OBJECTIVE: To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A (SV2A) influences the distribution of amyloid precursor protein (APP) in the trans-Golgi network (TGN), endolysosomal system, and cell membranes and to reveal the effects of SV2A on APP amyloid degradation. METHODS: Colocalization analysis of APP with specific tagged proteins in the TGN, ensolysosomal system, and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP. APP, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) expressions, and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing. RESULTS: APP localization was reduced in the TGN, early endosomes, late endosomes, and lysosomes, whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons. Moreover, Arl5b (ADP-ribosylation factor 5b), a protein responsible for transporting APP from the TGN to early endosomes, was upregulated by SV2A. SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis. In addition, products of APP amyloid degradation, including sAPPβ, Aβ _1-42, and Aβ _1-40, were decreased in SV2A-overexpressed cells. CONCLUSION These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway, which slows APP amyloid degradation.
Amyloid beta-Protein Precursor/genetics* ; Membrane Glycoproteins/genetics* ; Animals ; Protein Transport ; Nerve Tissue Proteins/genetics* ; Humans ; Mice ; Endosomes/metabolism* ; trans-Golgi Network/metabolism*

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective:To identify the relevant factors for the first-course remission of acute myeloid leukemia (AML) and to develop a predictive model as well as assess its predictive capability.Methods:Clinical data of 749 patients newly diagnosed with AML admitted to the Department of Hematology, the First Affiliated Hospital, Zhejiang University, School of Medicine from January 1, 2019, to April 30, 2023, were collected and randomly divided into training and validation sets. Multivariate logistic regression analysis was conducted to determine variables associated with complete remission in the first course of induction therapy, and a predictive model was established based on these variables. The receiver operating characteristic (ROC) curve of the predictive model was plotted, and the area under the curve (AUC) was calculated.Results:The indicators predicting the first remission course included peripheral blood white blood cell count during onset, CBF::MYH11 fusion gene, CEBPA bZIP region mutation, myelodysplastic syndrome-related gene mutation, and induction chemotherapy regimen selection as independent factors for the first remission course. The model’s area under the training and validation curves was 0.738 (95% CI: 0.696-0.780) and 0.726 (95% CI: 0.650-0.801), respectively. The Hosmer-Lemeshow test results yielded P-values of 0.993 and 0.335, respectively. Conclusion:In this study, the developed model demonstrates a strong predictive capability for the efficacy of the first course of patients with AML, providing valuable guidance to clinicians in assessing patient prognosis and selecting appropriate treatment strategies.

Objective To explore the mechanism of action of jolkinolide B in the treatment of gastric cancer by network pharmacology combined with molecular docking technique.Methods The SwissTargetPrediction database was used to obtain the targets of the active compounds.Search Genecards,OMIM,Drugbank,TTD,and PharmGKB databases to obtain targets for gastric cancer.The intersection between the targets of jolkinolide B and those of gastric cancer was identified pinpoint potential targets for jolkinolide B in treating gastric cancer.The String database was utilized construct a protein-protein interaction(PPI)network.Bioconductor bioinformatics packages with R software was employed conduct Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis on the shared targets.This process revealed significant regulatory pathways crucial for jolkinolide B's efficacy in treating gastric cancer.Cytoscape 3.7.1 software was utilized create the core network of"Potential Targets of Triptolide B in Gastric Cancer Treatment",and SYBYL-X2.1.1 software was employed conduct molecular docking validation of the selected main active ingredients and critical targets.Results Jolkinolide B may target multiple proteins,including MAPK1,glycogen synthase kinae-3β(GSK-3β),and JUN,impacting the proliferation,invasion,and metastasis of gastric cancer,ultimately inhibiting its growth.Conclusion We predicted the possible molecular mechanism of jolkinolide B in the treatment of gastric cancer to provide guide information for the subsequent experimental research and clinical application.

Objective To explore the mechanism of cinobufagin(CBG)in treating gastric cancer based on network pharmacology combined with bioinformatics and molecular docking technology.Methods Active ingredients and potential targets of CBG in treating gastric cancer were collected from PubChem,TCMSP,and SwissTargetPrediction databases.Transcriptional data of gastric cancer samples were obtained from TGGA database,and gastric cancer-related targets were identified through differential gene analysis.Intersection of targets between CBG and gastric cancer diseases was subjected to Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.Protein-protein interaction(PPI)network of common targets was constructed using STRING database,and core targets were selected using Cytoscape software.Molecular docking verification of core targets screened with SYBYL-X 2.1.1 software was conducted with CBG.Results CBG treatment of gastric cancer involved 59 targets,with 19 key targets identified.Key targets such as aurora kinase A(AURKA),cyclin-dependent kinase 1(CDK1),enhancer of zeste homolog 2(EZH2),hepatocyte growth factor receptor(MET),matrix metallopeptidase 3(MMP-3),progesterone receptor(PGR),prostaglandin-endoperoxide synthase 1(PTGS1),and thymidylate synthase(TYMS)which exhibited good binding activity with CBG and were closely associated with gastric cancer prognosis.Conclusion CBG may exert anti-gastric cancer effects through multiple targets and pathways.

Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.
Reperfusion Injury/drug therapy* ; Reactive Oxygen Species/metabolism* ; Reactive Nitrogen Species/metabolism* ; Humans ; Liver/drug effects* ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology*

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

The patient was a boy aged 1 year and 9 months who presented with 46,XY disorder of sex development (DSD), with severe undermasculinization of the external genitalia. Laboratory tests and ultrasound examinations showed normal functions of Leydig cells and Sertoli cells in the testes. Genetic testing revealed a novel pathogenic heterozygous variant, c.1186dupA (p.T396Nfs*17), in the PPP1R12A gene. Thirteen cases of PPP1R12A gene variants have been reported previously. These variants may cause isolated involvement of the genitourinary or neurological systems, or affect other systems/organs including the digestive tract, eyes, heart, etc. Patients with DSD typically present with a 46,XY karyotype and variable degrees of undermasculinization involving the external genitalia, gonads, and reproductive tract. This article reports a child with 46,XY DSD accompanied by growth retardation caused by a heterozygous variant in the PPP1R12A gene, which expands the clinical disease spectrum associated with PPP1R12A gene variants.
Humans ; Male ; Infant ; Disorder of Sex Development, 46,XY/etiology* ; Protein Phosphatase 1/genetics*

ObjectiveTo study the effect of Zuoguiwan on the development of skin barrier in the neonatal rat model of congenital kidney deficiency and unveil the underlying mechanism. MethodsSixty rats were paired in a female-to-male ratio of 2∶1， and the pregnant rats were assigned into control， congenital kidney deficiency， and low- and high-dose （2 and 8 g·kg^-1， respectively） Zuoguiwan groups. The pregnant rats in other groups except the control group were exposed to chronic unpredictable mild stress for the modeling of congenital kidney deficiency. The rats in the control group and congenital kidney deficiency group were administrated with normal saline by gavage， and those in Zuoguiwan groups with Zuoguiwan suspension by gavage from day 1 of pregnancy. The serum level of interleukin-6 （IL-6） in the neonatal rats on the day of birth was determined by enzyme-linked immunosorbent assay. The full-thickness skin of neonatal rats on the day of birth was removed from the same position on the back and stained with hematoxylin-eosin for observation of histopathological changes， measurement of skin thickness， and counting of hair follicles. Terminal deoxynucleotidyl transferase-mediated nick end labeling was used to detect the apoptosis of skin tissue cells. The expression of interleukin-6 receptor （IL-6R） and interleukin-17A （IL-17A） in the skin tissue was assessed by immunohistochemistry and Western blot， and the expression of occludin， connexin 43 （Cx43）， and zonula occludens-1 （ZO-1） in the skin tissue was assessed by immunofluorescence and Western blot. ResultsCompared with those in the control group， the neonatal rats in the congenital kidney deficiency group showed a rise in the serum IL-6 level （P<0.01）， decreases in stratum corneum thickness， skin thickness， and number of hair follicles （P<0.01）， increases in the expression of IL-6R and IL-17A in the skin tissue （P<0.01） and the number of apoptotic cells （P<0.01）， and decreases in the expression of occludin， Cx43， ZO-1 （P<0.05）. Compared with the congenital kidney deficiency group， the low- and high-dose Zuoguiwan groups showed declines in serum IL-6 level （P<0.05）. The low-dose group showed increased number of hair follicles （P<0.05）， and the high-dose group presented thickened stratum corneum （P<0.01）， increased number of hair follicles （P<0.01）， and down-regulated expression of IL-6R and IL-17A in the skin tissue （P<0.05， P<0.01）. Both Zuoguiwan groups showcased decreased number of apoptotic cells （P<0.05， P<0.01）， and the high-dose group showed up-regulated expression of occludin， Cx43， and ZO-1 in the skin tissue （P<0.05， P<0.01）. ConclusionZuoguiwan can reduce the levels of IL-6 in the serum and IL-6R and IL-17A in the skin tissue and improve the expression of intercellular junction proteins， thereby ameliorating the abnormal development of the skin barrier in the neonatal rat model of congenital kidney deficiency.