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1.
Artigo em Inglês | MEDLINE | ID: mdl-35615688

RESUMO

Quercetin (QUE), a health supplement, can improve renal function in diabetic nephropathy (DN) rats by ameliorating podocyte injury. Its clinical trial for renal insufficiency in advanced diabetes (NCT02848131) is currently underway. This study aimed to investigate the mechanism of QUE protecting against podocyte injury to attenuate DN through network pharmacology, microarray data analysis, and molecular docking. QUE-associated targets, genes related to both DN, and podocyte injury were obtained from different comprehensive databases and were intersected and analyzed to obtain mapping targets. Candidate targets were identified by constructing network of protein-protein interaction (PPI) of mapping targets and ranked to obtain key targets. The major pathways were obtained from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) term enrichment analysis of candidate targets via ClueGO plug-in and R project software, respectively. Potential receptor-ligand interactions between QUE and key targets were evaluated via Autodocktools-1.5.6. 41. Candidate targets, of which three key targets (TNF, VEGFA, and AKT1), and the major AGE-RAGE signaling pathway in diabetic complications were ascertained and associated with QUE against podocyte injury in DN. Molecular docking models showed that QUE could closely bind to the key targets. This study revealed that QUE could protect against podocyte injury in DN through the following mechanisms: downregulating inflammatory cytokine of TNF, reducing VEGF-induced vascular permeability, inhibiting apoptosis by stimulating AKT1 phosphorylation, and suppressing the AGE-induced oxidative stress via the AGE-RAGE signaling pathway.

2.
Oxid Med Cell Longev ; 2021: 4190098, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777686

RESUMO

Osteoarthritis (OA), a highly prevalent chronic joint disease, involves a complex network of inflammatory mediators that not only triggers pain and cartilage degeneration but also accelerates disease progression. Traditional Chinese medicinal shenjinhuoxue mixture (SHM) shows anti-inflammatory and analgesic effects against OA with remarkable clinical efficacy. This study explored the mechanism underlying anti-OA properties of SHM and evaluated its efficacy and safety via in vivo experiments. Through network pharmacology and published literature, we identified the key active phytochemicals in SHM, including ß-sitosterol, oleanolic acid, licochalcone A, quercetin, isorhamnetin, kaempferol, morusin, lupeol, and pinocembrin; the pivotal targets of which are TLR-4 and NF-κB, eliciting anti-OA activity. These phytochemicals can enter the active pockets of TLR-4 and NF-κB with docking score ≤ -3.86 kcal/mol, as shown in molecular docking models. By using surface plasmon resonance assay, licochalcone A and oleanolic acid were found to have good TLR-4-binding affinity. In OA rats, oral SHM at mid and high doses (8.72 g/kg and 26.2 g/kg) over 6 weeks significantly alleviated mechanical and thermal hyperalgesia (P < 0.0001). Accordingly, the expression of inflammatory mediators (TLR-4, interleukin (IL-) 1 receptor-associated kinase 1 (IRAK1), NF-κB-p65, tumor necrosis factor (TNF-) α, IL-6, and IL-1ß), receptor activator of the NF-κB ligand (RANKL), and transient receptor potential vanilloid 1 (TRPV1) in the synovial and cartilage tissue of OA rats was significantly decreased (P < 0.05). Moreover, pathological observation illustrated amelioration of cartilage degeneration and joint injury. In chronic toxicity experiment of rats, SHM at 60 mg/kg demonstrated the safety. SHM had an anti-inflammatory effect through a synergistic combination of active phytochemicals to attenuate pain and cartilage degeneration by inhibiting TLR-4 and NF-κB activation. This study provided the experimental foundation for the development of SHM into a more effective dosage form or new drugs for OA treatment.


Assuntos
Doenças das Cartilagens/prevenção & controle , Inflamação/prevenção & controle , NF-kappa B/antagonistas & inibidores , Osteoartrite/complicações , Dor/prevenção & controle , Compostos Fitoquímicos/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Doenças das Cartilagens/etiologia , Doenças das Cartilagens/metabolismo , Doenças das Cartilagens/patologia , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Dor/etiologia , Dor/metabolismo , Dor/patologia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia
3.
Ann Palliat Med ; 10(4): 3960-3975, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33832291

RESUMO

BACKGROUND: The complication, pulmonary fibrosis (PF) secondary to COVID-19, may have a second wave of late mortality, given the huge number of individuals infected by COVID-19. However, the molecular mechanisms of PF secondary to COVID-19 haven't been fully elucidated, making the identification of novel strategies for targeted therapy challenging. This study aimed to systematically identify the molecular mechanisms and high-frequency core traditional Chinese medicine (TCM) targeting PF secondary to COVID-19 through network pharmacology and data mining. METHODS: The molecular mechanisms of PF secondary to COVID-19 were identified by mapping the COVID-19 differentially expressed gene and known targets associated with PF, protein-protein interactions network analysis, and enrichment pathway analysis; then the high-frequency core TCM targeting PF secondary to COVID-19 were identified by data mining and "Key targets related to PF secondary to COVID-19 - Ingredients" and "Key ingredients-key herbs" network analysis; and last we validated the interaction between the key ingredients and key targets by molecular docking. RESULTS: The molecular mechanisms of PF secondary to COVID-19 were mainly related to tumor necrosis factor (TNF) signaling pathway, cytokine-cytokine receptor interaction pathway, and NF-κB signaling pathway. Among these, cytokines interleukin 6 (IL-6), TNF, and IL-1ß were identified as the key targets associated with PF secondary to COVID-19. The high-frequency core TCM targeting these key targets were identified, including ingredients of quercetin, epigallocatechin-3-gallate, emodin, triptolide, resveratrol, and herb of Polygonum cuspidatum. Finally, our results were validated by quercetin and resveratrol both well docked to IL-6, TNF, and IL-1ß protein, with the estimated docking energy <0 kcal/mol. CONCLUSIONS: This study identified the cytokines-related molecular mechanisms of PF secondary to COVID-19, and the high-frequency core TCM against PF by targeting IL-6, TNF, and IL-1ß. Which provides new ideas for the discovery of small molecular compounds with potential therapeutic effects on PF secondary to COVID-19.


Assuntos
COVID-19 , Medicamentos de Ervas Chinesas , Fibrose Pulmonar , Mineração de Dados , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , SARS-CoV-2
4.
J Ethnopharmacol ; 268: 113560, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33161027

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Compound XiongShao Capsule (CXSC), a traditional herb formula, has been approved for using to treat diabetic peripheral neuropathy (DPN) by the Shanghai Food and Drug Administration, with significant efficacy in clinic. AIM OF THE STUDY: This study aimed to investigate the multidimensional pharmacological mechanisms and synergism of CXSC against DPN in rats. METHODS: The quality analysis of CXSC was performed by high-performance liquid chromatography (HPLC) and thin-layer chromatography. Rats with DPNinduced by streptozotocin/high-fat diet for 4 weeks were treated with CXSC at three doses (1.2 g/kg, 0.36 g/kg, and 0.12 g/kg), or epalrestat (15 mg/kg) daily for 8 weeks continuously. During the treatment period, body weight, serum glucose levels, and nerve function, including nerve conduction velocity (NCV), and mechanical and thermal hyperalgesia were tested and assessed every 4 weeks. In the 13th week, the histopathological examination in the sciatic nerve was performed using a transmission electron microscope. The expression of apoptosis-related proteins of BAX, BCL2, and caspase-3 in the sciatic nerve was examined using hematoxylin and eosin staining. The serum levels of advanced glycation end products (AGEs), oxidative-nitrosative stress biomarkers of superoxide dismutase (SOD), and nitric oxide synthase (NOS) were measured using a rat-specific ELISA kit. RESULTS: CXSC had no significant effect on body weight or serum glucose levels (P > 0.05), but it significantly improved mechanical hyperalgesia (F5,36 = 18.24, P < 0.0001), thermal hyperalgesia (F5,36 = 8.45, P < 0.0001), and NCV (motor NCV: F5,36 = 7.644, P < 0.0001, sensory NCV: F5,36 = 12.83, P < 0.0001). Besides, it maintained myelin and axonal structure integrity, downregulated the expression of apoptosis-related proteins in the sciatic nerve tissue, reduced AGEs and NOS levels, and enhanced antioxidant enzyme SOD activities in the serum. CONCLUSION: CXSC exerted neuroprotective effects against rats with DPN through multidimensional pharmacological mechanisms including antiapoptotic activity in the sciatic nerve and downregulation of the level of serum NOS, SOD and AGEs.


Assuntos
Apoptose/efeitos dos fármacos , Neuropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/fisiologia , Cápsulas , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Estreptozocina/toxicidade
5.
J Ethnopharmacol ; 263: 113059, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32663591

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Shikonin, one of the main active ingredients of Chinese herbal medicine Lithospermum erythrorhizon, has been widely used to treat various disease including virus infection and inflammation in clinical. Its anti-tumor activity has been recorded in "Chinese herbal medicine". Recently, some studies about its anti-glioma effects have been reported. However, little is known about the molecular pharmacological activity of Shikonin in glioma. AIM: This study aimed to systematically uncover and validate the pharmacological mechanism of Shikonin against glioma. MATERIAL AND METHODS: Network pharmacology approach, survival analysis, and Pearson co-expression analysis were performed to uncover and test the pharmacological mechanisms of Shikonin in glioma. Apoptosis assay, Caspase-3 activity assay and immunoblot analysis were practiced to validate the mechanisms. RESULTS: Network pharmacology results suggested, anti-glioma effect of Shikonin by interfering endoplasmic reticulum (ER) stress-mediated tumor apoptosis targeting Caspase-3, and Bax/Bak-induced mitochondrial outer membrane permeabilization (MOMP) triggering cancer cell apoptosis. Survival analysis suggested the association of CASP3 with glioma (P < 0.05). Pearson correlation analysis indicated possible interaction of CASP3 with PERK through positive feedback regulation. Shikonin or in combination with 14G2a induced cell apoptosis in oligodendroglioma Hs683 cells in a dose-dependent manner with at a maximum apoptosis rate of 33%-37.5%, and 73%-77% respectively. Immunoblot analysis showed that Shikonin increased Caspase-3 activity to about 4.29 times, and increased 9 times when it combined with 14G2a. Shikonin increased also the expression levels of the proteins PERK and CHOP by about 4.4 and 5.6 folds, respectively, when it combined with 14G2a. CONCLUSIONS: This study highlights the pharmacological mechanisms of Shikonin in the induction of tumor apoptosis in glioma cells.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glioma/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Naftoquinonas/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Humanos , Membranas Mitocondriais/fisiologia
6.
Drug Des Devel Ther ; 14: 1145-1156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214800

RESUMO

BACKGROUND: Shenjin Huoxue Mixture (SHM), a classic traditional herb mixture has shown significant clinical efficacy against osteoarthritis (OA). Our previous experimental study has confirmed its anti-inflammatory and analgesic effect on acute soft tissue injury in rats, with the compound of glycyrrhizinate in SHM identified and the content of paeoniflorin in SHM determined by high-performance liquid chromatography (HPLC). However, the components and its pharmacological mechanisms of SHM against OA have not been systematically elucidated yet. Thus this study aimed to predict the key active ingredients and potential pharmacological mechanisms of SHM in the treatment of OA by network pharmacology approach and thin-layer chromatography (TLC) validation. METHODS: The active ingredients of SHM and their targets, as well as OA-related targets, were identified from databases. The key active ingredients were defined and ranked by the number of articles retrieved in PubMed using the keyword "(the active ingredients [Title/Abstract]) AND Osteoarthritis[Title/Abstract] ", and validated partially by TLC. The pharmacological mechanisms of SHM against OA were displayed by GO term and Reactome pathway enrichment analysis with Discovery Studio 3.0 software docking to testing the reliability. RESULTS: Finally, 16 key active ingredients were identified and ranked, including quercetin validated through TLC. Inflammatory response, IL-6 signaling pathway and toll-like receptor (TLR) cascades pathway were predicted as the main pharmacological mechanisms of SHM against OA. Especially, 12 out of 16 key active ingredients, including validated quercetin, were well docked to IL-6 proteins. CONCLUSION: Our results confirmed the anti-inflammatory and analgesic effect of SHM against OA through multiple components, multiple targets and multiple pathways, which revealed the theoretical basis of SHM against OA and may provide a new drug option for treating OA.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Osteoartrite/tratamento farmacológico , Mapas de Interação de Proteínas , Analgésicos/análise , Anti-Inflamatórios/análise , Cromatografia em Camada Fina , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/análise , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
7.
Artigo em Inglês | MEDLINE | ID: mdl-32025234

RESUMO

Shuangbai Tablets (SBT), a traditional herbal mixture, has shown substantial clinical efficacy. However, a systematic mechanism of its active ingredients and pharmacological mechanisms of action against proteinuria continues being lacking. A network pharmacology approach was effectual in discovering the relationship of multiple ingredients and targets of the herbal mixture. This study aimed to identify key targets, major active ingredients, and pathways of SBT against proteinuria by network pharmacology approach combined with thin layer chromatography (TLC). Human phenotype (HP) disease analysis, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and molecular docking were used in this study. To this end, a total of 48 candidate targets of 118 active ingredients of SBT were identified. Network analysis showed PTGS2, ESR1, and NOS2 to be the three key targets, and beta-sitosterol, quercetin, and berberine were the three major active ingredients; among them one of the major active ingredients, quercetin, was discriminated by TLC. These results of the functional enrichment analysis indicated that the most relevant disease including these 48 candidate proteins is proteinuria, SBT treated proteinuria by sympathetically regulating multiple biological pathways, such as the HIF-1, RAS, AGE-RAGE, and VEGF signaling pathways. Additionally, molecular docking validation suggested that major active ingredients of SBT were capable of binding to HIF-1A and VEGFA of the main pathways. Consequently, key targets, major active ingredients, and pathways based on data analysis of SBT against proteinuria were systematically identified confirming its utility and providing a new drug against proteinuria.

8.
Biomolecules ; 10(1)2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877715

RESUMO

Daphne genkwa, a Chinese medicinal herb, is used frequently in Southeast Asian countries to treat diseases; the flavonoid hydroxygenkwanin (HGK) is extracted from its flower buds. The bioactivity of HGK, particularly as an anti-liver cancer agent, has not been explored. In this study, human hepatocellular carcinoma (HCC) cell lines and an animal xenograft model were employed to investigate both the activity of HGK against liver cancer and its cellular signaling mechanisms. HCC cells treated with HGK were subjected to cell function assays. Whole transcriptome sequencing was used to identify genes whose expression was influenced by HGK, and the flavonoid's cancer suppression mechanisms were further investigated through gain- and loss-of-function assays. Finally, in vitro findings were tested in a mouse xenograft model. The data showed that HGK induced the expression of the microRNA miR-320a, which in turn inhibited the expression of the transcription factor 'forkhead box protein M1' (FOXM1) and downstream FOXM1-regulated proteins related to epithelial-mesenchymal transition, thereby leading to the suppression of liver cancer cell growth and invasion. Significant inhibition of tumor growth was also observed in HGK-treated mice. Hence, the present study demonstrated the activity of HGK against liver cancer and validated its potential use as a therapeutic agent.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/fisiopatologia , Medicamentos de Ervas Chinesas/administração & dosagem , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Flavonoides/administração & dosagem , Proteína Forkhead Box M1/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Daphne/química , Proteína Forkhead Box M1/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Masculino , Camundongos Nus , MicroRNAs/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-31210774

RESUMO

Compound XiongShao Capsule (CXSC), a traditional herb mixture, has shown significant clinical efficacy against diabetic peripheral neuropathy (DPN). However, its multicomponent and multitarget features cause difficulty in deciphering its molecular mechanisms. Our study aimed to identify the key active ingredients and potential pharmacological mechanisms of CXSC in treating DPN by network pharmacology and provide scientific evidence of its clinical efficacy. CXSC active ingredients were identified from both the Traditional Chinese Medicine Systems Pharmacology database, with parameters of oral bioavailability ≥ 30% and drug-likeness ≥ 0.18, and the Herbal Ingredients' Targets (HIT) database. The targets of those active ingredients were identified using ChemMapper based on 3D-structure similarity and using HIT database. DPN-related genes were acquired from microarray dataset GSE95849 and five widely used databases (TTD, Drugbank, KEGG, DisGeNET, and OMIM). Next, we obtained candidate targets with therapeutic effects against DPN by mapping active ingredient targets and DPN-related genes and identifying the proteins interacting with those candidate targets using STITCH 5.0. We constructed an "active ingredients-candidate targets-proteins" network using Cytoscape 3.61 and identified key active ingredients and key targets in the network. We identified 172 active ingredients in CXSC, 898 targets of the active ingredients, 110 DPN-related genes, and 38 candidate targets with therapeutic effects against DPN. Three key active ingredients, namely, quercetin, kaempferol, and baicalein, and 25 key targets were identified. Next, we input all key targets into ClueGO plugin for KEGG enrichment and molecular function analyses. The AGE-RAGE signaling pathway in diabetic complications and MAP kinase activity were determined as the main KEGG pathway and molecular function involved, respectively. We determined quercetin, kaempferol, and baicalein as the key active ingredients of CXSC and the AGE-RAGE signaling pathway and MAP kinase activity as the main pharmacological mechanisms of CXSC against DPN, proving the clinical efficacy of CXSC against DPN.

10.
Medicine (Baltimore) ; 96(2): e5646, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28079797

RESUMO

RATIONALE: Crossed cerebellar diaschisis (CCD) is a poor prognostic factor after stroke because without immediate cerebral reperfusion no further improvements in the patient's condition can be achieved. We investigated the clinical effects of intravascular laser irradiation therapy (ILIB) on CCD and evaluated the therapeutic effect in the sub-acute post-stroke stage. PATIENT CONCERNS: The 77-year-old male with cerebral infarction in the territory of the right anterior cerebral artery only underwent conservative treatment including hydration and aspirin in the acute post-stroke stage. DIAGNOSIS: He was diagnosed as stroke based on the clinical presentations and imaging findings. INTERVENTION: Once the patient was in stable condition, he underwent a daily hour-long ILIB (He-Ne laser) for ten consecutive days during the sub-acute post-stroke stage. OUTCOMES: We used single-photon emission computed tomography (SPECT) before and after intravascular laser irradiation to detect changes in cerebral and cerebellar perfusion. Then, we compared the two images. CCD was detected using the first SPECT. After intervention by ILIB, the second SPECT showed greater perfusion in the affected cerebellar hemisphere. LESSONS: We found that ILIB helped eliminate CCD, which was previously shown to be an untreatable condition using any intervention during the sub-acute post-stroke stage. Stroke patients could therefore greatly benefit from ILIB.


Assuntos
Doenças Cerebelares/terapia , Infarto da Artéria Cerebral Anterior/complicações , Terapia com Luz de Baixa Intensidade , Idoso , Doenças Cerebelares/etiologia , Procedimentos Endovasculares , Humanos , Masculino
11.
Neuroreport ; 27(12): 935-9, 2016 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-27348016

RESUMO

In recent studies, oxytocin showed potential for the treatment of mental diseases. CD38 is essential for oxytocin release, and hence plays a critical role in social behavior. CD38 catalyzes ß-NAD into cyclic ADP ribose (cADPR), which could elevate the intracellular Ca by Ca-permeable channels for oxytocin secretion. The temperature-sensitive cation channel, transient receptor potential melastatin-2 (TRPM2), is a cation-nonselective cation and has been shown to affect oxytocin indirectly. The aim of the present study was to verify the participation of temperature and TRPM2 in CD38-regulated oxytocin release. The crude membranes were prepared to isolate the nerve terminals from the posterior pituitary. At 34°C, 37°C, and 39°C, agonists (ß-NAD, ADPR, cADPR) and antagonists (8-Br-cADPR, 2-APB) were used to stimulate the nerve terminals. Oxytocin releases were investigated by enzyme-linked immunosorbent assay. In addition, the expression of TRPM2 and CD38 in the hypothalamus and pituitary was detected by western blotting and quantitative PCR. CD38 agonists (ß-NAD, cADPR) and antagonist (8-Br-cADPR) could increase or reduce the oxytocin release, respectively. TRPM2 agonist (ADPR) and antagonist (2-APB) alone could also regulate oxytocin release. Furthermore, temperature could increase agonist stimulation and attenuate the antagonist inhibition on oxytocin release. In addition, CD38 and TRPM2 were expressed in the hypothalamus and pituitary at both the mRNA and the protein level. TRPM2 in pituitary nerve terminals plays a role in oxytocin release. Temperature- enhanced oxytocin release by CD38 and TRPM2. TRPM2 might be involved in the process of CD38-regulated oxytocin release.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Ocitocina/metabolismo , Canais de Cátion TRPM/metabolismo , ADP-Ribosil Ciclase 1/agonistas , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Animais , Hipotálamo/metabolismo , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos Endogâmicos ICR , Neuro-Hipófise/metabolismo , Canais de Cátion TRPM/agonistas , Canais de Cátion TRPM/antagonistas & inibidores , Temperatura
12.
Invest Ophthalmol Vis Sci ; 51(12): 6566-74, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20702818

RESUMO

PURPOSE: To compare and contrast the T regulatory cells (Tregs) induced by anterior chamber (AC) injection of antigen with those induced by orthotopic corneal allografts. METHODS: Anterior chamber-associated immune deviation (ACAID) Tregs were induced by injecting C57BL/6 spleen cells into the AC of BALB/c mice. Delayed-type hypersensitivity responses to C57BL/6 alloantigens were evaluated by a conventional ear swelling assay. Corneal allograft Tregs were induced by applying orthotopic C57BL/6 corneal allografts onto BALB/c hosts. The effects of anti-CD25, anti-CD8, anti-interferon-γ (IFN-γ), anti-IL-17A, or cyclophosphamide treatments on corneal allograft survival and ACAID were evaluated. RESULTS: Administration of either anti-CD25 or anti-IFN-γ antibodies prevented the expression of ACAID and abolished the immune privilege of corneal allografts. By contrast, in vivo treatment with anti-CD8 antibody abrogated ACAID but had no effect on corneal allograft survival. Further discordance between ACAID and corneal allograft survival emerged in experiments in which the induction of allergic conjunctivitis or the administration of anti-IL-17A abolished the immune privilege of corneal allografts but had no effect on the induction or expression of ACAID. CONCLUSIONS: Although orthotopic corneal allografts are strategically located for the induction of ACAID by the sloughing of corneal cells into the AC, the results reported here indicate that the Tregs induced by orthotopic corneal allografts are remarkably different from the Tregs that are induced by AC injection of alloantigen. Although both of these Treg populations promote corneal allograft survival, they display distinctly different phenotypes.


Assuntos
Câmara Anterior/imunologia , Transplante de Córnea , Sobrevivência de Enxerto/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos/administração & dosagem , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Conjuntivite Alérgica/imunologia , Ciclofosfamida/farmacologia , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Hipersensibilidade Tardia/imunologia , Interferon gama/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Isoantígenos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pólen , Transplante Homólogo
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