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Vacuolar protein sorting 35 regulates retinal neurovascular function via astrocyte-mediated inflammatory response in a diabetic mouse model 认领 引用
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作者 Cheng Li Yuan-Rui Sun +6 位作者 Qiu-Mei Hu Lin-Lin Luo Xi Chen Shu-Hong Zhou Jie Xu Xue Li Wei Liu 《International Journal of Ophthalmology(English edition)》 SCIE CAS 2026年第8期1470-1483,共14页
●AIM:To explore how vacuolar protein sorting 35(VPS35)regulates astrocytic inflammation,impairs retinal endothelial function and drives early diabetic retinopathy(DR)neurovascular lesions in diabetic mouse model.●ME... ●AIM:To explore how vacuolar protein sorting 35(VPS35)regulates astrocytic inflammation,impairs retinal endothelial function and drives early diabetic retinopathy(DR)neurovascular lesions in diabetic mouse model.●METHODS:A streptozotocin(STZ)-induced C57BL/6J diabetic mouse model was established.Retinal tissues were collected from 0 to 12wk after successful induction of diabetes.Protein expression levels of VPS35,glial fibrillary acidic protein(GFAP),excitatory amino acid transporter 2(EAAT2),leucine-rich repeat kinase 2(LRRK2),and vascular endothelium-associated proteins were assessed by Western blotting(WB).The interaction between VPS35 and LRRK2 was verified by co-immunoprecipitation.Vascular leakage and astrocyte activation were evaluated by fundus fluorescein angiography and retinal flat-mount immunofluorescence staining.Primary astrocytes were cultured in vitro and subjected to high-glucose stimulation or VPS35 knockdown.Cell activation,expression of glutamate transport-associated proteins,and inflammatory cytokine expression were examined.Supernatant fluid from the primary astrocytes was applied to human umbilical vein endothelial cells(HUVECs)to assess cell migration,proliferation,and tube formation capacity.The expression of proteins related to the nuclear factor kappa-B(NF-κB)pathway was also evaluated.●RESULTS:In diabetic mice,retinal VPS35 protein expression exhibited a progressive decline beginning at 4wk post-diabetes onset,whereas GFAP protein expression increased significantly.By 8wk,marked astrocyte activation was observed,accompanied by retinal microvascular leakage and a reduction in vascular area.In vivo and in vitro experiments further confirmed that under high-glucose conditions,retinal VPS35 and EAAT2 protein levels were markedly decreased,while GFAP and LRRK2 protein levels were significantly elevated.Co-immunoprecipitation verified the physical interaction between VPS35 and LRRK2 in astrocytes.Finally,in vitro experiments demonstrated that both high-glucose stimulation and VPS35 knockdown led to astrocyte activation,upregulation of inflammatory cytokine expression,downregulation of EAAT2 and AMPA receptor subunit GLUA2,and upregulation of LRRK2.Treatment of HUVECs with supernatant fluid from these astrocytes enhanced cell migration but significantly inhibited cell proliferation and tube formation.WB analysis revealed markedly increased levels of NF-κB and phosphorylated NF-κB in the treated HUVECs.●CONCLUSION:During early DR in mice model,decreased retinal VPS35 protein expression induces astrocyte-mediated inflammatory responses and glutamate transport dysfunction.Through the interaction between VPS35 and LRRK2,paracrine inflammatory cytokines subsequently activate the NF-κB signaling pathway in vascular endothelial cells,leading to endothelial dysfunction and further driving DR-associated neurovascular injury.This study provides novel insights into the pathogenesis of DR and highlights the potential of VPS35 as a target for early intervention in DR. 展开更多
关键词 diabetic retinopathy vacuolar protein sorting 35 leucine-rich repeat kinase 2 nuclear factor kappa-B excitatory amino acid transporter 2 blood-retinal barrier astrocytes neurovascular unit mice
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Cancer stem cell-associated markers and their prognostic value in non-small cell lung cancer 认领 引用
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作者 Lin-Lin Luo Si-Cong Jiang +3 位作者 Shuo Li Guang-Yi Zhang Jian-Jun Tang You-Dan Guo 《World Journal of Stem Cells》 SCIE 2026年第6期81-91,共11页
BACKGROUND An urgent clinical need exists to stratify postoperative prognosis in patients with non-small cell lung cancer(NSCLC).However,the prognostic value of the cancer stem cell(CSC)markers CD133,aldehyde dehydrog... BACKGROUND An urgent clinical need exists to stratify postoperative prognosis in patients with non-small cell lung cancer(NSCLC).However,the prognostic value of the cancer stem cell(CSC)markers CD133,aldehyde dehydrogenase 1A1(ALDH1A1),and SRY-box transcription factor 2(SOX2)remains incompletely characterized.These markers are better viewed as complementary biomarkers for postoperative risk enrichment than as replacements for tumor-node-metastasis(TNM)staging or molecular classification.AIM To investigate expression levels of CD133,ALDH1A1 and SOX2,markers related to CSC,in NSCLC tissues for postoperative survival and prognosis.METHODS A total of 200 patients with pathologically confirmed NSCLC who underwent radical resection at Jiangxi Provincial People’s Hospital(The First Affiliated Hospital of Nanchang Medical College)between January 2023 and December 2025 were included retrospectively.Expressions of CD133,ALDH1A1,and SOX2 in tumor tissues was detected by immunohistochemistry,and the tumors were divided into high-and low-expression groups according to the immunoreactive score.All patients were followed up until December 2025 to record their overall survival(OS)and disease-free survival(DFS).The t-test orχ2 test was used for comparison between groups.The Kaplan-Meier method and log-rank test were used for survival analysis.Univariate and multivariate analyses were performed using a Cox proportional risk model,and a prognostic model including CSC markers was constructed to evaluate the C-index and area under the curve of the receiver operating characteristic curve for 2-year OS.The immunoreactive score cut-off selection was based on prior literature and cohort distribution rather than on receiver operating characteristic derivation.DFS was analyzed as a conventional composite endpoint and model discrimination was internally corrected using bootstrap resampling.RESULTS Among 200 patients,the high expression rates of CD133,ALDH1A1,and SOX2 were 44.00%(88/200),53.00%(106/200),and 40.00%(80/200),respectively.The median follow-up period was 23.50 months(interquartile range:14.20-31.60 months),resulting in 54 deaths(27.00%)and 70 recurrences/metastases(35.00%).After adjusting for age,gender,smoking history,histological type,differentiation degree,TNM stage,and adjuvant therapy,high expression of CD133[hazard ratio(HR)=1.450,95%confidence interval(CI):1.033-2.037,P=0.032],high expression of ALDH1A1(HR=1.380,95%CI:1.001-1.902,P=0.049),and TNM stage III(HR=1.980,95%CI:1.235-3.173,P=0.004 compared to stage I)were independent adverse prognostic factors for OS.Patients with CSC score≥2 had significantly shorter OS(P=0.004),and this association remained significant in the multivariate model(HR=1.550,95%CI:1.078-2.228,P=0.018).After adding the CSC score,the predicted area under the curve value for 2-year OS increased from 0.675 to 0.785.CONCLUSION High expressions of CD133 and ALDH1A1 in NSCLC suggests a worse survival outcome.Nonetheless,the CSC score should be interpreted together with the TNM stage,histological background,and molecular features rather than used in isolation for clinical decision-making. 展开更多
关键词 Non-small cell lung cancer Cancer stem cells CD133 Aldehyde dehydrogenase 1A1 SRY-box transcription factor 2 Prognosis
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