Caregivers suffer a long-term heavy care burden and pressure, which affects their physical and mental health. The present study aims at investigating health-related quality of life (HRQOL) among family caregivers of AD patients and exploring its influencing factors. METHODS: This study included 206 family caregivers (76 male, 130 female) of AD patients recruited from one Tier 3 hospital, one psychiatric hospital, two gerocomiums and three communities in Ganzhou city, Jiangxi Province, China. Measures included the World Health Organization (WHO) Quality of Life (WHO/ QOL-BREF) questionnaire, Zarit burden of care scale (ZBI), and social support rating scale (SSRS).We performed face-to-face or telephone interviews with patients and caregivers. The association between possible factors and changes in HRQOL was examined through stepwise multiple regression analysis. RESULTS: The majority of family caregivers felt moderate to severe level of burden. The average HRQOL score was 54.24 ± 10.36. The mean SSRS score was 30.4 ± 10.9. The average ZBI score was 41.2 ± 12.8. The HRQOL of family caregivers of AD patients was negatively correlated with the neuropsychiatric questionnaire score, ZBI score, and chronic diseases of caregivers (P < 0.05), and positively correlated with the SSRS score (P < 0.05). CONCLUSION: Reduced QOL was highly prevalent among AD patient family caregivers, and the level of burden, neuropsychiatric symptoms of patients, social support, and chronic diseases of caregivers were factors associated with HRQOL, and the effect of care burden is greatest. Interventions aimed at reducing the level of burden should focus not only on the patient but also on the caregiver.

Evaluation of the Influence of Etiological Factors on the Economic Burden of Ischemic Stroke in Younger Patients in China Using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) Classification.

BACKGROUND Worldwide, stroke results in healthcare costs and economic costs, particularly in patients aged <45 years. This study aimed to evaluate the factors influencing the economic burden of ischemic stroke in younger patients in China based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) etiological classification. MATERIAL AND METHODS Retrospective review of the medical records of 961 patients aged between 18-45 years, diagnosed with acute ischemic stroke, was performed to identify healthcare costs for one year. Stroke severity was assessed using the modified Rankin Scale (mRS) score and the National Institutes of Health Stroke Scale (NIHSS) score. Stroke was categorized according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification as being due to large artery atherosclerosis (LAA), cardioembolism (CE), small artery occlusion (SAO), other determined causes (OC), and undetermined etiology (UND). RESULTS Total direct medical costs at one-year follow-up were US$10,954.14, including inpatient cost of US$5,958.44, and outpatient cost of US$3,397.60. Inpatient and total costs at one year were significantly increased in the CE subtype (P<0.001), and were significantly less in the UND subtype (P<0.001). Multivariable logistic regression analysis showed that mRS score, TOAST category, NIHSS score, and the presence of atrial fibrillation were the significant factors influencing cost at one-year follow-up and total cost in younger patients with ischemic stroke. Overall, patient costs in China were less than those in high-income countries. CONCLUSIONS In the younger patient population in China, etiological factors influenced the economic burden of ischemic stroke.

Role of APACHE II scoring system in the prediction of severity and outcome of acute intracerebral hemorrhage.

PURPOSE: Acute intracerebral hemorrhage (ICH) is prone to multiple organ dysfunction and has high disability and mortality. This study was to determine the role of acute physiology and chronic health evaluation II (APACHE II) scoring system in the prediction of severity and outcome of acute ICH. METHODS: A total of 546 ICH patients were prospectively recruited between 1 January 2013 and 31 December 2014. Patients were divided into three groups according to the APACHE II scores: low score group (5-16), moderate score group (17-28) and high score group (≥29). The ICH volume and location, National Institutes of Health Stroke Scale (NIHSS) scores, Glasgow Coma Score and modified Rankin Scale (mRS) scores were used to assess the severity of acute ICH. Global outcome at three months was evaluated with the mRS. RESULTS: Of 479 patients, the average age was 56.4 ± 3.4 years, 287 (59.9%) survived and 192 (40.1%) died. Results showed that the higher the APACHE II score, the higher the mortality was; the average hospital stay, ICH volume, NIHSS scores, mRS scores and survival rate were significantly different among three APACHE II groups (p < 0.05). APACHE II scores were able to predict the mortality and correlated positively with actual mortality (r = 0.84, p < 0.01). CONCLUSIONS: APACHE II scoring system can be used to predict the severity and outcome of acute ICH.