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1.
Int Immunopharmacol ; 65: 108-118, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30312879

RESUMO

Immunosuppressive drugs are widely used for the treatment of immune-mediated diseases and inflammation, but the toxicity and side effects of the available immunosuppressors make the search of new agents of great relevance. Here, we evaluated the immunomodulatory activity of an N-acylhydrazone derivative, (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), a phosphodiesterase-4 (PDE-4) inhibitor. LASSBio-1386 inhibited lymphocyte activation in a concentration-dependent fashion, decreasing lymphoproliferation and IFN-γ and IL-2 production stimulated by anti-CD3/CD28 mAbs or concanavalin A (Con A) and inducing cell-cycle arrest in the G0/G1 phase. These effects were not blocked by RU486, a glucocorticoid receptor (GR) antagonist, indicating an effect independent of glucocorticoid receptor activation. Combination index-isobologram analysis indicates a synergistic effect between LASSBio-1386 and dexamethasone in lymphoproliferation inhibition. LASSBio-1386 presented immunomodulatory action in macrophage cultures, as observed by a significant and concentration-dependent decrease in NO and TNF-α production, an effect achieved by reducing IĸB expression and NF-κB activation. In the mouse model of endotoxic shock, LASSBio-1386 at 50 and 100 mg/kg protected 50 and 85% of mice against LPS-induced lethality, respectively. In agreement to its in vitro action, treatment with 100 mg/kg of LASSBio-1386 reduced TNF-α and IL-1ß serum levels, while increased IL-6 and IL-10. Finally, LASSBio-1386 reduced the paw edema in a BSA-induced delayed-type hypersensitivity model. These findings demonstrate the immunomodulatory and immunosuppressant effects of LASSBio-1386 and indicate this molecule is a promising pharmacologic agent for immune-mediated diseases.


Assuntos
Hidrazonas/farmacologia , Hipersensibilidade Tardia/tratamento farmacológico , Imunossupressores/farmacologia , Lipopolissacarídeos/toxicidade , Inibidores da Fosfodiesterase 4/farmacologia , Choque/tratamento farmacológico , Animais , Benzamidas , Citocinas/genética , Citocinas/metabolismo , Dexametasona/farmacologia , Antagonistas de Hormônios/farmacologia , Hidrazonas/química , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mifepristona/farmacologia , Estrutura Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7
2.
Eur J Pharmacol ; 815: 156-165, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28899698

RESUMO

Betulinic acid (BA) is a naturally occurring triterpenoid with several biological properties already described, including immunomodulatory activity. Here we investigated the immunomodulatory activity of eight semi-synthetic amide derivatives of betulinic acid. Screening of derivatives BA1-BA8 led to the identification of compounds with superior immunomodulatory activity than BA on activated macrophages and lymphocytes. BA5, the most potent derivative, inhibited nitric oxide and TNFα production in a concentration-dependent manner, and decreased NF-κB activation in Raw 264.7 cells. Additionally, BA5 inhibited the proliferation of activated lymphocytes and the secretion of IL-2, IL-4 IL-6, IL-10, IL-17A and IFNÉ£, in a concentration-dependent manner. Flow cytometry analysis in lymphocyte cultures showed that treatment with BA5 induces cell cycle arrest in pre-G1 phase followed by cell death by apoptosis. Moreover, BA5 also inhibited the activity of calcineurin, an enzyme that plays a critical role in the progression of cell cycle and T lymphocyte activation. BA5 has a synergistic inhibitory effect with dexamethasone on lymphoproliferation, showing a promising profile for drug combination. Finally, we observed immunosuppressive effects of BA5 in vivo in mouse models of lethal endotoxemia and delayed type hypersensitivity. Our results reinforce the potential use of betulinic acid and its derivatives in the search for potent immunomodulatory drugs.


Assuntos
Hipersensibilidade Tardia/tratamento farmacológico , Hipersensibilidade Tardia/imunologia , NF-kappa B/antagonistas & inibidores , Choque Séptico/tratamento farmacológico , Choque Séptico/imunologia , Triterpenos/química , Triterpenos/farmacologia , Amidas/química , Animais , Inibidores de Calcineurina/química , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Hipersensibilidade Tardia/induzido quimicamente , Hipersensibilidade Tardia/metabolismo , Imunomodulação/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Triterpenos Pentacíclicos , Células RAW 264.7 , Choque Séptico/induzido quimicamente , Choque Séptico/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Triterpenos/uso terapêutico , Ácido Betulínico
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