Background/Aims: Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed. Methods: We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models. Results: ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis. Conclusions ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.

Objective To investigate the mechanism of modified Guizhi Fuling Pills in treating diabetic kidney disease(DKD)through autophagy regulation based on network pharmacology and experimental validation.Methods Active components and action targets of modified Guizhi Fuling Pills were screened via the TCMSP database.DKD-related autophagy targets were obtained from GeneCards,TTD,DrugBank and PharmGKB.A protein-protein interaction network was constructed using STRING,followed by GO functional and KEGG pathway enrichment analyses via DAVID.Molecular docking of key components and core targets was performed using AutoDock Tools 1.5.7.DKD model rats were prepared.The rats were randomly divided into normal group,model group,valsartan group(50 mg/kg),and modified Guizhi Fuling Pills low-,medium-and high-dosage group(9.9,19.8 and 39.6 g/kg).After 8-week interventions,body mass and water intake were recorded;fasting blood glucose,24 h urinary total protein(24 hUTP),urinary albumin-to-creatinine ratio(UACR)were monitored.Renal histopathology was evaluated via HE and Masson staining.Western blot was used to detect protein expressions of AMPK/FOXO1 pathway(p-AMPK,AMPK,FOXO1)and autophagy markers(Beclin-1,p62),while quantitative real-time PCR was used to assess AMPK and FOXO1 mRNA expressions.Results A total of 146 active components of Guizhi Fuling Pills and 33 main targets for treating DKD were screened,with the core targets including FOXO1,BCL2,TP53 and PTEN.KEGG pathway enrichment analysis suggested that AMPK/FOXO1 signaling pathway,AGE-RAGE and insulin signaling pathways may play a core regulatory role.Guizhi Fuling Pills could significantly reduce the body mass of DKD rats,reduce water intake,decrease renal index,decrease fasting blood glucose,24 hUTP and UACR(P<0.05,P<0.01),improve renal tissue pathology,increase AMPK,FOXO1,Beclin-1 protein expressions and AMPK,FOXO1 mRNA expressions(P<0.05),and reduce p62 protein expression(P<0.05).Conclusion Modified Guizhi Fuling Pills may exert therapeutic effects on DKD by regulating the AMPK-FOXO1-autophagy axis.

Objective:To evaluate the efficacy and safety of nebulized inhalation of recombinant human interferon (IFN) α1b injection in the treatment of respiratory syncytial virus (RSV) associated lower respiratory tract infections (pneumonia and bronchiolitis) in children.Methods:A randomized, double-blind, parallel, placebo-controlled add-on design was used.Children with pneumonia or bronchiolitis aged 2 months to 5 years who tested positive for RSV antigen within 72 hours of onset from 30 clinical trial sites including Beijing Children′s Hospital, Capital Medical University between February 2021 and December 2022 were included in this study and randomly divided into 2 groups at a ratio of 1∶1 based on a stratified-block method.Both groups received basic treatments such as cough control, asthma relieving, expectorant treatment, fever reduction, oxygen therapy, etc.The experimental group received additional nebulized inhalation of IFN α1b injection at a dose of 2.0 μg/(kg·time), twice a day.The control group received nebulized inhalation of placebo twice a day.Clinical efficacy was evaluated based on indicators such as the duration of clinical symptoms and signs, and the Kaplan-Meier method was used to calculate the median and 95% CI of the duration of clinical symptoms and signs.The Log-rank test was used to compared data between groups.Safety was assessed through the incidence of adverse reactions and laboratory tests, and the Chi-square test was used to analyze the difference between groups. Results:There were 123 children in the experimental group and 122 children in the control group.The median durations of all the 5 clinical symptoms and signs [including shortness of breath, wheezing, dyspnea (visible retractions), decreased transcutaneous oxygen saturation, and abnormal mental state] in the experimental group after treatment were slightly shortened than those in the control group [2.7 d(95% CI: 1.9-3.0 d)] vs.[2.9 d(95% CI: 2.6-3.6 d), P=0.027].The improvement in dyspnea (retractions) was especially pronounced in the experimental group, with a relief rate of 50.0% (0, 100%) on the first day of administration[compared with 0 (0, 50.0%) in the control group ( Z=2.002, P=0.025)].The median duration of dyspnea in the experimental group was nearly 1 day shorter than that in the control group [1.0 d(95% CI: 0.7-1.7 d) vs.1.8 d(95% CI: 1.0-2.5 d), P=0.046].There were no significant difference in hospital stay [6.0(5.0, 8.0) d vs.6.5(5.0, 8.0) d, Z=0.675, P=0.500], oxygen therapy duration [32.0(14.0, 96.3) h vs.39.0 (24.0, 83.2) h, Z=0.094, P=0.925], the recovery rate from clinical symptoms during treatment [(105/106, 99.1%) vs.(96/101, 95.0%)], and recurrence rate [(0/106, 0) vs.(2/101, 2.0%)] between the 2 groups (all P>0.05).However, the above-mentioned four indicators in the experimental group showed a trend of clinical benefits.The quantitative virus detection results showed that the RSV viral load in both groups decreased after treatment compared to before treatment.After 2 days of treatment, the decline rate of RSV viral load from the baseline was 0.90 lg copies/(mL·d) in the experimental group and 0.25 lg copies/(mL·d)in the control group, with a statistically significant difference ( P<0.05).Furthermore, there was no statistically significant difference in the incidence of adverse reactions between the 2 groups ( P>0.05).Importantly, no drug-related serious adverse reactions occurred in both groups. Conclusions:The nebulized inhalation therapy of IFN α1b demonstrates efficacy and safety in treating pediatric RSV associated lower respiratory tract infections.It particularly offers outstanding clinical therapeutic value for severe children.

Stress urinary incontinence is one of the common symptoms of women during pregnancy and postpartum, which has a lasting impact on the life of patients, and is also one of the public health issues of concern in the world. In this study, the generation, development, construction process, prediction performance and management application of stress urinary incontinence risk prediction models during pregnancy and postpartum were reviewed, with a view to improving the understanding of health care workers on stress urinary incontinence risk prediction models during pregnancy and postpartum, and providing references for promoting the health management of female patients.

Objective To evaluate the short-term clinical effect(including curative efficacy,pain relief,and quality of life)of CT-assisted 3D printing template-guided implantation of 125I particles in treating head and neck malignancies.Methods A total of 12 patients with head and neck malignant tumors complicated by moderate to severe cancerous pain,who were admitted to Yichang Municipal second People's Hospital to receive treatment from September 2019 to July 2024,were enrolled in this study.All patients received CT-assisted 3D individualized template-guided implantation of 125I particles therapy.The short-term curative efficacy,pain relief,and quality of life of patients were evaluated.Results Three months after implantation of 125I particles,complete response(CR)was obtained in 3 patients,partial remission(PR)in 5 patients,and stable disease(SD)in 4 patients,with an objective response rate(ORR)of 66.67％and a disease control rate(DCR)of 100％.The preoperative mean NRS score was(5.58±0.79)points,and the postoperative 3-month mean NRS score was(2.08±0.67)points.The postoperative 3-month physiological well-being(PWB),emotional well-being(EWB),functional well-being(FWB),and the total score were significantly better than their preoperative values,the differences were statistically significant(P＜0.05).No statistically significant difference in social/family well-being(SWB)existed between its postoperative 3-month value and its preoperative value.Adverse reactions occurred in 2 patients,including local mucosal ulceration(n=1)and skin redness with swelling(n=1),which were improved after treatment.No serious complications occurred.Conclusion For the treatment of patients with head and neck malignant tumors complicated by moderate to severe cancerous pain,radioactive 125I particle implantation has a significant short-term effect,it can effectively relieve cancerous pain and improve quality of life of patients with reliable clinical safety.

Objective:To explore the molecular mechanism of TCM compound Shengxue Tongbian Granules in improving intestinal injury in septic rats through bioinformatics and experimental validation methods.Methods:The GSE131761 gene set was processed by bioinformatics to screen differential genes, then weighted gene co-expression network analysis (WGCNA) was applied to screen modular genes. The intersection of modular genes and differential genes was taken, and finally, the least absolute shrinkage and selection operator (LASSO) technique was applied to further obtain the key targets of sepsis, which was validated by experiments. Totally 72 SD rats were divided into sham-operation group, model group, dexamethasone group (0.15 mg/kg), Shengxue Tongbian Granules low- (0.3 g/kg), medium- (0.6 g/kg), and high-dosage (1.2 g/kg) groups, with 12 rats in each group. Corresponding drug interventions were administered to each treatment group before and 12 hours after modeling. The sham-operation group and the model group were gavaged daily with equal amounts of saline. Samples were collected after 24 hours. HE staining was used to detect the pathological morphology of intestinal tissues in each group of rats; ELISA was used to detect the levels of TNF-α, diamine oxidase (DAO), IL-6, IL-10, and myeloperoxidase (MPO) in rat serum. Immunohistochemistry was used to detect the protein expressions of MPO and neutrophil elastase (NE/LANE) in intestinal tissue, and Western blot was used to detect the protein expression of peptidyl arginine deaminase (PAD4) in intestinal tissue.Results:Seven final key genes related to sepsis were selected, namely ANXA3, CYP1B1, FCAR, LILRA5, PADI4, NOV, and S100A12. Experimental results showed that drug administration alleviated intestinal injury; compared with the model group, the levels of TNF-α, IL-6, MPO, and DAO decreased in the Shengxue Tongbian Granules high-dosage group ( P<0.05), the levels of ELANE and MPO were reduced in Shengxue Tongbian Granules low-, medium-, and high-dosage groups ( P<0.05), and PAD4 expression was reduced in the Shengxue Tongbian Granules high-dosage group ( P<0.05). Conclusion:Shengxue Tongbian Granules can improve the intestinal injury of septic rats, and the mechanism may be related to the inhibition of PAD4-mediated formation of NETs and the improvement of inflammatory response.

Background: Psoralea corylifolia L. (Buguzhi, BGZ), known for its efficacy in supporting pregnancy and preventing miscarriage, has been used in China for over 1000 years. Recently, BGZ has been identified as a potential cause of drug-induced liver injury. However, its safety during pregnancy remains unclear, which significantly hinders its routine clinical application. Objective: To investigate the effects of BGZ administration during pregnancy on the liver of mouse mothers and their weaned 21-day-old offspring. Methods: Mice were orally administered BGZ at doses of 2.5 and 10 g/kg during pregnancy, with BGZ withdrawal during the lactation period. Liver histopathology (hematoxylin-eosin staining), biochemical analysis, and evaluation of liver bile acid metabolism were performed after the lactation period. Results: BGZ administration at doses of 2.5 and 10 g/kg during pregnancy, followed by withdrawal during the lactation period, caused mild liver damage in both mothers and their 21-day-old offspring. Serum total bile acid (TBA) levels were elevated compared with those in the control group. Additionally, changes were observed in the levels and proportions of various bile acids (BAs) in the liver, suggesting mild effects on BA metabolism. Conclusion: BGZ administration during pregnancy caused mild liver damage and increased serum TBA levels in both mouse mothers and their 21-day-old offspring. This phenomenon may be associated with imbalanced BA metabolism in the liver. Based on the present study and the limited toxicological research on BGZ, pregnant women should avoid prolonged use of BGZ. If BGZ is administered during pregnancy, serum TBA levels should be monitored, and if elevated, BGZ should be discontinued.

Background: Aristolochic acid II (AAII), a major nephrotoxic and carcinogenic component of aristolochic acids (AAs), has been less studied compared with its well-characterized analog, aristolochic acid I (AAI). Although AAs are known to induce carcinogenesis via DNA adduct formation, the toxicity mechanisms, environmental prevalence, and long-term health impacts of AAII remain poorly understood. Objective: This study aimed to systematically evaluate AAII’s acute and chronic toxicity, carcinogenic mechanisms, and environmental exposure patterns using integrated murine models and phytochemical analyses to clarify its toxicological profile and associated health risks. Methods: C57BL/6J mice were used in the following experiments: (1) determination of AAII content in 3 commonly used Aristolochia medicinal materials via liquid chromatography-mass spectrometry/mass spectrometry; (2) acute toxicity testing with single doses of 10, 20, or 40 mg/kg; and (3) chronic exposure with 1 or 10 mg/kg administered every other day for 24 weeks, followed by 21 to 40 weeks of postexposure monitoring. Histopathological examination, whole-exome sequencing, biochemical assays, and micronucleus tests were performed to assess multi-organ damage, tumorigenesis, genomic mutation signatures, and direct clastogenicity. Phytochemical analyses were used to evaluate environmental distribution. Results: (1) A single 40 mg/kg dose of AAII induced dose-dependent renal tubular degeneration without hepatotoxicity; (2) the 10 mg/kg group showed significant mortality (20%), tumor incidence (33.3%, primarily forestomach and bladder transitional cell carcinomas), persistent renal interstitial fibrosis, and subclinical hepatic injury. Chronic exposure to 1 mg/kg still induced 13.3% mortality and 15.5% tumor incidence over a 64-week period; (3) whole-exome sequencing revealed a predominance of C>T mutations and pathway enrichment in chemical carcinogenesis and cytochrome P450-mediated metabolism, indicating reactive metabolite-driven mechanisms distinct from classical AA-DNA adducts; and (4) no histopathological changes were observed in nontarget organs (brain, heart, and testes), and micronucleus assays confirmed the absence of direct clastogenicity. Conclusion: This study highlights the delayed carcinogenic risks of low-dose chronic AAII exposure and emphasizes the need to update regulatory frameworks to ensure the safe use of aristolochiaceae-containing herbal products.

Objective To investigate the mechanism of modified Guizhi Fuling Pills in treating diabetic kidney disease(DKD)through autophagy regulation based on network pharmacology and experimental validation.Methods Active components and action targets of modified Guizhi Fuling Pills were screened via the TCMSP database.DKD-related autophagy targets were obtained from GeneCards,TTD,DrugBank and PharmGKB.A protein-protein interaction network was constructed using STRING,followed by GO functional and KEGG pathway enrichment analyses via DAVID.Molecular docking of key components and core targets was performed using AutoDock Tools 1.5.7.DKD model rats were prepared.The rats were randomly divided into normal group,model group,valsartan group(50 mg/kg),and modified Guizhi Fuling Pills low-,medium-and high-dosage group(9.9,19.8 and 39.6 g/kg).After 8-week interventions,body mass and water intake were recorded;fasting blood glucose,24 h urinary total protein(24 hUTP),urinary albumin-to-creatinine ratio(UACR)were monitored.Renal histopathology was evaluated via HE and Masson staining.Western blot was used to detect protein expressions of AMPK/FOXO1 pathway(p-AMPK,AMPK,FOXO1)and autophagy markers(Beclin-1,p62),while quantitative real-time PCR was used to assess AMPK and FOXO1 mRNA expressions.Results A total of 146 active components of Guizhi Fuling Pills and 33 main targets for treating DKD were screened,with the core targets including FOXO1,BCL2,TP53 and PTEN.KEGG pathway enrichment analysis suggested that AMPK/FOXO1 signaling pathway,AGE-RAGE and insulin signaling pathways may play a core regulatory role.Guizhi Fuling Pills could significantly reduce the body mass of DKD rats,reduce water intake,decrease renal index,decrease fasting blood glucose,24 hUTP and UACR(P<0.05,P<0.01),improve renal tissue pathology,increase AMPK,FOXO1,Beclin-1 protein expressions and AMPK,FOXO1 mRNA expressions(P<0.05),and reduce p62 protein expression(P<0.05).Conclusion Modified Guizhi Fuling Pills may exert therapeutic effects on DKD by regulating the AMPK-FOXO1-autophagy axis.

Objective To analyze the effectiveness and safety of low molecular weight heparin(LMWH)combined with urokinase thrombolysis in the treatment of elderly patients with acute ischemic stroke(AIS).Methods A total of 132 elderly AIS patients admitted in Department of Neurology of Wuhan No.1 Hospital from January 2023 to September 2024 were recruited,and randomized into control group,group A,group B and group C,with 33 cases in each group.Besides urokinase thrombolysis as basic treatment,the patients in groups A,B and C were given LMWH within 24,24-47 and 48-72 h after thrombolysis,respectively.After 1 week of treatment,the incidence rate of cerebrovascular re-occlusion was compared among the four groups.Plasma prothrombin time(PT),platelet count(PLT),fibrinogen(Fib),nerve growth factor(NGF),neuron-specific enolase(NSE),neurotrophic factor(NTF)and National Institutes of Health Stroke Scale(NIHSS)score were compared before and after treatment and among the four groups.The incidences of adverse reactions were also compared among them during treatment.Results Compared with the levels before treatment,the levels of NGF and NTF were significantly increased,while the PT,PLT,Fib and NSE levels and NIHSS score were obviously decreased in the four groups after 1 week of treatment(P＜0.05).At 1 week of treatment,group A obtained notably higher NGF and NTF levels,and remarkably lower PT,PLT,Fib and NSE levels and NIHSS score than the other three groups(P＜0.05).So were group B when compared with group C and control groups(P＜0.05),and group C when compared with control group(P＜0.05).There was no statistical significance in the comparison of total incidence rate of adverse reactions during treatment among the four groups(P＞0.05).Conclusion LMWH combined with urokinase thrombolytic therapy can effectively improve the coagulation status and neurological function for elderly AIS patients,and the earlier it is applied,the better the efficacy will be.