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.

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 establish a preparation method for Phellodendrine-11-O-β-D-glucuronide(M1),a metabolite of Phellodendrine(PHE),and to evaluate its regulatory effects on glycolipid metabolism disorder in insulin-resistant HepG2(IR-HepG2)cells.METHODS The preparation,extraction,separation,purification and identification of M1 were completed by in vitro incuba-tion of intestinal microsomes combined with liquid phase,mass spectrometry and NMR.With Metformin as positive control,IR-HepG2 cells were treated with low(25 μmol·L-1),medium(50 μmol·L-1)and high(100 μmol·L-1)doses of M1 for 24 h.Glucose con-sumption,glucose uptake,triglyceride(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL-C)and low density lipoprotein cholesterol(LDL-C)were quantified.The binding ability of M1 to the key targets INSR,IRS1,PI3K and AKT2 in the IRS1/PI3K/AKT pathway was explored through molecular docking technology.The effects of M1 on the mRNA and protein expression of these key targets in the IRS1/PI3K/AKT pathway were detected by qPCR and Western blot,respectively.RESULTS The purified product was confirmed by NMR as Phellodendrine-11-O-β-D-glucuronide(95%purity).Compared to the model group,all M1 do-ses significantly enhanced glucose consumption(P<0.01,P<0.001)and uptake(P<0.001)in IR-HepG2 cells,outperforming PHE(P<0.001).At medium and high doses,it could significantly reduce the content of TG and TC in cells(P<0.001),and its improve-ment effect at the TG level was better than that of PHE(P<0.01);while all concentrations decreased LDL-C(P<0.001)and in-creased HDL-C(P<0.01,P<0.001).Molecular docking revealed strong binding interactions between M1 and INSR,IRS1,PI3K,and AKT2.Compared with the model group,M1 administration group increased the expression of INSR,IRS1,PI3K,AKT2,and GLUT2 mRNA to varying degrees,downregulated the protein expression of p-IRS1/IRS1(P<0.001),and upregulated the protein ex-pression of PI3K,p-AKT/AKT,and p-GSK3β/GSK3β.CONCLUSION The established protocol enables high purity M1 prepara-tion.M1 alleviates IR by regulating IRS1/PI3K/AKT signaling pathway to improve the disorder of glycolipid metabolism.

Objective:To investigate the efficacy and safety of off-label use of flow diverters (FDs) in aneurysms beyond the circle of Willis.Methods:Seventy-one patients with aneurysms beyond the circle of Willis treated with FDs from January 2016 to September 2023 at Department of Cerebrovascular Surgery, Neurosurgery Center (Zhujiang Hospital of Southern Medical University), Department of Neurosurgery (Guangdong Provincial People's Hospital), Department of Neurosurgery (First Affiliated Hospital of Chongqing Medical University), and Department of Neurosurgery (Beijing Tiantan Hospital, Capital Medical University) were selected. The clinical and imaging data of these patients were analyzed retrospectively, and the clinical characteristics, aneurysm characteristics, endovascular treatments, perioperative complications, and clinical and imaging follow-up results were summarized and analyzed.Results:Among the 71 patients, 22 (31.0%) had ischemic stroke history and 43 (60.6%) had hypertension history. A total of 76 aneurysms were found, including 5 aneurysms (6.6%) at the anterior communicating artery, 10 (13.2%) at the anterior cerebral artery, 53 (69.7%) at the middle cerebral artery, and 8 (10.5%) at the posterior cerebral artery. The median aneurysm size (Inter Quartile Range) was 5.65 (3.63, 10.12) mm, and mean diameter of the parent artery was (2.70±0.57) mm. A total of 80 FDs were used, including 38 (47.5%) Pipeline embolization devices and 42 (52.5%) Tubridge embolization devices; the implantation success rate was 98.8% (79/80). Seven patients (9.9%) had perioperative complications, of which 2 (2.8%) were permanent (1 patient with visual field defect and 1 patient with intracranial hemorrhage). Seventy-one patients had clinical follow-up for (19.73±11.90) months, of which 68 patients (95.8%) had good outcome (modified Rankin scale score of 0-2), 10 patients (14.1%) had ischemic complications, and one patient (1.4%) had hemorrhage complications. Sixty-seven aneurysms (88.2%) underwent angiographic follow-up for 7 (6-12) months, of which 44 aneurysms (65.7%) were completely occluded and 10 (14.9%) had in-stent stenosis.Conclusion:The results of this study preliminarily confirm that off-label use of FDs is relatively safe and effective in aneurysms beyond the circle of Willis.

Objective:To evaluate the efficacy and safety of intrasaccular flow disruptor in wide-necked intracranial aneurysms.Methods:One hundred and seventeen patients with wide-necked intracranial aneurysms treated with intrasaccular flow disruptor were collected from Department of Neurointervention (First Affiliated Hospital of Zhengzhou University), Department of Neurosurgery (Beijing Tiantan Hospital, Capital Medical University), Department of Cerebrovascular Surgery, Neurosurgery Center (Zhujiang Hospital, Southern Medical University), and Department of Neurosurgery (First Affiliated Hospital of Harbin Medical University) from August 2022 to March 2024. Raymond-Roy Occlusion Classification (RROC) was employed to evaluate aneurysm embolization immediately after procedure; cranial CT or MRI within 48 hours of embolization were performed to identify any new intracranial hemorrhage, subarachnoid hemorrhage, or new symptomatic cerebral infarction related to the intracranial aneurysms. Modified Rankin Scale (mRS) was used to assess the neurological function at discharge. Imaging follow-up and outpatient follow-up were performed at 6 months after embolization to evaluate the aneurysm occlusion degree and complications.Results:A total of 117 intrasaccular flow disruptors were implanted in 117 patients, with a technical success rate of 100%; 115 patients (98.3%) enjoyed successful one-time release of their disruptors, and 2 patients (1.7%) required retrieval and redirection of the disruptors before second successful attempt. Flow disruptor plus stent was performed in 13 patients (11.1%). Immediately after procedure, RROC grading I was noted in 3 patients, grading II in 51 patients and grading III in 63 patients. Cranial CT or MRI within 48 hours of embolization indicated no new intracranial hemorrhage, subarachnoid hemorrhage, or symptomatic cerebral infarction related to the intracranial aneurysms. All patients had mRS score of 0 at discharge. Eighty-three patients completed a 6-month follow-up (RROC grading I in 41 patients, grading II in 33 patients and grading III in 9 patients), without ischemic or hemorrhagic adverse events.Conclusion:The results of this study preliminarily suggest that intrasaccular flow disruptor is effective and safe in wide-necked intracranial aneurysms.

Objective:To evaluate the efficacy and safety of Neuroform Atlas stent-assisted coil embolization in patients with middle cerebral artery bifurcation aneurysms.Methods:A retrospective analysis was performed; the clinical data of 46 patients with middle cerebral artery bifurcation aneurysms accepted Neuroform Atlas stent-assisted coil embolization in First Affiliated Hospital of Zhengzhou University, Beijing Tiantan Hospital Affiliated to Capital Medical University, First Affiliated Hospital of Harbin Medical University, Zhujiang Hospital of Southern Medical University and First Affiliated Hospital of Chongqing Medical University from January 2022 to March 2024 were collected. There were 28 ruptured aneurysms (60.87%) and 18 unruptured aneurysms (39.13%). Follow-up was performed for more than 3 months; Raymond-Roy grading was used to evaluate the aneurysm embolization immediately after embolization and during follow-up; perioperative hemorrhagic or ischemic complications were recorded; modified Rankin Scale (mRS) was used to evaluate the prognosis of the patients at discharge and during follow-up (mRS score≤2: good prognosis, and mRS score>2: poor prognosis).Results:Coil embolization was successful in all 46 patients. DSA immediately after embolization showed that 41 patients (89.13%) had completely occluded aneurysms (Raymond-Roy grading I), 2 patients (4.35%) had residual aneurysm neck (Raymond-Roy grading Ⅱ) and 3 patients (6.52%) had partially occluded aneurysms (Raymond-Roy grading Ⅲ). Perioperative complications occurred in 5 patients, including 2 with postoperative cerebral infarction, 1 with hydrocephalus, 1 with postoperative pneumonia leading to respiratory failure, and 1 with stent thrombosis during embolization. Both at discharge and 3 months after embolization, 43 patients (93.48%) had good prognosis and 3 patients (6.52%) had poor prognosis. No obvious ischemic complications (such as stent restenosis) or hemorrhagic complications (such as re-rupture of the aneurysms) were found in all patients. Thirty patients (65.22%) had imaging follow-up for 6-12 months: 26 (86.67%) had Raymond-Roy grading I, 3 (10.00%) had Raymond-Roy grading II, and 1 (3.33%) had Raymond-Roy grading III.Conclusion:Neuroform Atlas stent-assisted coil embolization has good short-term efficacy and high safety in middle cerebral artery bifurcation aneurysms, but long-term follow-up observation is still needed to verify its efficacy.

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.

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.

AIM:To investigate the regulatory role and molecular mechanisms of the p62-NIMA(never in mi-tosis gene A)-related kinase 7(NEK7)-gasdermin D(GSDMD)-mediated pyroptosis axis in a mouse model of gouty arthri-tis.METHODS:C57BL/6 mice were randomly divided into control group,model group,and colchicine group(n=5 per group).Conditional knockout mouse models of p62,GSDMD,and p62-GSDMD were constructed and assigned to p62-/-group,GSDMD-/-group,and p62-/--GSDMD-/-group,respectively(n=5 per group).The gouty arthritis model was in-duced by monosodium urate crystal injection into the ankle joint in all groups except control.The colchicine group re-ceived oral colchicine pretreatment for 3 days prior to MSU injection,continuing for 5 days total.Ankle joint swelling was measured using a vernier caliper at 0,6,12,24,and 48 hours post-injection.Serum levels of p62,GSDMD,caspase-1,interleukin-1β(IL-1β),and IL-18 were quantified by ELISA.Immunohistochemistry staining was performed to assess nu-cleotide-binding oligomerization domain-like receptor protein 3(NLRP3),apoptosis-associated speck-like protein contain-ing a caspase recruitment domain(ASC),cleaved caspase-1,and IL-1β expression in joint tissues.Western blot was con-ducted to detect protein expression of p62,GSDMD,NLRP3,ASC,cleaved caspase-1,and IL-1β in mouse ankle joints,while RT-qPCR was used to measure mRNA expression of p62,NEK7,GSDMD,NLRP3,caspase-1 and IL-1β.RE-SULTS:Serum p62 levels and p62 protein and mRNA expression in ankle joints were significantly elevated in the model group.Following p62 gene knockout,the protein expression of NLRP3,ASC,caspase-1,and IL-1β in ankle joints showed a marked increase.Both GSDMD-/-and p62-/--GSDMD-/-groups exhibited attenuated ankle joint swelling,reduced serum levels of caspase-1,IL-1β,and IL-18,along with downregulated expression of p62,NLRP3,ASC,caspase-1,and IL-1β at both mRNA and protein levels in ankle joints.The NEK7 mRNA expression was similarly suppressed in these groups.CONCLUSION:Our findings demonstrate that MSU crystals activate macrophages through the coordinated action of p62,NEK7,and GSDMD,triggering NLRP3 inflammasome-mediated pyroptosis and ultimately promoting joint inflammation in gout mice.The p62-NEK7-GSDMD axis represents a critical regulatory mechanism in the canonical pyrop-tosis signaling pathway.