Zinc(II)-Quinoline module and ROS cleavable crosslinker functionalized self-fluorescent siRNA vectors for selective gene silencing of cancer cells.

A highly efficient siRNA vector (Zn-PQD) capable of selectively silencing genes in cancer cells was obtained by using ROS-cleavable DED to crosslink low molecular weight (LMW) polyethylene imine (PEI) modified by self-fluorescent metal coordinatied multifunctional module Zn-QS. Under the combined action of DED cross-linking and Zn-QS modification, Zn-PQD performs well in the siRNA delivery process in cancer cells, including siRNA condensation, cell uptake, endosome escape, and siRNA release. Zn-PQD exhibited higher transfection efficiency than commercial PEI25k and Lipo2k in multiple cancer cell lines including HepG2, HeLa, 4 T1, H520 and PANC-1, as well as cancer treatment-related stem cell rADSC. Ultimately, Zn-PQD can achieve extremely high and selective gene silencing effects in cancer cells (with a gene silencing rate of 98.3% in HepG2). This work is expected to provide an efficient and safe siRNA carrier for the future tumor siRNA therapy and its study of fluorescence mediated mechanism.

Tet1 peptide and zinc (II)-adenine multifunctional module functionalized polycations as efficient siRNA carriers for Parkinson's disease.

A bioreducible Zn (II)-adenine multifunctional module (BS) and Tet1 peptide were used to modify low-molecular-weight PEI3.5k (polyethyleneimine with molecular weight of 3.5 kDa)into a siRNA vector Zn-PB-T with high transfection efficiency in neurons. A GSH-responsive breakable disulfide spacer was introduced into BS to realize the controlled release of siRNA from the polyplexes in cytoplasm. Zn-PB showed >90% transfection rates in multiple cell lines (3 T3, HK-2, HepG2, 293 T, HeLa, PANC-1)，and 1.8-folds higher EGFP knockdown rates than commercial Lipo2k in normal cell line 293 T and cancer cell line HepG2. And Zn-PB-T1 showed 4.7-4.9- and 8.0-8.1-folds higher transfection efficiency comparing to commercial Lipo2k and PEI25k (polyethyleneimine with molecular weight of 25 kDa) in PC12 cells respectively, 2.1-fold EGFP gene silencing efficiency (96.6% EGFP knockdown rates) superior to commercial Lipo2k in neurons. In Parkinson's model, Zn-PB-T1/SNCA-siRNA can effectively protect neurons against MPP+-induced cell death and apoptosis, increasing the cell survival rate to 84.6% and reducing the cell apoptosis rate to 10.8%. This work demonstrated the promising application prospects of the resulting efficient siRNA carriers in siRNA-mediated gene therapy of Parkinson's disease.

High-intensity interval training improves cognitive impairment of vascular dementia rats by up-regulating expression of brain-derived neurotrophic factor in the hippocampus.

The present study aims to investigate the effect and its potential mechanism of high-intensity intermittent training (HIIT) on cognitive function in vascular dementia (VD) rats. The VD rats with the cognitive impairment were induced by bilateral common carotid artery occlusion (BCCAO), and the ones in the moderate-intensity continuous training (MICT) group and HIIT group received MICT or HIIT for 5 consecutive weeks, respectively. The swimming speed, endurance, and grip strength of rats were all measured after training. The effect and mechanisms of HIIT on ameliorating the cognitive dysfunction were further evaluated by the Morris water maze test, histomorphological analysis, and Western blot analysis. As a result, no significant difference in motor function between VD rats and sham rats was observed. After 5-week HIIT, the motor function of VD rats was significantly enhanced. The results of the Morris water maze test revealed that HIIT significantly reduced escape latency as well as distance to find the platform compared with the sedentary control group (SED group), indicating the improvement in cognitive function. In addition, the hippocampal tissue damage of VD rats measured by H&E staining was markedly ameliorated after 5-week HIIT. Moreover, brain-derived neurotrophic factor (BDNF) expression level in the cerebral cortex and hippocampus tissue detected by Western blot were significantly up-regulated in HIIT group compared to SED group and MICT group. In conclusion, HIIT can improve BCCAO-induced cognitive impairment via up-regulating BDNF expression in VD rats.

Relationship between glycemic control and cognitive impairment: A systematic review and meta-analysis.

Background: Diabetes mellitus, or hyperglycemia, is an independent risk factor for cognitive impairment. Here we systematically analyzed whether glycemic control could improve cognitive impairment in patients with diabetes mellitus (DM), hyperglycemia, or insulin resistance. Methods: Three databases (PubMed, EMBASE, and Cochrane Library) and ClinicalTrials.gov were searched for randomized controlled trials analyzing the relationship between glycemic control and cognitive function assessments, published from database inception to June 2022. Patients in experimental groups were treated with antidiabetic drugs, while control groups were treated with a placebo or alternative antidiabetic drugs. Data analysis was conducted using RevMan 5.3 and StataSE-64, and standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated. Results: Thirteen studies comprising 19,314 participants were included. Analysis revealed that glycemic control significantly attenuated the degree of decline in cognitive function assessment scores (SMD = 0.15; 95% CI 0.05, 0.26; p < 0.00001), and funnel plots confirmed no publication bias. Seven studies used Mini-Mental State Examination as the primary cognitive function assessment, showing that glycemic control significantly delayed the degree of decline in cognitive function assessment scores (SMD = 0.18; 95% CI 0.03, 0.34; p = 0.02). Similar results were seen in two studies using the Montreal Cognitive Assessment scale, but without significant difference (SMD = 0.05; 95% CI-0.10, 0.21; p = 0.51). One study using Auditory Word Learning Test (AVLT) showed that glycemic control significantly delayed the decline in cognitive function assessment scores (SMD = 0.52; 95% CI 0.11,0.93; p = 0.01), and another used Wechsler Memory Scale Revised, showing similar results (SMD = 1.45; 95% CI 0.86, 2.04; p < 0.00001). Likewise, a study that used Modified Mini-Mental State scale showed that glycemic control significantly delayed the decline in cognitive function assessment scores (SMD = -0.10; 95% CI-0.16, -0.03; p = 0.005). Lastly, one study used AVLT subtests to show that glycemic control delayed the decline in cognitive function assessment scores, although not statistically significant (SMD = 0.09; 95% CI-0.53, 0.71; p = 0.78). Conclusion: Glycemic control through antidiabetic treatment correlates with the improvement of cognitive impairment in patients with DM, hyperglycemia or insulin resistance. However, further studies are needed to validate the results of this study. Systematic Review Registration: PROSPERO, identifier CRD42022342260.

Alterations of Brain Networks in Alzheimer's Disease and Mild Cognitive Impairment: A Resting State fMRI Study Based on a Population-specific Brain Template.

This study aimed to investigate the alterations in brain networks in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) based on a population-specific brain template. Previous studies on AD brain networks using graph theory rarely adopted brain templates specific for certain ethnicities. In this study, patients were divided into 3 groups: AD (n = 24), MCI (n = 27), and healthy controls (HCs, n = 33), and all of the subjects are Chinese. Functional brain networks were constructed for each group based on a Chinese brain template using resting-state functional magnetic resonance imaging (rs-fMRI) data; several graph metrics were calculated. Graph metrics with significant differences after false discovery rate (FDR) correction were analyzed with respect to correlations with four neuropsychological test scores: Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL), and Clinical Dementia Rating (CDR), which assessed the subjects' cognitive functions and ability to engage in ADL. Graph metrics including assortativity coefficient, nodal degree centrality, nodal clustering coefficient, nodal efficiency, and nodal local efficiency of the frontal gyrus and cerebellum were significantly altered in AD and MCI compared with HC. Several graph metrics were significantly correlated with cognitive function and the ability to engage in daily activities. The findings suggest that altered graph metrics in the frontal gyrus may reflect brain plasticity, and that patients with MCI may have unique graph metric alterations in the cerebellum. Future graph analysis studies on functional brain networks in AD and MCI based on population-specific brain atlases for particular ethnicities may prove valuable.

Dysregulation of Respiratory Center Drive (P0.1) and Muscle Strength in Patients With Early Stage Idiopathic Parkinson's Disease.

Objective: The goal of this study is to evaluate pulmonary function and respiratory center drive in patients with early-stage idiopathic Parkinson's disease (IPD) to facilitate early diagnosis of Parkinson's Disease (PD). Methods: 43 IPD patients (Hoehn and Yahr scale of 1) and 41 matched healthy individuals (e.g., age, sex, height, weight, BMI) were enrolled in this study. Motor status was evaluated using the Movement Disorders Society-Unified PD Rating Scale (MDS-UPDRS). Pulmonary function and respiratory center drive were measured using pulmonary function tests (PFT). All IPD patients were also subjected to a series of neuropsychological tests, including Non-Motor Symptoms Questionnaire (NMSQ), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Beck Depression Inventory (BDI) and Mini Mental State Examination (MMSE). Results: IPD patients and healthy individuals have similar forced vital capacity (FVC), forced expiratory volume in 1s (FEV1), forced expiratory volume in 1s/forced vital capacity (FEV1/FVC), peak expiratory flow (PEF), and carbon monoxide diffusion capacity (DLCOcSB). Reduced respiratory muscle strength, maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) was seen in IPD patients (p = 0.000 and p = 0.002, respectively). Importantly, the airway occlusion pressure after 0.1 s (P0.1) and respiratory center output were notably higher in IPD patients (p = 0.000) with a remarkable separation of measured values compared to healthy controls. Conclusion: Our findings suggest that abnormal pulmonary function is present in early stage IPD patients as evidenced by significant changes in PImax, PEmax, and P0.1. Most importantly, P0.1 may have the potential to assist with the identification of IPD in the early stage.

Corrigendum: Evaluation of Metformin on Cognitive Improvement in Patients With Non-dementia Vascular Cognitive Impairment and Abnormal Glucose Metabolism.

[This corrects the article DOI: 10.3389/fnagi.2018.00227.].

Evaluation of Metformin on Cognitive Improvement in Patients With Non-dementia Vascular Cognitive Impairment and Abnormal Glucose Metabolism.

Objective: Recent studies have suggested that metformin can penetrate the blood-brain barrier, protecting neurons via anti-inflammatory action and improvement of brain energy metabolism. In this study, we aim to investigate the effect of metformin on cognitive function in patients with abnormal glucose metabolism and non-dementia vascular cognitive impairment (NDVCI). Methods: One hundred patients with NDVCI and abnormal glucose metabolism were randomly allocated into two groups: metformin and donepezil (n = 50) or acarbose and donepezil (n = 50). The neuropsychological status, glucose metabolism, and common carotid arteries intima-media thickness (CCA-IMT) before and after a year of treatment, were measured and compared between the groups. Results: Ninety four patients completed all the assessment and follow-up. After a year of treatment, there was a decrease in Alzheimer's disease Assessment Scale-Cognitive Subscale scores and the duration of the Trail Making Test in the metformin-donepezil group. Furthermore, these patients showed a significant increase in World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test scores after treatment (all P < 0.05). However, there was no obvious improvement in cognitive function in the acarbose-donepezil group. We also observed a significant decrease in the level of fasting insulin and insulin resistance (IR) index in the metformin-donepezil group, with a lower CCA-IMT value than that in the acarbose-donepezil group after a year of treatment (P < 0.05). Conclusion: We conclude that metformin can improve cognitive function in patients with NDVCI and abnormal glucose metabolism, especially in terms of performance function. Improved cognitive function may be related to improvement of IR and the attenuated progression of IMT. Trial Registration: ChiCTR-IPR-17011855.