Objective To investigate the association of serum total testosterone(TT),free testosterone(FT),sex hormone-binding globulin(SHBG),and estradiol(E_2)with all-cause mortality rate(AMR)in males and to evaluate their predictive value. Methods Based on data from the National Health and Nutrition Examination Survey(NHANES)cycles(1999—2004 and 2013—2016),the relationships between different sex hormones and AMR was analyzed with Cox proportional hazards regression models. The dose-response relationships between different sex hormones and male AMR were assessed with restricted cubic splines(RCS). The predictive performances of different sex hormones for male AMR were compared with receiver operating characteristic(ROC)curves and the area under the curve(AUC). The survival differences across varying sex hormone levels were evaluated with Kaplan-Meier survival curves and log-rank tests. Results This study involved 3632 adult male participants with a median follow-up of 6.5 years,during which 320 AMR occurred(8.8%). Cox univariate analysis indicated that TT,FT and SHBG were risk factors for AMR(P＜0.001). Cox multivariate analysis revealed that FT and SHBG were independent risk factors for AMR(FT:HR=0.90,95%CI:0.86-0.94; SHBG:HR=1.01,95%CI:1.01-1.02). RCS revealed a U-shaped nonlinear relationship between TT,FT and AMR(P＜0.001); SHBG showed a positive dose-response relationship with AMR(P＜0.001). The AUCs of FT predicting the 5-year,10-year,and 15-year AMR were 0.78(95%CI:0.73-0.82),0.80(95%CI:0.76-0.84),and 0.84(95%CI: 0.80-0.88),respectively,significantly outperforming other indicators. Subgroup analysis revealed that FT was negatively correlated with male AMR,but this association was modulated by age,race,smoking status and diabetes status(P_(interaction)＜0.05). Kaplan-Meier survival analysis showed that different levels of TT and FT(Q1-Q4)were significantly positively correlated with survival rate(P＜0.001),while different levels of SHBG were significantly negatively correlated with survival rate,with patients in the Q4 group having the highest risk of death(P＜0.001). Conclusion Based on US NHANES,studies have shown that the FT and SHBG are independent risk factors for male AMR,and FT demonstrates greater predictive value for male AMR than TT.

Objective:To investigate the effect of asiaticoside on renal fibrosis in chronic renal failure(CRF)rats by regulating the Hippo-YAP associated protein(YAP)signaling pathway.Methods:The CRF rat model was established by gavage of Adenine.They were randomly grouped into model group,low dose asiaticoside group(16 mg/kg),high dose asiaticoside group(32 mg/kg),empty load group,high dose asiaticoside(32 mg/kg)+YAP overexpression group,with 12 rats in each group,another 12 SD rats were taken as the control group by gavage with an equal dose of 0.9%sodium chloride solution,after grouping and treated with asiaticoside,empty plasmid and YAP overexpression plasmid,the renal function indicators such as blood creatinine(Scr),endogenous creatinine clearance rate(Ccr),24-hour urine protein content and renal index were measured;HE staining was applied to detect the pathologi-cal morphology of renal tissue;Masson staining was applied to detect renal tissue fibrosis;kits were applied to determine the levels of TNF-α,C-reactive protein(CRP),malondialdehyde(MDA)and superoxide dismutase(SOD)in kidney tissue and serum;Western blot was applied to detect the expressions of fibronectin(FN),Collagen Ⅲ and Hippo-YAP signal related proteins(YAP1,TAZ)in renal tissue.Results:Compared with control group,the renal tissue of rats in model group showed obvious pathological damage symp-toms,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tissue and serum TNF-α,CRP and MDA levels,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein expression were obviously increased(P<0.05),the levels of SOD in renal tissue and serum were obviously reduced(P<0.05).Compared with model group,the pathological damage symptoms of kidney tissue in the low and high dose asiaticoside groups were improved,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tissue and serum TNF-α,CRP and MDA levels,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein ex-pression were all reduced(P<0.05),the levels of SOD in renal tissue and serum were increased(P<0.05);the pathological damage symptoms of kidney tissue in the high-dose asiaticoside group were further improved compared to the low-dose asiaticoside group,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tissue and serum TNF-α,CRP and MDA lev-els,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein expression were further reduced(P<0.05),the levels of SOD in renal tis-sue and serum were further increased(P<0.05);there was no obvious change in all indicators of the unloaded group(P>0.05).Com-pared with the high-dose asiaticoside group,the kidney tissue pathological damage symptoms of rats in the high-dose asiaticoside+YAP overexpression group worsened,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tis-sue and serum TNF-α,CRP and MDA levels,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein expression were increased(P<0.05),the levels of SOD in renal tissue and serum were decreased(P<0.05).Conclusion:Asiaticoside can inhibit inflammation and oxidative stress response in CRF rats by reducing Hippo-YAP signaling activity,thereby reducing renal tissue damage and fibrosis,and promoting the recovery of renal function.

Objective:To investigate the effect of asiaticoside on renal fibrosis in chronic renal failure(CRF)rats by regulating the Hippo-YAP associated protein(YAP)signaling pathway.Methods:The CRF rat model was established by gavage of Adenine.They were randomly grouped into model group,low dose asiaticoside group(16 mg/kg),high dose asiaticoside group(32 mg/kg),empty load group,high dose asiaticoside(32 mg/kg)+YAP overexpression group,with 12 rats in each group,another 12 SD rats were taken as the control group by gavage with an equal dose of 0.9%sodium chloride solution,after grouping and treated with asiaticoside,empty plasmid and YAP overexpression plasmid,the renal function indicators such as blood creatinine(Scr),endogenous creatinine clearance rate(Ccr),24-hour urine protein content and renal index were measured;HE staining was applied to detect the pathologi-cal morphology of renal tissue;Masson staining was applied to detect renal tissue fibrosis;kits were applied to determine the levels of TNF-α,C-reactive protein(CRP),malondialdehyde(MDA)and superoxide dismutase(SOD)in kidney tissue and serum;Western blot was applied to detect the expressions of fibronectin(FN),Collagen Ⅲ and Hippo-YAP signal related proteins(YAP1,TAZ)in renal tissue.Results:Compared with control group,the renal tissue of rats in model group showed obvious pathological damage symp-toms,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tissue and serum TNF-α,CRP and MDA levels,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein expression were obviously increased(P<0.05),the levels of SOD in renal tissue and serum were obviously reduced(P<0.05).Compared with model group,the pathological damage symptoms of kidney tissue in the low and high dose asiaticoside groups were improved,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tissue and serum TNF-α,CRP and MDA levels,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein ex-pression were all reduced(P<0.05),the levels of SOD in renal tissue and serum were increased(P<0.05);the pathological damage symptoms of kidney tissue in the high-dose asiaticoside group were further improved compared to the low-dose asiaticoside group,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tissue and serum TNF-α,CRP and MDA lev-els,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein expression were further reduced(P<0.05),the levels of SOD in renal tis-sue and serum were further increased(P<0.05);there was no obvious change in all indicators of the unloaded group(P>0.05).Com-pared with the high-dose asiaticoside group,the kidney tissue pathological damage symptoms of rats in the high-dose asiaticoside+YAP overexpression group worsened,the Scr and Ccr levels,24-hour urine protein content,renal index,renal tissue CVF,renal tis-sue and serum TNF-α,CRP and MDA levels,renal tissue FN,Collagen Ⅲ,YAP1 and TAZ protein expression were increased(P<0.05),the levels of SOD in renal tissue and serum were decreased(P<0.05).Conclusion:Asiaticoside can inhibit inflammation and oxidative stress response in CRF rats by reducing Hippo-YAP signaling activity,thereby reducing renal tissue damage and fibrosis,and promoting the recovery of renal function.

Objective:To assess the efficacy and safety of Gongxuening Capsules in reducing post-abortion bleeding following artificial abortion.Methods:A multicenter, randomized, double-blind study was conducted. From May 31, 2022 to March 31, 2023, 484 women who underwent vacuum aspiration abortion for early intrauterine pregnancy were enrolled in 11 centers and randomly assigned to control group and the study group at a 1∶1 ratio using a center-block randomization method. Control group were administered a placebo of Gongxuening Capsules for 9 d, while the study group received the actual Gongxuening Capsules for the same duration. The outcomes measured included vaginal bleeding volume, duration of vaginal bleeding, endometrial thickness, time to menstrual recovery, and complications.Results:1) A total of 484 subjects were enrolled, and 472 completed the study. Totally 450 subjects were included in the efficacy analysis set, with 224 in control group and 226 in the study group; 468 subjects were included in the safety analysis set, with 236 in control group and 232 in the study group. The baseline characteristics of the two groups were comparable (all P>0.05). 2) The vaginal bleeding volume was lower in the study group [(13.30±12.14) mL] than in control group [(19.00±17.67) mL, P<0.001]. The proportion of subjects in the study group with bleeding days less than 4 d [29.65% (67/226)] was higher than that in control group [19.20% (43/224), P=0.010]. 3) No significant differences were observed between the two groups in terms of time to menstrual recovery and endometrial thickness (all P>0.05). 4) In the study group, 3 subjects experienced non-therapeutic-related complications, while 11 subjects in control group. The incidence of complications was lower in the study group [1.29% (3/232)] than in control group [4.66% (11/236), P=0.033]. Conclusion:The administration of Gongxuening Capsules to women following artificial abortion significantly reduced vaginal bleeding volume and was associated with good safety, with the treatment being well-tolerated by the subjects.

AIM:To investigate the role of SET and MYND domain-containing protein 3(SMYD3)-mediated histone H3 lysine 4 trimethylation(H3K4me3)dysregulation in pulmonary vascular remodeling in a rat model of pulmo-nary arterial hypertension associated with atrial septal defect(PAH-ASD).METHODS:The PAH-ASD rat model was created using transseptal puncture and radiofrequency ablation techniques.The rats were randomly assigned to 5 groups:normal,sham,PAH-ASD,PAH-ASD+vehicle(Veh),and PAH-ASD+BCI-121(SMYD3 inhibitor).Four weeks after modeling,lung tissues and pulmonary vessels were harvested for subsequent analysis.Western blot analysis was conducted to evaluate the protein levels of SMYD3,H3K4me3,transforming growth faction-β1(TGF-β1),and collagen type Ⅲ(Col Ⅲ).The mRNA expression of TGF-β1 was quantified using RT-qPCR.Histological assessment of pulmonary vascu-lar fibrosis,vascular wall thickness and smooth muscle proliferation was executed through Masson's trichrome and HE staining.Co-immunoprecipitation(Co-IP)assay was performed to investigate the interactions among SMYD3,H3K4me3,and TGF-β1.Hemodynamic parameters,including mean pulmonary artery pressure(mPAP),were quantified using a computerized physiological signal acquisition system.RESULTS:The Western blot analysis indicated a significant in-crease in the protein levels of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 in the PAH-ASD group compared with the sham group(P<0.05).RT-qPCR corroborated the elevation of TGF-β1 mRNA expression in the PAH-ASD group(P<0.05).Furthermore,Masson's trichrome and HE staining techniques revealed more pronounced pulmonary vascular fibrosis,an augmented vascular wall area,and an elevated vascular area index within the PAH-ASD group(P<0.05).Additionally,the right ventricular hypertrophy index(RVHI)and mPAP were significantly elevated in the PAH-ASD group(P<0.05).The administration of BCI-121 resulted in a significant reduction of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 levels(P<0.05),while also mitigating pulmonary vascular fibrosis,RVHI,mPAP,pulmonary vascular area,and area index(P<0.05).Co-IP confirmed direct interactions among SMYD3,H3K4me3,and TGF-β1.CONCLUSION:Histone methyl-transferase SMYD3-mediated histone H3K4me3 modification plays a role in the pulmonary vascular remodeling of PAH-ASD model rats.The underlying mechanism may involve the regulation of pulmonary vascular proliferation and fibrosis me-diated by the overexpression of TGF-β1 and Col Ⅲ.

With the rapid development of generative artificial intelligence(GAI)technologies,their widespread application in academic research and writing is continuously expanding the boundaries of sci-entific inquiry.However,this trend has also raised a series of ethical and regulatory challenges,inclu-ding issues related to authorship,content authenticity,citation accuracy,and accountability.In light of the growing involvement of AI in generating academic content,establishing an open,controllable,and trustworthy ethical governance framework has become a key task for safeguarding research integrity and maintaining trust within the academic community.This expert consensus outlines ethical requirements across key stages of AI-assisted academic writing-including topic selection,data management,citation practices,and authorship attribution.It aims to clarify the boundaries and ethical obligations surrounding AI use in academic writing,ensuring that technological tools enhance efficiency without compromising in-tegrity.The goal is to provide guidance and institutional support for building a responsible and sustainable research ecosystem.

AIM:To investigate the role of SET and MYND domain-containing protein 3(SMYD3)-mediated histone H3 lysine 4 trimethylation(H3K4me3)dysregulation in pulmonary vascular remodeling in a rat model of pulmo-nary arterial hypertension associated with atrial septal defect(PAH-ASD).METHODS:The PAH-ASD rat model was created using transseptal puncture and radiofrequency ablation techniques.The rats were randomly assigned to 5 groups:normal,sham,PAH-ASD,PAH-ASD+vehicle(Veh),and PAH-ASD+BCI-121(SMYD3 inhibitor).Four weeks after modeling,lung tissues and pulmonary vessels were harvested for subsequent analysis.Western blot analysis was conducted to evaluate the protein levels of SMYD3,H3K4me3,transforming growth faction-β1(TGF-β1),and collagen type Ⅲ(Col Ⅲ).The mRNA expression of TGF-β1 was quantified using RT-qPCR.Histological assessment of pulmonary vascu-lar fibrosis,vascular wall thickness and smooth muscle proliferation was executed through Masson's trichrome and HE staining.Co-immunoprecipitation(Co-IP)assay was performed to investigate the interactions among SMYD3,H3K4me3,and TGF-β1.Hemodynamic parameters,including mean pulmonary artery pressure(mPAP),were quantified using a computerized physiological signal acquisition system.RESULTS:The Western blot analysis indicated a significant in-crease in the protein levels of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 in the PAH-ASD group compared with the sham group(P<0.05).RT-qPCR corroborated the elevation of TGF-β1 mRNA expression in the PAH-ASD group(P<0.05).Furthermore,Masson's trichrome and HE staining techniques revealed more pronounced pulmonary vascular fibrosis,an augmented vascular wall area,and an elevated vascular area index within the PAH-ASD group(P<0.05).Additionally,the right ventricular hypertrophy index(RVHI)and mPAP were significantly elevated in the PAH-ASD group(P<0.05).The administration of BCI-121 resulted in a significant reduction of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 levels(P<0.05),while also mitigating pulmonary vascular fibrosis,RVHI,mPAP,pulmonary vascular area,and area index(P<0.05).Co-IP confirmed direct interactions among SMYD3,H3K4me3,and TGF-β1.CONCLUSION:Histone methyl-transferase SMYD3-mediated histone H3K4me3 modification plays a role in the pulmonary vascular remodeling of PAH-ASD model rats.The underlying mechanism may involve the regulation of pulmonary vascular proliferation and fibrosis me-diated by the overexpression of TGF-β1 and Col Ⅲ.

With the rapid development of generative artificial intelligence(GAI)technologies,their widespread application in academic research and writing is continuously expanding the boundaries of sci-entific inquiry.However,this trend has also raised a series of ethical and regulatory challenges,inclu-ding issues related to authorship,content authenticity,citation accuracy,and accountability.In light of the growing involvement of AI in generating academic content,establishing an open,controllable,and trustworthy ethical governance framework has become a key task for safeguarding research integrity and maintaining trust within the academic community.This expert consensus outlines ethical requirements across key stages of AI-assisted academic writing-including topic selection,data management,citation practices,and authorship attribution.It aims to clarify the boundaries and ethical obligations surrounding AI use in academic writing,ensuring that technological tools enhance efficiency without compromising in-tegrity.The goal is to provide guidance and institutional support for building a responsible and sustainable research ecosystem.

OBJECTIVE: To investigate the impact of early antimicrobial therapy on the prognosis of patients with suspected sepsis in emergency and outpatient settings. METHODS: A prospective cohort study was conducted. Patients with suspected sepsis admitted to the emergency department of Taizhou Hospital, Zhejiang Province, from May 1, 2022, to July 31, 2023, were enrolled. Participants were divided into an early group (0-1 hour) and a delayed group (> 1 hour) according to duration from admission to antimicrobial administration. General information, initial vital signs, laboratory parameters within 24 hours after admission, disease severity scores, vasoactive drug usage, and clinical outcomes of the patient were collected. Kaplan-Meier survival curve was used to analyze 28-day survival. Multivariate Cox proportional hazards regression was performed to identify independent risk factors for prognosis of the patients with suspected sepsis in emergency and outpatient settings. Sensitivity analyses were conducted through subgroup analyses. RESULTS: A total of 143 patients with suspected sepsis were enrolled in the analysis, with 66 patients in the early group and 77 in the delayed group. No statistically significant differences were observed in baseline characteristics (age, gender, vital signs, laboratory parameters, disease severity scores) or clinical outcomes [vasoactive drug usage rate, mechanical ventilation duration, length of intensive care unit (ICU) stay, total hospitalization duration] between the two groups. The 28-day mortality, multidrug resistance rate and sepsis confirmation rate did not differ significantly between the early group and delay group [28-day mortality: 18.2% (12/66) vs. 20.8% (16/77), multidrug resistance rate: 3.0% (2/66) vs. 2.6% (2/77), sepsis confirmation rate: 87.9% (58/66) vs. 88.3% (68/77), all P > 0.05]. Kaplan-Meier survival curve analysis showed no difference in 28-day cumulative survival between the two groups (Log-Rank test: χ² = 2.528, P = 0.112). Multivariate Cox proportional hazards regression identified vasoactive drug usage [hazard ration (HR) = 2.465, 95% confidence interval (95%CI) was 1.019-5.961, P = 0.045] and endotracheal intubation (HR = 5.516, 95%CI was 2.195-13.858, P < 0.001) as independent risk factors for 28-day death of the patients with suspected sepsis in emergency and outpatient settings. Further exploration of the impact of early antimicrobial therapy on 28-day death in different subgroups of the patients with suspected sepsis in emergency and outpatient settings was conducted through subgroup analysis. The results showed that in the patients with different ages (< 60 years old: HR = 1.214, 95%CI was 0.535-2.751, P = 0.643; ≥ 60 years old: HR = 2.085, 95%CI was 0.233-18.668, P = 0.511), sequential organ failure assessment (SOFA) scores (< 6: HR = 1.411, 95%CI was 0.482-4.128, P = 0.530; ≥ 6: HR = 0.869, 95%CI was 0.292-2.587, P = 0.801), shock indexes (< 1: HR = 1.095, 95%CI was 0.390-3.077, P = 0.863; ≥ 1: HR = 1.364, 95%CI was 0.458-4.059, P = 0.577) and whether diagnosed with sepsis or not (yes: HR = 0.943, 95%CI was 0.059-15.091, P = 0.967; no: HR = 1.207, 95%CI was 0.554-2.628, P = 0.636) subgroups, early usage of antibiotics had not shown any advantage in improving prognosis compared with delayed usage. CONCLUSION Early antimicrobial therapy does not improve the prognosis of patients with suspected sepsis in emergency and outpatient settings.
Humans ; Sepsis/drug therapy* ; Prospective Studies ; Prognosis ; Emergency Service, Hospital ; Outpatients ; Female ; Male ; Anti-Infective Agents/therapeutic use* ; Middle Aged ; Aged ; Proportional Hazards Models ; Treatment Outcome

OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology