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1.
Front Immunol ; 15: 1415004, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38895119

RESUMO

Introduction: This study examined the impact of 5'-(N- ethylcarboxamido)adenosine (NECA) in the peripheral blood of healthy individuals, those with diabetes mellitus, diabetic retinopathy (DR), and C57BL/6 mice, both in vivo and in vitro. Methods: Enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM) were used to evaluate the effects of NECA on dendritic cells (DCs) and mouse bone marrow-derived dendritic cells (BMDCs) and the effects of NECA-treated DCs on Treg and Th17 cells. The effect of NECA on the Toll-like receptor (TLR) pathway in DCs was evaluated using polymerase chain reaction (PCR) and western blotting (WB). Results: FCM and ELISA showed that NECA inhibited the expression of surface markers of DCs and BMDCs, increased anti-inflammatory cytokines and decreased proinflammatory cytokines. PCR and WB showed that NCEA decreased mRNA transcription and protein expression in the TLR-4-MyD88-NF-kß pathway in DCs and BMDCs. The DR severity in streptozocin (STZ) induced diabetic mice was alleviated. NECA-treated DCs and BMDCs were co-cultivated with CD4+T cells, resulting in modulation of Treg and Th17 differentiation, along with cytokine secretion alterations. Conclusion: NECA could impair DCs' ability to present antigens and mitigate the inflammatory response, thereby alleviating the severity of DR.


Assuntos
Células Dendríticas , Retinopatia Diabética , Camundongos Endogâmicos C57BL , Transdução de Sinais , Receptores Toll-Like , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Retinopatia Diabética/imunologia , Retinopatia Diabética/metabolismo , Camundongos , Humanos , Masculino , Receptores Toll-Like/metabolismo , Diabetes Mellitus Experimental/imunologia , Feminino , Células Th17/imunologia , Células Th17/metabolismo , Citocinas/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Pessoa de Meia-Idade , Inflamação/imunologia
2.
Mol Med ; 29(1): 151, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37914992

RESUMO

BACKGROUND: 5α-Hydroxycostic acid is a eudemane sesquiterpene that is isolated from the natural plant, Laggera alata. It exerts anti-inflammatory and anti-angiogenic effects on human breast cancer cells, but its role and underlying mechanism in choroidal neovascularization (CNV) are still unclear. We conducted a study to verify that 5α-Hydroxycostic acid can inhibit the formation and leakage of CNV, and describe the possible dual pathway by which it exerts its inhibitory effects in this process. METHODS: An in vitro model of choroidal neovascularization was established using VEGF164, while a rat model of choroidal neovascularization was established using a 532 nm laser. In both models, the effects of 5α-Hydroxycostic acid in vivo and in vitro were evaluated to determine its inhibitory effect on abnormal cell proliferation, migration and tubule formation, as well as its effect on pathological changes in choroidal tissues and the area of neovascularization leakage in rats. The levels of components in the VEGF/VEGFR and Ang2/Tie2 signaling pathways were measured in tissues and cells. RESULTS: In vitro experiments have shown that 5α-Hydroxycostic acid can inhibit abnormal cell proliferation, migration and angiogenesis. Additionally, 5α-Hydroxycostic acid enhances cell adhesion by inhibiting the phosphorylation pathways of VEGFR2 and Tie2. In vivo experiments demonstrated that 5α-Hydroxycostic acid has a positive therapeutic effect on choroidal neovascularization in rats. It can effectively reduce vascular leakage, consistent with the results of the cell experiments. CONCLUSION: 5α-Hydroxycostic acid can inhibit choroidal neovascularization by interfering with the VEGF- and Ang2/Tie2-related pathways, and it may be a good candidate drug for treating CNV.


Assuntos
Neovascularização de Coroide , Fator A de Crescimento do Endotélio Vascular , Ratos , Humanos , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Angiopoietina-2 , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Transdução de Sinais , Modelos Animais de Doenças
3.
Acta Biomater ; 166: 536-551, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37196903

RESUMO

Choroidal neovascularization (CNV) is the main cause of vision loss in patients with wet age-related macular degeneration (AMD). Currently, treatment of these conditions requires repeated intravitreal injections, which may lead to complications such as infection and hemorrhage. So, we have developed a noninvasive method for treating CNV with nanoparticles, namely, Angiopoietin1-anti CD105-PLGA nanoparticles (AAP NPs), which targets the CNV to enhance drug accumulation at the site. These nanoparticles, with PLGA as a carrier, can slowly release encapsulated Angiopoietin 1 (Ang 1) and target the choroidal neovascularization marker CD105 to enhance drug accumulation, increases vascular endothelial cadherin (VE-cadherin) expression between vascular endothelial cells, effectively reduce neovascularization leakage and inhibit Angiopoietin 2(Ang 2) secretion by endothelial cells. In a rat model of laser-induced CNV, intravenous injection of AAP NPs exerted a good therapeutic effect in reducing CNV leakage and area. In short, these synthetic AAP NPs provide an effective alternative treatment for AMD and meet the urgent need for noninvasive treatment in neovascular ophthalmopathy. STATEMENT OF SIGNIFICANCE: This work describes the synthesis, injection-mediated delivery, in vitro and in vivo efficacy of targeted nanoparticles with encapsulated Ang1; via these nanoparticles, the drug can be targeted to choroidal neovascularization lesions for continuous treatment. The release of Ang1 can effectively reduce neovascularization leakage, maintain vascular stability, and inhibit Ang2 secretion and inflammation. This study provides a new approach for the treatment of wet age-related macular degeneration.


Assuntos
Neovascularização de Coroide , Nanopartículas , Degeneração Macular Exsudativa , Ratos , Animais , Células Endoteliais/metabolismo , Neovascularização de Coroide/metabolismo , Degeneração Macular Exsudativa/tratamento farmacológico , Inflamação , Nanopartículas/uso terapêutico , Modelos Animais de Doenças
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