ObjectiveTo explore the role of lead exposure in the phenotypic transformation of vascular smooth muscle cells (VSMC), and to provide new insights for the mechanism of lead impact on vascular lesions. MethodsMouse aortic smooth muscle cells (MOVAS) were divided into a control group (0 μmol·L^-1), low concentration lead groups (0.1, 1, 5, and 10 μmol·L^-1), and high concentration lead groups (15, 25, and50 μmol·L^-1). MTT assays were used to assess the proliferation of the cells, and scratch assays were implicated to measure migration ability of the cells. Fluorescence quantitative PCR was employed to determine levels of mRNA expression for smooth muscle actin α (α⁃SMA), smooth muscle 22 alpha (SM22α), synthetic phenotype-related genes osteopontin (OPN), matrix metalloproteinase 9 (MMP9), and the transcription factor SOX9. Immunoblotting was used to determine levels of protein expression for α-SMA, OPN, and MMP9. ResultsProliferation of MOVAS was observed under the lead ions concentrations of 0‒50 µmol·L^-1, with a significant increase of proliferation compared to the control group at the concentrations of 5‒50 µmol·L^-1 (all P<0.05). The migration ability of cells gradually increased at the concentrations of 0‒10 µmol·L^-1, with a significant increase at 5 (q=4.574, P=0.003) and 10 µmol·L^-1 (q=10.570, P<0.001) compared to the control group. The 10 µmol·L^-1 lead ions significantly reduced the levels of mRNA expression for vascular smooth muscle contractile phenotype genes α⁃SMA (q=7.426, P<0.001) and SM22α (q=4.766, P=0.001), while significantly increasing the levels of mRNA expression for OPN (q=11.330, P<0.001), MMP9 (q=7.842, P<0.001), and SOX9 (q=11.120, P<0.001) genes. Furthermore, the 10 µmol·L^-1 lead ions significantly reduced the levels of protein expression for the vascular smooth muscle contractile phenotype marker α-SMA protein (q=2.897, P=0.049), while significantly increasing the levels of protein expression for the synthetic markers OPN (q=3.188, P=0.031) and MMP9 (q=3.292, P=0.026), compared to the control group. ConclusionTreatment with lead in vitro induced VSMC to differentiate from contractile phenotype to synthetic phenotype, indicating that a certain dose of lead exposure might be detrimental to the cardiovascular system.

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.

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

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.

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

Objective:To explore the psychological experience of reproductive concerns in female patients of childbearing age with systemic lupus erythematosus (SLE), and to provide evidence for formulating targeted intervention measures.Methods:From April to May 2024, phenomenological research methods of qualitative study and purposive sampling were used to conduct semi-structured interviews with 13 female SLE patients of childbearing age who were outpatient or hospitalized in the Third Affiliated Hospital of Southern Medical University. Colaizzi′s seven-step method was used for data analysis.Results:A total of 13 female patients of childbearing age with SLE were interviewed, aged 21-36 (27.08 ± 3.88) years. Six themes were identified: concerns about fertility, concerns about one′s own health, concerns about the safety of the offspring, concerns about unmet fertility information, the need for positive emotional transmission, negative psychological experience caused by childbearing related problems ( inferiority and depression caused by difficulty in maintaining intimate relationships, anxiety and guilt caused by reproductive pressure, pain and panic caused by failure reproductive experience, and restlessness and anxiety caused by the burden of reproductive costs).Conclusions:Female patients of childbearing age with SLE have many concerns about fertility issues. Medical staff should pay attention to the psychological experience related to fertility among female patients of childbearing age with SLE, and give targeted scientific and effective intervention to alleviate the negative psychological experience of patients with reproductive.

Objective To explore the repair effect and mechanism of human amniotic mesenchymal stem cells(hAMSCs)on endometrial injury.Methods hAMSCs were isolated using a two-enzyme digestion and then cultured.The third-passage(P3)cells were harvested to detect the surface markers by flow cytometry and to identify their trilineage differentiation potentials.Eighteen nulliparous female SD rats(8～9 weeks old,weighing 250～280 g)were randomly divided into 3 groups(n=6):normal control group,model group,and hAMSCs group.A rat model of intrauterine adhesions(IUA)was established in SD rats by using curettage combined with lipopolysaccharide(LPS)infection.In 2 weeks after modeling,the hAMSCs group received a bilateral uterine horn transplantation of 0.2 mL hAMSCs(1.0×10? cells/mL),while the model group received a same volume of PBS into both uterine horns.All rats were sacrificed in 2 weeks after transplantation.HE and Masson staining was used to observe endometrial thickness and gland number as well as endometrial fibrosis area.RT-qPCR and Western blotting were performed to detect the mRNA and protein levels of TGF-β1,Smad3,Smad7,epithelial-mesenchymal transition(EMT)markers(E-cadherin,Vimentin),fibrosis factor α-SMA,and endometrial estrogen receptor(ER)and progesterone receptor(PR)in endometrial tissues.Results The obtained cells were identified as hAMSCs due to the characteristics of surface markers and differentiation potentials.Compared with the normal control group,the model group showed decreased endometrial thickness,reduced gland number,increased fibrosis area,and enhanced mRNA and protein levels of fibrosis-related factors TGF-β1,Smad3,Vimentin,and α-SMA(P<0.01),while down-regulation of fibrosis-inhibiting molecule Smad7,the EMT marker E-cadherin,and endometrial receptors ER and PR at both mRNA and protein levels(P<0.01).hAMSCs transplantation increased endometrial thickness and gland number,decreased fibrosis area,and down-regulated mRNA expression of the aforementioned fibrosis-related factors(P<0.01),and up-regulated the mRNA expression levels of Smad7,E-cadherin,ER,and PR(P<0.01).The hAMSCs group also exhibited obviously down-regulated protein levels of TGF-β1,Smad3,and α-SMA(P<0.05),while enhanced protein levels of Smad7 and PR(P<0.05).Conclusion Intrauterine transplantation of hAMSCs can promote the repair of endometrial injury,and inhibits endometrial EMT and fibrosis through the TGF-β1/Smad7 signaling pathway.

Objective:To develop and validate a predictive model for massive hemorrhage during brain tumor resection in pediatric patients.Methods:A retrospective analysis was performed on the clinical data from pediatric patients who underwent elective brain tumor resection under general anesthesia at the Women and Children′s Medical Center Affiliated to Guangzhou Medical University from December 2016 to October 2023. The patients were randomly divided into model group and internal validation group in a ratio of 8∶2. Pediatric patients who underwent elective brain tumor resection under general anesthesia at Qilu Hospital of Shandong University from January 2021 to July 2024 were selected and served as external validation group. Relevant characteristic variables were screened through Lasso regression. A multivariate logistic regression was used to develop the model and plot the nomogram for intraoperative massive hemorrhage. The performance of the model was evaluated using the area under the receiver operating characteristic curve and calibration curve.Results:Through Lasso regression and multivariate logistic regression analyses, 11 independent influencing factors were identified: age ( OR=0.323, 95% confidence interval [ CI]: 0.280-0.374, P<0.001), weight ( OR=0.164, 95% CI: 0.135-0.199, P<0.001), activated partial thromboplastin time ( OR=1.133, 95% CI: 1.036-1.239, P=0.006), thrombin time ( OR=1.141, 95% CI: 1.048-1.243, P=0.002), red blood cell count ( OR=0.941, 95% CI: 0.888-0.996, P=0.035), hemoglobin concentration ( OR=0.873, 95% CI: 0.822-0.926, P<0.001), platelet count ( OR=1.062, 95% CI: 1.001-1.127, P=0.048), maximum tumor diameter ( OR=2.384, 95% CI: 2.241-2.536, P<0.001), tumor invasiveness ( OR=2.376, 95% CI: 2.071-2.726, P<0.001), hydrocephalus ( OR=2.409, 95% CI: 2.139-2.713, P<0.001), and centered midline structure ( OR=0.509, 95% CI: 0.465-0.557, P<0.001). Based on this, a nomogram prediction model was established. The receiver operating characteristic curve showed that the area under the curve of this model in predicting the risk of massive hemorrhage during brain tumor resection was 0.936 (95% CI: 0.90-0.959) in model group, 0.863 (95% CI: 0.744-0.948) in internal validation group, and 0.855 (95% CI: 0.726-0.955) in external validation group. The calibration curve indicated good model consistency, and the Hosmer-Lemeshow goodness-of-fit test result showed a P value of 0.979 ( P>0.05). Conclusions:Age, body weight, activated partial thromboplastin time, thrombin time, red blood cell count, hemoglobin concentration, platelet count, maximum tumor diameter, tumor invasiveness, hydrocephalus and midline structure are independent influencing factors for major bleeding during brain tumor resection in pediatric patients, and the prediction model established based on this histogram has high accuracy.

Objective To construct and implement a swallowing disorder assessment and management program for tracheal intubated patients after extubation based on the 4R crisis management theory,providing standardized and scientific interventions for oral feeding.Methods Utilizing the expert meeting method with the 4R crisis management theory framework,a swallowing disorder assessment and management program was developed for post-extubation tracheal intubated patients.A convenience sampling method was employed to select patients with tracheal intubations treated from July to December 2023 in the emergency ICU,central ICU,and cardiovascular surgery ICU of a tertiary hospital in Zhejiang Province.The patients treated from October to December were assigned to an experimental group(n=68),while those treated from July to September were designated as a control group(n=58).The experimental group received the 4R crisis management-based intervention,whereas the control group received standard ICU assessment and management.Outcomes indicators included the incidence of post-extubation swallowing disorders,time to first oral intake,incidence of aspiration during initial feeding,nasogastric and nasointestinal tube placement duration,incidence of aspiration pneumonia during hospitalization,re-intubation rates,ICU readmission rates,ICU stay duration,and total hospitalization days.Results Of the initially recruited subjects,68 in the experimental group and 54 in the control group were included in the final analysis.After the intervention,the experimental group exhibited significantly lower rates of post-extubation swallowing disorders,shorter time to first liquid oral intake,aspiration incidence during first feeding,shorter durations of nasogastric and nasointestinal tube placement,aspiration pneumonia,ICU readmission compared to the control group(P＜0.05).No significant differences were observed between the groups in time to first regular oral intake,re-intubation rates(P＞0.05).Conclusion The risk management program for dysphagia following tracheal extubation based on the 4R crisis management theory is scientifically robust and safe,offering a valuable reference for clinical assessments and management of swallowing and eating post-extubation in tracheal intubated patients.

Objective:To explore the association between the systemic immune-inflammation index (SII) and obesity metabolic phenotypes, as well as metabolic features in children and adolescents.Methods:A cross-sectional study was conducted using the random cluster sampling method from March 2023 to May 2024. Children and adolescents aged 9-17 years in Guangzhou were surveyed through questionnaires, physical measurements, and blood tests. According to BMI and metabolic status, participants were classified into normal-weight groups [metabolically healthy normal weight (MHNW) and metabolically unhealthy normal weight (MUNW)] and overweight/obese groups [metabolically healthy overweight/obese (MHO/O) and metabolically unhealthy overweight/obese (MUO/O)]. After natural log-transformation of SII values (lnSII), multinomial logistic regression was used to assess the association between SII and obesity metabolic phenotypes, while binary logistic regression was applied to assess the relationship between SII and metabolic phenotypes in the overweight/obese subgroup. Linear regression model and restricted cubic spline (RCS) were employed to examine the relationship between SII and metabolic features among the entire population.Results:A total of 3 749 participants were included. After adjusting for covariates, for every unit increase in lnSII, the risk of MHO/O and MUO/O increased by 93% ( OR=1.93, 95% CI: 1.56-2.40, P<0.001) and 156% ( OR=2.56, 95% CI: 2.02-3.25, P<0.001), respectively. In the overweight/obesity subgroup, for every unit increase in lnSII, the risk of MUO/O increased by 37% ( OR=1.37, 95% CI: 1.01-1.87, P=0.045). Linear regression model and RCS showed that lnSII was positively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) (SBP: β=1.39, 95% CI: 0.67-2.11, P<0.001; DBP: β=1.27, 95% CI: 0.79-1.75, P<0.001). lnSII also had a non-linear relationship with triglyceride ( Pnonlinear=0.032) and high-density lipoprotein cholesterol ( Pnonlinear=0.002). Conclusion:Elevated SII levels are associated with unfavorable obesity metabolic phenotypes, higher blood pressure, and altered lipid profiles in children and adolescents. SII may be a potential driving factor for metabolic heterogeneity in children and adolescents.