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Métodos Terapêuticos e Terapias MTCI
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Cell Commun Signal ; 17(1): 81, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331327

RESUMO

BACKGROUND: Inflammatory reaction in the dysfunction of retinal endotheliocytes has been considered to play a vital role in diabetic retinopathy (DR). Anti-inflammatory therapy so far gains poor outcome as DR treatment. This study aims to identify a novel therapeutic target of DR from the OMICs studies of a traditional anti-DR botanical products TNTL. METHODS: Hyperglycemic mice were treated with TNTL. The anti-hyperglycemic effect of TNTL was validated to confirm the biological consistency of the herbal products from batches. Improvement of DR by TNTL was examined by various assays on the retina. Next-generation transcriptome sequencing and cytokine array was used to identify the therapeutic targets. In vitro study was performed to validate the target. RESULTS: We observed that TNTL at its high doses possessed anti-hyperglycemic effect in murine type I diabetic model, while at its doses without reducing blood glucose, it suppressed DR incidence. TNTL restored the blood-retina barrier integrity, suppressed retinal neovascularization, and attenuated the retinal ganglion cell degeneration. Transcriptomic analysis on the retina tissue of hyperglycemic mice with or without TNTL revealed that the inflammatory retina microenvironment was significantly repressed. TNTL treatment suppressed pro-inflammatory macrophages in the retina, which resulted in the inactivation of endothelial cell migration, restoration of endothelial cell monolayer integrity, and prevention of leakage. Cytokine array analysis suggested that TNTL could significantly inhibit the secretion of MIP1γ from pro-inflammatory macrophages. Prevention of endothelial dysfunction by TNTL may be mediated by the inhibition of MIP1γ/CCR1 axis. More specifically, TNTL suppressed MIP1γ release from pro-inflammatory macrophages, which in turn inhibited the activation of CCR1-associated signaling pathways in endothelial cells. CONCLUSION: Our findings demonstrated that TNTL might be an alternative treatment to DR, and the primary source of potential drug candidates against DR targeting MIP1γ/CCR1 axis in the retinal microenvironment.


Assuntos
Quimiocinas CC/metabolismo , Retinopatia Diabética/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Terapia de Alvo Molecular , Animais , Linhagem Celular , Retinopatia Diabética/complicações , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Progressão da Doença , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Masculino , Camundongos , Retina/efeitos dos fármacos , Retina/patologia
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