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1.
Purinergic Signal ; 19(1): 135-144, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35167016

RESUMO

The choroid plexus (CP) is one of the key gateways regulating the entry of peripheral immune cells into the CNS. However, the neuromodulatory mechanisms of maintaining its gateway activity are not fully understood. Here, we identified adenosine A2A receptor (A2AR) activity as a regulatory signal for the activity of CP gateway under physiological conditions. In association with a tightly closed CP gateway, we found that A2AR was present at low density in the CP. The RNA-seq analysis revealed that the A2AR antagonist KW6002 affected the expression of the cell adhesion molecules' (CAMs) pathway and cell response to IFN-γ in the CP. Furthermore, blocking or activating A2AR signaling in the CP resulted in a decreased and an increased, respectively, expression of lymphocyte trafficking determinants and disruption of the tight junctions (TJs). Furthermore, A2AR signaling regulates the CP permeability. Thus, A2AR activity in the CP may serve as a therapeutic target for remodeling the immune homeostasis in the CNS with implications for the treatment of neuroimmunological disorders.


Assuntos
Plexo Corióideo , Receptor A2A de Adenosina , Receptor A2A de Adenosina/metabolismo , Plexo Corióideo/metabolismo , Adenosina/metabolismo , Transdução de Sinais
2.
Small ; 18(4): e2104657, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35083856

RESUMO

Fungal keratitis (FK) remains a serious clinical problem worldwide, so the ultimate goal of the treatment is to develop a minimally invasive, safe, and effective method for ocular drug delivery. Here, a minimally invasive delivery system is reported for treating FK by using a dissolving microneedle (MN)-array patch based on Poly(D,L-lactide) (PLA) and hyaluronic acid (HA). By altering the concentration of PLA, MN patches with excellent properties are modified and optimized. The 30% PLA-HA MN patches penetrate the corneal epithelial layer reversibly with no apparent ocular irritation as well as a short recovery time of less than 12 h, and increase the residence time by 2.5 h in the conjunctival sac, thereby offering higher drug bioavailability. Remarkably, the rabbit model of FK shows that the topical MN(+) patch medication exerts superior therapeutic effects compared with the conventional eye drop formulation, and also presents comparable therapeutic efficacy with that of the clinical mainstay strategy (i.e., intrastromal injection). Therefore, the MN patch, acting as an ocular drug delivery system with high efficacy and ability of rapid corneal healing, promises a cost-effective household solution for the treatment of FK, which may also lead to a new approach for treating FK in clinics.


Assuntos
Sistemas de Liberação de Medicamentos , Infecções Oculares Fúngicas , Animais , Córnea , Sistemas de Liberação de Medicamentos/métodos , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Agulhas , Soluções Oftálmicas/farmacologia , Soluções Oftálmicas/uso terapêutico , Coelhos
3.
J Pharmacol Exp Ther ; 382(2): 113-122, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35688477

RESUMO

Nafamostat is an approved short-acting serine protease inhibitor. However, its administration is also associated with anaphylactic reactions. One mechanism to augment hypersensitivity reactions could be inhibition of diamine oxidase (DAO). The chemical structure of nafamostat is related to the potent DAO inhibitors pentamidine and diminazene. Therefore, we tested whether nafamostat is a human DAO inhibitor. Using different activity assays, nafamostat reversibly inhibited recombinant human DAO with an IC50 of 300-400 nM using 200 µM substrate concentrations. The Ki of nafamostat for the inhibition of putrescine and histamine deamination is 27 nM and 138 nM, respectively For both substrates, nafamostat is a mixed mode inhibitor with P values of <0.01 compared with other inhibition types. Using 80-90% EDTA plasma, the IC50 of nafamostat inhibition was approximately 360 nM using 20 µM cadaverine. In 90% EDTA plasma, the IC50 concentrations were 2-3 µM using 0.9 µM and 0.18 µM histamine as substrate. In silico modeling showed a high overlap compared with published diminazene crystallography data, with a preferred orientation of the guanidine group toward topaquinone. In conclusion, nafamostat is a potent human DAO inhibitor and might increase severity of anaphylactic reaction by interfering with DAO-mediated extracellular histamine degradation. SIGNIFICANCE STATEMENT: Treatment with the short-acting anticoagulant nafamostat during hemodialysis, leukocytapheresis, extracorporeal membrane oxygenator procedures, and disseminated intravascular coagulation is associated with severe anaphylaxis in humans. Histamine is a central mediator in anaphylaxis. Potent inhibition of the only extracellularly histamine-degrading enzyme diamine oxidase could augment anaphylaxis reactions during nafamostat treatment.


Assuntos
Amina Oxidase (contendo Cobre) , Anafilaxia , Amina Oxidase (contendo Cobre)/metabolismo , Benzamidinas , Diminazena , Ácido Edético , Guanidinas/efeitos adversos , Histamina/efeitos adversos , Histamina/metabolismo , Humanos
4.
Glycobiology ; 31(4): 444-458, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-32985651

RESUMO

Human diamine oxidase (hDAO) rapidly inactivates histamine by deamination. No pharmacokinetic data are available to better understand its potential as a new therapeutic modality for diseases with excess local and systemic histamine, like anaphylaxis, urticaria or mastocytosis. After intravenous administration of recombinant hDAO to rats and mice, more than 90% of the dose disappeared from the plasma pool within 10 min. Human DAO did not only bind to various endothelial and epithelial cell lines in vitro, but was also unexpectedly internalized and visible in granule-like structures. The uptake of rhDAO into cells was dependent on neither the asialoglycoprotein-receptor (ASGP-R) nor the mannose receptor (MR) recognizing terminal galactose or mannose residues, respectively. Competition experiments with ASGP-R and MR ligands did not block internalization in vitro or rapid clearance in vivo. The lack of involvement of N-glycans was confirmed by testing various glycosylation mutants. High but not low molecular weight heparin strongly reduced the internalization of rhDAO in HepG2 cells and HUVECs. Human DAO was readily internalized by CHO-K1 cells, but not by the glycosaminoglycan- and heparan sulfate-deficient CHO cell lines pgsA-745 and pgsD-677, respectively. A docked heparin hexasaccharide interacted well with the predicted heparin binding site 568RFKRKLPK575. These results strongly imply that rhDAO clearance in vivo and cellular uptake in vitro is independent of N-glycan interactions with the classical clearance receptors ASGP-R and MR, but is mediated by binding to heparan sulfate proteoglycans followed by internalization via an unknown receptor.


Assuntos
Amina Oxidase (contendo Cobre) , Proteoglicanas de Heparan Sulfato , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Células CHO , Cricetinae , Glicosaminoglicanos , Heparitina Sulfato/metabolismo , Humanos , Camundongos , Ratos
5.
Molecules ; 25(6)2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32178384

RESUMO

Two members of the copper-containing amine oxidase family are physiologically important proteins: (1) Diamine oxidase (hDAO; AOC1) with a preference for diamines is involved in degradation of histamine and (2) Vascular adhesion protein-1 (hVAP-1; AOC3) with a preference for monoamines is a multifunctional cell-surface receptor and an enzyme. hVAP-1-targeted inhibitors are designed to treat inflammatory diseases and cancer, whereas the off-target binding of the designed inhibitors to hDAO might result in adverse drug reactions. The X-ray structures for both human enzymes are solved and provide the basis for computer-aided inhibitor design, which has been reported by several research groups. Although the putative off-target effect of hDAO is less studied, computational methods could be easily utilized to avoid the binding of VAP-1-targeted inhibitors to hDAO. The choice of the model organism for preclinical testing of hVAP-1 inhibitors is not either trivial due to species-specific binding properties of designed inhibitors and different repertoire of copper-containing amine oxidase family members in mammalian species. Thus, the facts that should be considered in hVAP-1-targeted inhibitor design are discussed in light of the applied structural bioinformatics and structural biology approaches.


Assuntos
Amina Oxidase (contendo Cobre)/química , Moléculas de Adesão Celular/genética , Desenho de Fármacos , Desenvolvimento de Medicamentos/tendências , Amina Oxidase (contendo Cobre)/genética , Amina Oxidase (contendo Cobre)/uso terapêutico , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/uso terapêutico , Histamina/química , Humanos
6.
Heliyon ; 10(15): e35191, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39165954

RESUMO

In this study, we screened novel dipeptidyl peptidase IV (DPP4) inhibitors from the ConMedNP library consisting of 3507 molecules. Interestingly, molecular docking, ADMET, and the anti-diabetic activity predictions suggest that three molecules, namely OTH_UD_XX06_1, GB19, and BMC_000104, have a high binding affinity toward DPP4. The molecular dynamics (MD) simulation results suggest that these hit molecules have a stable binding pose and occupy the binding pockets throughout the 200 ns simulation. The presence of intermolecular H-bonding between the ligands and DPP4 was observed throughout the simulation period. Thus, docking and MD results, predicted that the three compounds were the most potent DPP4 inhibitors that could putatively bind to the DPP4 active site via both conventional H-bonding and hydrophobic interactions. These results could aid the discovery of new drugs to treat type 2 diabetes.

7.
Int Rev Neurobiol ; 170: 185-223, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37741692

RESUMO

Emerging evidence suggests that both selective and non-selective Adenosine A2A receptor (A2AR) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used animal model for multiple sclerosis (MS) research. Meanwhile, the recent FDA approval of Nourianz® (istradefylline) in 2019 as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes, along with its proven clinical safety, has prompted us to explore the potential of A2AR antagonists in treating multiple sclerosis (MS) through clinical trials. However, despite promising findings in experimental autoimmune encephalomyelitis (EAE), the complex and contradictory role of A2AR signaling in EAE pathology has raised concerns about the feasibility of using A2AR antagonists as a therapeutic approach for MS. This review addresses the potential effect of A2AR antagonists on EAE/MS in both the peripheral immune system (PIS) and the central nervous system (CNS). In brief, A2AR antagonists had a moderate effect on the proliferation and inflammatory response, while exhibiting a potent anti-inflammatory effect in the CNS through their impact on microglia, astrocytes, and the endothelial cells/epithelium of the blood-brain barrier. Consequently, A2AR signaling remains an essential immunomodulator in EAE/MS, suggesting that A2AR antagonists hold promise as a drug class for treating MS.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Astrócitos , Sistema Nervoso Central , Encefalomielite Autoimune Experimental/tratamento farmacológico , Células Endoteliais , Esclerose Múltipla/tratamento farmacológico , Antagonistas do Receptor A2 de Adenosina/uso terapêutico
8.
Biochem Pharmacol ; 197: 114917, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35041813

RESUMO

Noninfectious (autoimmune and immune-mediated) uveitis is one of the primary diseases leading to blindness in the world. Due to the limitation of current first-line drugs for clinical uveitis, novel drugs and targets against uveitis are urgently needed. Ganciclovir (GCV), an FDA-approved antiviral drug, is often used to treat cytomegalovirus-induced retinitis in clinical patients. Recently, GCV was found to suppress neuroinflammation via targeting STING signaling because the STING pathway plays a pivotal role in autoimmune diseases. However, until now, the effect of GCV on non-infectious uveitis has never been explored. In this work, using the rat experimental autoimmune uveitis (EAU) model, we first found STING to be highly expressed in infiltrating cells (CD68+, CD45+, and CD4+) and retinal glial cells (Iba1+ and GFAP+) of the immunized retina. More importantly, GCV treatment can significantly suppress the initiation and progression of EAU by inhibiting infiltration of Th17 and inflammatory cells into the retina. Mechanistically, we found that GCV could reverse the levels of pro-inflammatory factors (such as IL-1ß) and chemokine-related factors (such as Cxcr3), possibly via targeting the STING pathway. The present results suggest that GCV may be considered as a novel therapeutic strategy against human uveitis.


Assuntos
Doenças Autoimunes/prevenção & controle , Ganciclovir/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Retina/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Uveíte/prevenção & controle , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Progressão da Doença , Relação Dose-Resposta a Droga , Proteínas do Olho/toxicidade , Ganciclovir/farmacologia , Humanos , Mediadores da Inflamação/imunologia , Masculino , Ratos , Ratos Endogâmicos Lew , Retina/imunologia , Retina/patologia , Proteínas de Ligação ao Retinol/toxicidade , Células Th17/imunologia , Células Th17/patologia , Uveíte/induzido quimicamente , Uveíte/imunologia , Uveíte/patologia
9.
Bioact Mater ; 10: 420-429, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34901557

RESUMO

Boosting transcorneal permeability and pharmacological activity of drug poses a great challenge in the field of ocular drug delivery. In the present study, we propose a drug-peptide supramolecular hydrogel based on anti-inflammatory drug, dexamethasone (Dex), and Arg-Gly-Asp (RGD) motif for boosting transcorneal permeability and pharmacological activity via the ligand-receptor interaction. The drug-peptide (Dex-SA-RGD/RGE) supramolecular hydrogel comprised of uniform nanotube architecture formed spontaneously in phosphate buffered saline (PBS, pH = 7.4) without external stimuli. Upon storage at 4 °C, 25 °C, and 37 °C for 70 days, Dex-SA-RGD in hydrogel did not undergo significant hydrolysis, suggesting great long-term stability. In comparison to Dex-SA-RGE, Dex-SA-RGD exhibited a more potent in vitro anti-inflammatory efficacy in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages via the inhibition of nuclear factor кB (NF-κB) signal pathway. More importantly, using drug-peptide supramolecular hydrogel labeled with 7-nitro-2,1,3-benzoxadiazole (NBD), the Dex-SA-K(NBD)RGD showed increased performance in terms of integrin targeting and cellular uptake compared to Dex-SA-K(NBD)RGE, as revealed by cellular uptake assay. On topical instillation in rabbit's eye, the proposed Dex-SA-K(NBD)RGD could effectively enhance the transcorneal distribution and permeability with respect to the Dex-SA-K(NBD)RGE. Overall, our findings demonstrate the performance of the ligand-receptor interaction for boosting transcorneal permeability and pharmacological activity of drug.

10.
Front Mol Biosci ; 9: 889825, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936791

RESUMO

Peptidoglycan is a cross-linked polymer responsible for maintaining the bacterial cell wall integrity and morphology in Gram-negative and Gram-positive bacteria. The peptidoglycan pathway consists of the enzymatic reactions held in three steps: cytoplasmic, membrane-associated, and periplasmic. The Mur enzymes (MurA-MurF) are involved in a cytoplasmic stage. The UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme is responsible for transferring the enolpyruvate group from phosphoenolpyruvate (PEP) to UDP-N-acetylglucosamine (UNAG) to form UDP-N-acetylglucosamine enolpyruvate (EP-UNAG). Fosfomycin is a natural product analogous to PEP that acts on the MurA target enzyme via binding covalently to the key cysteine residue in the active site. Similar to fosfomycin, other MurA covalent inhibitors have been described with a warhead in their structure that forms a covalent bond with the molecular target. In MurA, the nucleophilic thiolate of Cys115 is pointed as the main group involved in the warhead binding. Thus, in this minireview, we briefly describe the main recent advances in the design of MurA covalent inhibitors.

11.
RSC Adv ; 12(29): 18834-18847, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35873314

RESUMO

The shikimate pathway enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) catalyzes a reaction involved in the production of amino acids essential for plant growth and survival. EPSPS is the main target of glyphosate, a broad-spectrum herbicide that acts as a competitive inhibitor concerning phosphoenolpyruvate (PEP), which is the natural substrate of EPSPS. In the present study, we introduce a natural compound library, named Anagreen, which is a compendium of herbicide-like compounds obtained from different natural product databases. Herein, we combined the structure- and ligand-based virtual screening strategies to explore Anagreen against EPSPS using the structure of glyphosate complexed with a T102I/P106S mutant of EPSPS from Eleusine indica (EiEPSPS) as a starting point. First, ligand-based pharmacophore screening was performed to select compounds with a similar pharmacophore to glyphosate. Then, structure-based pharmacophore modeling was applied to build a model which represents the molecular features of glyphosate. Then, consensus docking was performed to rank the best poses of the natural compounds against the PEP binding site, and then molecular dynamics simulations were performed to analyze the stability of EPSPS complexed with the selected ligands. Finally, we have investigated the binding affinity of the complexes using free energy calculations. The selected hit compound, namely AG332841, showed a stable conformation and binding affinity to the EPSPS structure and showed no structural similarity to the already known weed EPSPS inhibitors. Our computational study aims to clarify the inhibition of the mutant EiEPSPS, which is resistant to glyphosate, and identify new potential herbicides from natural products.

12.
J Control Release ; 344: 261-271, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35278493

RESUMO

In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 µM. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs.


Assuntos
Sistemas de Liberação de Medicamentos , Uveíte , Animais , Olho/patologia , Hidrogéis/química , Peptídeos/química , Coelhos , Uveíte/patologia
13.
Elife ; 102021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477104

RESUMO

Background: Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis, or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations. Methods: Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined. Results: Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, binding to heparin and heparan sulfate was strongly reduced. The double mutant rhDAO-R568S/R571T showed minimal cellular uptake. The short α-distribution half-life of the wildtype protein was eliminated, and the clearance was significantly reduced in rodents. Conclusions: The successful decrease in plasma clearance of rhDAO by mutations of the heparin-binding motif with unchanged histamine-degrading activity represents the first step towards the development of rhDAO as a first-in-class biopharmaceutical to effectively treat diseases characterized by excessive histamine concentrations in plasma and tissues. Funding: Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).


Assuntos
Amina Oxidase (contendo Cobre) , Motivos de Aminoácidos/genética , Produtos Biológicos , Heparina/metabolismo , Antagonistas dos Receptores Histamínicos , Amina Oxidase (contendo Cobre)/química , Amina Oxidase (contendo Cobre)/genética , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/metabolismo , Humanos , Camundongos , Mutação/genética , Ligação Proteica/genética , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
14.
J Genet Genomics ; 48(3): 237-247, 2021 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-33573880

RESUMO

Chromatin interactions functionally affect genome architecture and gene regulation, but to date, only fresh samples must be used in High-through chromosome conformation capture (Hi-C) to keep natural chromatin conformation intact. This requirement has impeded the advancement of 3D genome research by limiting sample collection and storage options for researchers and severely limiting the number of samples that can be processed in a short time. Here, we develop a freeze substitution Hi-C (FS-Hi-C) technique that overcomes the need for fresh samples. FS-Hi-C can be used with samples stored in liquid nitrogen (LN2): the water in a vitreous form in the sample cells is replaced with ethanol via automated freeze substitution. After confirming that the FS step preserves the natural chromosome conformation during sample thawing, we tested the performance of FS-Hi-C with Drosophila melanogaster and Gossypium hirsutum. Beyond allowing the use of frozen samples and confirming that FS-Hi-C delivers robust data for generating contact heat maps and delineating A/B compartments and topologically associating domains, we found that FS-Hi-C outperforms the in situ Hi-C in terms of library quality, reproducibility, and valid interactions. Thus, FS-Hi-C will probably extend the application of 3D genome structure analysis to the vast number of experimental contexts in biological and medical research for which Hi-C methods have been unfeasible to date.


Assuntos
Drosophila melanogaster , Animais , Análise Custo-Benefício , Substituição ao Congelamento
15.
Biochem Pharmacol ; 180: 114108, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32569628

RESUMO

Noninfectious (autoimmune and immune-mediated) uveitis is an ocular inflammatory disease which can lead to blindness in severe cases. Due to the potential side effects of first-line drugs for clinical uveitis, novel drugs and targets against uveitis are still urgently needed. In the present study, using rat experimental autoimmune uveitis (EAU) model, we first found that minocycline treatment can substantially inhibit the development of EAU and improve the retinal function by suppressing the retinal microglial activation, and block the infiltration of inflammatory cells, including Th17, into the retina by decreasing the major histocompatibility complex class II (MHC II) expression in resident and infiltrating cells. Moreover, we demonstrated that minocycline treatment can remodel the gut microenvironment of EAU rats by restoring the relative abundance of Ruminococcus bromii, Streptococcus hyointestinalis, and Desulfovibrio sp. ABHU2SB and promoting a functional shift in the gut via reversing the levels of L-proline, allicin, aceturic acid, xanthine, and leukotriene B4, and especially increasing the production of propionic acid, histamine, and pantothenic acid. At last, we revealed that minocycline treatment can significantly attenuate the progression of EAU after inflammation onset, which may be explained by the role of minocycline in the remodeling of the gut microenvironment since selective elimination of retinal microglia on the later stages of EAU was shown to have little effect. These data clearly demonstrated that inhibition of microglial activation and remodeling of the gut microenvironment can suppress the development and progression of experimental autoimmune uveitis. Considering the excellent safety profile of minocycline in multiple clinical experiments, we suggest that minocycline may have therapeutic implications for clinical uveitis.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Microglia/efeitos dos fármacos , Minociclina/uso terapêutico , Retina/efeitos dos fármacos , Uveíte/tratamento farmacológico , Animais , Doenças Autoimunes/imunologia , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/imunologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Masculino , Microglia/imunologia , Ratos , Ratos Endogâmicos Lew , Retina/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/patologia , Uveíte/imunologia , Uveíte/patologia
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