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1.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
2.
Drugs ; 79(8): 887-891, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31093950

RESUMO

Peficitinib [Smyraf® (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clinical trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Antirreumáticos/farmacologia , Aprovação de Drogas , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores
3.
Arch. Soc. Esp. Oftalmol ; 94(5): 237-241, mayo 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-180829

RESUMO

Varón de 30 años de edad con leucemia mieloblástica aguda y síndrome mielodisplásico secundario que desarrolló una enfermedad injerto contra huésped. El paciente fue tratado con ruxolitinib, un inhibidor de la Janus quinasa. A los 3 meses de haber iniciado el tratamiento se produjo una necrosis retiniana por Aspergillus, sin respuesta al tratamiento. El tratamiento con inhibidores de la Janus quinasa favorecería un aumento en la incidencia de infecciones oportunistas. El uso de estos fármacos podría dar lugar a una menor eficacia de los tratamientos empleados


A 30 year-old man with acute myeloblastic leukaemia and secondary myelodysplastic syndrome developed graft-versus-host disease. The patient was treated with ruxolitinib. After being treated for 3 months with ruxolitinib, an inhibitor of Janus kinase, he developed Aspergillus retinal necrosis resistant to common treatment. Treatment with Janus kinase inhibitors may lead to an increased incidence of opportunistic infections. Janus kinase inhibitor administration may result in poor treatment efficacy


Assuntos
Humanos , Masculino , Adulto , Síndrome de Necrose Retiniana Aguda/microbiologia , Infecções Oportunistas/microbiologia , Aspergilose/complicações , Janus Quinases/antagonistas & inibidores , Síndromes Mielodisplásicas/tratamento farmacológico , Evolução Fatal
4.
Trends Pharmacol Sci ; 40(5): 298-308, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30948191

RESUMO

Defective regulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway in cancers, haematological diseases, and chronic inflammatory conditions highlights its clinical significance. While several biologic and small molecule therapeutics targeting this pathway have been developed, these have several limitations. Therefore, there is a need to identify new targets for intervention. Suppressor of cytokine signalling (SOCS) proteins are a family of inducible inhibitors of cytokine receptors that activate the JAK-STAT pathway. Here we propose that newly identified mechanisms controlling SOCS function could be exploited to develop molecularly targeted drugs with unique modes of action to inhibit JAK-STAT signalling in disease.


Assuntos
Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Humanos , Janus Quinases/antagonistas & inibidores , Terapia de Alvo Molecular , Fatores de Transcrição STAT/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas Supressoras da Sinalização de Citocina/antagonistas & inibidores
5.
Immunity ; 50(4): 1007-1023, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995492

RESUMO

Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in immunity, tissue regeneration, and metabolism. Rapid production of IL-6 contributes to host defense during infection and tissue injury, but excessive synthesis of IL-6 and dysregulation of IL-6 receptor signaling is involved in disease pathology. Therapeutic agents targeting the IL-6 axis are effective in rheumatoid arthritis, and applications are being extended to other settings of acute and chronic inflammation. Recent studies reveal that selective blockade of different modes of IL-6 receptor signaling has different outcomes on disease pathology, suggesting novel strategies for therapeutic intervention. However, some inflammatory diseases do not seem to respond to IL-6 blockade. Here, we review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Ensaios Clínicos como Assunto , Receptor gp130 de Citocina/antagonistas & inibidores , Receptor gp130 de Citocina/imunologia , Humanos , Inflamação/imunologia , Interleucina-6/biossíntese , Interleucina-6/deficiência , Interleucina-6/imunologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Knockout , Receptores de Interleucina-6/imunologia , Ribonucleases/deficiência , Fator de Transcrição STAT3/fisiologia , Proteína 1 Supressora da Sinalização de Citocina/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas/fisiologia
6.
Immunity ; 50(4): 832-850, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995502

RESUMO

The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.


Assuntos
Citocinas/classificação , Subunidade gama Comum de Receptores de Interleucina/genética , Família Multigênica/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/genética , Citocinas/imunologia , Evolução Molecular , Regulação da Expressão Gênica , Terapia Genética , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Janus Quinase 3/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Subpopulações de Linfócitos/imunologia , Camundongos , Terapia de Alvo Molecular , Família Multigênica/genética , Neoplasias/genética , Neoplasias/imunologia , Subunidades Proteicas , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais , Pesquisa Médica Translacional , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
7.
Pharm Res ; 36(4): 64, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30859327

RESUMO

BACKGROUND: Tofacitinib (Tofa) has been approved for moderately to severely active ulcerative colitis (UC). To improve its therapeutic efficacy and limit dose-dependent toxicity, we developed a macromolecular prodrug of Tofa (P-Tofa). If the prodrug design improves the potency and duration of Tofa therapy, it would widen its therapeutic window, potentially leading to improved safety and better clinical management of UC. METHODS: P-Tofa was synthesized by conjugating Tofa to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer via a cleavable carbamate linker. DSS-induced UC mouse model were treated with Tofa (daily oral gavage, from day 8), P-Tofa (single intravenous administration on day 8, dose equivalent to Tofa treatment) and saline. Healthy mice were used as a positive control. The therapeutic efficacy was evaluated using disease activity index (DAI), endoscopic score and end-point histology. The optical imaging, immunohistochemistry and flow cytometry were used to understand P-Tofa's working mechanism. RESULTS: DAI results suggested that a single dose P-Tofa treatment was more efficacious than dose equivalent daily Tofa treatment. Endoscopic evaluation and histology analyses confirmed that while both P-Tofa and Tofa protected the colon, P-Tofa treated group was observed with better colon integrity with less tissue damage. Optical imaging, flow cytometry and immunohistochemistry results showed that P-Tofa passively targeted the inflamed colon and being retained via cellular sequestration. CONCLUSIONS: Single intravenous administration of P-Tofa was more effective than dose equivalent daily oral Tofa gavage in ameliorating DSS-induced colitis. This observed superior therapeutic efficacy may be attributed to P-Tofa's passive targeting to and retention by the inflamed colon.


Assuntos
Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo/efeitos dos fármacos , Sulfato de Dextrana/farmacologia , Janus Quinases/antagonistas & inibidores , Pró-Fármacos/farmacologia , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Metacrilatos/química , Camundongos , Piperidinas/farmacologia , Polímeros/química , Pirimidinas/farmacologia , Pirróis/farmacologia
8.
J Drugs Dermatol ; 18(3): s115-s116, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30909355

RESUMO

Hypopigmentation and depigmentation of the skin can be due to multiple causes and has a broad differential diagnosis. The most common cause of depigmentation worldwide is vitiligo. This disorder affects 1-2% of the world's population and is seen in all races. Vitiligo is an autoimmune disorder in which the predominant cause is an attack by CD8+ cytotoxic T cells on melanocytes in the epidermis. This condition can have a significant negative impact on the quality of life of affected individuals. Treatment options currently include psychological counseling, topical therapy, systemic therapy, phototherapy, surgical therapy, and depigmentation. In patients with stable, refractory disease, successful repigmentation has been achieved using mini-punch grafting, blister grafting, and non-cultured epidermal suspension (NCES) grafting. Emerging therapies include the Janus kinase (JAK) inhibitors ruxolitinib and tofacitinib. Further studies exploring the pathogenesis of vitiligo are warranted in order to optimize treatment for affected patients. J Drugs Dermatol. 2019;18(3 Suppl):s115-116.


Assuntos
Doenças Autoimunes/terapia , Qualidade de Vida , Vitiligo/terapia , Administração Cutânea , Administração Oral , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Doenças Autoimunes/psicologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Aconselhamento/métodos , Fármacos Dermatológicos/uso terapêutico , Diagnóstico Diferencial , Epiderme/transplante , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Melanócitos/transplante , Micose Fungoide/diagnóstico , Fototerapia/métodos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , Pigmentação da Pele/imunologia , Tinha Versicolor/diagnóstico , Vitiligo/diagnóstico , Vitiligo/imunologia , Vitiligo/psicologia
9.
Molecules ; 24(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871017

RESUMO

Capsazepine is a synthetic analogue of capsaicin that can function as an antagonist of TRPV1. Capsazepine can exhibit diverse effects on cancer (prostate cancer, breast cancer, colorectal cancer, oral cancer, and osteosarcoma) growth and survival, and can be therapeutically used against other major disorders such as colitis, pancreatitis, malaria, and epilepsy. Capsazepine has been reported to exhibit pleiotropic anti-cancer effects against numerous tumor cell lines. Capsazepine can modulate Janus activated kinase (JAK)/signal transducer and activator of the transcription (STAT) pathway, intracellular Ca2+ concentration, and reactive oxygen species (ROS)-JNK-CCAAT/enhancer-binding protein homologous protein (CHOP) pathways. It can inhibit cell proliferation, metastasis, and induce apoptosis. Moreover, capsazepine can exert anti-inflammatory effects through the downregulation of lipopolysaccharide (LPS)-induced nuclear transcription factor-kappa B (NF-κB), as well as the blockage of activation of both transient receptor potential cation channel subfamily V member 1 (TRPV1) and transient receptor potential cation channel, subfamily A, and member 1 (TRPA1). This review briefly summarizes the diverse pharmacological actions of capsazepine against various cancers and inflammatory conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Capsaicina/análogos & derivados , Animais , Capsaicina/farmacologia , Linhagem Celular Tumoral , Humanos , Janus Quinases/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/efeitos dos fármacos
10.
BioDrugs ; 33(1): 15-32, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30701418

RESUMO

Cytokines, many of which signal through the JAK-STAT (Janus kinase-Signal Transducers and Activators of Transcription) pathway, play a central role in the pathogenesis of inflammatory and autoimmune diseases. Currently three JAK inhibitors have been approved for clinical use in USA and/or Europe: tofacitinib for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, baricitinib for rheumatoid arthritis, and ruxolitinib for myeloproliferative neoplasms. The clinical JAK inhibitors target multiple JAKs at high potency and current research has focused on more selective JAK inhibitors, almost a dozen of which currently are being evaluated in clinical trials. In this narrative review, we summarize the status of the pan-JAK and selective JAK inhibitors approved or in clinical trials, and discuss the rationale for selective targeting of JAKs in inflammatory and autoimmune diseases.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Artrite Reumatoide/enzimologia , Doenças Autoimunes/enzimologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Humanos , Janus Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia
11.
Clin Exp Rheumatol ; 37(4): 694-704, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767864

RESUMO

Numerous cytokines have been implicated in the pathogenesis of inflammatory diseases, and their dysregulation is a main feature of rheumatoid arthritis (RA). Cytokines stimulate signal transduction through several intracellular pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to changes in cell activation, proliferation and survival. Consequently, agents that selectively target elements of the JAK/STAT pathways have received significant attention in recent years as potential new treatments for the disease. Baricitinib, an oral selective inhibitor of JAK1 and JAK2, offers an effective treatment for RA in a wide range of patients. The in vitro selectivity of different JAK inhibitors is an important consideration given that key cytokines, growth factors and hormone receptors involved in the pathogenesis of RA signal through specific JAKs. However, it is complex and far from understood how the in vitro effects of JAK inhibitors extrapolate into in vivo and clinical effects in individual patients. This narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide , Janus Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/enzimologia , Azetidinas/uso terapêutico , Humanos , Janus Quinase 1 , Janus Quinase 2 , Sulfonamidas/uso terapêutico
12.
Reumatol. clín. (Barc.) ; 15(1): 43-53, ene.-feb. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-176076

RESUMO

Objectives: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. Methods: Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. Results: 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. Conclusions: In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population


Objetivos: Tofacitinib es un inhibidor de la cinasa Janus para el tratamiento de la artritis reumatoide (AR). Se evaluaron la eficacia y la seguridad de tofacitinib en pacientes mexicanos a partir de los estudios fase 3 y de extensión a largo plazo (ELP) de AR. Métodos: Datos de pacientes mexicanos con AR y respuesta inadecuada a fármacos antirreumáticos modificadores de la enfermedad (FARME) fueron tomados de 4 estudios fase 3 y de un estudio abierto de ELP de tofacitinib. Los pacientes recibieron tofacitinib 5 o 10mg 2 veces al día, adalimumab (en un estudio fase 3) o placebo (en 4 estudios fase 3) como monoterapia o en combinación con FARME sintético convencional. Se evaluó la eficacia al mes 12 (fase 3) y al mes 36 (ELP) por medio de las tasas de respuesta del Colegio Americano de Reumatología 20/50/70, el puntaje de actividad de la enfermedad (DAS) 28-4, velocidad de sedimentación globular y el índice de discapacidad del cuestionario de evaluación de la salud (HAQ-DI). Se evaluó la seguridad a través de los estudios, incluyendo tasas de incidencia (IR; pacientes con evento/100 pacientes-año). Resultados: Ciento diecinueve y 212 pacientes mexicanos fueron incluidos en el análisis de los estudios fase 3 y de extensión a largo plazo, respectivamente. Pacientes tratados con tofacitinib en los estudios fase 3, numéricamente, tuvieron una mayor mejoría en las respuestas de eficacia en comparación con el placebo al mes 3. La eficacia fue sostenida en los estudios fase 3 y de extensión a largo plazo. Las tasas de incidencia de los eventos adversos de especial interés fueron similares a aquellas con tofacitinib en la población global y latinoamericana. Conclusiones: En pacientes mexicanos del programa global de tofacitinib en AR, la eficacia de tofacitinib se demostró hasta el mes 12 en los estudios fase 3 y hasta el mes 36 en el estudio de extensión a largo plazo, con un perfil de seguridad consistente con el de la población global de los estudios de tofacitinib


Assuntos
Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Artrite Reumatoide/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Tempo , Segurança do Paciente , México/epidemiologia , Resultado do Tratamento , Ensaios Clínicos Fase III como Assunto
13.
Zhongguo Fei Ai Za Zhi ; 22(1): 45-51, 2019 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-30674393

RESUMO

Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is one of the downstream pathways of cytokine signaling transduction. It regulates cell development, differentiation, proliferation, apoptosis and so on. The pathway is not only involved in the regulation of normal physiological processes, but also significant in the development of tumors, especially in hematologic malignancies. In recent years, with the further research of JAK/STAT signaling pathway, it has been found that the pathway also plays a key role in the development of solid tumors. Here we reviewed the research advances of JAK/STAT signaling pathway in lung cancer, especially the mechanisms of development, metastasis and drug resistance, and the application of inhibitors which targeting JAK/STAT signaling pathway in the treatment of lung cancer.
.


Assuntos
Janus Quinases/metabolismo , Neoplasias Pulmonares/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/uso terapêutico , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Humanos , Janus Quinases/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Fatores de Transcrição STAT/antagonistas & inibidores
14.
Biomed Pharmacother ; 109: 2136-2144, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551471

RESUMO

Metformin is one of the most commonly prescribed antidiabetic drugs. A recent clinical study has highlighted the protective role of metformin against cardiac complications in type I diabetes. Curcumin is a natural compound with well-known antioxidant and anti-inflammatory properties. The present study was designed to investigate the possible role of curcumin in potentiating metformin`s putative effects. Rats received single injection of 52.5 mg/kg streptozocin and the diabetic rats were treated with metformin (200 mg/kg/day), curcumin (100 mg/kg/day) and their combination for 6 weeks. Diabetic rats showed degenerated myocardium as well as significant increase in Creatine Kinase-MB (CK-MB), troponin I and TGF-ß1 levels. In addition, cardiac levels of lipid peroxidation, IL-6, and NF-κB were significantly elevated. Although treatment with metformin restored most of the measured parameters, it showed insignificant improvement in histopathological architecture accompanied by absence of antioxidant effect. Interestingly, concomitant administration of curcumin along with metformin revealed more protection than metformin alone. Inhibition of JAK/STAT pathway and activation of Nrf2/HO-1 pathway seems to be among the mechanisms mediating the effects of curcumin and metformin. The findings of this study highlight the benefits of metformin/curcumin combination in preventing diabetic cardiomyopathy.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Cardiotônicos/administração & dosagem , Curcumina/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Metformina/administração & dosagem , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Sinergismo Farmacológico , Coração/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Resultado do Tratamento
15.
J Steroid Biochem Mol Biol ; 185: 137-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30125658

RESUMO

Angiotensin 1-7 (Ang 1-7), which is a protein cleaved from angiotensin II (A-II), binds to the MAS receptor. Ang 1-7 has been demonstrated to exert protective effects against A-II-mediated cardiac, atherosclerotic, and renal damages. The aims of our study were to demonstrate the inhibitory role of Ang 1-7 in A-II-mediated aldosterone production by interacting with the MAS receptor in human adrenocortical carcinoma (HAC15) cells, and clarify the intracellular signaling mechanisms underlying the inhibition of aldosterone production by Ang 1-7. Ang 1-7 significantly suppressed A-II-stimulated aldosterone production, and partially abrogated A-II-induced upregulation of CYP11B2 expression. Treatment with a selective Ang 1-7 antagonist abrogated Ang 1-7-mediated inhibition of aldosterone production in HAC15 cells. Incubation of A-II-treated HAC15 cells with conditioned medium containing Ang 1-7 was demonstrated to suppress A-II-mediated aldosterone production and CYP11B2 expression. Proteomic analysis showed that Ang 1-7 predominantly inhibited the phosphorylation of JAK-STAT proteins in A-II stimulated HAC15 cells. Treatment of HAC15 cells with a STAT3 inhibitor partially but significantly repressed A-II-mediated aldosterone production by 63.2%. Similarly, treatment with a STAT5 inhibitor significantly abrogated A-II-stimulated aldosterone production in HAC15 cells by 60.7%. In conclusion, we demonstrated that Ang 1-7 negatively regulates A-II-mediated aldosterone production, and the observed inhibition of aldosterone production was associated with JAK/STAT signaling in human adrenal cells. Therefore, activation of Ang 1-7 or stimulation of the MAS receptor, which inhibits aldosterone production, is a promising therapeutic approach for the prevention of cardiovascular events that can directly affect the target organs.


Assuntos
Aldosterona/biossíntese , Angiotensina II/metabolismo , Angiotensina I/metabolismo , Janus Quinases/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Carcinoma Adrenocortical/metabolismo , Angiotensina I/antagonistas & inibidores , Doenças Cardiovasculares/tratamento farmacológico , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Citocromo P-450 CYP11B2/biossíntese , Humanos , Fragmentos de Peptídeos/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
Cancer ; 125(2): 194-204, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30561755

RESUMO

BCR/ABL1-like acute lymphoblastic leukemia (ALL) accounts for 15% to 30% of B-lineage ALL, with a peak of incidence occurring in adolescence. This subgroup of patients is characterized by a peculiar transcriptional profile that resembles that of true BCR/ABL1-positive cases, and have a heterogeneous genetic background and a poor outcome. Next-generation sequencing studies have demonstrated that the majority of patients carry rearrangements of tyrosine kinases or cytokine receptors and mutations of janus kinase (JAK)/signal transducer and activator of transcription (STAT), thus opening the way to the possible use of targeted therapeutic approaches. However, several issues remain unresolved at both the diagnostic and therapeutic level, such as the definition of a standardized method to identify BCR/ABL1-like ALL and the design of ad hoc clinical trials examining tyrosine kinase inhibitors or other tailored treatments. These aspects are discussed in this review.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Masculino , Mutação , Fragmentos de Peptídeos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade
17.
J Immunol Res ; 2018: 7897263, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581877

RESUMO

IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes.


Assuntos
Inflamação/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Queratinócitos/fisiologia , Piperidinas/uso terapêutico , Psoríase/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Imiquimode , Imunomodulação , Inflamação/imunologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas/farmacologia , Psoríase/induzido quimicamente , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais
18.
N Engl J Med ; 379(26): 2540-2546, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30586518

RESUMO

There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).


Assuntos
Janus Quinases/antagonistas & inibidores , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sarcoidose/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Pele/patologia , Feminino , Humanos , Imuno-Histoquímica , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Indução de Remissão , Fatores de Transcrição STAT/metabolismo , Sarcoidose/genética , Sarcoidose/patologia , Sarcoidose Pulmonar/tratamento farmacológico , Análise de Sequência de RNA , Transdução de Sinais , Pele/metabolismo , Dermatopatias/genética , Dermatopatias/patologia
19.
Hematol Oncol ; 36(4): 701-708, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30105794

RESUMO

Ruxolitinib is the first Janus kinase (JAK) inhibitor approved for the treatment of myelofibrosis, where its efficacy is often associated with cytopenia. It is possible that the severity of cytopenia is in part driven by Cmax . A once-daily sustained-release (SR) formulation of ruxolitinib was therefore developed to decrease the Cmax /Cmin ratio relative to twice-daily immediate-release (IR) ruxolitinib. An SR formulation was identified based on pharmacokinetic evaluation in a phase 1 study in healthy adults (N = 9). This was followed by an open-label phase 2 study in patients with myelofibrosis (N = 41). Ruxolitinib SR treatment was well tolerated with blood cell counts relatively unchanged through week 16. In terms of efficacy, 7 patients (17.1%) had clinical improvement and 33 (80.5%) had stable disease. While this study has raised the possibility of an increased therapeutic index for ruxolitinib via an SR formulation, further studies are required to validate the hypothesis.


Assuntos
Mielofibrose Primária/tratamento farmacológico , Pirazóis/administração & dosagem , Adolescente , Adulto , Preparações de Ação Retardada , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Adulto Jovem
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