Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

The rapid screening of bioactive constituents within traditional Chinese medicine (TCM) presents a significant challenge to researchers. Prevailing strategies for the screening of active components in TCM often overlook trace components owing to their concealment by more abundant constituents. To address this limitation, a fishing strategy based on offline two-dimensional liquid chromatography (2D-LC) combined with surface plasmon resonance (SPR) was utilized to screen bioactive trace components targeting peroxiredoxin 3 (PRDX3), using Uncaria alkaloids (UAs) as a case study. Initially, an orthogonal preparative offline 2D-LC system combining a positively charged C₁₈ column and a conventional C₁₈ column under disparate mobile phase conditions was constructed. To fully reveal the trace alkaloids, 13 2D fractions of UAs were prepared, and their components were characterized using mass spectrometry (MS). Subsequently, employing PRDX3 as the targeting protein, a SPR-based screening approach was established and rigorously validated with geissoschizine methyl ether (GSM) serving as a positive control for binding. Employing this refined strategy, 29 candidate binding alkaloids were fished from the 13 2D fractions. Notably, combining offline 2D-LC with SPR increased the yield of candidate binding components from 10 to 29 when compared to SPR-based screening alone. Subsequent binding affinity assays confirmed that PRDX3 was a direct binding target for the 12 fished alkaloids, with isovallesiachotamine (IV), corynoxeine N-oxide (CO-N), and cadambine (CAD) demonstrating the highest affinity for PRDX3. Their interactions were further validated through molecular docking analysis. Subsequent intracellular H₂O₂ measurement assays and transfection experiments confirmed that these three trace alkaloids enhanced PRDX3-mediated H₂O₂ clearance. In conclusion, this study introduced an innovative strategy for the identification of active trace components in TCM. This approach holds promise for accelerating research on medicinal components within this field.

Background and objective The pathological types of lung ground glass nodules(GGNs)show great significance to the clinical treatment.This study was aimed to predict pathological types of GGNs based on computed tomog-raphy(CT)quantitative parameters.Methods 389 GGNs confirmed by postoperative pathology were selected,including 138 cases of precursor glandular lesions[atypical adenomatous hyperplasia(AAH)and adenocarcinoma in situ(AIS)],109 cases of microinvasive adenocarcinoma(MIA)and 142 cases of invasive adenocarcinoma(IAC).The morphological characteristics of nodules were evaluated subjectively by radiologist,as well as artificial intelligence(AI).Results In the subjective CT signs,the maximum diameter of nodule and the frequency of spiculation,lobulation and pleural traction increased from AAH+AIS,MIA to IAC.In the AI quantitative parameters,parameters related to size and CT value,proportion of solid component,energy and entropy increased from AAH+AIS,MIA to IAC.There was no significant difference between AI quantitative parameters and the subjective CT signs for distinguishing the pathological types of GGNs.Conclusion AI quantitative parameters were valu-able in distinguishing the pathological types of GGNs.

In order to understand the difference and expression of genes in CEK cells before and af-ter baicalin interferes with IBV,further reveal and analyze the mechanism of baicalin interfering IBV replication in CEK cells in vitro.After IBV infected CEK cells for 2 h,9.75 mg/L baicalin liq-uid was added to interfere with CEK cells,which was recorded as the baicalin(H-IBV)group,and three replicate wells were set in the control group and the IBV(IBV)infection group.After 36 h culture,cell samples were collected and subject to transcriptome for sequencing.The results showed that there were 102 differentially expressed genes in H-IBV group compared with IBV in-fection group,among which 48 genes weresignificantly up-regulated and 54 genes were significantly down-regulated.Through functional annotation in GO and KEGG databases,it was found that dif-ferentially expressed genes were mainly annotated in biological processes such as cellular proces-ses,biological regulation,metabolism,and secondary pathways such as viral infectious diseases,signal transduction and interaction.Retinol metabolism pathway,phospholipid transfer to mem-brane,IL-27 mediated signaling pathway,MDA5/RIG-I and Toll-like receptor signaling pathway were significantly enriched in CEK cells,and the production of type Ⅰ interferon and interferon al-pha and the process of antiviral infection were also positively regulated.There were more differen-tial genes enriched in nucleic acid catalysis,immune system,and reaction,and interbiological reac-tion.Through the STRING network interaction map,it was found that most immune-related genes could form a 36-node interaction network centered on IRF7,TLR3 and STAT1.Therefore,com-pared with IBV group,the differentially expressed genes after baicalin treatment were mainly an-notated and enriched in the biological process,and the immune system and response were en-hanced,mainly through the positive regulation of IRF7 in the MDA5/RIG-I receptor signaling pathway and the inhibition of TLR3 signal transduction in the Toll-like receptor signaling path-way.Positive regulation of IL-27 mediated pathway and regulation of JAK-STAT signaling path-way were supplemented by activation of the expression of IRF7,TLR3,STAT1 and other related genes,and interaction with corresponding downstream proteins to promote the expression of IFN-α and regulatory cytokines,coupled with negative regulation of viral(defense)response and viral processes.Thus,baicalin interferes with IBV replication in CEK cells.

Objective:To investigate the correlation and predictive value of fibrinogen-to-albumin ratio (FAR) and clinical outcomes after intravenous thrombolysis in patients with acute ischemic stroke.Methods:Patients with acute ischemic stroke received intravenous thrombolysis treatment at Fuyang People's Hospital from November 2019 to August 2022 were retrospectively included. Their clinical, imaging, and laboratory data were collected. After 3 months of onset, a modified Rankin Scale was used for clinical outcome evaluation and a score >2 were defined as poor outcome. Multivariate logistic regression analysis was used to determine the correlation between FAR and poor outcome. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value of FAR on adverse outcomes after intravenous thrombolysis in patients with acute ischemic stroke. Results:A total of 162 patients were included. There were 114 patients (70.4%) in the good outcome group and 48 (29.6%) in the poor outcome group. Univariate analysis showed that the baseline National Institutes of Health Stroke Scale (NIHSS) score, fasting blood glucose, fibrinogen, and FAR in the poor outcome group were significantly higher than those in the good outcome group, while the serum albumin was significantly lower than that of the good outcome group (all P<0.05). Multivariate logistic regression analysis showed that the baseline NIHSS score (odds ratio [ OR] 1.176, 95% confidence interval [ CI] 1.082-1.227; P<0.001), fasting blood glucose ( OR 1.206, 95% CI 1.018-1.430; P=0.030), and FAR ( OR 1.448, 95% CI 1.449-1.824; P=0.002) were the independent risk factors for poor outcome. The ROC curve analysis showed that the area under the curve of FAR for predicting poor outcomes was 0.706 (95% CI 0.616-0.796). When the FAR cutoff value was 8.06, the sensitivity and specificity were 66.7% and 78.2%, respectively. Conclusion:There is a significant correlation between FAR and outcomes after intravenous thrombolysis therapy in patients with acute ischemic stroke. Higher FAR has certain predictive value for poor outcomes of patients.

Humans ; Aminoquinolines/therapeutic use* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation/genetics* ; Standard of Care

Congenital thrombotic thrombocytopenic purpura, also known as Upshaw-Schulman syndrome, is a rare autosomal recessive genetic disorder. The main pathogenesis is homozygous or compound heterozygous variants of von Willebrand factor lyase (ADAMTS13) gene mapped to chromosome 9q34, which may result in severe lack of ADAMTS13 which cleaves von Willebrand factor (vWF) multimers in the plasma and increase the risk of microvascular thrombosis, leading to various complications. The advance of research on the pathogenesis of cTTP, recombinant human ADAMTS13 and gene therapy have made breakthroughs which may lead to cure of cTTP. This article has provided a review for the latest progress made in the diagnosis and treatment of cTTP.
ADAM Proteins/genetics* ; ADAMTS13 Protein/genetics* ; Homozygote ; Humans ; Purpura, Thrombotic Thrombocytopenic/therapy* ; von Willebrand Factor/genetics*

Objective:To explore the clinical and electro-physiological characteristics of reflex epilepsy induced by thinking activities.Methods:Five patients of reflex epilepsy induced by thinking activities during electroencephalogram (EEG) monitoring in the EEG Monitoring Center, Department of Neurology, Xijing Hospital,the Air Force Military Medical University from January 2017 to September 2019 were studied and followed up.Results:All the 5 patients are male, aged 14 to 33 years, with the disease course of 3 to 9 years and the follow-up of 1 to 4 years. The myoclonic jerks, spasms seizure and generalized tonic and clonic seizure occured to the 5 patients. The EEG background of low amplitude alpha rhythm was recorded in the 5 patiens. The ictal-EEG of 2 cases showed the spike wave or spike slow complex waves in the central, parietal area, and the ictal-EEG of 1 case showed the generalized spike-wave discharge. There were no seizures occuring to the 2 cases during video-electroencephalography monitoring. There were no abnormalities in cranial magnetic resonance imaging. The arterial spin labeling of 2 cases suggested that the right cerebral hemisphere cerebral blood flow was lower than contralateral. Antiseizure drugs (levetiracetam in 4 cases and levetiracetam+magnesium valproate in 1 case) were administered, 4 cases were seizure free and 1 case was uncontrolled.Conclusions:The reflex epilepsy induced by thinking activities is common in young men, and the EEG background with low amplitude alpha rhythm may be the characteristic of the reflex epilepsy induced by thinking activities. The levetiracetam may be the good choice for the reflex epilepsy induced by thinking activities and the prognosis of reflex epilepsy induced by thinking activities is good.

Objective:To explore the status quo of symptom management self-efficacy based on patient reported outcomes of nasopharyngeal carcinoma patients and analyze its related factors.Methods:From January to April 2021, 230 patients with nasopharyngeal carcinoma who were treated in Zhejiang Cancer Hospital were selected as the study subject by convenient sampling. The General Information Questionnaire and Patient-Reported Outcome Measurement Information System-Self-Efficacy for Managing Symptoms (PROMIS-SEMSX) were used to investigate. Single factor analysis and multiple linear regression analysis were used to explore the influencing factors of symptom management self-efficacy in patients with nasopharyngeal carcinoma.Results:A total of 230 questionnaires were distributed, 220 were recovered, and 205 were valid. The score of symptom management self-efficacy of patients with nasopharyngeal carcinoma was (97.74±20.00) , which was above the middle level, and the lowest score dimension was confidence, which was (23.52±5.91) . Multiple linear regression showed that gender, education level, medical expense payment method, economic level, tumor stage, course of disease, tumor recurrence and metastasis were the influencing factors of symptom management self-efficacy of nasopharyngeal carcinoma patients ( P<0.05) . A total of 41.5% of the total variation was explained. Conclusions:The self-efficacy of symptom management in patients with nasopharyngeal carcinoma needs to be improved. The medical and nursing staff should focus on the patients with low educational level, heavy economic burden, late tumor, recurrence and metastasis, and focus on providing specific health guidance to alleviate their discomfort symptoms during treatment, and improve their self-efficacy of symptom management.

Objective:To explore the association between short-term exposures to fine particulate matter (PM 2.5) on blood lipids in the elderly. Methods:In this panel study, five repeated measurements were performed on 76 people aged 60-69 in Jinan city. Each participant had a PM 2.5 monitor for 72 hours before each health examination, including a questionnaire survey, physical examination, and biological sample collection. Serum triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were examined, and non-HDL-C concentrations were calculated by subtracting HDL-C from TC. The generalized linear mixed-effects model was used to quantify the association of personal PM 2.5 exposure at different lag with blood lipids and dyslipidemia. Results:The age of 70 participants was (65.0±2.8) years, of which 48.6% (34/70) were males. The BMI of participants was (25.0±2.5) kg/m 2. Their TC, TG, LDL-C, HDL-C, and non-HDL-C concentrations were (5.75±1.32), (1.55±0.53), (3.27±0.94), (1.78±0.52), and (3.97±1.06) mmol/L, respectively. Generalized linear mixed-effects model showed that after adjusting for confounding factors, at lag 72 hours, each 10 μg/m 3 increase in PM 2.5 was associated with the percentage change in TC, LDL-C, HDL-C and non-HDL-C about 1.77% (95% CI: 1.22%-2.32%), 1.90% (95% CI: 1.18%-2.63%), 1.99% (95% CI: 1.37%-2.60%) and 1.74% (95% CI: 1.11%-2.37%), and the OR values (95% CI) of hypercholesterolemia, hypertriglyceridemia and hyperbetalipoproteinemia were 1.11 (1.01-1.22), 1.33 (1.03-1.71) and 1.15 (1.01-1.31), respectively. Conclusion:There is a significant association of short-term PM 2.5 exposure with the concentration of blood lipids and the risk of dyslipidemia in the elderly.