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 investigate the protective effect and mechanism of vincamine derivative Vin24 on the pathological symptoms of diabetic peripheral neuropathy(DPN)in mice.METHODS Forty 8-week-old male C57BL/6N mice were randomly di-vided into control group(Control),model group(STZ),vincamine group(STZ+Vin)and Vin24 group(STZ+Vin24).Except the con-trol group,the rest three groups of mice were intraperitoneally injected with streptozocin(STZ,150 mg·kg-1)to induce type 1 diabe-tes and administration was started six weeks later.Thirty 18-week-old male db/db mice were randomly divided into model group(db/db),vincamine group(db/db+Vin)and Vin24 group(db/db+Vin24).Ten age-matched wild-type mice were used as a control group(db/m).The vincamine group were gavaged 30 mg·kg-1 of vincamine daily.The Vin24 group was gavaged 46.8 mg·kg-1 of Vin24,while the control and model group were given the same amount of saline daily,for four weeks.Sensory functions of the mice were as-sessed by assays against tactile and thermal allodynia threshold.A Laser Speckle Imaging System was used to detect the peripheral blood flow.The epidermal tissues of foot pads were collected for PGP9.5 immunofluorescence to measure the intraepidermal nerve fiber(IENF)density.Primary dorsal root ganglia(DRG)neurons were isolated for β-tubulin Ⅲ immunofluorescence to evaluate neurite outgrowth.Additionally,DRG tissues were extracted for ATF3 immunofluorescence for the evaluation of DRG neuronal apoptosis,and Western blot analysis was used to measure the protein levels of Bcl-2,Bax,Cleaved-Caspase3 and Caspase3.RESULTS The tact-ile and thermal allodynia thresholds were decreased(P<0.01,P<0.001),and peripheral blood flow was increased(P<0.001)in Vin24-treated DPN mice.The IENF density was increased(P<0.05,P<0.01)and DRG neurite outgrowth was improved(P<0.001)in Vin24 group compared with that in the model group.Immunofluorescence assay results indicated that the number of ATF3(a marker of neuronal apoptosis)-positive neurons was obviously decreased(P<0.01,P<0.001)in DRG tissues of Vin24-treated DPN mice.Western blot results demonstrated that the protein level of anti-apoptotic protein Bcl-2 was significantly increased(P<0.05),and the protein levels of pro-apoptotic proteins Bax and Cleaved-Caspase3 were significantly decreased(P<0.05)in DRG tissues of Vin24-treated DPN mice.CONCLUSION Vincamine derivative Vin24 inhibits the activation of Cleaved-Caspase3 and reduces the neuronal apoptosis levels by regulating Bcl-2/Bax/Caspase3 pathway,and eventually alleviates DRG neuronal damage and improves peripheral neuropathy in diabetic mice.

BACKGROUND:The content of serum thrombin in patients with osteoarthritis is significantly higher than that in normal individuals,and thrombin can induce inflammatory degeneration of rat chondrocytes,suggesting that inhibiting the function of thrombin may become a method for treating osteoarthritis.Celecoxib is a common therapeutic drug for the clinical treatment of osteoarthritis.It is not yet known whether it improves chondrocyte degeneration by inhibiting the activity of thrombin. OBJECTIVE:To investigate the effect of celecoxib on thrombin-induced degeneration of rat chondrocytes. METHODS:Thrombin levels in the serum of osteoarthritis patients and normal individuals were detected by an ELISA kit.Primary chondrocytes of neonatal Sprague-Dawley rats were isolated,and all experiments were performed with cells from passage one.Chondrocytes were randomly divided into three groups:control group,thrombin group,and celecoxib group.The cell morphology of the three groups was observed under an inverted microscope,and an Edu kit was used to detect the cell proliferation.qRT-PCR was used to detect the expression of extracellular matrix components(aggrecan,elastin,cartilage oligomeric matrix proteins),inflammatory factors(interleukin-1,interleukin-6,and tumor necrosis factor-α),and chemokines(monocyte chemotactic protein 2,monocyte chemotactic protein 7,granulocyte chemotactic protein 6).The expression of type 2 collagen α1 was detected by immunofluorescence.Western blot method was used to detect the expression of catabolic metabolism genes,such as matrix metalloproteinase 9,matrix metalloproteinase 13,and cyclooxygenase 2. RESULTS AND CONCLUSION:Patients with osteoarthritis had higher levels of thrombin in the serum compared with normal individuals.Under the microscope,celecoxib was found to significantly inhibit fibroid changes in chondrocytes.Compared with the thrombin group,celecoxib inhibited the proliferation of chondrocytes.The downregulation of extracellular matrix gene expression,such as type II collagen α1,in the thrombin group was inhibited by celecoxib(P<0.05).Thrombin promoted the expression of inflammatory factors(interleukin-1,interleukin-6,and tumor necrosis factor-α),chemokines(monocyte chemotactic protein 2,monocyte chemotactic protein 7,granulocyte chemotactic protein 6),as well as catabolic genes(matrix metalloproteinase 9,matrix metalloproteinase 13,and cyclooxygenase 2),and under the intervention of celecoxib,the expression of these genes could be downregulated(P<0.05).Overall,these findings indicate that celecoxib inhibits the pro-inflammatory effects of thrombin and thereby ameliorates chondrocyte degeneration in rats.

Objective To analyze the effects of nasal endoscopic continuous penetrating suture and nasal packing on discomfort and complications in patients undergoing deflection of nasal septum(DNS)plasty.Methods 116 patients undergoing DNS plasty were enrolled between March 2018 and March 2023,including 69 cases in packing group score(nasal packing)and 47 cases in suture group(continuous penetrating suture).The scores of pain[evaluated by visual analogue scale(VAS)]and epistaxis caused by nasal dressing changes at 3 and 7 d after surgery,subjective discomfort score(headache,dry mouth,epiphora,sleep difficulties,nasal obstruction and nasal pain)at 3 d after surgery,total inspiratory and expiratory resistance before and at 14 d after surgery,and the occurrence of complications at 1 month after surgery were compared between the two groups.Results At 3 d after surgery,VAS of pain and epistaxis score caused by nasal dressing changes were lower in suture group than packing group(P<0.05),and score of subjective discomfort was lower in suture group(P<0.05).At 14 d after surgery,total inspiratory and expiratory resistance were lower in suture group than packing group(P<0.05).The total incidence of postoperative complications was lower in suture group than packing group(P<0.05).Conclusion Compared with nasal packing,nasal endoscopic continuous penetrating suture can reduce pain and bleeding,improve postoperative subjective discomfort and nasal ventilation function,and reduce complications after DNS plasty.

Objective:To understand the real experience of caregivers of children with craniopharyngioma-associated hypothalamic obesity (CP-HO) based on the chronic disease trajectory model, so as to provide a reference for formulating corresponding disease management plans.Methods:From May 2023 to July 2023, semi-structured interviews were conducted with 17 caregivers of children with CP-HO who were admitted to the Department of Neurosurgery, Nanfang Hospital, Southern Medical University through purposive sampling. The interview data were analyzed by Colaizzi 7-step analysis method.Results:The 17 caregivers of children with CP-HO were 24 to 46 years old, including 3 males and 14 females. A total of 3 themes were extracted. Prodromal phase of weight: lack of disease cognition and weakening of self-concept; during the period of weight increase, the demand burden became prominent and the life pattern changed; weight stability: pressure, hope, and insight into the value of life.Conclusions:For promoting a good disease response of caregivers and improving the weight management effect of children and the quality of family life, medical staff should pay attention to and understand the disease care experience of children with CP-HO, and provide comprehensive and systematic solution strategies.

Purpose To explore the value of the new generation tau PET tracer 18F-Florzolotau in Alzheimer's disease(AD)at different stages.Materials and Methods Twenty-five MCI patients and sixty-one AD patients with positive β-amyloid status in Huashan Hospital,Fudan University from February 2020 to January 2022 were retrospectively enrolled with 18F-Florzolotau PET imaging and demographic and clinical data.The pre-processed PET images were analyzed by SPM two-sample t-test between MCI and AD groups,and the standardized uptake value ratios(SUVR)were extracted from the region of interest defined by SPM analysis(P＜0.001);scaled subprofile model/principal component analysis was used to construct the different tau related patterns(MCItauRP,ADtauRP)and calculate the corresponding expression values.The classification efficiency of SUVR and MCItauRP,ADtauRP expression values was evaluated by receiver operating characteristic curve.Results Compared with MCI patients,tau protein deposition of AD patients was increased mainly in the bilateral temporal,occipital lobe(P＜0.001),and the SUVR of these brain region in the AD group was higher than that in the MCI group(Z=-3.164,P＜0.00l);the expression values of MCItauRP and ADtauRP were significantly different between the AD group and MCI group(t=3.72,Z=-3.51;both P＜0.001),and these expression values of AD patients were higher than those in the MCI group;the accuracy of tauRP expression values and SUVR for the differentiation between the AD and MCI group were 61.63％,65.12％and 65.12％,respectively;the sensitivity was 88.00％,96.00％and 100.00％,respectively;the specificity was 50.82％,52.46％and 50.82％,respectively.Conclusion The new tau PET can identify and distinguish the differences in tau protein deposition between AD and MCI patients.However,the classification and diagnosis efficiency is not high.In the future,it is necessary to find a more ideal analysis method.