Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Objective: To explore the key factors affecting the selection and effectiveness of bladder management modalities in patients with spinal cord injury，so as to provide reference for the optimization of individualized bladder management strategies. Methods: The clinical and follow-up data of 78 patients with spinal cord injury treated in our hospital during Jan.1,2013 and Dec.31,2022 were retrospectively analyzed.The distribution of bladder management modalities among different grades of injuries was analyzed. Bowker symmetry test was used to evaluate the difference between bladder management modalities at discharge and at the end of follow-up. Multiple linear regression was used to explore the influencing factors of bladder management effects. Plotting Kaplan-Meier survival curves were adopted to calculate the median time of changes in bladder management. Results: At discharge，there were 9 cases of self-catheterization，19 cases of intermittent catheterization，22 cases of reflexive voiding，26 cases of long-term catheterization，and 2 cases using urinary collector.At the end of follow-up，there were 15 cases of self-catheterization，8 cases of intermittent catheterization，34 cases of reflexive voiding，14 cases of long-term catheterization，and 7 cases using urinary collector.There was a significant difference between the modalities of bladder management at discharge and at the end of follow-up (χ =21.43，P=0.018).Multiple linear regression showed a significant decrease of 8.60 in the total neurogenic bladder symptom score (NBSS) for grade D injuries compared with grade A injuries (P=0.026). The median time to bladder management change was 7.93 months (95%CI:5.44-9.44), with approximately 50% of patients experiencing a change in bladder management within 8 months after discharge. Conclusion: The modalities of bladder management changed significantly after discharge.The grade of injury was a key factor affecting the effectiveness of bladder management.Higher grade was associated with worse effectiveness of bladder management.

BackgroundNon-suicidal self-injury （NSSI） behavior among adolescents has become a global public health concern. Anxiety and depression are considered key factors influencing NSSI behavior， while social support may play a protective role in alleviating emotional and behavioral issues. However， existing research has primarily focused on the direct impact of individual factors on NSSI behavior， with insufficient exploration of the combined effects of anxiety， depression and social support. ObjectiveTo investigate the direct effect of anxiety on NSSI， the mediating role of depression and the moderating role of social support in relationship between anxiety and NSSI behavior， thus to provide references for the prevention and intervention of NSSI behavior among adolescents. MethodsIn February 2022， a total of 40 820 students in grades 7 to 12 across 10 middle schools in a district of Chengdu were selected as participants， and they were assessed using Generalized Anxiety Disorder Scale-7 item （GAD-7）， Patient's Health Questionnaire Depression Scale-9 item （PHQ-9）， Social Support Scale for Urban Students （SSSUS） and Adolescent Self-Harm Scale （ASHS）. Pearson correlation analysis was conducted to examine the correlations between scale scores among adolescents with NSSI behaviors. Mediation and moderation analyses were performed using Process 3.5 in SPSS， and the significance was tested with bootstrapping. The interaction was visualized by using simple slope analysis. ResultsAmong 34 534 （84.60%） valid respondents， 542 adolescents （1.57%） reported engaging in NSSI behavior. Significant differences in gender， GAD-7 scores， PHQ-9 scores， and SSSUS scores were observed between NSSI behavior group and non-NSSI group （χ²/t=62.889， 71.120， 94.365， -41.464， P<0.01）.Adolesents with NSSI showed positive correlations between GAD-7 scores and both ASHS and PHQ-9 scores （r=0.158， 0.166， P<0.01）. PHQ-9 scores were positively correlated with ASHS scores （r=0.364， P<0.01）， but negatively correlated with SSSUS scores （r=-0.290， P<0.01）. SSSUS scores were negatively correlated with ASHS scores （r=-0.247， P<0.01）. Depression partially mediated the relationship between anxiety and NSSI behavior， with an effect size of 0.544 （95% CI： 0.162~0.944）， accounting for 35.79% of the total effect. Social support moderated the relationship between depression and NSSI bahavior， with an effect value of -0.082 （95% CI： -0.135~-0.029）. ConclusionAnxiety not only directly influences NSSI bahavior among adolescents， also indirectly exacerbates it through depression， while social support mitigates the impact of depression on NSSI behavior. ［Funded by Youth Project of National Natural Science Foundation of China （number， 82401812）； Project of Health Commission of Sichuan Province （number， 24LCYJPT18）］

ObjectiveTraditional Chinese medicine (TCM) constitutes a valuable cultural heritage and an important source of antitumor compounds. Poria (Poria cocos (Schw.) Wolf), the dried sclerotium of a polyporaceae fungus, was first documented in Shennong’s Classic of Materia Medica and has been used therapeutically and dietarily in China for millennia. Traditionally recognized for its diuretic, spleen-tonifying, and sedative properties, modern pharmacological studies confirm that Poria exhibits antioxidant, anti-inflammatory, antibacterial, and antitumor activities. Pachymic acid (PA; a triterpenoid with the chemical structure 3β-acetyloxy-16α-hydroxy-lanosta-8,24(31)-dien-21-oic acid), isolated from Poria, is a principal bioactive constituent. Emerging evidence indicates PA exerts antitumor effects through multiple mechanisms, though these remain incompletely characterized. Neuroblastoma (NB), a highly malignant pediatric extracranial solid tumor accounting for 15% of childhood cancer deaths, urgently requires safer therapeutics due to the limitations of current treatments. Although PA shows multi-mechanistic antitumor potential, its efficacy against NB remains uncharacterized. This study systematically investigated the potential molecular targets and mechanisms underlying the anti-NB effects of PA by integrating network pharmacology-based target prediction with experimental validation of multi-target interactions through molecular docking, dynamic simulations, and in vitro assays, aimed to establish a novel perspective on PA’s antitumor activity and explore its potential clinical implications for NB treatment by integrating computational predictions with biological assays. MethodsThis study employed network pharmacology to identify potential targets of PA in NB, followed by validation using molecular docking, molecular dynamics (MD) simulations, MM/PBSA free energy analysis, RT-qPCR and Western blot experiments. Network pharmacology analysis included target screening via TCMSP, GeneCards, DisGeNET, SwissTargetPrediction, SuperPred, and PharmMapper. Subsequently, potential targets were predicted by intersecting the results from these databases via Venn analysis. Following target prediction, topological analysis was performed to identify key targets using Cytoscape software. Molecular docking was conducted using AutoDock Vina, with the binding pocket defined based on crystal structures. MD simulations were performed for 100 ns using GROMACS, and RMSD, RMSF, SASA, and hydrogen bonding dynamics were analyzed. MM/PBSA calculations were carried out to estimate the binding free energy of each protein-ligand complex. In vitro validation included RT-qPCR and Western blot, with GAPDH used as an internal control. ResultsThe CCK-8 assay demonstrated a concentration-dependent inhibitory effect of PA on NB cell viability. GO analysis suggested that the anti-NB activity of PA might involve cellular response to chemical stress, vesicle lumen, and protein tyrosine kinase activity. KEGG pathway enrichment analysis suggested that the anti-NB activity of PA might involve the PI3K/AKT, MAPK, and Ras signaling pathways. Molecular docking and MD simulations revealed stable binding interactions between PA and the core target proteins AKT1, EGFR, SRC, and HSP90AA1. RT-qPCR and Western blot analyses further confirmed that PA treatment significantly decreased the mRNA and protein expression of AKT1, EGFR, and SRC while increasing the HSP90AA1 mRNA and protein levels. ConclusionIt was suggested that PA may exert its anti-NB effects by inhibiting AKT1, EGFR, and SRC expression, potentially modulating the PI3K/AKT signaling pathway. These findings provide crucial evidence supporting PA’s development as a therapeutic candidate for NB.

Objective To evaluate the pharmacokinetics characteristics of single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects.Methods This was a single-center,randomized,double-blind,placebo-controlled study.Twelve healthy adult Chinese subjects were randomized to receive single-dose of Etripamil nasal spray 70 mg(n=10)or placebo nasal spray(n=2).Blood and urine samples were collected prior and post dose.Etripamil in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry.The pharmacokinetic parameters were calculated by WinNonlin non-compartmental model.Results Following the single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects,the peak concentration of Etripamil in plasma was quickly attained,with a Cmax of(66.76±56.61)ng·mL-1 and a median(range)tmax of 4.00(3.00-5.00)min.The plasma concentrations of Etripamil had fallen approximately 65％from peak value at 25 min after dosing,and close to 80％within 50 min.The AUC0-last and AUC0-∞ were(3 104.16±2 654.46)and(4 048.77±2 682.38)ng·min·mL-1,respectively.The urine excretion percentage of Etripamil during 24 h was(0.01±0.01)％.Among the 12 subjects who were treated with Etripamil or placebo,10 subjects reported a total of 29 treatment-emergent adverse events(TEAEs).All of the TEAEs were mild in severity.The most common TEAEs were rhinorrhoea and lacrimation increased.Conclusion Etripamil was quickly absorbed after intranasal administration,followed by rapid distribution and elimination(not primarily excreted by renal);Etripamil 70 mg was safe and well tolerated by the healthy Chinese adult subjects.

Objective: To investigate the clinical characteristics of induced labor in twin pregnancy and the related factors of induced labor failure. Methods: The clinical data of twin pregnant women who underwent induced labor in Peking University Third Hospital from January 2016 to December 2022 were retrospectively analyzed. According to whether they had labor or not after induction, pregnant women were divided into the success group (pregnant women who had labor after induction, 72 cases) and the failure group (pregnant women who did not have labor after induction, 30 cases). Logistic regression was used to analyze the related factors of induction failure in twin pregnant women. Results: The parity and cervical Bishop score in the failure group were significantly lower than those in the success group, while the proportion of dichorionic diamniotic twins, assisted reproductive technology pregnancy and cervical Bishop score <6, postpartum hospital stay and total hospital stay in the failure group were significantly higher than those in the success group (all P<0.05). The proportion of induced labor by artificial rupture of membranes ± oxytocin intravenous infusion in the success group was 72.2% (52/72), which was significantly higher than that in the failure group (46.7%, 14/30; P=0.030). There were no significant differences between the two groups in the gestational age at delivery, the incidence of severe postpartum hemorrhage and blood transfusion, the amount of postpartum hemorrhage, the neonatal weight of two fetuses, the incidence of neonatal asphyxia, and the proportion of neonates admitted to the neonatal intensive care unit (all P>0.05). There were no severe perineal laceration and hysterectomy in all pregnant women. Multivariate logistic regression analysis showed that primipara (OR=3.064, 95%CI: 1.112-8.443; P=0.030) and cervical Bishop score <6 (OR=5.208, 95%CI: 2.008-13.508; P=0.001) were the independent risk factors for induction failure in twin pregnancy. Conclusions: Elective induction of labor in twin pregnancy is safe and feasible. It is helpful to improve the success rate of induction of labor by strictly grasping the timing and indications of termination of pregnancy, choosing the appropriate method of induction according to the condition of the cervix, and actively promoting cervical ripening .
Infant, Newborn ; Pregnancy ; Female ; Humans ; Pregnancy Trimester, Third ; Pregnancy, Twin ; Postpartum Hemorrhage/etiology* ; Retrospective Studies ; Labor, Induced/methods* ; Cervical Ripening

OBJECTIVE: To assess the risk of aristolochic acid (AA)-associated cancer in patients with AA nephropathy (AAN). METHODS: A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014. Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer. The primary endpoint was the incidence of liver cancer, and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014. RESULTS: A total of 337 patients diagnosed with AAN were included in this study. From the initiation of taking AA to the termination of follow-up, 39 patients were diagnosed with cancer. No cases of liver cancer were observed throughout the entire follow-up period, with urinary cancer being the predominant type (34/39, 87.17%). Logistic regression analysis showed that age, follow-up period, and diabetes were potential risk factors, however, the dosage of the drug was not significantly associated with urinary cancer. CONCLUSIONS No cases of liver cancer were observed at the end of follow-up. However, a high prevalence of urinary cancer was observed in AAN patients. Establishing a direct causality between AA and HCC is challenging.
Humans ; Retrospective Studies ; Incidence ; Carcinoma, Hepatocellular ; Liver Neoplasms/epidemiology* ; Kidney Diseases/chemically induced* ; Aristolochic Acids/adverse effects*

Idiosyncratic drug-induced liver injury (IDILI) has long posed a challenging and pivotal concern in pharmaceutical research. The complex composition of traditional Chinese medicine (TCM) has introduced a bottleneck in current research, hindering the elucidation of the component basis associated with IDILI in TCM. Using Epimedii Folium (EF) and Psoraleae Fructus (PF) as illustrative examples, this study endeavors to establish an in vitro evaluation model, providing a high-throughput and preliminary assessment method for screening components related to TCM-induced IDILI. A TNF-α-mediated HepG2 susceptible model was first established in this study, with the focus on the index components present in EF and PF. The release of lactate dehydrogenase (LDH) in the cell supernatant served as the detection index. A concentration-toxicity response curve was constructed, and the hepatotoxic components of EF and PF were identified utilizing the synergistic toxicity index. The LDH results unveiled the hepatotoxic effects of bavachin, backuchiol, isobavachin, neobavaisoflavone, psoralidin, isobavachalcone, icarisid I, and icarisid II on both normal and susceptible cells, categorizing these 8 components as both direct hepatotoxicity components and idiosyncratic hepatotoxicity components. Bavachin and neobavaisoflavone exhibited no hepatotoxicity on normal cells but demonstrated significant effects on susceptible cells, designating them as potential idiosyncratic susceptible hepatotoxicity components. The study further delineated that 10 EF components and 3 PF components were direct immune-promoting hepatotoxicity components. Additionally, 14 idiosyncratic immune-promoting hepatotoxicity components were identified, encompassing 10 EF components and 4 PF components, with neobavaisoflavone, bavachinin, and isobavachin being potential idiosyncratic susceptible immune-promoting hepatotoxicity components. Synergistic toxicity index results indicated that 13 idiosyncratic immune-promoting hepatotoxicity components (except anhydroicaritin) combined with bavachin demonstrated synergistic hepatotoxicity on susceptible cells. Notably, 3 idiosyncratic susceptible immune-promoting hepatotoxicity components combined with bavachin exhibited synergistic hepatotoxicity, with neobavaisoflavone displaying the highest synergistic toxicity index and bavachinin the lowest. In summary, this methodology successfully screens hepatotoxic and immune-promoting hepatotoxic components in EF and PF, distinguishing the types of components inducing hepatotoxicity, evaluating the hepatotoxicity degree of each component, and elucidating the synergistic relationships among them. Importantly, these findings align with the characteristics of IDILI. The method provides an effective model tool for the fundamental research of TCM-related IDILI components.