Gallic Acid Alleviates Cognitive Impairment by Promoting Neurogenesis via the GSK3ß-Nrf2 Signaling Pathway in an APP/PS1 Mouse Model.

Background: Neuronal loss occurs early and is recognized as a hallmark of Alzheimer's disease (AD). Promoting neurogenesis is an effective treatment strategy for neurodegenerative diseases. Traditional Chinese herbal medicines serve as a rich pharmaceutical source for modulating hippocampal neurogenesis. Objective: Gallic acid (GA), a phenolic acid extracted from herbs, possesses anti-inflammatory and antioxidant properties. Therefore, we aimed to explore whether GA can promote neurogenesis and alleviate AD symptoms. Methods: Memory in mice was assessed using the Morris water maze, and protein levels were examined via western blotting and immunohistochemistry. GA's binding site in the promoter region of transcription regulator nuclear factor erythroid 2-related factor 2 (Nrf2) was calculated using AutoDock Vina and confirmed by a dual luciferase reporter assay. Results: We found that GA improved spatial memory by promoting neurogenesis in the hippocampal dentate gyrus zone. It also improved synaptic plasticity, reduced tau phosphorylation and amyloid-ß concentration, and increased levels of synaptic proteins in APP/PS1 mice. Furthermore, GA inhibited the activity of glycogen synthase kinase-3ß (GSK-3ß). Bioinformatics tools revealed that GA interacts with several amino acid sites on GSK-3ß. Overexpression of GSK-3ß was observed to block the protective effects of GA against AD-like symptoms, while GA promoted neurogenesis via the GSK-3ß-Nrf2 signaling pathway in APP/PS1 mice. Conclusions: Based on our collective findings, we hypothesize that GA is a potential pharmaceutical agent for alleviating the pathological symptoms of AD.

Brain network centrality and connectivity are associated with clinical subtypes and disease progression in Parkinson's disease.

To investigate brain network centrality and connectivity alterations in different Parkinson's disease (PD) clinical subtypes using resting-state functional magnetic resonance imaging (RS-fMRI), and to explore the correlation between baseline connectivity changes and the clinical progression. Ninety-two PD patients were enrolled at baseline, alongside 38 age- and sex-matched healthy controls. Of these, 85 PD patients underwent longitudinal assessments with a mean of 2.75 ± 0.59 years. Two-step cluster analysis integrating comprehensive motor and non-motor manifestations was performed to define PD subtypes. Degree centrality (DC) and secondary seed-based functional connectivity (FC) were applied to identify brain network centrality and connectivity changes among groups. Regression analysis was used to explore the correlation between baseline connectivity changes and clinical progression. Cluster analysis identified two main PD subtypes: mild PD and moderate PD. Two different subtypes within the mild PD were further identified: mild motor-predominant PD and mild-diffuse PD. Accordingly, the disrupted DC and seed-based FC in the left inferior frontal orbital gyrus and left superior occipital gyrus were severe in moderate PD. The DC and seed-based FC alterations in the right gyrus rectus and right postcentral gyrus were more severe in mild-diffuse PD than in mild motor-predominant PD. Moreover, disrupted DC were associated with clinical manifestations at baseline in patients with PD and predicted motor aspects progression over time. Our study suggested that brain network centrality and connectivity changes were different among PD subtypes. RS-fMRI holds promise to provide an objective assessment of subtype-related connectivity changes and predict disease progression in PD.

Identification of personalized neoantigen-based vaccines and immune subtype characteristic analysis of glioblastoma based on abnormal alternative splicing.

The development of personalized neoantigen-based vaccines in cancer immunotherapy has shown promise. In this study, a large-scale bioinformatics analysis was performed to identify potential GBM-associated neoantigens based on abnormal alternative splicing, and then screen suitable patients for vaccination. Gene expression profiles and clinical information were collected from TCGA. We filtered the percent-spliced-in (PSI) spectrum of alternative splicing events in the dataset to identify abnormal alternative splicing events. MAF package was used to identify and analyse tumour mutation burden (TMB) in cancer samples. Tumour Immune Estimation Resource (TIMER) was used to calculate and visualize the infiltration of antigen presenting cells (APCs). In addition, consistent clustering algorithm utilized to identify immune subtypes of GBM. Five potential tumour neoantigens (LRP1, TCF12, DERL3, WIPI2, and TSHZ3) were identified in GBM by selecting genes both with abnormal alternative splicing (upregulated) and gene frameshift mutations, in which LRP1 was significantly associated with APCs. According to the expressions of five potential tumour neoantigens, 160 patients with GBM were divided into three immune subtypes. Patients in cluster3 exhibited good prognoses. Furthermore, the characteristics, including TMB, abnormal alternative splicing events, immune activity, immune cells proportion, and association with tumour biomarkers, were unique in each immune subtypes. The characteristics of cluster3 illustrated that cluster3 participants were more suitable candidates for vaccination. LRP1 was identified as a potential neoantigen for immunotherapy against GBM, and patients in cluster3 were more suitable for vaccination. Our findings provide important guidance for the development of novel neoantigens and therapeutic targets in patients with GBM.

Efficacy comparison of oxcarbazepine and levetiracetam monotherapy among patients with newly diagnosed focal epilepsy in China: A multicenter, open-label, randomized study.

AIMS: This multicenter, open-label, randomized study (Registration No. ChiCTR-OCH-14004528) aimed to compare the efficacy and effects of oxcarbazepine (OXC) with levetiracetam (LEV) as monotherapies on patient quality of life and mental health for patients with newly diagnosed focal epilepsy from China. METHODS: Patients with newly diagnosed focal epilepsy who had experienced 2 or more unprovoked seizures at greater than a 24-h interval during the previous year were recruited. Participants were randomly assigned to the OXC group or LEV group. Efficacy, safety, quality of life, and mental health were evaluated over 12-week and 24-week periods. RESULTS: In total, we recruited 271 newly diagnosed patients from 23 centers. Forty-four patients were excluded before treatment for reasons. The rate of seizure freedom of OXC was significantly superior to that of LEV at 12 weeks and 24 weeks (p < 0.05). The quality of life (except for the seizure worry subsection) and anxiety scale scores also showed significant differences from before to after treatment in the OXC and LEV groups. CONCLUSIONS: OXC monotherapy may be more effective than LEV monotherapy in patients with newly diagnosed focal epilepsy. Both OXC and LEV could improve the quality of life and anxiety state in adult patients with focal epilepsy.

Acute psychological impact on COVID-19 patients in Hubei: a multicenter observational study.

We conducted a multicentre cross-sectional survey of COVID-19 patients to evaluate the acute psychological impact on the patients with coronavirus disease 2019 (COVID-19) during isolation treatment based on online questionnaires from 2 February to 5 March 2020. A total of 460 COVID-19 patients from 13 medical centers in Hubei province were investigated for their mental health status using online questionnaires (including Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Patient Health Questionnaire-15, and Insomnia Severity Index scales). Among all 460 COVID-19 patients, 187 (40.65%) of them were healthcare workers (HCWs). 297 (64.57%) of them were females. The most common psychological problems were somatization symptoms (66.09%, n = 304), followed by depression (53.48%, n = 246), anxiety (46.30%, n = 213), problems of insomnia (42.01%, n = 171), and then self-mutilating or suicidal thoughts (23.26%, n = 107). Of all the patients, 15.65% (n = 72) had severe somatization symptoms, and 2.83% (n = 13) had severe (almost every day) self-mutilating or suicidal thoughts. The most common psychological problems for HCWs were somatization symptoms (67.84%, n = 125), followed by depression (51.87%, n = 97), anxiety (44.92%, n = 84), problems of insomnia (36.18%, n = 55), and then self-mutilating or suicidal thoughts (20.86%, n = 39). Patients with lower education levels were found to be associated with higher incidence of self-mutilating or suicidal thoughts (odds ratio [OR], 2.68, 95% confidence interval [95% CI], 1.66-4.33 [P < 0.001]). Patients with abnormal body temperature were found to be associated with higher incidence of self-mutilating or suicidal thoughts (OR, 3.97, 95% CI, 2.07-7.63 [P < 0.001]), somatic symptoms (OR, 2.06, 95% CI, 1.20-3.55 [P = 0.009]) and insomnia (OR, 1.66, 95% CI, 1.04-2.65 [P = 0.033]). Those with suspected infected family members displayed a higher prevalence of anxiety than those without infected family members (OR, 1.61, 95% CI, 1.1-2.37 [P = 0.015]). Patients at the age of 18-44 years old had fewer somatic symptoms than those aged over 45 years old (OR, 1.91, 95% CI, 1.3-2.81 [P = 0.001]). In conclusion, COVID-19 patients tended to have a high prevalence of adverse psychological events. Early identification and intervention should be conducted to avoid extreme events such as self-mutilating or suicidal impulsivity for COVID-19 patients, especially for those with low education levels and females who have undergone divorce or bereavement.

Prevalence of psychological disorders in the COVID-19 epidemic in China: A real world cross-sectional study.

OBJECTIVE: This study aimed to explore the prevalence of psychological disorders and associated factors at different stages of the COVID-19 epidemic in China. METHODS: The mental health status of respondents was assessed via the Patient Health Questionnaire-9 (PHQ-9), Insomnia Severity Index (ISI) and the Generalized Anxiety Disorder 7 (GAD-7) scale. RESULTS: 5657 individuals participated in this study. History of chronic disease was a common risk factor for severe present depression (OR 2.2, 95% confidence interval [CI], 1.82-2.66, p < 0.001), anxiety (OR 2.41, 95% CI, 1.97-2.95, p < 0.001), and insomnia (OR 2.33, 95% CI, 1.83-2.95, p < 0.001) in the survey population. Female respondents had a higher risk of depression (OR 1.61, 95% CI, 1.39-1.87, p < 0.001) and anxiety (OR 1.35, 95% CI, 1.15-1.57, p < 0.001) than males. Among the medical workers, confirmed or suspected positive COVID-19 infection as associated with higher scores for depression (confirmed, OR 1.87; suspected, OR 4.13), anxiety (confirmed, OR 3.05; suspected, OR 3.07), and insomnia (confirmed, OR 3.46; suspected, OR 4.71). LIMITATION: The cross-sectional design of present study presents inference about causality. The present psychological assessment was based on an online survey and on self-report tools, albeit using established instruments. We cannot estimate the participation rate, since we cannot know how many potential subjects received and opened the link for the survey. CONCLUSIONS: Females, non-medical workers and those with a history of chronic diseases have had higher risks for depression, insomnia, and anxiety. Positive COVID-19 infection status was associated with higher risk of depression, insomnia, and anxiety in medical workers.

Posttraumatic stress disorder symptoms in healthcare workers after the peak of the COVID-19 outbreak: A survey of a large tertiary care hospital in Wuhan.

This study examined the prevalence of posttraumatic stress disorder (PTSD) symptoms and assessed mental illness via an online survey among healthcare workers (HCWs) at the Central Hospital of Wuhan after the peak of the COVID-19 outbreak. PTSD symptoms were measured using the PTSD Checklist Civilian Version (PCL-C), with a cutoff score of 50. Among the 642 HCWs, the prevalence of probable PTSD was 20.87%. Additionally, 88.88%, 82.09%, 100%, and 95.52% of HCWs with probable PTSD reported varying degrees of anxiety, depression, somatic symptoms, and insomnia, respectively. HCWs with probable PTSD scored higher on the Hospital Anxiety and Depression Scale (HADS), Patient Health questionnaire-15 (PHQ-15), and Insomnia Severity Index (ISI) than non-PTSD HCWs (all p < 0.05). Multivariate regression analysis revealed that HCWs with negative COVID-19 tests (OR, 0.35; 95% CI, 0.21-0.58; p < 0.00), those with high Social Support Self-Rating Scale (SSRS) scores (OR, 0.30; 95% CI, 0.17-0.52; p < 0.00), and HCWs whose family members tested negative (OR, 0.64; 95% CI, 0.42-0.96; p = 0.03) were less likely to have probable PTSD. This study found a high prevalence of probable PTSD and severe mental illness among local HCWs. Our finding emphasizes the need to provide mental health support for HCWs.

Thyroid Hormone in the Pathogenesis of Congenital Intestinal Dysganglionosis.

INTRODUCTION: The objective of this study is to investigate the role of thyroid hormone (TH) in the pathogenesis of intestinal dysganglionosis (ID). METHODS: A zebrafish model of congenital hypothyroidism (CH) was created by exposing the larvae to the 6-propyl-2-thiouracil (PTU). The enteric neurons were labeled with anti-HuC/D antibodies. The number of enteric neurons was counted. The larval intestine was dissociated and stained with anti-p75 and anti-α4 integrin antibodies. Mitosis and apoptosis of the p75+ α4 integrin+ enteric neural crest cells (ENCCs) were studied using flow cytometry. Intestinal motility was studied by analyzing the transit of fluorescent tracers. RESULTS: PTU (25 mg/L) significantly reduced TH production at 6- and 9-days post fertilization without changing the body length, body weight, and intestinal length of the larvae. Furthermore, PTU inhibited mitosis of ENCCs and reduced the number of enteric neurons throughout the larval zebrafish intestine. Importantly, PTU inhibited intestinal transit of fluorescent tracers. Finally, thyroxine supplementation restored ENCC mitosis, increased the number of enteric neurons, and recovered intestinal motility in the PTU-treated larvae. CONCLUSIONS: PTU inhibited TH production, reduced the number of enteric neurons, impaired intestinal motility, and impeded ENCC mitosis in zebrafish, suggesting a possible role of CH in the pathogenesis of ID.

Biomarkers for Early Diagnostic of Mild Cognitive Impairment in Type-2 Diabetes Patients: A Multicentre, Retrospective, Nested Case-Control Study.

BACKGROUND: Both type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are common age-associated disorders and T2DM patients show an increased risk to suffer from AD, however, there is currently no marker to identify who in T2DM populations will develop AD. Since glycogen synthase kinase-3ß (GSK-3ß) activity, ApoE genotypes and olfactory function are involved in both T2DM and AD pathogenesis, we investigate whether alterations of these factors can identify cognitive impairment in T2DM patients. METHODS: The cognitive ability was evaluated using Minimum Mental State Examination (MMSE) and Clinical Dementia Rating (CDR), and the mild cognitive impairment (MCI) was diagnosed by Petersen's criteria. GSK-3ß activity in platelet, ApoE genotypes in leucocytes and the olfactory function were detected by Western/dot blotting, the amplification refractory mutation system (ARMS) PCR and the Connecticut Chemosensory Clinical Research Center (CCCRC) test, respectively. The odds ratio (OR) and 95% confidence intervals (95% CI) of the biomarkers for MCI diagnosis were calculated by logistic regression. The diagnostic capability of the biomarkers was evaluated by receiver operating characteristics (ROC) analyses. FINDINGS: We recruited 694 T2DM patients from Jan. 2012 to May. 2015 in 5 hospitals (Wuhan), and 646 of them met the inclusion criteria and were included in this study. 345 patients in 2 hospitals were assigned to the training set, and 301 patients in another 3 hospitals assigned to the validation set. Patients in each set were randomly divided into two groups: T2DM without MCI (termed T2DM-nMCI) or with MCI (termed T2DM-MCI). There were no significant differences for sex, T2DM years, hypertension, hyperlipidemia, coronary disease, complications, insulin treatment, HbA1c, ApoE ε2, ApoE ε3, tGSK3ß and pS9GSK3ß between the two groups. Compared with the T2DM-nMCI group, T2DM-MCI group showed lower MMSE score with older age, ApoE ε4 allele, higher olfactory score and higher rGSK-3ß (ratio of total GSK-3ß to Ser9-phosphorylated GSK-3ß) in the training set and the validation set. The OR values of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 1.09, 2.09, 1.51, 10.08 in the training set, and 1.06, 2.67, 1.47, 7.19 in the validation set, respectively. The diagnostic accuracy of age, ApoE ε4 gene, olfactory score and rGSK-3ß were 0.76, 0.72, 0.66, 0.79 in the training set, and 0.70, 0.68, 0.73, 0.79 in the validation set, respectively. These four combined biomarkers had the area under the curve (AUC) of 82% and 86%, diagnostic accuracy of 83% and 81% in the training set and the validation set, respectively. INTERPRETATION: Aging, activation of peripheral circulating GSK-3ß, expression of ApoE ε4 and increase of olfactory score are diagnostic for the mild cognitive impairment in T2DM patients, and combination of these biomarkers can improve the diagnostic accuracy.

microRNA-9 attenuates amyloidß-induced synaptotoxicity by targeting calcium/calmodulin-dependent protein kinase kinase 2.

The calcium/calmodulin-dependent protein kinase kinase 2, adenosine monophosphate-activated protein kinase (CAMKK2-AMPK) pathway mediated amyloid ß42 (Aß42)-induced synaptotoxicity and blockage of CAMKK2-protected neurons against the effect of Aß42. Numerous microRNAs (miRNAs) were downregulated in response to Aß42, including miR-9, a synapse-enriched miRNA that is decreased in Alzheimer's disease. In the present study the effect of miR-9 on Aß42­triggered CAMKK2-AMPK activation and the synaptotoxic impairment was investigated. Aß42 oligomers were identified to be capable of inducing CAMKK2-AMPK pathway activation, which was attenuated by miR-9 overexpression. CAMKK2 was predicted to be a target of miR-9 using Pictar and Targetscan 6.2 Bioinformatics' algorithms. A luciferase activity assay and western blot analysis confirmed that miR-9 significantly inhibited CAMKK2 expression. Additionally, overexpression of miR-9 was sufficient to restore Aß42-induced dendritic spine loss and rescued Aß42-induced τ phosphorylation at Ser-262 mediated by the CAMKK2-AMPK pathway. The results of the present study demonstrated that miR-9 attenuated Aß-induced synaptotoxicity by targeting CAMKK2.

Berberine rescues D-galactose-induced synaptic/memory impairment by regulating the levels of Arc.

Synaptic communication forms the basis of learning and memory. Disruptions of synaptic function and memory have been widely reported in many neurological diseases, such as dementia. Thus, restoration of impaired synaptic communication is a potential therapeutic approach for these diseases. In this study, we demonstrated that supplementation with berberine, a plant alkaloid with a long history of medicinal usage in Chinese medicine, effectively reverses the synaptic deficits induced by D-galactose. We also found that berberine rescued D-galactose-induced memory impairment and additionally rescued the mRNA and protein levels of Arc/Arg3.1, an important immediate early gene that is crucial for maintaining normal synaptic plasticity. Our study provides the first piece of evidence supporting the potential use of berberine in the treatment of neural diseases with synaptic/memory impairments.