Sleep deprivation (SD) has emerged as a significant modifiable risk factor for Alzheimer’s disease (AD), with mounting evidence demonstrating its multifaceted role in accelerating AD pathogenesis through diverse molecular, cellular, and systemic mechanisms. SD is refined within the broader spectrum of sleep-wake and circadian disruption, emphasizing that both acute total sleep loss and chronic sleep restriction destabilize the homeostatic and circadian processes governing glymphatic clearance of neurotoxic proteins. During normal sleep, concentrations of interstitial Aβ and tau fall as cerebrospinal fluid oscillations flush extracellular waste; SD abolishes this rhythm, causing overnight rises in soluble Aβ and tau species in rodent hippocampus and human CSF. Orexinergic neurons sustain arousal, and become hyperactive under SD, further delaying sleep onset and amplifying Aβ production. At the molecular level, SD disrupts Aβ homeostasis through multiple converging pathways, including enhanced production via beta-site APP cleaving enzyme 1 (BACE1) upregulation, coupled with impaired clearance mechanisms involving the glymphatic system dysfunction and reduced Aβ-degrading enzymes (neprilysin and insulin-degrading enzyme). Cellular and histological analyses revealed that these proteinopathies are significantly exacerbated by SD-induced neuroinflammatory cascades characterized by microglial overactivation, astrocyte reactivity, and sustained elevation of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) through NF‑κB signaling and NLRP3 inflammasome activation, creating a self-perpetuating cycle of neurotoxicity. The synaptic and neuronal consequences of chronic SD are particularly profound and potentially irreversible, featuring reduced expression of critical synaptic markers (PSD95, synaptophysin), impaired long-term potentiation (LTP), dendritic spine loss, and diminished neurotrophic support, especially brain-derived neurotrophic factor (BDNF) depletion, which collectively contribute to progressive cognitive decline and memory deficits. Mechanistic investigations identify three core pathways through which SD exerts its neurodegenerative effects: circadian rhythm disruption via BMAL1 suppression, orexin system hyperactivity leading to sustained wakefulness and metabolic stress, and oxidative stress accumulation through mitochondrial dysfunction and reactive oxygen species overproduction. The review critically evaluates promising therapeutic interventions including pharmacological approaches (melatonin, dual orexin receptor antagonists), metabolic strategies (ketogenic diets, and Mediterranean diets rich in omega-3 fatty acids), lifestyle modifications (targeted exercise regimens, cognitive behavioral therapy for insomnia), and emerging technologies (non-invasive photobiomodulation, transcranial magnetic stimulation). Current research limitations include insufficient understanding of dose-response relationships between SD duration/intensity and AD pathology progression, lack of long-term longitudinal clinical data in genetically vulnerable populations (particularly APOE ε4 carriers and those with familial AD mutations), the absence of standardized SD protocols across experimental models that accurately mimic human chronic sleep restriction patterns, and limited investigation of sex differences in SD-induced AD risk. The accumulated evidence underscores the importance of addressing sleep disturbances as part of multimodal AD prevention strategies and highlights the urgent need for clinical trials evaluating sleep-focused interventions in at-risk populations. The review proposes future directions focused on translating mechanistic insights into precision medicine approaches, emphasizing the need for biomarkers to identify SD-vulnerable individuals, chronotherapeutic strategies aligned with circadian biology, and multi-omics integration across sleep, proteostasis and immune profiles may delineate precision-medicine strategies for at-risk populations. By systematically examining these critical connections, this analysis positions sleep quality optimization as a viable strategy for AD prevention and early intervention while providing a comprehensive roadmap for future mechanistic and interventional research in this rapidly evolving field.

Jiuwei Xifeng Granules have become a Chinese patent medicine in the market. Because the formula contains Os Draconis, a top-level protected fossil of ancient organisms, the formula was to be improved by replacing Os Draconis with Ostreae Concha. To evaluate whether the improved formula has the same effectiveness and safety as the original formula, a randomized, double-blind, parallel-controlled, equivalence clinical trial was conducted. This study enrolled 288 tic disorder(TD) of children and assigned them into two groups in 1∶1. The treatment group and control group took the modified formula and original formula, respectively. The treatment lasted for 6 weeks, and follow-up visits were conducted at weeks 2, 4, and 6. The primary efficacy endpoint was the difference in Yale global tic severity scale(YGTSS)-total tic severity(TTS) score from baseline after 6 weeks of treatment. The results showed that after 6 weeks of treatment, the declines in YGTSS-TSS score showed no statistically significant difference between the two groups. The difference in YGTSS-TSS score(treatment group-control group) and the 95%CI of the full analysis set(FAS) were-0.17[-1.42, 1.08] and those of per-protocol set(PPS) were 0.29[-0.97, 1.56], which were within the equivalence boundary [-3, 3]. The equivalence test was therefore concluded. The two groups showed no significant differences in the secondary efficacy endpoints of effective rate for TD, total score and factor scores of YGTSS, clinical global impressions-severity(CGI-S) score, traditional Chinese medicine(TCM) response rate, or symptom disappearance rate, and thus a complete evidence chain with the primary outcome was formed. A total of 6 adverse reactions were reported, including 4(2.82%) cases in the treatment group and 2(1.41%) cases in the control group, which showed no statistically significant difference between the two groups. No serious suspected unexpected adverse reactions were reported, and no laboratory test results indicated serious clinically significant abnormalities. The results support the replacement of Os Draconis by Ostreae Concha in the original formula, and the efficacy and safety of the modified formula are consistent with those of the original formula.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Double-Blind Method ; Drugs, Chinese Herbal/therapeutic use* ; Tic Disorders/drug therapy* ; Treatment Outcome

This paper aimed to investigate the therapeutic effect and mechanism of action of the Yiqi Fumai Formula(YQFM), a kind of traditional Chinese medicine(TCM), on mice with experimental heart failure based on the "heart-gut axis" theory. Based on the network pharmacology integrated with the group collaboration algorithm, the active ingredients were screened, a "component-target-disease" network was constructed, and the potential pathways regulated by the formula were predicted and analyzed. Next, the model of experimental heart failure was established by intraperitoneal injection of adriamycin at a single high dose(15 mg·kg~(-1)) in BALB/c mice. After intraperitoneal injection of YQFM(lyophilized) at 7.90, 15.80, and 31.55 mg·d~(-1) for 7 d, the protective effects of the formula on cardiac function were evaluated using indicators such as ultrasonic electrocardiography and myocardial injury markers. Combined with inflammatory factors in the cardiac and colorectal tissue, as well as targeted assays, the relevant indicators of potential pathways were verified. Meanwhile, 16S rDNA sequencing was performed on mouse fecal samples using the Illumina platform to detect changes in gut flora and analyze differential metabolic pathways. The results show that the administration of injectable YQFM(lyophilized) for 7 d significantly increased the left ventricular end-systolic internal diameter, fractional shortening, and ejection fraction of cardiac tissue of mice with experimental heart failure(P<0.05). Moreover, markers of myocardial injury were significantly decreased(P<0.05), indicating improved cardiac function, along with significantly suppressed inflammatory responses in cardiac and intestinal tissue(P<0.05). Additionally, the species of causative organisms was decreased, and the homeostasis of gut flora was improved, involving a modulatory effect on PI3K-Akt signaling pathway-related inflammation in cardiac and colorectal tissue. In conclusion, YQFM can affect the "heart-gut axis" immunity through the homeostasis of the gut flora, thereby exerting a therapeutic effect on heart failure. This finding provides a reference for the combination of TCM and western medicine to prevent and treat heart failure based on the "heart-gut axis" theory.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Heart Failure/microbiology* ; Mice ; Mice, Inbred BALB C ; Male ; Disease Models, Animal ; Gastrointestinal Microbiome/drug effects* ; Heart/physiopathology* ; Humans ; Signal Transduction/drug effects*

OBJECTIVE: To explore the role of nuclear receptor-binding SET-domain protein 1 (NSD1) in the pathogenesis of nonobstructive azoospermia (NOA) by regulating the expressions of relevant genes. METHODS: We detected the expression of NSD1 in the testis tissue of 7 male patients with obstructive azoospermia (OA) and 18 with NOA by qPCR and immunofluorescence assay, and determined the modification level of H3K36me2 in the testes of two groups of patients by immunofluorescence staining, Western blot and immunoprecipitation (IP). We examined the difference in the enrichment of H3K36me2 in the testis tissue by chromatin IP-based sequencing (ChIP-Seq), analyzed the genomic distribution and target genes using bioinformatics, and verified the expression levels of the target genes in the testes of the two groups of patients by qPCR. RESULTS: Compared with the patients with OA, those with NOA showed dramatically decreased mRNA and protein expressions of NSD1 (P=0.000 8). The binding of NSD1 to H3K36me2 was observed in the testis tissue of both the two groups of patients, while the modification level of H3K36me2 was evidently reduced in the NOA males. H3K36me2 was distributed mainly in the intergenic region in the testes of the two groups of patients, but the enrichment of H3K36me2 was obviously decreased in the NOA group. The differentially H3K36me2-enriched genes were involved in various biological processes, including tissue development, and cell morphogenesis. Results of ChIP-Seq and qPCR showed significantly down-regulated expressions of the target genes KIT, SPO11 and ACRV1 in the testis tissue of the NOA males compared with those in the OA patients (P<0.01). CONCLUSION The levels of NSD1 and H3K36me2 are decreased in testis tissue of the NOA patient, H3K36me2 is highly enriched in the spermatogenesis-related key genes KIT, SPO11 and ACRV1, and the down-regulated expression of NSD1 impairs spermatogenesis.
Humans ; Male ; Azoospermia/genetics* ; Testis/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Histones/metabolism*

OBJECTIVES: Bladder cancer is a common malignancy with high incidence and poor prognosis. N⁶-methyladenosine (m⁶A) modification is widely involved in diverse physiological processes, among which the m⁶A recognition protein YTH N⁶-methyladenosine RNA binding protein F2 (YTHDF2) plays a crucial role in bladder cancer progression. This study aims to elucidate the molecular mechanism by which O-linked N-acetylglucosamine (O-GlcNAc) modification of YTHDF2 regulates its downstream target, period circadian regulator 1 (PER1), thereby promoting bladder cancer cell proliferation. METHODS: Expression of YTHDF2 in bladder cancer was predicted using The Cancer Genome Atlas (TCGA). Twenty paired bladder cancer and adjacent normal tissues were collected at the clinical level. Normal bladder epithelial cells (SV-HUC-1) and bladder cancer cell lines (T24, 5637, EJ-1, SW780, BIU-87) were examined by quantitative real-time PCR (RT-qPCR), Western blotting, and immunohistochemistry for expression of YTHDF2, PER1, and proliferation-related proteins [proliferating cell nuclear antigen (PCNA), minichromosome maintenance complex component 2 (MCM2), Cyclin D1]. YTHDF2 was silenced in 5637 and SW780 cells, and cell proliferation was assessed by Cell Counting Kit-8 (CCK-8), colony formation, and EdU assays. Bioinformatics was used to predict glycosylation sites of YTHDF2, and immunoprecipitation (IP) was performed to detect O-GlcNAc modification levels of YTHDF2 in tissues and cells. Bladder cancer cells were treated with DMSO, OSMI-1 (O-GlcNAc inhibitor), or Thiamet G (O-GlcNAc activator), followed by cycloheximide (CHX), to assess YTHDF2 ubiquitination by IP. YTHDF2 knockdown and Thiamet G treatment were further used to evaluate PER1 mRNA stability, PER1 m⁶A modification, and cell proliferation. TCGA was used to predict PER1 expression in tissues; SRAMP predicted potential PER1 m⁶A sites. Methylated RNA immunoprecipitation (MeRIP) assays measured PER1 m⁶A modification. Finally, the effects of knocking down YTHDF2 and PER1 on 5637 and SW780 cell proliferation were assessed. RESULTS: YTHDF2 expression was significantly upregulated in bladder cancer tissues compared with adjacent tissues (mRNA: 2.5-fold; protein: 2-fold), which O-GlcNAc modification levels increased 3.5-fold (P<0.001). YTHDF2 was upregulated in bladder cancer cell lines, and its knockdown suppressed cell viability (P<0.001), downregulated PCNA, MCM2, and CyclinD1 (all P<0.05), reduced colony numbers 3-fold (P<0.01), and inhibited proliferation. YTHDF2 exhibited elevated O-GlcNAc modification in cancer cells. OSMI-1 reduced YTHDF2 protein stability (P<0.01) and enhanced ubiquitination, while Thiamet G exerted opposite effects (P<0.001). Thiamet G reversed the proliferation-suppressive effects of YTHDF2 knockdown, promoting cell proliferation (P<0.01) and upregulating PCNA, MCM2, and CyclinD1 (all P<0.05). Mechanistically, YTHDF2 targeted PER1 via m⁶A recognition, promoting PER1 mRNA degradation. Rescue experiments showed that PER1 knockdown reversed the inhibitory effect of YTHDF2 knockdown on cell proliferation, upregulated PCNA, MCM2, and Cyclin D1 (all P<0.05), and promoted bladder cancer cell proliferation (P<0.001). CONCLUSIONS O-GlcNAc modification YTHDF2 promotes bladder cancer development by downregulating the tumor suppressor gene PER1 through m⁶A-mediated post-transcriptional regulation.
Humans ; Urinary Bladder Neoplasms/metabolism* ; RNA-Binding Proteins/genetics* ; Cell Proliferation ; Cell Line, Tumor ; Disease Progression ; Acetylglucosamine/metabolism* ; Adenosine/metabolism* ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor

Objective:To explore the value of a scoring system based on preoperative abdominal computed tomography (CT) for predicting the difficulty of laparoscopic cholecystectomy (LC).Methods:A retrospective analysis was conducted on 105 patients diagnosed with gallstones or cholecystitis who underwent LC at Beijing Jishuitan Hospital, Capital Medical University from January 2021 and February 2022. Based on surgical video reviews, patients were divided into the easy group ( n=58) and the difficult group ( n=47) according to the intraoperative Parkland Grading Scale (PGS), with PGS grades 1-2 assigned to the easy group, and PGS grades 3-5 assigned to the difficult group. The normally distributed measurement data were expressed as mean±standard deviation ( ± s), and compared using independent samples t-test; the non-normally distributed measurement data were expressed as median (interquartile range) [ M ( Q1, Q3)], and compared using the rank-sum test. The count data were expressed as the number of cases and percentage, and compared using the Chi-square test or Fisher exact probability method. Univariate analysis and cut-off value determination: for continuous CT variables, univariate Logistic regression and stepwise regression analyses (with surgical difficulty grouping as the dependent variable) were performed to identify the optimal combination of predictive variables and establish a scoring system. For each significantly associated continuous variable or important CT image feature from a clinical perspective, receiver operating characteristic (ROC) curve analysis was used to evaluate its predictive performance for difficult surgery. The area under the curve (AUC) was calculated, and the optimal cut-off value was determined using the Youden index to maximize the sum of sensitivity and specificity. The categorical CT image features were scored according to their original groups. The Kappa consistency test was used to assess the strength of agreement between the preoperative abdominal CT score (grouped by the optimal cut-off) and PGS grades (easy/difficult). Decision curve analysis (DCA) was employed to validate the predictive performance of the model. Results:Stepwise Logistic regression identified seven key imaging features as the optimal predictive variables for constructing the preoperative abdominal CT scoring system: maximum gallbladder cross-sectional diameter, maximum gallbladder cross-sectional width, gallbladder wall thickness, common bile duct diameter, pericholecystic fat stranding, periductal fat stranding, and impacted cystic duct stones. Each case was scored after assigning scores based on the optimal cut-off values. The total score of the preoperative abdominal CT scoring system was ≥3 points predicted difficult LC with an AUC of 0.745 (95% CI: 0.650-0.839), sensitivity of 66.0%, and specificity of 75.9%. DCA confirmed the model′s reliable predictive performance, and the preoperative abdominal CT scoring system showed good agreement with PGS grades ( Kappa value was 0.420, P<0.001). Conclusions:The preoperative abdominal CT scoring system based on pericholecystic imaging features can effectively predict the difficulty of LC with good discriminative ability. It provides a quantitative tool for preoperative assessment, surgical scheduling, and ambulatory surgery management.

Due to decreased estrogen levels in patients with genitourinary syndrome of menopause(GSM), changes occur in the vaginal environment, including changes in vaginal tissue structure, the vaginal microbiota and vaginal mucosal immunity, resulting in a series of symptoms and signs.To develop effective treatment methods for GSM, it is necessary to fully understand potential molecular mechanisms underlying these changes.Mesenchymal stem cells(MSCs)can promote the regeneration of aging tissues, secrete growth factors, and have excellent immune regulation and anti-inflammatory capabilities.They are a powerful treatment option for reproductive aging.Therefore, it is essential to understand changes of the vaginal environment in GSM patients and progress on the use of MSCs as an intervention, in order to gain insight into research on the treatment of GSM.

Objective:To evaluate the effect of automated flexible endoscope channel brushing system (AFECBS) on endoscope reprocessing.Methods:A prospective randomized controlled study was conducted. The used endoscopes were divided into automatic group and manual group by random number table method, 200 in each group. In the automatic group, the AFECBS was used to scrub each tube 3 times during endoscope cleaning; and in the manual group, scrubbing and disinfection personnel routinely brushed each pipeline for 3 times. The primary end point was the qualified rate of endoscopic cleaning quality in the two groups, and the secondary end point was the time spent by the scrubbing and disinfection personnel on the two groups.Results:The qualified rate of overall cleaning in the automatic group was 90.0% (180/200), and in the manual group was 81.0% (162/200). The qualified rate of the automatic group was higher than that of the manual group ( χ2=6.534, P=0.011). The qualified rate of gastroscope cleaning in the automatic group was higher than that in the manual group [92.0% (127/138) VS 81.6% (120/147), χ2=6.658, P=0.010]. There was no significant difference in the qualified rate of colonoscope cleaning between the automatic group and the manual group [85.5% (53/62) VS 79.2% (42/53), χ2=0.774, P=0.379]. When the cleaning personnel scoured 5 endoscopes in each of the two groups, the time of the automatic group (5.17±0.42 min) was shorter than that of the manual group (9.60±0.53 min) ( t=92.644, P<0.001). Conclusion:Compared with manual scrubbing, AFECBS can improve the qualified rate of endoscope cleaning and the work efficiency of scrubbing and disinfection personnel, which is worthy of clinical application.

Aim To study the regulatory effect of poly-datin on D-galactose-induced aging model mice.Methods Fifty-six ICR mice(half male and half fe-male)were divided into normal group,model group,positive group,low,medium and high polydatin treat-ment groups.Aging model was established by subcuta-neous injection of D-galactose(500 mg·kg-1)into the back of neck every day.During the modeling peri-od,the positive group was given donepezil hydrochlo-ride tablets(0.75 mg·kg-1)by gavage,the treat-ment group was given polydatin(40,70,100 mg·kg1)by gavage,and the normal group was given the same amount of normal saline.The learning and cogni-tive ability of mice was evaluated by nesting experi-ment,new object recognition experiment and Morris water maze experiment.The heart,liver,spleen,kid-ney and thymus of mice were taken to calculate the or-gan index.The pathological changes of whole brain tis-sue in mice were observed by hematoxylin-eosin(HE)staining.The levels of T-SOD,MDA,GSH-Px and AchE in serum and whole brain tissue of mice were de-tected by ELISA.The protein expression levels of Keap1,Nrf2 and HO-1 in hippocampus of mice were detected by Western blot.Results Compared with the model group,the nesting ability,the ability to recog-nize new objects and the ability to find platforms under-water of the mice in the positive group and the low,medium and high dose groups of polydatin were im-proved.The organ index increased.The neuronal dam-age in the cerebral cortex and hippocampus was signifi-cantly ameliorated.The activities of T-SOD and GSH-Px in serum and brain tissue increased and the activi-ties of MDA and AchE decreased.The expression lev-els of Nrf2 and HO-1 protein in hippocampus in-creased,and the expression level of Keap1 protein de-creased.Conclusions Polydatin can ameliorate the learning and cognitive impairment in D-galactose-in-duced aging model mice,and its mechanism may be related to the Keap1/Nrf2/HO-1 pathway.

As key tools of diagnosis and treatment of cardiac arrhythmias,medical devices of cardiac electrophysiology are complex in composition and diverse in variety,bringing heavy economic burden to arrhythmia patients.Thus,it is crucial to scientifically select the medical devices of cardiac electrophysiology that meet the needs of clinic and management,and that have reasonably price.Based on clinical usage and management of medical devices of cardiac electrophysiology,an expert consensus of the assessment on the comprehensive value of medical devices of cardiac electrophysiology has been formed by China Association of Medical Equipment-Application Evaluation Branch,so as to provide references for medical institutions in grasping and identifying the essential value points of medical devices of cardiac electrophysiology.