ObjectiveTo explore the mechanism by which Sini San （SNS） inhibits ferroptosis， alleviates inflammation and myocardial injury， and improves myocardial infarction （MI）. MethodsThe active ingredients of SNS were obtained by searching the Traditional Chinese Medicine System Pharmacology Platform （TCMSP） database， its target sites were predicted using the SwissTargetPrediction Database， and the core components were screened out using the CytoNCA plug-in. The targets of MI and ferroptosis were obtained by using GeneCards， Online Mendelian Inheritance in Man （OMIM） database， DrugBank， Therapeutic Target Database （TTD）， FerrDb database and literature review， respectively. The intersection of these targets of SNS-MI-ferroptosis was plotted as a Venn diagram. The protein-protein interaction （PPI） network was constructed using the STRING database， and the visualization graph was prepared using Cytoscape. The core targets were screened out using the CytoNCA plug-in， and the biological functions were clustered by the MCODE plug-in. Gene Ontology （GO） functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis were performed using the David database. Molecular docking was performed using AutoDock and visualized with PyMOL2.5.2. The Kunming mice were randomly divided into the control group， the model group， the SNS group， and the trimetazidine （TMZ） group. The mice were subcutaneously injected with isoprenaline （ISO， 5 mg·kg^-1·d^-1） to establish an MI model. The drug was continuously intervened for 7 days. The ST-segment changes were recorded by electrocardiogram （ECG）， and the tissue morphology changes were observed by hematoxylin-eosin （HE） staining. Cardiomyocyte ferroptosis was investigated by transmission electron microscopy. Serum creatine kinase （CK）， creatine kinase isoenzyme （CK-MB）， lactate dehydrogenase （LDH）， reduced glutathione （GSH）， and malondialdehyde （MDA） levels were detected by biochemical assay. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of interleukin （IL）-6 and 4-hydroxynonenal （4-HNE）. Immunohistochemical staining was employed to detect IL-6 and phosphorylated signal transducer and transcription activator 3 （p-STAT3） in cardiac tissues. Western blot was used to detect STAT3 and p-STAT3 in cardiac tissues. Real-time PCR was used to detect the levels of IL-6， IL-18， solute carrier family 7 member 11 （SLC7A11）， arachidonic acid 15-lipoxygenase （ALOX15）， and glutathione peroxidase 4 （GPx4） in cardiac tissues. ResultsA total of 121 active ingredients of SNS were obtained， and 58 potential targets of SNS in the treatment of MI by regulating ferroptosis were screened. The three protein modules with a score5 were mainly related to the inflammatory response. The GO function was mainly related to inflammation， and KEGG enrichment analysis showed that SNS mainly regulated ferroptosis- and inflammation- related signaling pathways. Molecular docking indicated that the core component had a higher binding force to the target site. Animal experiments confirmed that SNS reduced the level of p-STAT3 （P0.01）， down-regulated the expression of ALOX15 mRNA （P0.01）， up-regulated the level of serum GSH， and the expressions of SLC7A11 and GPx4 mRNA， reduced MDA and 4-HNE levels （P0.05， P0.01）. Additionally， SNS improved the mitochondrial injury induced by cardiomyocyte ferroptosis， reduced the area of MI， alleviated inflammation and myocardial injury， lowered the levels of serum CK， CK-MB， LDH， IL-6， and the mRNA expression levels of IL-16 and IL-18 （P0.05）， and improved ST segment elevation. ConclusionSNS can reduce ISO-induced STAT3 phosphorylation levels， inhibit ferroptosis in cardiomyocytes， alleviate inflammation and myocardial injury， thereby improving MI.

ObjectiveTo explore the mechanism by which Sini San （SNS） inhibits ferroptosis， alleviates inflammation and myocardial injury， and improves myocardial infarction （MI）. MethodsThe active ingredients of SNS were obtained by searching the Traditional Chinese Medicine System Pharmacology Platform （TCMSP） database， its target sites were predicted using the SwissTargetPrediction Database， and the core components were screened out using the CytoNCA plug-in. The targets of MI and ferroptosis were obtained by using GeneCards， Online Mendelian Inheritance in Man （OMIM） database， DrugBank， Therapeutic Target Database （TTD）， FerrDb database and literature review， respectively. The intersection of these targets of SNS-MI-ferroptosis was plotted as a Venn diagram. The protein-protein interaction （PPI） network was constructed using the STRING database， and the visualization graph was prepared using Cytoscape. The core targets were screened out using the CytoNCA plug-in， and the biological functions were clustered by the MCODE plug-in. Gene Ontology （GO） functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis were performed using the David database. Molecular docking was performed using AutoDock and visualized with PyMOL2.5.2. The Kunming mice were randomly divided into the control group， the model group， the SNS group， and the trimetazidine （TMZ） group. The mice were subcutaneously injected with isoprenaline （ISO， 5 mg·kg^-1·d^-1） to establish an MI model. The drug was continuously intervened for 7 days. The ST-segment changes were recorded by electrocardiogram （ECG）， and the tissue morphology changes were observed by hematoxylin-eosin （HE） staining. Cardiomyocyte ferroptosis was investigated by transmission electron microscopy. Serum creatine kinase （CK）， creatine kinase isoenzyme （CK-MB）， lactate dehydrogenase （LDH）， reduced glutathione （GSH）， and malondialdehyde （MDA） levels were detected by biochemical assay. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of interleukin （IL）-6 and 4-hydroxynonenal （4-HNE）. Immunohistochemical staining was employed to detect IL-6 and phosphorylated signal transducer and transcription activator 3 （p-STAT3） in cardiac tissues. Western blot was used to detect STAT3 and p-STAT3 in cardiac tissues. Real-time PCR was used to detect the levels of IL-6， IL-18， solute carrier family 7 member 11 （SLC7A11）， arachidonic acid 15-lipoxygenase （ALOX15）， and glutathione peroxidase 4 （GPx4） in cardiac tissues. ResultsA total of 121 active ingredients of SNS were obtained， and 58 potential targets of SNS in the treatment of MI by regulating ferroptosis were screened. The three protein modules with a score5 were mainly related to the inflammatory response. The GO function was mainly related to inflammation， and KEGG enrichment analysis showed that SNS mainly regulated ferroptosis- and inflammation- related signaling pathways. Molecular docking indicated that the core component had a higher binding force to the target site. Animal experiments confirmed that SNS reduced the level of p-STAT3 （P0.01）， down-regulated the expression of ALOX15 mRNA （P0.01）， up-regulated the level of serum GSH， and the expressions of SLC7A11 and GPx4 mRNA， reduced MDA and 4-HNE levels （P0.05， P0.01）. Additionally， SNS improved the mitochondrial injury induced by cardiomyocyte ferroptosis， reduced the area of MI， alleviated inflammation and myocardial injury， lowered the levels of serum CK， CK-MB， LDH， IL-6， and the mRNA expression levels of IL-16 and IL-18 （P0.05）， and improved ST segment elevation. ConclusionSNS can reduce ISO-induced STAT3 phosphorylation levels， inhibit ferroptosis in cardiomyocytes， alleviate inflammation and myocardial injury， thereby improving MI.

Objective With the vigorous development of nuclear reactors and controlled thermonuclear fusion research, the release of tritium, the predominant radionuclide in nuclear wastewater, into the environment has attracted widespread attention. Its impact on human health has also become a hot topic of research. This article presents a visual analysis of the literature on the biological effects of tritium ingestion by organisms over the past 70 years, with the aim of elucidating the biological effects of tritiated water and identifying current research hotspots and emerging trends. Methods We retrieved articles on the biological effects of tritium radiation published in the China National Knowledge Infrastructure (CNKI) and Web of Science (WOS) over the past 70 years. CiteSpace software was used to generate visual maps, including annual number of publications, countries of publication, keyword clustering, keyword timeline, keyword burst, and literature co-citation. Results A total of 437 articles were included. The cumulative number of annual publications exhibited a linear growth trend. Research hotspots focused on low-radioactivity tritiated water, dose rate effect, DNA double-strand break damage, genetic effect, and cancer mortality. Emerging research frontiers included human lymphocyte immune injury, oxidase activity, comparison of marine organisms in different living environments, comparison of tritium and ionizing radiation effects, changes in mitochondrial ATP content, and the hormetic effect of low-dose radiation. Conclusion In cellular and animal models, high doses of tritium exposure induce negative biological effects. However, whether low doses of tritium esposure elicit beneficial biological effects remains to be further explored. It is suggested that domestic and foreign teams enhance academic collaboration and discussions, focusing on current hotspots and frontiers to deepen our understanding of the biological effects induced by tritium radiation. This will provide scientific solutions for disease treatment and establish a scientific basis for the safe utilization of nuclear energy and the formulation of safety standards for nuclear wastewater discharge.

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.

OBJECTIVES: To explore the mechanism by which Pulsatilla saponin D (PSD) inhibits invasion and metastasis of triple-negative breast cancer (TNBC). METHODS: The public databases were used to identify the potential targets of PSD and the invasion and metastasis targets of TNBC to obtain the intersection targets between PSD and TNBC. The "PSD-target-disease" interaction network was constructed and protein-protein interaction (PPI) analysis was performed to obtain the core targets, which were analyzed for KEGG pathway and GO functional enrichment. Molecular docking study of the core targets and PSD was performed, and the therapeutic effect and mechanism of PSD were verified using Transwell assay and Western blotting in cultured TNBC cells. RESULTS: Network pharmacology analysis identified a total of 285 potential PSD targets and 26 drug-disease intersection core targets. GO analysis yielded 175 entries related to the binding of biomolecules (protein, DNA and RNA), enzyme activities, and regulation of gene transcription. KEGG analysis yielded 46 entries involving pathways in cancer, chemical carcinogenesis-receptor activation, microRNAs in cancer, chemical carcinogenesis-reactive oxygen species, PD-L1 expression and PD-1 checkpoint pathway in cancer. Molecular docking showed high binding affinities of PSD to MTOR, HDAC2, ABL1, CDK1, TLR4, TERT, PIK3R1, NFE2L2 and PTPN1. In cultured TNBC cells, treatment with PSD significantly inhibited cell invasion and migration and lowered the expressions of MMP2, MMP9, N-cadherin and the core proteins p-mTOR, ABL1, TERT, PTPN1, HDAC2, PIK3R1, CDK1, TLR4 as well as NFE2L2 expressionin the cell nuclei. CONCLUSIONS The inhibitory effects of PSD on TNBC invasion and metastasis are mediated by multiple targets and pathways.
Humans ; Triple Negative Breast Neoplasms/metabolism* ; Saponins/pharmacology* ; Pulsatilla/chemistry* ; Female ; Molecular Docking Simulation ; Cell Line, Tumor ; Neoplasm Invasiveness ; Protein Interaction Maps ; Neoplasm Metastasis ; Signal Transduction/drug effects* ; Cell Movement/drug effects*

Objective To assess the current status and influencing factors of high-risk populations for osteosarcopenia in elderly community residents,and to construct a health portrait for this group,revealing population characteristics and differences.Methods A convenience sampling method was employed to recruit 800 community-dwelling older adults in Hangzhou,China,between August and December 2024.Data were collected using the following validated instruments,namely the General Information Questionnaire,Age-adjusted Charlson Comorbidity Index,Chinese version of the Nutritional Form for the Elderly,Osteoporosis Self-Efficacy Scale,Social Frailty Screening Tool,Osteoporosis Risk One-Minute Test,and Osteoporosis Self-Assessment Tool for Asians.Additionally,objective physical measurements were obtained,including calf circumference,handgrip strength,and five-times sit-to-stand test time.The influencing factors were analyzed using univariate analysis and binary logistic regression,and two-step cluster analysis was employed for clustering to construct group profiles.Results 770 valid questionnaires were collected.The detection rate of high-risk osteosarcopenia in the elderly community is 27.53％.Older age,low BMI,prolonged sitting,chronic pain,low intake of soy products,low osteoporosis self-efficacy,and high social frailty are associated with a higher risk of osteosarcopenia.Totally 3 population portraits were constructed through clustering,including health-maintenance type,risk-ignoring type,and active management type.Conclusion The detection rate of high-risk elderly individuals with osteosarcopenia in communities is relatively high,with significant differences across groups.Intervention strategies can be proposed based on different group characteristics,providing a reference for precise interventions.

Objective:To evaluate the safety and effectiveness of fuzuloparib for the treatment of ovarian epithelial cancer patients in the real world setting.Methods:A retrospective analysis was conducted on the baseline data of 4 620 ovarian cancer patients who had received fuzuloparib monotherapy or combination therapy. Another 224 ovarian cancer patients who were willing to receive fuzuloparib monotherapy or combination therapy were prospectively enrolled, and their baseline characteristics, drug effectiveness, and safety data were analyzed.Results:(1) Among the 4 620 patients in the retrospective cohort, the median age of patients was 60 years; tumor types: 89.8% (4 149/4 620) had ovarian cancer. Among patients with clearly documented information, the vast majority had a histological type of serous carcinoma (82.9%, 3 770/4 546) and International Federation of Gynecology and Obstetrics (FIGO) staging of Ⅲ-Ⅳ (90.9%, 1 537/1 691). (2) Among the 224 patients in the prospective cohort, the median age of patients was 57 years; tumor types: 83.9% (188/224) had ovarian cancer. Among patients with clearly documented records, the predominant pathologic type was serous carcinoma (91.9%, 193/210), and FIGO stage was Ⅲ-Ⅳ in 79.9% (139/174). (3) Among the 224 prospective patients: 84 patients received first-line fluzoparib maintenance therapy, 92 patients received fluzoparib maintenance therapy after platinum-sensitive recurrence, 23 patients received direct fluzoparib treatment after platinum-sensitive recurrence, 19 patients received direct fluzoparib treatment after platinum-resistant recurrence. The median follow-up durations were 8.5, 8.7, 7.9, and 6.7 months, respectively. The median durations of fluzoparib treatment were 6.7, 4.8, 3.1, and 1.9 months, respectively. The median progression-free survival (PFS) times were not reached during follow-up, 12.6 months, not reached during follow-up, and 4.8 months, respectively. The 1-year PFS rates were 84.1%, 55.0%, 69.8%, and 45.5%, respectively. The remaining 6 patients received other fluzoparib regimens. (4) Among the 224 patients in the prospective dataset, 205 had safety data recorded. Of these, 127 patients (62.0%, 127/205) experienced treatment-related adverse events, with common events including anemia (24.4%, 50/205), thrombocytopenia (21.0%, 43/205), and leukopenia (19.5%, 40/205). Among the 205 patients, 43 (21.0%, 43/205) experienced grade 3 or higher treatment-related adverse events, with common events including anemia (8.3%, 17/205) and thrombocytopenia (8.3%, 17/205).Conclusions:The effectiveness of fuzuloparib in clinical application is generally consistent with other drugs in the same class, with good safety. This study provids new clinical evidence for the treatment of ovarian cancer with fuzuloparib.

Objective:To explore the feasibility and clinical outcomes of transperineal prostate multimodal image fusion-targeted biopsy under the day surgery model.Methods:Clinical data of 258 patients who underwent transperineal prostate biopsy at the Second Affiliated Hospital of Xi’an Jiaotong University between December 2022 and June 2024 were retrospectively analyzed. Patients were divided into two groups，and the experimental group（ n = 141）underwent transperineal prostate multi-modal image-fusion targeted biopsy in the day-surgery mode，with age of（70.0 ± 8.8）years，median prostate-specific antigen（PSA）level of 11.10（7.63?17.06）ng/ml，and median Prostate Imaging Reporting and Data System（PI-RADS）score of 4（3，5）. The control group（ n = 117）underwent traditional transperineal systematic biopsy，with age of（69.3 ± 7.4）years，median PSA of 25.20（16.18-54.40）ng/ml，and median PI-RADS score of 4（3，5）. The experimental group was given the day surgery mode：preoperatively，multiparametric magnetic resonance imaging（mpMRI）of the prostate was multimodally fused with ultrasound images，the location of target lesions in the prostate was manually mapped，and a targeted biopsy plan was developed. Intraoperatively，under ultrasound guidance，precise puncture was performed at the lesion sites，followed by systematic biopsy. After the operation，the patients were observed for 4-6 hours，and could be discharged if there were no obvious abnormalities，with the total hospitalization time within 24 hours. For the control group，the conventional biopsy mode was used. Intraoperatively，under ultrasound guidance，the standard 12-core transperineal systematic biopsy protocol was adopted，and sampling was conducted according to the anatomical regions of the prostate（base，midportion，apex，transition zone，and peripheral zone）to cover the entire gland. Patients in this group required routine hospitalization，with a hospital stay of 3-5 days. Operative time，intraoperative pain Numerical Rating Scale（NRS）score，complications within one week postoperatively，treatment costs，overall prostate cancer detection rate，and clinically significant prostate cancer（csPCa，defined as Gleason score ≥ 7 or pathological stage ≥ T 2b）detection rate were compared between the two groups. Results:All procedures were successfully completed without special incidents. The operative time was（13.49 ± 2.00）min in the experimental group and（13.05 ± 2.89）min in the control group，showing no significant difference（ P > 0.05）. The intraoperative pain NRS scores were（3.01 ± 1.17）and（3.10 ± 1.25）in the experimental and control groups，respectively，with no significant difference（ P > 0.05）. Pathological examination revealed that the overall prostate cancer detection rates were 46.8%（66/141）in the experimental group and 42.7%（50/117）in the control group，while the csPCa detection rates were 35.5%（50/141）and 31.6%（37/117），respectively. The differences were not statistically significant（ P > 0.05）. The complication rate was 6.4%（9/141）in the experimental group（including 2 cases of acute urinary retention，3 hematuria，3 fever，and 1 sepsis）and 6.0%（7/117）in the control group（including 3 acute urinary retention，1 hematuria，2 fever，and 1 sepsis），with no significant difference（ P > 0.05）. All complications improved after symptomatic treatment. The treatment costs were（4 063.25 ± 67.26）yuan in the experimental group and（5 185.14 ± 469.15）yuan in the control group，demonstrating a statistically significant difference（ P < 0.05）. Conclusions:Transperineal prostate multimodal image fusion-targeted biopsy can be safely performed under the day surgery model，offering advantages including a relatively high detection rate for csPCa，low complication rate，and better cost-effectiveness.

Objective To explore the mechanism by which Pulsatilla saponin D(PSD)inhibits invasion and metastasis of triple-negative breast cancer(TNBC).Methods The public databases were used to identify the potential targets of PSD and the invasion and metastasis targets of TNBC to obtain the intersection targets between PSD and TNBC.The"PSD-target-disease"interaction network was constructed and protein-protein interaction(PPI)analysis was performed to obtain the core targets,which were analyzed for KEGG pathway and GO functional enrichment.Molecular docking study of the core targets and PSD was performed,and the therapeutic effect and mechanism of PSD were verified using Transwell assay and Western blotting in cultured TNBC cells.Results Network pharmacology analysis identified a total of 285 potential PSD targets and 26 drug-disease intersection core targets.GO analysis yielded 175 entries related to the binding of biomolecules(protein,DNA and RNA),enzyme activities,and regulation of gene transcription.KEGG analysis yielded 46 entries involving pathways in cancer,chemical carcinogenesis-receptor activation,microRNAs in cancer,chemical carcinogenesis-reactive oxygen species,PD-L1 expression and PD-1 checkpoint pathway in cancer.Molecular docking showed high binding affinities of PSD to MTOR,HDAC2,ABL1,CDK1,TLR4,TERT,PIK3R1,NFE2L2 and PTPN1.In cultured TNBC cells,treatment with PSD significantly inhibited cell invasion and migration and lowered the expressions of MMP2,MMP9,N-cadherin and the core proteins p-mTOR,ABL1,TERT,PTPN1,HDAC2,PIK3R1,CDK1,TLR4 as well as NFE2L2 expressionin the cell nuclei.Conclusion The inhibitory effects of PSD on TNBC invasion and metastasis are mediated by multiple targets and pathways.