Facile Synthesis of Quinoline-Substituted 3-Hydroxy-2-oxindoles and 3-Amino-2-oxindoles via a Palladium-Catalyzed Cascade Intramolecular Cyclization/Intermolecular Nucleophilic Addition Reaction.

An efficient cascade intramolecular cyclization/intermolecular nucleophilic addition reaction of allenyl benzoxazinone with isatin or isatin-derived ketimine has been established by using Pd0-π-Lewis base catalysis. A series of 3-hydroxy-2-oxindoles and 3-amino-2-oxindoles with quaternary carbon atoms at the C3 position were synthesized in good yields under mild conditions through this protocol.

The Association Between Dietary Magnesium Intake with Chronic Obstructive Pulmonary Disease and Lung Function in US Population: a Cross-sectional Study.

Chronic obstructive pulmonary disease (COPD) is now considered among the top three contributors to mortality globally. There is limited understanding surrounding the contribution of magnesium to the progression of COPD. This survey aims to evaluate the connection between dietary magnesium intake and both lung function and COPD prevalence among the US population. The research comprised 4865 participants in the National Health and Nutrition Examination Survey (NHANES) program conducted from 2007 to 2012. To evaluate the association between dietary magnesium intake and lung function as well as COPD, the study conducted multiple regression analyses, stratified analyses, and smoothed curves. In this study, we explored the relationship between higher magnesium intake and higher FEV1 [ß = 0.21 (95% CI 0.12, 0.30)] and FVC [ß = 0.25 (95% CI 0.14, 0.36)] after accounting for all potential confounding factors. We demonstrated a relationship between increased magnesium intake and reduced odds of developing COPD [OR = 0.9993 (95% CI 0.9987, 1.0000)]. The results of stratified analyses further indicated that the relationship between magnesium intake and the risk of COPD is more pronounced in the 40-60 age group and males. The study demonstrated positive associations between the intake of dietary magnesium and both FEV1 and FVC. Additionally, an adverse relationship between magnesium intake and the prevalence of COPD was also observed, suggesting that supplementation with magnesium may be a practical approach to preventing and managing COPD.

Electroacupuncture promotes neurogenesis in the dentate gyrus and improves pattern separation in an early Alzheimer's disease mouse model.

BACKGROUND: Impaired pattern separation occurs in the early stage of Alzheimer's disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memory discrimination impairment can be improved by promoting the hippocampal DG granule cell neogenesis-mediated pattern separation in the early stage of AD by electroacupuncture (EA). METHODS: Five familial AD mutations (5 × FAD) mice received EA treatment at Baihui and Shenting points for 4 weeks. During EA, mice were intraperitoneally injected with BrdU (50 mg/kg) twice a day. rAAV containing Wnt5a shRNA was injected into the bilateral DG region, and the viral efficiency was evaluated by detecting Wnt5a mRNA levels. Cognitive behavior tests were conducted to assess the impact of EA treatment on cognitive function. The hippocampal DG area Aß deposition level was detected by immunohistochemistry after the intervention; The number of BrdU+/CaR+ cells and the gene expression level of calretinin (CaR) and prospero homeobox 1(Prox1) in the DG area of the hippocampus was detected to assess neurogenesis by immunofluorescence and western blotting after the intervention; The gene expression levels of FZD2, Wnt5a, DVL2, p-DVL2, CaMKII, and p-CaMKII in the Wnt signaling pathway were detected by Western blotting after the intervention. RESULTS: Cognitive behavioral tests showed that 5 × FAD mice had impaired pattern separation (P < 0.001), which could be improved by EA (P < 0.01). Immunofluorescence and Western blot showed that the expression of Wnt5a in the hippocampus was decreased (P < 0.001), and the neurogenesis in the DG was impaired (P < 0.001) in 5 × FAD mice. EA could increase the expression level of Wnt5a (P < 0.05) and promote the neurogenesis of immature granule cells (P < 0.05) and the development of neuronal dendritic spines (P < 0.05). Interference of Wnt5a expression aggravated the damage of neurogenesis (P < 0.05), weakened the memory discrimination ability (P < 0.05), and inhibited the beneficial effect of EA (P < 0.05) in AD mice. The expression level of Wnt pathway related proteins such as FZD2, DVL2, p-DVL2, CAMKII, p-CAMKII increased after EA, but the effect of EA was inhibited after Wnt5a was knocked down. In addition, EA could reduce the deposition of Aß plaques in the DG without any impact on Wnt5a. CONCLUSION: EA can promote hippocampal DG immature granule cell neogenesis-mediated pattern separation to improve spatial memory discrimination impairment by regulating Wnt5a in 5 × FAD mice.

Overexpression of miR-124 in astrocyte improves neurological deficits in rat with ischemic stroke via DLL4 modulation.

BACKGROUND: Astrocytes have been demonstrated to undergo conversion into functional neurons, presenting a promising approach for stroke treatment. However, the development of small molecules capable of effectively inducing this cellular reprogramming remains a critical challenge. METHODS: Initially, we introduced a glial cell marker gene, GFaABC1D, as the promoter within an adeno-associated virus vector overexpressing miR-124 into the motor cortex of an ischemia-reperfusion model in rats. Additionally, we administered NeuroD1 as a positive control. Lentiviral vectors overexpressing miR-124 were constructed and transfected into primary rat astrocytes. We assessed the cellular distribution of GFAP, DCX, and NeuN on days 7, 14, and 28, respectively. RESULTS: In rats with ischemic stroke, miR-124-transduced glial cells exhibited positive staining for the immature neuron marker doublecortin (DCX) and the mature neuron marker NeuN after 4 weeks. In contrast, NeuroD1-overexpressing model rats only expressed NeuN, and the positive percentage was higher in co-transfection with miR-124 and NeuroD1. Overexpression of miR-124 effectively ameliorated neurological deficits and motor functional impairment in the model rats. In primary rat astrocytes transduced with miR-124, DCX was not observed after 7 days of transfection, but it appeared at 14 days, with the percentage further increasing to 44.6% at 28 days. Simultaneously, 15.1% of miR-124-transduced cells exhibited NeuN positivity, which was not detected at 7 and 14 days. In vitro, double fluorescence assays revealed that miR-124 targeted Dll4, and in vivo experiments confirmed that miR-124 inhibited the expression of Notch1 and DLL4. CONCLUSIONS: The overexpression of miR-124 in astrocytes demonstrates significant potential for improving neurological deficits following ischemic stroke by inhibiting DLL4 expression, and it may facilitate astrocyte-to-neuronal transformation.

Effects of Exercise Training Under Hypoxia versus Normoxia on Cognitive Function in Clinical and Non-Clinical Populations: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare the effects of exercise training under hypoxia versus normoxia on cognitive function in clinical and non-clinical populations. DATA SOURCES: From inception to June 13th, 2022, a systematic search was performed on PubMed, Web of Science, Embase, Scopus, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Randomized controlled trials comparing the effects of exercise under hypoxic vs normoxic on cognition in clinical and non-clinical populations were included. The systematic search generated 14,894 relevant studies, of which 12 were finally included. DATA EXTRACTION: Two reviewers independently extracted data from included studies. Results were expressed as standardized mean difference (SMD). Each included study was assessed using the Cochrane Risk of Bias 1.0 (RoB1.0) tool. Finally, the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to rate the certainty of evidence for each outcome. DATA SYNTHESIS: Overall, 12 studies with a total of 338 participants met the inclusion criteria. The pooled results suggested that hypoxia exercise had a small but not statistically significant positive effect on overall cognitive function (SMD=0.064, 95% confidence interval (CI): -0.156-0.284, P=.567, very low-certainty evidence), when compared with normoxic exercise. Regarding the domain-specific cognitive functions, there was a medium and significant positive effect on memory (SMD=0.594, 95% CI: 0.068 to 1.120, P=.027, very low-certainty evidence), while effects on visuospatial function (SMD=0.490, 95% CI: -0.030 to 1.010, P=.065, very low-certainty evidence), attention (SMD=0.037, 95% CI: -0.340 to 0.414, P=.847, very low-certainty evidence), executive function (SMD=0.096, 95% CI: -0.268 to 0.460, P=.605, very low-certainty evidence), and processing speed (SMD=-0.145, 95% CI: -0.528 to 0.239, P=.459, very low-certainty evidence) were not statistically significant. CONCLUSIONS: The current pooled results revealed that hypoxic exercise was related to improved cognitive performance. Nevertheless, exercise under hypoxia did not have a significant advantage in cognitive promotion when compared with exercise under normoxia.

Efficacy and safety of acupuncture combined with rehabilitation training for poststroke cognitive impairment: A systematic review and meta-analysis.

BACKGROUND: Accumulated evidence has proven that both acupuncture and rehabilitation therapy are beneficial for stroke sequelae. However, there is no systematic review to identify the efficacy and safety of acupuncture combined with rehabilitation training for poststroke cognitive impairment (PSCI). Therefore, the aim of this study was to assess the efficacy and safety of acupuncture combined with rehabilitation therapy for patients with PSCI. METHODS: We searched nine databases, including PubMed, Embase, Scopus, Web of Science, EBSCO, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wan Fang, from their inception to September 2022. Randomized controlled trials (RCTs) examining the effect of acupuncture combined with rehabilitation on PSCI were included. The primary outcomes were the Mini-Mental State Examination (MMSE) score, Montreal Cognitive Assessment (MoCA) score, Modified Barthel Index (MBI) score, and Fugl-Meyer Assessment (FMA) score. The quality of the methodology was evaluated by Cochrane's risk of bias tool. Meta-analyses were performed by Revman 5.3 software. RESULTS: A total of 18 RCTs involving 1654 patients were included. The overall methodological quality of the included studies was low. Pooled results demonstrated that acupuncture combined with rehabilitation could significantly improve the clinical efficacy of PSCI (OR=3.23, 95% CI: 2.13 to 4.89), MMSE score (MD= 2.85, 95% CI: 2.56 to 3.15), MoCA score (MD= 2.18, 95% CI: 1.38 to 2.97), MBI score (MD= 9.23, 95% CI: 5.62 to 12.84), and FMA score (MD=5.72, 95% CI: 3.48 to 7.96). CONCLUSIONS: Acupuncture combined with rehabilitation may produce better outcomes than rehabilitation alone in the treatment of PSCI. However, the safety of combined interventions is still unclear. Therefore, research with more rigorous study designs and RCTs with larger sample sizes is still needed.

Electroacupuncture protective effects after cerebral ischemia are mediated through miR-219a inhibition.

BACKGROUND: Electroacupuncture (EA) is a complementary and alternative therapy which has shown protective effects on vascular cognitive impairment (VCI). However, the underlying mechanisms are not entirely understood. METHODS: Rat models of VCI were established with cerebral ischemia using occlusion of the middle cerebral artery or bilateral common carotid artery. The brain structure and function imaging were measured through animal MRI. miRNA expression was detected by chip and qPCR. Synaptic functional plasticity was detected using electrophysiological techniques. RESULTS: This study demonstrated the enhancement of Regional Homogeneity (ReHo) activity of blood oxygen level-dependent (BOLD) signal in the entorhinal cortical (EC) and hippocampus (HIP) in response to EA treatment. miR-219a was selected and confirmed to be elevated in HIP and EC in VCI but decreased after EA. N-methyl-D-aspartic acid receptor1 (NMDAR1) was identified as the target gene of miR-219a. miR-219a regulated NMDAR-mediated autaptic currents, spontaneous excitatory postsynaptic currents (sEPSC), and long-term potentiation (LTP) of the EC-HIP CA1 circuit influencing synaptic plasticity. EA was able to inhibit miR-219a, enhancing synaptic plasticity of the EC-HIP CA1 circuit and increasing expression of NMDAR1 while promoting the phosphorylation of downstream calcium/calmodulin-dependent protein kinase II (CaMKII), improving overall learning and memory in VCI rat models. CONCLUSION: Inhibition of miR-219a ameliorates VCI by regulating NMDAR-mediated synaptic plasticity in animal models of cerebral ischemia.

Effect of Multicomponent Exercise on Cognition, Physical Function and Activities of Daily Life in Older Adults With Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-analysis.

OBJECTIVE: To review the evidence for the effectiveness of multicomponent exercise (an exercise program combining aerobic, endurance, balance, and flexibility exercises) on cognition, physical function, and activities of daily living in people with dementia and mild cognitive impairment (MCI). DATA SOURCES AND STUDY SELECTION: We conducted this study under the guidance of a designated protocol (PROSPERO CRD42022324641). Pertinent randomized controlled trials were selected from PubMed, Embase, Web of Science, and the Cochrane Library by 2 independent authors through May 2022. DATA EXTRACTION: Two authors independently extracted the data and assessed the quality of the included studies following the Cochrane Risk of Bias tool. Outcome data were extracted in a random effects model and estimated as Hedges' g and 95% confidence interval (CI). To validate specific results, the Egger test combined the Duval and Tweedie "trim and fill" method and sensitivity analysis with study removed were performed. DATA SYNTHESIS: A total of 21 publications were eligible for the quantitative analysis. In dementia, estimates of Hedges' g showed effects on global cognition (g=0.403; 95% CI, 0.168-0.638; P<.05), especially executive function (g=0.344; 95% CI, 0.111-0.577; P<.05), flexibility (g=0.671; 95% CI, 0.353-0.989; P<.001), agility and mobility (g=0.402; 95% CI, 0.089-0.714; P<.05), muscle strength (g=1.132; 95% CI, 0.420-1.845; P<.05), and activities of daily living (g=0.402; 95% CI, 0.188-0.615; P<.05). Also, a positive trend was observed in gait speed. Additionally, multicomponent exercise had positive effects on global cognition (g=0.978; 95% CI, 0.298-1.659; P<.05) and executive function (g=0.448; 95% CI, 0.171-0.726; P<.05) in patients with MCI. CONCLUSIONS: Our findings confirm the viability of multicomponent exercise as a management strategy for patients with dementia and MCI.

Ischemic stroke rehabilitation through optogenetic modulation of parvalbumin neurons in the contralateral motor cortex.

BACKGROUND: Based on the theory of interhemispheric inhibition and the bimodal balance-recovery model in stroke, we explored the effects of excitation/inhibition (E/I) of parvalbumin (PV) neurons in the contralateral primary motor cortex (cM1) connecting the ipsilateral M1 (iM1) via the corpus callosum (cM1-CC-iM1) of ischemic stroke rats by optogenetic stimulation. METHODS: We tested this by injecting anterograde and retrograde virus in rats with middle cerebral artery occlusion (MCAO), and evaluated the neurological scores, motor behavior, volume of cerebral infarction and the E/I balance of the bilateral M1 two weeks after employing optogenetic treatment. RESULTS: We found that concentrations of Glu and GABA decreased and increased, respectively, in the iM1 of MCAO rats, and that the former increased in the cM1, suggesting E/I imbalance in bilateral M1 after ischemic stroke. Interestingly, optogenetic stimulation improved M1 E/I imbalance, as illustrated by the increase of Glu in the iM1 and the decrease of GABA in both iM1 and cM1, which were accompanied by an improvement in neurological deficit and motor dysfunction. In addition, we observed a reduced infarct volume, an increase in the expression of the NMDAR and AMPAR, and a decrease in GAD67 in the iM1 after intervention. CONCLUSIONS: Optogenetic modulation of PV neurons of the iM1-CC-cM1 improve E/I balance, leading to reduced neurological deficit and improved motor dysfunction following ischemic stroke in rats.

Neurogranin as an important regulator in swimming training to improve the spatial memory dysfunction of mice with chronic cerebral hypoperfusion.

BACKGROUND: Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) has become a hot issue worldwide. Aerobic exercise positively contributes to the preservation or restoration of cognitive abilities; however, the specific mechanism has remained inconclusive. And recent studies found that neurogranin (Ng) is a potential biomarker for cognitive impairment. This study aims to investigate the underlying role of Ng in swimming training to improve cognitive impairment. METHODS: To test this hypothesis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system was utilized to construct a strain of Ng conditional knockout (Ng cKO) mice, and bilateral common carotid artery stenosis (BCAS) surgery was performed to prepare the model. In Experiment 1, 2-month-old male and female transgenic mice were divided into a control group (wild-type littermate, n = 9) and a Ng cKO group (n = 9). Then, 2-month-old male and female C57BL/6 mice were divided into a sham group (C57BL/6, n = 12) and a BCAS group (n = 12). In Experiment 2, 2-month-old male and female mice were divided into a sham group (wild-type littermate, n = 12), BCAS group (n = 12), swim group (n = 12), BCAS + Ng cKO group (n = 12), and swim + Ng cKO group (n = 12). Then, 7 days after BCAS, mice were given swimming training for 5 weeks (1 week for adaptation and 4 weeks for training, 5 days a week, 60 min a day). After intervention, laser speckle was used to detect cerebral blood perfusion in the mice, and the T maze and Morris water maze were adopted to test their spatial memory. Furthermore, electrophysiology and Western blotting were conducted to record long-term potential and observe the expressions of Ca2+ pathway-related proteins, respectively. Immunohistochemistry was applied to analyze the expression of relevant markers in neuronal damage, inflammation, and white matter injury. RESULTS: The figures showed that spatial memory impairment was detected in Ng cKO mice, and a sharp decline of cerebral blood flow and an impairment of progressive spatial memory were observed in BCAS mice. Regular swimming training improved the spatial memory impairment of BCAS mice. This was achieved by preventing long-term potential damage and reversing the decline of Ca2+ signal transduction pathway-related proteins. At the same time, the results suggested that swimming also led to improvements in neuronal death, inflammation, and white matter injury induced by CCH. Further study adopted the use of Ng cKO transgenic mice, and the results indicated that the positive effects of swimming training on cognitive impairments, synaptic plasticity, and related pathological changes caused by CCH could be abolished by the knockout of Ng. CONCLUSION: Swimming training can mediate the expression of Ng to enhance hippocampal synaptic plasticity and improve related pathological changes induced by CCH, thereby ameliorating the spatial memory impairment of vascular cognitive impairment.

Palladium-Catalyzed Asymmetric Cascade Intramolecular Cyclization/Intermolecular Michael Addition Reaction of Allenyl Benzoxazinones with 1-Azadienes.

We herein designed and synthesized allenyl benzoxazinones of a novel type, which were then involved in a Pd-catalyzed asymmetric cascade intramolecular cyclization/intermolecular Michael addition reaction with 1-azadienes. A broad range of chiral C2-functionalized quinoline derivatives were afforded in moderate to good yields (up to 93%) with high enantioselectivities (up to 93% ee) in this reaction.

Electroacupuncture Increases the Hippocampal Synaptic Transmission Efficiency and Long-Term Plasticity to Improve Vascular Cognitive Impairment.

Studies have shown that electroacupuncture (EA) can effectively improve vascular cognitive impairment (VCI), but its mechanisms have not been clearly elucidated. This study is aimed at investigating the mechanisms underlying the effects of EA treatment on hippocampal synaptic transmission efficiency and plasticity in rats with VCI. Methods. Sprague-Dawley rats were subjected to VCI with bilateral common carotid occlusion (2VO). EA stimulation was applied to Baihui (GV20) and Shenting (GV24) acupoints for 30 min once a day, five times a week, for four weeks. Our study also included nonacupoint groups to confirm the specificity of EA therapy. The Morris water maze (MWM) was used to assess cognitive function. Electrophysiological techniques were used to detect the field characteristics of the hippocampal CA3-CA1 circuit in each group of rats, including input-output (I/O), paired-pulse facilitation ratios (PPR), field excitatory postsynaptic potential (fEPSP), and excitatory postsynaptic current (EPSC). The expression of synapse- and calcium-mediated signal transduction associated proteins was detected through western blotting. Results. The MWM behavioural results showed that EA significantly improved cognitive function in VCI model rats. EA increased the I/O curve of VCI model rats from 20 to 90 µA. No significant differences were observed in hippocampal PPR. The fEPSP of the hippocampal CA3-CA1 circuit was significantly increased after EA treatment compared with that after nonacupuncture treatment. We found that EA led to an increase in the EPSC amplitude and frequency, especially in the decay and rise times. In addition, the protein expression and phosphorylation levels of N-methyl-D-aspartate receptor 2B, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor 1, and Ca2+-calmodulin-dependent protein kinase II increased to varying degrees in the hippocampus of VCI model rats. Conclusion. EA at GV20 and GV24 acupoints increased the basic synaptic transmission efficiency and synaptic plasticity of the hippocampal CA3-CA1 circuit, thereby improving learning and memory ability in rats with VCI.

Effect of Physical Activity on Cognitive Impairment in Patients With Cerebrovascular Diseases: A Systematic Review and Meta-Analysis.

Background and Purpose: This study investigates the effect of physical activity (PA) on cognition in patients with cerebrovascular disease and explored the maximum benefit of different PA characteristics. Methods: Databases, such as Pubmed, Web of Science, Embase, and Cochrane Library, were searched from their inception to May 31, 2021. Standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated to generate a forest plot. In addition, subgroup analysis, moderation analysis, and regression analysis were performed to explore the possible adjustment factors. Results: In total, 22 studies that met the criteria were included, demonstrating data from 1,601 participants. The results indicated that PA produced a positive effect on the global cognition for patients with cerebrovascular disease (SMD: 0.20 [95% CI: 0.12-0.27]), at the same time, PA training prominently improved executive function (SMD: 0.09 [95% CI: 0.00-0.17]) and working memory (SMD: 0.25 [95% CI: 0.10-0.40]). Furthermore, patients with baseline cognitive impairment received the greater benefit of PA on cognition (SMD: 0.24 [95% CI: 0.14-0.34]) than those without cognitive impairment before intervention (SMD: 0.15 [95% CI: 0.04-0.26]). For patients in the acute stage (≤ 3 months), PA did not rescue impairment dysfunction significantly (SMD: 0.08 [95% CI: -0.04-0.21]) and remarkable cognitive gains were detected in the chronic stage of participants (>3 months) (SMD: 0.25 [95% CI: 0.16-0.35]). Moderate intensity PA showed a larger pooled effect size (SMD: 0.23 [95% CI: 0.11-0.36]) than low intensity (SMD: -0.01 [95% CI: -0.44-0.43]) and high intensity (SMD: 0.16 [95% CI: 0.03-0.29]). However, the different types, duration, and frequency of PA resulted in no differences in the improvement of cognitive function. Further regression analysis demonstrated that the beneficial effects of PA on cognition are negatively correlated with age (p < 0.05). Conclusions: This study revealed that PA can prominently improve the cognitive ability in patients with cerebrovascular diseases and strengthened the evidence that PA held promise as a widely accessible and effective non-drug therapy for vascular cognitive impairment (VCI).

Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer's disease: a meta-analysis and systematic review.

Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aß1-42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).

Enhanced Medial Prefrontal Cortex and Hippocampal Activity Improves Memory Generalization in APP/PS1 Mice: A Multimodal Animal MRI Study.

Memory generalization allows individuals to extend previously learned movement patterns to similar environments, contributing to cognitive flexibility. In Alzheimer's disease (AD), the disturbance of generalization is responsible for the deficits of episodic memory, causing patients with AD to forget or misplace things, even lose track of the way home. Cognitive training can effectively improve the cognition of patients with AD through changing thinking mode and memory flexibility. In this study, a T-shaped maze was utilized to simulate cognitive training in APP/PS1 mice to elucidate the potential mechanisms of beneficial effects after cognitive training. We found that cognitive training conducted by a T-shaped maze for 4 weeks can improve the memory generalization ability of APP/PS1 mice. The results of functional magnetic resonance imaging (fMRI) showed that the functional activity of the medial prefrontal cortex (mPFC) and hippocampus was enhanced after cognitive training, and the results of magnetic resonance spectroscopy (MRS) showed that the neurochemical metabolism of N-acetyl aspartate (NAA) and glutamic acid (Glu) in mPFC, hippocampus and reuniens (Re) thalamic nucleus were escalated. Furthermore, the functional activity of mPFC and hippocampus was negatively correlated with the escape latency in memory generalization test. Therefore, these results suggested that cognitive training might improve memory generalization through enhancing the functional activity of mPFC and hippocampus and increasing the metabolism of NAA and Glu in the brain regions of mPFC, hippocampus and Re nucleus.

Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer's disease.

BACKGROUND: The degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer's disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models. METHODS: Novel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aß plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively. RESULTS: We found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in APP/PS1 mice aged 4, 6, and 8 months. In terms of pathology, we observed that the deposition of Aß plaques gradually aggravated throughout the cerebral cortex and hippocampus in APP/PS1 mice aged 6 and 8 months, while no Aß deposition was detected in the basal forebrain. In contrast, the activity of choline acetyltransferase (ChAT) enzyme in the basal forebrain was decreased at 6 months of age and the cholinergic neurons were lost in the basal forebrain at 8 months of age. In addition, the activation of the cholinergic circuit from the MS and VDB to the hippocampus using chemical genetics is able to improve learning and reduce memory impairment in APP/PS1 mice. Similarly, the levels of Cho in the basal forebrain; NAA in the hippocampus, as well as the expression of ChAT and vesicular acetylcholine transporter (vAchT) in the basal forebrain; and muscarinic acetylcholine receptor 2 (CHRM2) in the hippocampus all increased. CONCLUSIONS: These findings demonstrate that the neurochemical Cho and NAA of the cholinergic circuit can be used as biomarkers to enable the early diagnosis of AD. In addition, memory impairment in APP/PS1 mice can be attenuated using chemical genetics-driven Ach cycle activity of the cholinergic circuit.

Acute Effects of Nicotine on Physiological Responses and Sport Performance in Healthy Baseball Players.

There is interest in whether nicotine could enhance attention in sporting performance, but evidence on the acute effect of nicotine on physical response and sports performance in baseball players remains scant. This was an observational study to examine whether nicotine gum chewed before exercise could provide acute effects on physiological responses and sport performance. Accordingly, heart rate variability (HRV), saliva cotinine concentration and α-amylase activity, cognitive function, muscle strength, and baseball-hitting performance were measured. Thirteen healthy male non-smoker baseball players were recruited. Conducting two sequences with 7-day intervals, they chewed nicotine gum (nicotine group) or flavor-matched placebo gum (placebo group) for 30 min. HRV and saliva analyses were conducted before gum consumption (S1), after gum consumption (S2), and after test completion (S3). Cognitive, muscle strength, and baseball-hitting performance tests were performed after nicotine or placebo gum chewing. The outcomes of all assessed variables were compared within and between the groups. Significant changes in HRV, α-amylase, testosterone, and cortisol were observed in the nicotine group at S2 and S3 (p < 0.05). Compared with the placebo group, the nicotine group exhibited enhanced motor reaction times, grooved pegboard test (GPT) results on cognitive function, and baseball-hitting performance, and small effect sizes were noted (d = 0.47, 0.46 and 0.41, respectively). Nicotine could induce changes in endocrine and sympathetic nerve activity and enhance cognitive function and baseball-hitting performance. However, no increase in muscle strength was observed after nicotine intake.

Meta-Analysis of Neurochemical Changes Estimated via Magnetic Resonance Spectroscopy in Mild Cognitive Impairment and Alzheimer's Disease.

The changes of neurochemicals in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients has been observed via magnetic resonance spectroscopy in several studies. However, whether it exists the consistent pattern of changes of neurochemicals in the encephalic region during the progression of MCI to AD were still not clear. The study performed meta-analysis to investigate the patterns of neurochemical changes in the encephalic region in the progress of AD. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases, and finally included 63 studies comprising 1,086 MCI patients, 1,256 AD patients, and 1,907 healthy controls. It showed that during the progression from MCI to AD, N-acetyl aspartate (NAA) decreased continuously in the posterior cingulate (PC) (SMD: -0.42 [95% CI: -0.62 to -0.21], z = -3.89, P < 0.05), NAA/Cr (creatine) was consistently reduced in PC (SMD: -0.58 [95% CI: -0.86 to -0.30], z = -4.06, P < 0.05) and hippocampus (SMD: -0.65 [95% CI: -1.11 to -0.12], z = -2.44, P < 0.05), while myo-inositol (mI) (SMD: 0.44 [95% CI: 0.26-0.61], z = 4.97, P < 0.05) and mI/Cr (SMD: 0.43 [95% CI: 0.17-0.68], z = 3.30, P < 0.05) were raised in PC. Furthermore, these results were further verified by a sustained decrease in the NAA/mI of PC (SMD: -0.94 [95% CI: -1.24 to -0.65], z = -6.26, P < 0.05). Therefore, the levels of NAA and mI were associated with the cognitive decline and might be used as potentially biomarkers to predict the possible progression from MCI to AD. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42020200308.

Longitudinal tracing of neurochemical metabolic disorders in working memory neural circuit and optogenetics modulation in rats with vascular cognitive impairment.

Chronic cerebral ischemia leads to vascular cognitive impairment (VCI) that exacerbates along with ischemia time and eventually develops into dementia. Recent advances in molecular neuroimaging contribute to understand its pathological characteristics. We previously traced the anisotropic diffusion of water molecules suggests that chronic cerebral ischemia leads to irreversible progressive damage to white matter integrity. However, the abnormalities of gray matter activity following chronic cerebral ischemia remains not entirely understood. In this study, in vivo hydrogen proton magnetic resonance spectroscopy (1H-MRS) was applied to longitudinally track the neurochemical metabolic disorder of gray matter associated with working memory, and optogenetics modulation of neurochemical metabolism was performed for targeted treatment of VCI. The results showed that the concentration of N-acetylaspartate (NAA) in the right hippocampus, left hippocampus, right medial prefrontal cortex (mPFC) and mediodorsal thalamus was decreased as early as 7 days after chronic cerebral ischemia, subsequently gamma-aminobutyric acid (GABA) declined whereas myo-inositol (mI) and glutamate (Glu) increased at 14 days, as well as choline (Cho) lost at 28 days, concurrently the change of Glu and GABA in the mPFC and hippocampus was ischemia time-dependent manner within 1 month. Behaviorally, working memory and object recognition memory were impaired at 14 days, 28 days that significantly correlated with neurochemical metabolic disorders. Interestingly, using optogenetics modulation of PV neurons in the mPFC, the metabolic abnormalities of NAA and GABA in working memory neural circuit could be repaired after chronic cerebral ischemia, together with behavior improvements. These findings suggested that as early as 1∼4 weeks after chronic cerebral ischemia, the metabolism of NAA, Glu, mI and Cho was synchronously impaired in neural circuit of hippocampus-mediodorsal thalamus-mPFC, and the loss of GABA delayed in the hippocampus, and optogenetics modulation of parvalbumin (PV) neurons in the mPFC can improve the neurochemical metabolism of working memory neural circuit and enhance working memory.

Construction of cyclopentane-fused coumarins via DBU-catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes.

The metal-free DBU catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes proceeded smoothly to furnish the corresponding highly functionalized cyclopentane-fused coumarins with excellent diastereoselectivity and complete chemoselectivity and in good yields under mild conditions.