UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.

BACKGROUND: The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. METHOD: Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. RESULT: We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. CONCLUSION: These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

Morphological and molecular biology identification of Cystoisospora sp. in the blue fox, Alopex lagopus (Linnaeus, 1758).

To investigate the prevalence and molecular characteristics of Cystoisospora sp. in blue fox (Alopex lagopus), Sheather's sugar floatation method was conducted to detect coccidia in 423 fresh fecal samples randomly collected from blue fox farms from three cities in China. The overall prevalence of coccidia was 1.4% (6/423), and three Cystoisospora sp. (Cystoisospora fennechi, Cystoisospora sp. I and Cystoisospora vulpina) were identified by their morphological characteristics. The 18S ribosomal RNA (rRNA) and cytochrome c oxidase subunit I (COI) locus sequences were sequenced for molecular biological identification, homology comparison, and phylogenetic analysis of Cystoisospora sp. by single-oocyst selection technology and multi-locus-nested PCR amplification. At the 18S rRNA and COI loci, C. vulpina had 99.48% and 99.59% homology, respectively, with Cystoisospora canis and Cystoisospora ohioensis from canines. Phylogenetic analysis indicated that C. vulpina was clustered in a clade with Cystoisospora sp. from Canidae, which the relatives are consistent with the hosts. To our knowledge, this is the first report on molecular identification and evolutionary analysis of C. vulpina at two different loci.

Kukoamine A Protects against NMDA-Induced Neurotoxicity Accompanied with Down-Regulation of GluN2B-Containing NMDA Receptors and Phosphorylation of PI3K/Akt/GSK-3ß Signaling Pathway in Cultured Primary Cortical Neurons.

Kukoamine (KuA) is a spermine alkaloid present in traditional Chinese medicine Cortex Lycii radices, which possesses various pharmacological properties. Our previous studies have demonstrated that KuA exerts neuroprotective effects against H2O2-induced oxidative stress, radiation-induced neuroinflammation, oxidative stress and neuronal apoptosis, as well as neurotoxin-induced Parkinson's disease through apoptosis inhibition and autophagy enhancement. The present study aimed to investigate the neuroprotective effects of KuA against NMDA-induced neuronal injury in cultured primary cortical neurons and explore the underlying mechanism. Incubation with 200 µM NMDA for 30 min induced excitotoxicity in primary cultured cortical neurons. The results demonstrated that pretreatment with KuA attenuated NMDA induced cell injury, LDH leakage and neuronal apoptosis. KuA also regulated apoptosis-related proteins. Thus, incubation with the alkaloid decreased the ratio of Bax/Bcl-2, and inhibited the release of cytochrome C, the expression of p53 and the cleavage of caspase-3. Moreover, KuA prevented the upregulation of GluN2B-containing NMDA receptors (NMDAR). Additionally, pretreatment with KuA reversed NMDA-induced dephosphorylation of Akt and GSK-3ß and the protective effect of KuA on NMDA-induced cytotoxicity was abolished by wortmannin, a PI3K inhibitor. Taken together, these results indicated that KuA exerted neuroprotective effects against NMDA-induced neurotoxicity in cultural primary cortical neurons and caused the down-regulation of GluN2B-containing NMDARs as well as the phosphorylation of proteins belonging to the PI3K/Akt/GSK-3ß signaling pathway.

Neuroprotection by Kukoamine A against oxidative stress may involve N-methyl-D-aspartate receptors.

BACKGROUND: Accumulative evidences have indicated that oxidative-stress and over-activation of N-methyl-d-aspartate receptors (NMDARs) are important mechanisms of brain injury. This study investigated the neuroprotection of Kukoamine A (KuA) and its potential mechanisms. METHODS: Molecular docking was used to discover KuA that might have the ability of blocking NMDARs. Furthermore, the MTT assay, the measurement of LDH, SOD and MDA, the flow cytometry for ROS, MMP and Annexin V-PI double staining, the laser confocal microscopy for intracellular Ca2+ and western-blot analysis were employed to evaluate the neuroprotection of KuA. RESULTS: KuA attenuated H2O2-induced cell apoptosis, LDH release, ROS production, MDA level, MMP loss, and intracellular Ca2+ overload (both induced by H2O2 and NMDA), as well as increased the SOD activity. In addition, it could modulate the apoptosis-related proteins (Bax, Bcl-2, p53, procaspase-3 and procaspase-9), the SAPKs (ERK, p38), AKT, CREB, NR2A and NR2B expression. CONCLUSIONS: All the results indicated that KuA has the ability of anti-oxidative stress and this effect may partly via blocking NMDARs in SH-SY5Y cells. GENERAL SIGNIFICANCE: KuA might have the potential therapeutic interventions for brain injury.

E2F1-regulated USP5 contributes to the tumorigenic capacity of glioma stem cells through the maintenance of OCT4 stability.

Mesenchymal glioma stem cells (MES GSCs) are a subpopulation of cells in glioblastoma (GBM) that contribute to a worse prognosis owing to their highly aggressive nature and resistance to radiation therapy. Here, OCT4 is characterized as a critical factor in sustaining the stemness phenotype of MES GSC. We find that OCT4 is expressed intensively in MES GSC and is intimately associated with poor prognosis, moreover, OCT4 depletion leads to diminished invasive capacity and impairment of the stem phenotype in MES GSC. Subsequently, we demonstrated that USP5 is a deubiquitinating enzyme which directly interacts with OCT4 and preserves OCT4 stability through its deubiquitination. USP5 was additionally proven to be aberrantly over-expressed in MES GSCs, and its depletion resulted in a noticeable diminution of OCT4 and consequently a reduced self-renewal and tumorigenic capacity of MES GSCs, which can be substantially restored by ectopic expression of OCT4. In addition, we detected the dominant molecule that regulates USP5 transcription, E2F1, with dual luciferase reporter gene analysis. In combination, targeting the E2F1-USP5-OCT4 axis is a potentially emerging strategy for the therapy of GBM.

Prevention of dementia using mobile phone applications (PRODEMOS): a multinational, randomised, controlled effectiveness-implementation trial.

BACKGROUND: The expected increase of dementia prevalence in the coming decades will mainly be in low-income and middle-income countries and in people with low socioeconomic status in high-income countries. This study aims to reduce dementia risk factors in underserved populations at high-risk using a coach-supported mobile health (mHealth) intervention. METHODS: This open-label, blinded endpoint, hybrid effectiveness-implementation randomised controlled trial (RCT) investigated whether a coach-supported mHealth intervention can reduce dementia risk in people aged 55-75 years of low socioeconomic status in the UK or from the general population in China with at least two dementia risk factors. The primary effectiveness outcome was change in cardiovascular risk factors, ageing, and incidence of dementia (CAIDE) risk score from baseline to after 12-18 months of intervention. Implementation outcomes were coverage, adoption, sustainability, appropriateness, acceptability, fidelity, feasibility, and costs assessed using a mixed-methods approach. All participants with complete data on the primary outcome, without imputation of missing outcomes were included in the analysis (intention-to-treat principle). This trial is registered with ISRCTN, ISRCTN15986016, and is completed. FINDINGS: Between Jan 15, 2021, and April 18, 2023, 1488 people (601 male and 887 female) were randomly assigned (734 to intervention and 754 to control), with 1229 (83%) of 1488 available for analysis of the primary effectiveness outcome. After a mean follow-up of 16 months (SD 2·5), the mean CAIDE score improved 0·16 points in the intervention group versus 0·01 in the control group (mean difference -0·16, 95% CI -0·29 to -0·03). 1533 (10%) invited individuals responded; of the intervention participants, 593 (81%) of 734 adopted the intervention and 367 (50%) of 734 continued active participation throughout the study. Perceived appropriateness (85%), acceptability (81%), and fidelity (79%) were good, with fair overall feasibility (53% of intervention participants and 58% of coaches), at low cost. No differences in adverse events between study arms were found. INTERPRETATION: A coach-supported mHealth intervention is modestly effective in reducing dementia risk factors in those with low socioeconomic status in the UK and any socioeconomic status in China. Implementation is challenging in these populations, but those reached actively participated. Whether this intervention will result in less cognitive decline and dementia requires a larger RCT with long follow-up. FUNDING: EU Horizon 2020 Research and Innovation Programme and the National Key R&D Programmes of China. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Inhibitory neuron map of sevoflurane induced neurotoxicity model in young primates.

Introduction: Sevoflurane, one of the most commonly used anesthetic agents in children, may induce neuronal dysfunction and cognitive impairment. Exposure to sevoflurane might induce an imbalance between neural excitation and inhibition which could be a mechanism behind anesthesia-induced cognitive and affective dysfunctions. However, the underlying mechanisms remain unclear. Methods: In this study, we used two rhesus macaques in the control group, and one rhesus macaques in the anesthesia group. We employed single-nucleus RNA sequencing (snRNA-seq) technology to explore alterations in distinct types of inhibitory neurons involved in the long-term cognitive impairment caused by sevoflurane in young macaques. Results: Following sevoflurane treatment, an upregulation was observed in the SST+ inhibitory neuron in the LHX6+ neighborhood in the hippocampus of rhesus macaques. This alteration might impact brain development by influencing interneuron migration and maturation. Additionally, we proposed a novel classification of inhibitory neurons, defined by CNR1 and LHX6 applicable to both humans and macaques. Discussion: Our study proposed a novel classification of inhibitory neurons defined by LHX6 and CNR1, relevant in macaques and humans. We also provide evidence that sevoflurane upregulated the SST+ inhibitory neuron in the LHX6+ neighborhood in the hippocampus of rhesus macaques, which may underlie the potential neurotoxic effects induced by general anesthetics. Our results also offer a more reliable approach for studying the structure and function of the human brain.

The association of psychological stress with metabolic syndrome and its components: cross-sectional and bidirectional two-sample Mendelian randomization analyses.

Background: Metabolic syndrome (MetS) is a group of co-occurring conditions that increase the risk of cardiovascular disease, which include the conditions of hypertension, overweight or obesity, hyperglycemia, and dyslipidemia. Psychological stress is gradually being taken seriously, stemming from the imbalance between environmental demands and individual perceptions. However, the potential causal relationship between psychological stress and MetS remains unclear. Method: We conducted cross-sectional and bidirectional Mendelian randomization (MR) analyses to clarify the potential causal relationship of psychological stress with MetS and its components. Multivariable logistic regression models were used to adjust for potential confounders in the cross-sectional study of the Chinese population, including 4,933 individuals (70.1% men; mean age, 46.13 ± 8.25). Stratified analyses of sexual characteristics were also performed. Bidirectional MR analyses were further carried out to verify causality based on summary-level genome-wide association studies in the European population, using the main analysis of the inverse variance-weighted method. Results: We found that higher psychological stress levels were cross-sectionally associated with an increased risk of hypertension in men (odds ratio (OR), 1.341; 95% confidence interval (CI), 1.023-1.758; p = 0.034); moreover, higher levels of hypertension were cross-sectionally associated with an increased risk of psychological stress in men and the total population (men: OR, 1.545 (95% CI, 1.113-2.145); p = 0.009; total population: OR, 1.327 (95% CI, 1.025-1.718); p = 0.032). Genetically predicted hypertension was causally associated with a higher risk of psychological stress in the inverse-variance weighted MR model (OR, 2.386 (95% CI, 1.209-4.710); p = 0.012). However, there was no association between psychological stress and MetS or the other three risk factors (overweight or obesity, hyperglycemia, and dyslipidemia) in cross-sectional and MR analyses. Conclusion: Although we did not observe an association between psychological stress and MetS, we found associations between psychological stress and hypertension both in cross-sectional and MR studies, which may have implications for targeting hypertension-related factors in interventions to improve mental and metabolic health. Further study is needed to confirm our findings.

Altered spontaneous activity in Alzheimer's disease and mild cognitive impairment revealed by Regional Homogeneity.

Alzheimer's disease (AD), the most prevalent cause of dementia in the elderly, is characterized by progressive cognitive and intellectual deficits. Most patients with mild cognitive impairment (MCI) are thought to be in a very early stage of AD. Resting-state functional magnetic resonance imaging reflects spontaneous brain activities and/or the endogenous/background neurophysiological process of the human brain. Regional Homogeneity (ReHo) can provide a fast method for mapping regional activity across the whole brain. Little has been previously published about where or how spontaneous activity differs between MCI and AD, although many previous fMRI studies have shown that the activity pattern is altered in MCI/AD. In the present study, we first used the ReHo method to explore differences in regional spontaneous activities throughout the whole brain between normal controls (NC) and people with MCI and with AD. A one-way ANOVA was performed to determine the regions in which the ReHo differs between the three groups, and then a post hoc analysis was performed to evaluate differences in the pattern among the three groups. Finally a correlation analysis was done between the ReHo index of these regions and clinical variables in order to evaluate the relationship between ReHo and cognitive measures in the AD and MCI groups. An exploratory classification analysis also demonstrated that ReHo measures were able to correctly separate subjects in 71.4% of the cases. Altered brain spontaneous activations were found in the medial prefrontal cortex, the bilateral posterior cingulate gyrus/precuneus and the left inferior parietal lobule (IPL) in both MCI and AD. In MCI, the ReHo index in the left IPL was higher than that of the NC, which could indicate the presence of a compensatory mechanism in MCI. More obviously, the correlation analysis indicated that the lower the memory and other cognitive abilities, the lower the ReHo in patients with MCI and AD. Combining our findings with the results in earlier studies, we propose that the spontaneous activity pattern in the resting state could potentially be used as a clinical marker for MCI/AD.

Anesthesia and developing brain: What have we learned from recent studies.

Anesthesia is unavoidable in surgical procedures. However, whether the general anesthetics are neurotoxic to immature brains remains undefined. Neurodevelopmental impairment induced by anesthesia has been a critical health issue and topic of concern. This review summarizes recent progress made in clinical and preclinical studies to provide useful suggestions and potential therapeutic targets for the protection of the immature brain. On the one hand, clinical researchers continue the debate about the effect of single and multiple exposures to anesthesia on developing brains. On the other hand, preclinical researchers focus on exploring the mechanisms of neurotoxic effects of general anesthesia on immature brains and seeking novel solutions. Rodent models have always been used in preclinical studies, but it is still unclear whether the mechanisms observed in rodent models have clinical relevance. Compared with these models, non-human primates (NHPs) are more genetically similar to humans. However, few research institutions in this area can afford to use NHP models in their studies. One way to address both problems is by combining single-cell sequencing technologies to screen differential gene expression in NHPs and perform in vivo validation in rodents. The mechanism of anesthesia-induced neurotoxicity still requires further elucidation in primates.

The effects and the mechanisms of naringenin from Artemisia ordosica Krasch on allergic rhinitis based on mast cell degranulation model and network pharmacology.

OBJECTIVES: The ethyl acetate extraction of Artemisia ordosica Krasch (AOK) root showed anti-allergic rhinitis (AR) effect, while the active compounds and pharmacological targets were unknown. METHODS: The P815 degranulation was established by cell counting kit 8 assay, ß-hexosaminidase releasing assay and toluidine blue staining. The flavonoids were screened in vitro. Then toluidine blue staining and ELISA were carried out to investigate the anti-inflammatory effects of the active compound. Network pharmacology was implemented to explain the mechanisms of the active compound. iGEMDOCK was used to investigate the binding between active compound and hub targets. KEY FINDINGS: C48/80 was the optimum reagent in triggering P815 degranulation. Naringenin could significantly decrease P815 degranulation. Meanwhile, naringenin could remarkably increase the IL-4 and decrease the tumour necrosis factor-α. The effect of naringenin on AR was achieved by regulating multiple targets (e.g. AKT1, MAPK3, VEGFA) and pathways (e.g. pathways in cancer, VEGF signalling pathway). Nine hub proteins were obtained by topological analysis. Multiple hydrogen bonds and van der Waals forces were formed between the naringenin and the residues of hub proteins. CONCLUSIONS: Naringenin might be one of the effective ingredients of AOK against AR. And its effects could achieve through regulating multiple targets and pathways.

Sevoflurane exposure may cause dysplasia of dendritic spines and result in fine motor dysfunction in developing mouse through the PI3K/AKT/mTOR pathway.

Sevoflurane has become one of the most widely used volatile anesthetics in pediatric surgery. However, sevoflurane exposure may interfere with dendritic development and synaptogenesis, resulting in brain function impairment. The PI3K/AKT/mTOR pathway plays an important role in dendritic development and synaptic plasticity. Here we investigated whether sevoflurane exposure would affect the morphological proportions of dendritic spines in developing mouse and explored the role of the change of plasticity of dendritic spines in sevoflurane-induced neurodevelopmental toxicity. The related signaling pathway was also examined. C57BL/6 mice at postnatal day (PND) 7 were exposed to 2% sevoflurane for 3 h. The PI3k/AKT/mTOR agonist IGF-1 or the mTOR phosphorylation inhibitor KU0063794 was intraperitoneally injected 30 min before sevoflurane or O2 exposure at PND7. Hippocampi were harvested 6 h after sevoflurane exposure. Western blotting was applied to measure the protein expression of PI3K/AKT/mTOR pathway phosphorylation. At PND14, brains from all groups were harvested for Golgi staining, and the morphology of dendritic spines of hippocampal neurons was observed by an oil immersion lens. When the mice grew to adolescence (PND48), fine motor function was measured by the Beam walking test. Here we showed that exposure to 2% sevoflurane for 3 h decreased the proportion of thin dendritic spines and increased the proportion of mushroom dendritic spines, but not changed the density of the dendritic spines. Sevoflurane exposure also suppressed the phosphorylation of the PI3K/AKT/mTOR pathway in immature mice hippocampi, and eventually led to long-term fine motor dysfunction. Meanwhile, IGF-1 pretreatment could rescue and KU0063794 pretreatment could aggravate the impairment induced by sevoflurane. In conclusion, sevoflurane exposure may cause a change of proportions of the types of dendritic spines through impacting the phosphorylation expression of the PI3K/AKT/mTOR pathway, and eventually led to long-term fine motor dysfunction in developing mouse.

Identification of Potential miRNA-mRNA Regulatory Network Contributing to Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease, and the mechanism underlying PD pathogenesis is not completely understood. Increasing evidence indicates that microRNAs (miRNAs) play a critical regulatory role in the pathogenesis of PD. This study aimed to explore the miRNA-mRNA regulatory network for PD. The differentially expressed miRNAs (DEmis) and genes (DEGs) between PD patients and healthy donors were screened from the miRNA dataset GSE16658 and mRNA dataset GSE100054 downloaded from the Gene Expression Omnibus (GEO) database. Target genes of the DEmis were selected when they were predicted by three or four online databases and overlapped with DEGs from GSE100054. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then conducted by Database for Annotation, Visualization and Integrated Discovery (DAVID) and Metascape analytic tools. The correlation between the screened genes and PD was evaluated with the online tool Comparative Toxicogenomics Database (CTD), and protein-protein interaction (PPI) networks were built by the STRING platform. We further investigated the expression of genes in the miRNA-mRNA regulatory network in blood samples collected from PD patients and healthy donors via qRT-PCR. We identified 1505 upregulated and 1302 downregulated DEGs, and 77 upregulated and 112 downregulated DEmis were preliminarily screened from the GEO database. Further functional enrichment analysis identified 10 PD-related hub genes, including RAC1, IRS2, LEPR, PPARGC1A, CAMKK2, RAB10, RAB13, RAB27B, RAB11A, and JAK2, which were mainly involved in Rab protein signaling transduction, AMPK signaling pathway, and signaling by Leptin. A miRNA-mRNA regulatory network was then constructed with 10 hub genes, and their interacting miRNAs overlapped with DEmis, including miR-30e-5p, miR-142-3p, miR-101-3p, miR-32-3p, miR-508-5p, miR-642a-5p, miR-19a-3p, and miR-21-5p. Analysis of clinical samples verified significant upregulation of LEPR and downregulation of miR-101-3p and miR-30e-5p in PD patients as compared with healthy donors. Thus, the miRNA-mRNA regulatory network was initially constructed and has the potential to provide novel insights into the pathogenesis and treatment of PD.

Needs and views on healthy lifestyles for the prevention of dementia and the potential role for mobile health (mHealth) interventions in China: a qualitative study.

OBJECTIVES: Over the coming decades, China is expected to face the largest worldwide increase in dementia incidence. Mobile health (mHealth) may improve the accessibility of dementia prevention strategies, targeting lifestyle-related risk factors. Our aim is to explore the needs and views of Chinese older adults regarding healthy lifestyles to prevent cardiovascular disease (CVD) and dementia through mHealth, supporting the Prevention of Dementia using Mobile Phone Applications (PRODEMOS) study. DESIGN: Qualitative semi-structured interview study, using thematic analysis. SETTING: Primary and secondary care in Beijing and Tai'an, China. PARTICIPANTS: Older adults aged 55 and over without dementia with an increased dementia risk, possessing a smartphone. Participants were recruited through seven hospitals participating in the PRODEMOS study, purposively sampled on age, sex, living area and history of CVD and diabetes. RESULTS: We performed 26 interviews with participants aged 55-86 years. Three main themes were identified: valuing a healthy lifestyle, sociocultural expectations and need for guidance. First, following a healthy lifestyle was generally deemed important. In addition to generic healthy behaviours, participants regarded certain specific Chinese lifestyle practices as important to prevent disease. Second, the sociocultural context played a crucial role, as an important motive to avoid disease was to limit the care burden put on family members. However, time-consuming family obligations and other social values could also impede healthy behaviours such as regular physical activity. Finally, there seemed to be a need for reliable and personalised lifestyle advice and for guidance from a health professional. CONCLUSIONS: The Chinese older adults included in this study highly value a healthy lifestyle. They express a need for personalised lifestyle support in order to adopt healthy behaviours. Potentially, the PRODEMOS mHealth intervention can meet these needs through blended lifestyle support to improve risk factors for dementia and CVD. TRIAL REGISTRATION NUMBER: ISRCTN15986016; Pre-results.

Prevention of dementia using mobile phone applications (PRODEMOS): protocol for an international randomised controlled trial.

INTRODUCTION: Profiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%-40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk. METHODS AND ANALYSIS: The prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness-implementation hybrid design, taking place in the UK and China. People are eligible if they are 55-75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention. ETHICS AND DISSEMINATION: The PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London-Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People's Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN15986016.

Cognitive stimulation therapy in the treatment of neuropsychiatric symptoms in Alzheimer's disease: a randomized controlled trial.

OBJECTIVE: to determine the efficacy of cognitive stimulation therapy (CST) in the treatment of neuropsychiatric symptoms in patients with Alzheimer's disease. DESIGN: a randomized, controlled, rater-blind clinical trial. SETTING: the military sanatorium. SUBJECTS: thirty-two patients with mild to moderate Alzheimer's disease exhibiting marked neuropsychiatric symptoms were included in the study. INTERVENTION: all 32 patients were randomly assigned to a cognitive stimulation therapy group (n = 16) or a control group (n = 16) for 10 weeks. MAIN MEASURE: the efficacy measures included the Mini Mental State Examination and the Neuropsychiatric Inventory. RESULTS: patients receiving cognitive stimulation therapy showed a greater improvement in the Neuropsychiatric Inventory total score (mean change - 2.06 points versus 0.00 points, t = -4.766, P<0.001) and in the Mini Mental State Examination total score (mean change 0.81 points versus -0.19 points, t =3.106, P =0.004) compared to control at week 10. Analysis of the individual Neuropsychiatric Inventory domains revealed a statistically significant benefit for cognitive stimulation therapy-treated patients in the areas of apathy (mean change -1.06 points versus -0.31 points, P =0.017) and depression/dysphoria (mean change -0.50 points versus 0.06 points, P =0.047). There were no statistically significant benefits for cognitive stimulation therapy-treated patients in the other individual Neuropsychiatric Inventory domains or in the caregiver distress score. CONCLUSIONS: cognitive stimulation therapy has significant efficacy in lowering apathy and depression symptomatology and in the Mini Mental State Examination in patients with mild to moderate Alzheimer's disease.

Ethno-medicinal study of Artemisia ordosica Krasch. (traditional Chinese/Mongolian medicine) extracts for the treatment of allergic rhinitis and nasosinusitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia ordosica Krasch. (AOK) has been used for rheumatic arthritis, cold headache, sore throat, etc. in traditional Chinese/Mongolian medicine and is used for nasosinusitis by local Mongolian "barefoot" doctors. Up to now, their mechanisms are still unclear. AIM: To evaluate the in vivo anti-inflammatory and allergic rhinitis (AR) alleviating effect as well as in vitro antimicrobial activities of AOK extracts to verify its ethno-medicinal claims. MATERIALS AND METHODS: Crude extracts (methanol/95%-ethanol/ethyl acetate) of AOK root/stem/leaf and fractions (petroleum ether/ethyl acetate/n-butanol/aqueous) of AOK root extract were prepared. Xylene-induced ear swelling model in mouse and ovalbumin (OVA)-induced AR model in guinea pig were established. Ear swelling degrees of mice were measured. The numbers of rubbing movement and sneezes of guinea pigs were counted to evaluate the symptoms of AR. The serum levels of histamine, INF-γ, IL-2/4/10, and VCAM-1 were measured by ELISA assay. The histological changes of nasal mucosa were investigated by light microscope after H&E staining. Antimicrobial activities of AOK extracts were also tested. LC-MS/MS analysis was performed to characterize the constituents of active extract and molecular docking was conducted to predict the biological mechanism. RESULTS: In ear-swelling model, extract (100.00 mg/kg) from the ethyl acetate layer of 95% ethanol (100.00 mg/kg) showed better swelling inhibition in mice than positive control (dexamethasone, 191.91 mg/kg). In AR model, extract from the ethyl acetate layer of 95% ethanol significantly alleviated the AR symptoms in guinea pigs, decreased the serum levels of histamine, INF-γ, IL-2/4/10, and VCAM-1, and reduced the infiltration of eosinophil in nasal mucosa. For Staphylococcus aureus, the ethyl acetate extract of AOK stem showed the highest inhibition (MIC=1.25 mg/mL), for Escherichia coli, n-butanol layer of 95% ethanol extract of AOK root showed the highest inhibition (MIC=15.00 mg/mL), for Candida glabrata, 95%-ethyl acetate extract of AOK leaf showed the best inhibition (MIC=0.064 mg/mL), while ethyl acetate and n-butanol layers showed similar inhibition on MRSA (MIC=7.50 mg/mL). LC-MS/MS characterization showed that dicaffeoylquinic acids account for more than 30% of ethyl acetate layer of AOK extract. Dicaffeoylquinic acids bind with histamine-1 receptor with high affinities and interesting modes. CONCLUSIONS: Extracts from AOK had interesting anti-inflammatory activity in mice, alleviating effect against OVA-induced AR in guinea pigs, and antimicrobial activities in vitro, which support the ethno-medicinal use of it. The main constituents in ethyl acetate layer of AOK root extract are dicaffeoylquinic acids and could bind with histamine-1 receptor well. These findings highlighted the importance of natural product chemistry study of AOK.

Comparison of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular outcomes in hypertensive patients with type 2 diabetes mellitus: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Previous studies seem to show different effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on cardiovascular (CV) events in hypertensive patients with type 2 diabetes mellitus (T2DM). Our objective was to analyze which are preferable on the incidence of all-cause mortality, CV death, and major CV events in hypertensive patients with T2DM. METHODS: PubMed, MEDLINE, and EMBASE were searched for randomized controlled trials (RCTs) published up to June 2016 with ACEI or ARBs as the intervention for hypertensive patients with T2DM. The primary end points were all-cause mortality and CV death. The secondary end points were myocardial infarction (MI), stroke, heart failure (HF), and CV events. Two investigators extracted the information independently. Data were pooled using a fixed-effects model or a random-effects model if significant heterogeneity was present. RESULTS: A total of 13 trials were included for analysis, 5 ACEI trials (24,976 patients) and 8 ARB trials (22,032 patients) followed for a mean of 3.8 years. Treatment with ACEI was associated with significantly reduction in all-cause mortality [odds ratio (OR) 0.87; 95% confidence interval (95% CI), 0.80-0.94], CV death (OR 0.81; 95% CI, 0.68-0.98), and other CV outcomes such as MI (0R 0.77; 95% CI, 0.66-0.90), stroke (OR 0.88; 95% CI, 0.78-0.99), HF (OR 0.65; 95% CI, 0.47-0.90), and CV events (OR 0.83; 95% CI, 0.73-0.95), whereas ARBs therapy had no significant reduction in the results of many primary and secondary outcomes. CONCLUSION: This meta-analysis suggests that treatment with ACEI showed a significant CV protection for all-cause mortality, CV death, and major CV events, whereas ARBs had no benefits on these outcomes except MI. In consideration of high mortality and morbidity, ACEI was preferable than ARBs on patients with hypertension and T2DM.

Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1.

Impaired hippocampal neurogenesis and neuroinflammation are involved in the pathogenesis of radiation-induced brain injury. Kukoamine A (KuA) was demonstrated to have neuroprotective effects through inhibiting oxidative stress and apoptosis after whole-brain irradiation (WBI) in rats. The aim of this study was to investigate whether administration of KuA would prevent radiation-induced neuroinflammation and the detrimental effect on hippocampal neurogenesis. For this study, male Wistar rats received either sham irradiation or WBI (30 Gy single dose of X-rays) followed by the immediate injection of either KuA or vehicle intravenously. The dose of KuA was 5, 10, and 20 mg/kg, respectively. The levels of pro-inflammatory cytokines were assayed by ELISA kits. The newborn neurons were detected by 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclei (NeuN) double immunofluorescence. Microglial activation was measured by Iba-1 immunofluorescence. The expression of Cox-2 and the activation of nuclear factor κB (NF-κB), activating protein 1(AP-1), and PPARδ were evaluated by western blot. WBI led to a significant increase in the level of TNF-α, IL-1ß, and Cox-2, and it was alleviated by KuA administration. KuA attenuated microglial activation in rat hippocampus after WBI. Neurogenesis impairment induced by WBI was ameliorated by KuA. Additionally, KuA alleviated the increased translocation of NF-κB p65 subunit and phosphorylation of c-jun induced by WBI and elevated the expression of PPARδ. These data indicate that KuA could ameliorate the neuroinflammatory response and protect neurogenesis after WBI, partially through regulating the activation of NF-κB, AP-1, and PPARδ.

Neuroprotective effects of Kukoamine B against hydrogen peroxide-induced apoptosis and potential mechanisms in SH-SY5Y cells.

Oxidative stress mediates the cell damage in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease (AD) and Parkinson's disease (PD). This study aimed at investigating the protective effects of Kukoamine B (KuB) against hydrogen peroxide (H2O2) induced cell injury and potential mechanisms in SH-SY5Y cells. Our results revealed that treatment with KuB prior to H2O2 exposure effectively increased the cell viability, and restored the mitochondria membrane potential (MMP). Furthermore, KuB enhanced the antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and decreased the malondialdehyde (MDA) content. Moreover, KuB minimized the ROS formation and inhibited mitochondria-apoptotic pathway, MAPKs (p-p38, p-JNK, p-ERK) pathways, but activated PI3K-AKT pathway. In conclusion, we believed that KuB may potentially serve as an agent for prevention of several human neurodegenerative and other disorders caused by oxidative stress.