This study aims to investigate the mechanism by which resveratrol(RES) alleviates cerebral vascular endothelial damage in sepsis-associated encephalopathy(SAE) through network pharmacology and animal experiments. By using network pharmacology, the study identified common targets and genes associated with RES and SAE and constructed a protein-protein interaction( PPI) network. Gene Ontology(GO) analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed to pinpoint key signaling pathways, followed by molecular docking validation. In the animal experiments, a cecum ligation and puncture(CLP) method was employed to induce SAE in mice. The mice were randomly assigned to the sham group, CLP group, and medium-dose and high-dose groups of RES. The sham group underwent open surgery without CLP, and the CLP group received an intraperitoneal injection of 0. 9% sodium chloride solution after surgery. The medium-dose and high-dose groups of RES were injected intraperitoneally with 40 mg·kg-1 and 60 mg·kg~(-1) of RES after modeling, respectively, and samples were collected 12 hours later. Neurological function scores were assessed, and the wet-dry weight ratio of brain tissue was detected. Serum superoxide dismutase(SOD), catalase( CAT) activity, and malondialdehyde( MDA) content were measured by oxidative stress kit. Histopathological changes in brain tissue were examined using hematoxylin-eosin(HE) staining. Transmission electron microscopy was employed to evaluate tight cell junctions and mitochondrial ultrastructure changes in cerebral vascular endothelium. Western blot analysis was performed to detect the expression of zonula occludens1( ZO-1), occludin, claudins-5, optic atrophy 1( OPA1), mitofusin 2(Mfn2), dynamin-related protein 1(Drp1), fission 1(Fis1), and hypoxia-inducible factor-1α(HIF-1α). Network pharmacology identified 76 intersecting targets for RES and SAE, with the top five core targets being EGFR, PTGS2, ESR1, HIF-1α, and APP. GO enrichment analysis showed that RES participated in the SAE mechanism through oxidative stress reaction. KEGG enrichment analysis indicated that RES participated in SAE therapy through HIF-1α, Rap1, and other signaling pathways. Molecular docking results showed favorable docking activity between RES and key targets such as HIF-1α. Animal experiment results demonstrated that compared to the sham group, the CLP group exhibited reduced nervous reflexes, decreased water content in brain tissue, as well as serum SOD and CAT activity, and increased MDA content. In addition, the CLP group exhibited disrupted tight junctions in cerebral vascular endothelium and abnormal mitochondrial morphology. The protein expression levels of Drp1, Fis1, and HIF-1α in brain tissue were increased, while those of ZO-1, occludin, claudin-5, Mfn2, and OPA1 were decreased. In contrast, the medium-dose and high-dose groups of RES showed improved neurological function, increased water content in brain tissue and SOD and CAT activity, and decreased MDA content. Cell morphology in brain tissue, tight junctions between endothelial cells, and mitochondrial structure were improved. The protein expressions of Drp1, Fis1, and HIF-1α were decreased, while those of ZO-1, occludin, claudin-5, Mfn2, and OPA1 were increased. This study suggested that RES could ameliorate cerebrovascular endothelial barrier function and maintain mitochondrial homeostasis by inhibiting oxidative stress after SAE damage, potentially through modulation of the HIF-1α signaling pathway.
Animals ; Mice ; Network Pharmacology ; Resveratrol/administration & dosage* ; Male ; Sepsis-Associated Encephalopathy/genetics* ; Signal Transduction/drug effects* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Endothelium, Vascular/metabolism* ; Molecular Docking Simulation ; Protein Interaction Maps/drug effects* ; Humans ; Sepsis/complications* ; Oxidative Stress/drug effects*

Traditional Chinese medicine(TCM), a treasure of the Chinese nation, contains abundant chemical components and demonstrates unique pharmacological activities, showing important values in clinical applications. With profound connotations and broad application prospects, TCM urgently needs us to further explore and conduct systematic research. Puerarin is a small-molecule natural isoflavonoid carbon glycoside extracted from plants of Pueraria. It is also the main active ingredient of Puerariae Lobata Radix, a Chinese herbal medicine with both medicinal and edible values. Puerarin has a variety of pharmacological effects such as blood pressure-lowering, anti-atherosclerosis, anti-ischemia-reperfusion injury, antithrombotic, anti-tumor, anti-inflammatory, liver-protecting, nerve cell-protecting, and intestinal microbiota-regulating effects. It is also an active ingredient that has been widely studied. This article comprehensively reviews the research progress in the pharmacological effects and molecular mechanisms of puerarin over the years, aiming to provide references and theoretical support for the in-depth research and development as well as clinical application of puerarin.
Isoflavones/chemistry* ; Humans ; Animals ; Drugs, Chinese Herbal/chemistry* ; Pueraria/chemistry*

PURPOSE: To investigate the incidence and influencing factors of bone loss in patients with spinal cord injury (SCI). METHODS: A retrospective case-control study was conducted. Patients with SCI in our hospital from January 2019 to March 2023 were collected. According to the correlation between bone mineral density (BMD) at different sites, the patients were divided into the lumbar spine group and the hip joint group. According to the BMD value, the patients were divided into the normal bone mass group (t > -1.0 standard deviation) and the osteopenia group (t ≤ -1.0 standard deviation). The influencing factors accumulated as follows: gender, age, height, weight, cause of injury, injury segment, injury degree, time after injury, start time of rehabilitation, motor score, sensory score, spasticity, serum value of alkaline phosphatase, calcium, and phosphorus. The trend chart was drawn and the influencing factors were analyzed. SPSS 26.0 was used for statistical analysis. Correlation analysis was used to test the correlation between the BMD values of the lumbar spine and bilateral hips. Binary logistic regression analysis was used to explore the influencing factors of osteoporosis after SCI. p < 0.05 was considered statistically significant. RESULTS: The incidence of bone loss in patients with SCI was 66.3%. There was a low concordance between bone loss in the lumbar spine and the hip, and the hip was particularly susceptible to bone loss after SCI, with an upward trend in incidence (36% - 82%). In this study, patients with SCI were divided into the lumbar spine group (n = 100) and the hip group (n = 185) according to the BMD values of different sites. Then, the lumbar spine group was divided into the normal bone mass group (n = 53) and the osteopenia group (n = 47); the hip joint group was divided into the normal bone mass group (n = 83) and the osteopenia group (n = 102). Of these, lumbar bone loss after SCI is correlated with gender and weight (p = 0.032 and < 0.001, respectively), and hip bone loss is correlated with gender, height, weight, and time since injury (p < 0.001, p = 0.015, 0.009, and 0.012, respectively). CONCLUSIONS The incidence of bone loss after SCI was high, especially in the hip. The incidence and influencing factors of bone loss in the lumbar spine and hip were different. Patients with SCI who are male, low height, lightweight, and long time after injury were more likely to have bone loss.
Humans ; Spinal Cord Injuries/complications* ; Male ; Female ; Retrospective Studies ; Incidence ; Adult ; Bone Density ; Middle Aged ; Case-Control Studies ; Osteoporosis/etiology* ; Lumbar Vertebrae ; Bone Diseases, Metabolic/etiology* ; Aged ; Risk Factors

The development of anticancer drugs to treat triple-negative breast cancer (TNBC) is an ongoing challenge. Immunogenic cell death (ICD) has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy. However, only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC. Therefore, new agents with potentially effective chemoimmunotherapeutic response are required. In this study, five new cyclometalated Ir(III) complexes containing isoquinoline alkaloid CˆN ligands were designed and synthesized. Among them, Ir-1 exhibited the highest in vitro cytotoxicity. Mechanistically, Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase (IDO) inhibition via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in MDA-MB-231 cells. When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells, antitumor CD8⁺ T-cell response and Foxp3⁺ T-cell depletion were induced, resulting in long-lasting antitumor immunity in TNBC cells. Moreover, combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects. Based on these results, Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage.

OBJECTIVE: Treating peripheral nerve injury (PNI) presents a clinical challenge due to limited axon regeneration. Strychni Semen, a traditional Chinese medicine, is clinically used for numbness and hemiplegia. However, its role in promoting functional recovery after PNI and the related mechanisms have not yet been systematically studied. METHODS: A mouse model of sciatic nerve crush (SNC) injury was established and the mice received drug treatment via intragastric gavage, followed by behavioral assessments (adhesive removal test, hot-plate test and Von Frey test). Transcriptomic analyses were performed to examine gene expression in the dorsal root ganglia (DRGs) from the third to the sixth lumbar vertebrae, so as to identify the significantly differentially expressed genes. Immunofluorescence staining was used to assess the expression levels of superior cervical ganglia neural-specific 10 protein (SCG10). The ultra-trace protein detection technique was used to evaluate changes in gene expression levels. RESULTS: Strychni Semen and its active compounds (brucine and strychnine) improved functional recovery in mice following SNC injury. Transcriptomic data indicated that Strychni Semen and its active compounds initiated transcriptional reprogramming that impacted cellular morphology and extracellular matrix remodeling in DRGs after SNC, suggesting potential roles in promoting axon regeneration. Imaging data further confirmed that Strychni Semen and its active compounds facilitated axon regrowth in SNC-injured mice. By integrating protein-protein interaction predictions, ultra-trace protein detection, and molecular docking analysis, we identified myeloperoxidase as a potentially critical factor in the axon regenerative effects conferred by Strychni Semen and its active compounds. CONCLUSION Strychni Semen and its active compounds enhance sensory function by promoting axonal regeneration after PNI. These findings establish a foundation for the future applications of Strychni Semen and highlight novel therapeutic strategies and drug targets for axon regeneration. Please cite this article as: Zhang Y, Zhao XY, Liu MT, Zhou ZC, Cheng HB, Jiang XH, Zheng YR, Chen Z. Strychni Semen and its active compounds promote axon regeneration following peripheral nerve injury by suppressing myeloperoxidase in the dorsal root ganglia. J Integr Med. 2025; 23(2): 169-181.
Animals ; Nerve Regeneration/drug effects* ; Mice ; Peripheral Nerve Injuries/physiopathology* ; Male ; Ganglia, Spinal/enzymology* ; Axons/physiology* ; Peroxidase/antagonists & inhibitors* ; Mice, Inbred C57BL ; Drugs, Chinese Herbal/pharmacology* ; Disease Models, Animal ; Strychnine/pharmacology*

BACKGROUND: In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration. METHODS: A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases. RESULTS: MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05). CONCLUSIONS The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.
Humans ; Lung Neoplasms/genetics* ; Adenocarcinoma of Lung/genetics* ; China ; Prognosis ; Transcription Factors

Objective To investigate the risk factors of periprosthetic femoral fracture(PFF)after total knee arthroplasty(TKA)in the elderly and to construct a predictive model for the prevention of PFF after clinical operation.Methods The clinical data of 537 elderly patients who underwent TKA in the orthopedic department of the First Affiliated Hospital of Air Medical University from October 2016 to October 2021 were retrospectively analyzed.The occurrence of PFF during the follow-up period was statistically analyzed and the clinical data were collected.Binary Logistic regression was used to analyze the risk factors of PFF after TKA in the elderly,and a predictive model of PFF after TKA in the elderly was constructed based on the risk factors.Receiver operating characteristic(ROC)curve and Hosmer-Lemeshow(H-L)were used to test the discrimination and calibration of prediction model.Results The patients were followed up for 12 to 72 months after discharge,with a median time of 47 months.During the follow-up period,31 patients(5.77%)developed PFF.Age,osteoporosis,Parkinson's disease and anterior femoral notch(AFN)were the risk factors for PFF after TKA in the elderly(P<0.05),and cross fixation of prosthesis and bone cement fixation were the protective factors(P<0.05).The results of H-L test showed that the risk prediction model of PFF after TKA in the elderly had good calibration(P>0.05).ROC curve analysis showed that the risk prediction model of PFF after TKA in the elderly has high discrimination(area under the curve was 0.858,95%CI:0.826 to 0.887),the sensitivity was 83.87%,the specificity was 88.34%.Conclusion The risk of PFF after TKA in the elderly is high,and prevention should be carried out according to the high risk factors.The prediction model constructed based on the high risk factors has good prediction efficiency.

Objective To explore the neuroprotective effect of coenzyme Q10 and its possible mechanism in mice with chronic restraint stress(CRS).Methods Mouse models of CRS were treated with intraperitoneal injections of coenzyme Q10 at low,moderate and high doses(50,100 and 200 mg/kg,respectively,n=8),VX765(a caspase-1 specific inhibitor,50 mg/kg,n=8),or fluoxetine(10 mg/kg,n=8)on a daily basis for 4 weeks,and the changes in depression-like behaviors of the mice were assessed by sugar water preference test,forced swimming test and tail suspension test.The expression of glial fibrillary acidic protein(GFAP)in the hippocampus of the mice was detected using immunohistochemistry,and the number of synaptic spines was determined with Golgi staining.Western blotting was performed to detect the changes in the expressions of GFAP and pyroptosis-related proteins in the hippocampus,and the colocalization of neurons and caspase-1 p10 was examined with immunofluorescence assay.Results Compared with the normal control mice,the mouse models of CRS showed significantly reduced sugar water preference and increased immobility time in forced swimming and tail suspension tests(P<0.05),and these depression-like behaviors were obviously improved by treatment with coenzyme Q10,VX765 or FLX.The mouse models showed a significantly decreased positive rate of GFAP and lowered GFAP protein expression in the hippocampus with obviously decreased synaptic spines,enhanced expressions of GSDMD-N,caspase-1 and IL-1β,and increased colocalization of neurons and caspase-1 p10(all P<0.05).All these changes were significantly ameliorated in the mouse models after treatment with Q10.Conclusion Coenzyme Q10 can alleviate depression-like behaviors in mice with CRS by down-regulating the pyroptosis signaling pathway.

Objective The aim of this study was to assess the impact of bisphenol A (BPA) and its substitute, bisphenol F (BPF), on the colonic fecal community structure and function of mice.Methods We exposed 6-8-week-old male C57BL/6 mice to 5 mg/(kg·day) and 50 μg/(kg·day) of BPA or BPF for 14 days. Fecal samples from the colon were analyzed using 16S rRNA sequencing. Results Gut microbiome community richness and diversity, species composition, and function were significantly altered in mice exposed to BPA or BPF. This change was characterized by elevated levels of Ruminococcaceae UCG-010 and Oscillibacter and decreased levels of Prevotella 9 and Streptococcus. Additionally, pathways related to carbohydrate and amino acid metabolism showed substantial enrichment. Conclusion Mice exposed to different BP analogs exhibited distinct gut bacterial community richness, composition, and related metabolic pathways. Considering the essential role of gut bacteria in maintaining intestinal homeostasis, our study highlights the intestinal toxicity of BPs in vertebrates.

Objective To explore the neuroprotective effect of coenzyme Q10 and its possible mechanism in mice with chronic restraint stress(CRS).Methods Mouse models of CRS were treated with intraperitoneal injections of coenzyme Q10 at low,moderate and high doses(50,100 and 200 mg/kg,respectively,n=8),VX765(a caspase-1 specific inhibitor,50 mg/kg,n=8),or fluoxetine(10 mg/kg,n=8)on a daily basis for 4 weeks,and the changes in depression-like behaviors of the mice were assessed by sugar water preference test,forced swimming test and tail suspension test.The expression of glial fibrillary acidic protein(GFAP)in the hippocampus of the mice was detected using immunohistochemistry,and the number of synaptic spines was determined with Golgi staining.Western blotting was performed to detect the changes in the expressions of GFAP and pyroptosis-related proteins in the hippocampus,and the colocalization of neurons and caspase-1 p10 was examined with immunofluorescence assay.Results Compared with the normal control mice,the mouse models of CRS showed significantly reduced sugar water preference and increased immobility time in forced swimming and tail suspension tests(P<0.05),and these depression-like behaviors were obviously improved by treatment with coenzyme Q10,VX765 or FLX.The mouse models showed a significantly decreased positive rate of GFAP and lowered GFAP protein expression in the hippocampus with obviously decreased synaptic spines,enhanced expressions of GSDMD-N,caspase-1 and IL-1β,and increased colocalization of neurons and caspase-1 p10(all P<0.05).All these changes were significantly ameliorated in the mouse models after treatment with Q10.Conclusion Coenzyme Q10 can alleviate depression-like behaviors in mice with CRS by down-regulating the pyroptosis signaling pathway.