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1.
Adv Exp Med Biol ; 1152: 271-281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456189

RESUMO

Rapidly emerging ground-breaking discoveries have provided near to complete resolution of breast cancer signaling landscape and scientists have mapped the knowledge gaps associated with proteins encoded by the human genome. Based on the insights gleaned from decades of research, it seems clear that ligands transmit distinct information through specific receptors that is processed into characteristically unique biological outputs. Advances in imaging, structural biology, proteomics and genome editing have helped us to gain new insights into JAK-STAT signaling and how alterations in this pathway contributed to development of breast cancer and metastatic spread. Data obtained through high-throughput technologies has started to shed light on signal-transducer complexes formed during JAK-STAT signaling. Pharmacologists and molecular biologists are focusing on the strategies to therapeutically target this pathway to overcome drug resistance associated with breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Terapia de Alvo Molecular
2.
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
3.
Nat Commun ; 10(1): 2498, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175312

RESUMO

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.


Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/terapia , Proteínas de Membrana/imunologia , Transplante de Células-Tronco Mesenquimais , Adulto , Antígenos CD1/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Interferon gama/farmacologia , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/terapia , Masculino , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Homólogo , Adulto Jovem
4.
Nat Commun ; 10(1): 2541, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186414

RESUMO

Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFß, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.


Assuntos
Astrócitos/metabolismo , Citocinas/metabolismo , Glioblastoma/imunologia , Microglia/metabolismo , Astrócitos/citologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação , Janus Quinases/metabolismo , Microglia/citologia , Fenótipo , Fatores de Transcrição STAT/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Técnicas de Cultura de Tecidos
5.
Nat Commun ; 10(1): 2764, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235699

RESUMO

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Medicina de Precisão/métodos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida , Carcinoma Anaplásico da Tireoide/mortalidade , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/terapia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Regulação para Cima
6.
Eur J Pharmacol ; 854: 307-319, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31039343

RESUMO

Interleukin 33 (IL33) has been found to be cardioprotective on various cardiovascular pathologies. However, it is not clear whether IL33 may inhibit myocardial infarction-related ventricular remodeling through inducing macrophage polarization. The objective of present study is to assess whether IL33 can improve ventricular remodeling after myocardial infarction by inducing macrophage polarization. In this study, the direct influence of IL33 on the polarization of macrophages and its mechanism in vitro were investigated. The potential protective effects of IL33 on acute and chronic myocardial infarction (MI) in vivo as well as its underlying mechanism through macrophage polarization were also determined. We found that IL33 significantly enhanced M2 macrophage and decreased the proportion of M1 macrophage. Importantly, IL33 induced M2 macrophage polarization by activating the JAK/STAT signaling pathway. In vivo, IL33 weaken the inflammatory level and myocardial apoptosis after MI and improved the systolic and diastolic function of the heart. Furthermore, IL33 significantly reduced infarct area and prevented the progression of fibrosis by inducing M2 macrophage polarization. The protective effects of IL33 were suppressed by JAK/STAT signaling pathway inhibitor. Our findings highlighted that IL33 not only reduced the early inflammatory response and inhibited myocardial apoptosis, but also increased the number of M2 macrophage in the infarcted area, significantly reduced infarct area and prevented the progression of fibrosis by activating JAK/STAT pathway. Therefore, IL33 may be a novel cardiac protective cytokine for myocardial infarction.


Assuntos
Interleucina-33/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Células RAW 264.7 , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Int J Nanomedicine ; 14: 2945-2959, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114201

RESUMO

Background: Gold nanoparticles (AuNPs) have potential applications in the treatment and diagnosis process, which are attributed to their biocompatibility and high efficiency of drug delivery. In the current study, we utilized an extract of Euphrasia officinalis, a traditional folk medicine, to synthesize gold nanoparticles (EO-AuNPs), and investigated their anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Materials and methods: The AuNPs were synthesized from an ethanol extract of E. officinalis leaves and characterized using several analytical techniques. Anti-inflammatory activities of EO-AuNPs were detected by a model of LPS-induced upregulation of inflammatory mediators and cytokines including nitric oxide (NO), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6 in RAW 264.7 cells. The activation of nuclear factor (NF)-κB and Janus kinase/signal transducer and activators of transcription (JAK/STAT) signaling pathways was investigated by Western blot. Results: The results confirmed the successful synthesis of AuNPs by E. officinalis. Transmission electron microscopy images showed obvious uptake of EO-AuNPs and internalization into intracellular membrane-bound compartments, resembling endosomes and lysosomes by RAW 264.7 cells. Cell viability assays showed that EO-AuNPs exhibited little cytotoxicity in RAW 264.7 cells at 100 µg/mL concentration after 24 hours. EO-AuNPs significantly suppressed the LPS-induced release of NO, TNF-α, IL-1ß, and IL-6 as well as the expression of the iNOS gene and protein in RAW 264.7 cells. Further experiments demonstrated that pretreatment with EO-AuNPs significantly reduced the phosphorylation and degradation of inhibitor kappa B-alpha and inhibited the nuclear translocation of NF-κB p65. In addition, EO-AuNPs suppressed LPS-stimulated inflammation by blocking the activation of JAK/STAT pathway. Conclusion: The synthesized EO-AuNPs showed anti-inflammatory activity in LPS-induced RAW 264.7 cells, suggesting they may be potential candidates for treating inflammatory-mediated diseases.


Assuntos
Euphrasia/química , Ouro/química , Química Verde/métodos , Macrófagos/patologia , Nanopartículas Metálicas/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Transdução de Sinais , Animais , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Janus Quinases/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Nanopartículas Metálicas/ultraestrutura , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Cancer Sci ; 110(6): 1931-1946, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974024

RESUMO

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.


Assuntos
Epigênese Genética , Janus Quinases/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Fatores de Transcrição STAT/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Células Jurkat , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Terapêutica com RNAi/métodos , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Transplant Proc ; 51(3): 972-978, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979490

RESUMO

BACKGROUND/AIMS: Kidney ischemia and reperfusion injury could cause microvascular barrier dysfunction, lung inflammatory cascades activation, and programmed cell death of pulmonary endothelium, leading to acute lung injury. Our study aimed at determining whether erythropoietin (EPO) can ameliorate lung dysfunction following renal ischemia and reperfusion (IR) injury and explored the underlying mechanisms. METHODS: In vivo, C57BL/6 mice received EPO (6000 U/kg) before right renal vascular pedicles clamping for 30 minutes, followed by 24 hours of reperfusion. The lung histopathologic changes and inflammatory cytokines expression were assessed. In vitro, cultured human umbilical vein endothelial cells were treated with EPO, and apoptosis rate, proliferation capacity, and phosphorylation status of the Janus kinase-signal transducer and activator of transcription 3 (Jak-STAT3) pathway were measured respectively in the presence or absence of lipopolysaccharide stimulation. RESULTS: In vivo, EPO remarkably attenuated pulmonary interstitial and alveolar epithelial edema caused by renal IR injury. In vitro, the proliferation capacity of human umbilical vein endothelial cells was significantly increased under EPO stimulation, which correlated with changes in Jak-STAT3 signaling. CONCLUSION: Our data indicated that EPO is able to ameliorate acute lung tissue damage induced by renal IR, and at least in part, via the Jak-STAT3 pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Eritropoetina/farmacologia , Janus Quinases/metabolismo , Nefropatias/tratamento farmacológico , Rim/irrigação sanguínea , Fator de Transcrição STAT3/metabolismo , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos
10.
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
11.
Invest Ophthalmol Vis Sci ; 60(4): 921-932, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30835784

RESUMO

Purpose: We previously reported increased expression of cell proliferation and Jak-Stat pathway-related genes in chronic experimental glaucoma model optic nerve heads (ONH) with early, mild injury. Here, we confirm these observations by localizing, identifying, and quantifying ONH cellular proliferation and Jak-Stat pathway activation in this model. Methods: Chronic intraocular pressure (IOP) elevation was achieved via outflow pathway sclerosis. After 5 weeks, ONH longitudinal sections were immunolabeled with proliferation and cell-type markers to determine nuclear densities in the anterior (unmyelinated) and transition (partially myelinated) ONH. Nuclear pStat3 labeling was used to detect Jak-Stat pathway activation. Nuclear density differences between control ONH (uninjected) and ONH with either early or advanced injury (determined by optic nerve injury grading) were identified by ANOVA. Results: Advanced injury ONH had twice the nuclear density (P < 0.0001) of controls and significantly greater astrocyte density in anterior (P = 0.0001) and transition (P = 0.006) ONH regions. An increased optic nerve injury grade positively correlated with increased microglia/macrophage density in anterior and transition ONH (P < 0.0001, both). Oligodendroglial density was unaffected. In glaucoma model ONH, 80% of anterior and 66% of transition region proliferating cells were astrocytes. Nuclear pStat3 labeling significantly increased in early injury anterior ONH, and 95% colocalized with astrocytes. Conclusions: Astrocytes account for the majority of proliferating cells, contributing to a doubled nuclear density in advanced injury ONH. Jak-Stat pathway activation is apparent in the early injury glaucoma model ONH. These data confirm dramatic astrocyte cell proliferation and early Jak-Stat pathway activation in ONH injured by elevated IOP.


Assuntos
Glaucoma/patologia , Janus Quinases/metabolismo , Neuroglia/patologia , Disco Óptico/patologia , Traumatismos do Nervo Óptico/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores/metabolismo , Proliferação de Células , Doença Crônica , Glaucoma/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Pressão Intraocular , Masculino , Modelos Animais , Neuroglia/metabolismo , Disco Óptico/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Fator de Transcrição PAX2/metabolismo , Ratos , Ratos Endogâmicos BN , Fatores de Transcrição SOXB1/metabolismo , Tonometria Ocular
12.
Pharm Biol ; 57(1): 48-54, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30905241

RESUMO

CONTEXT: Heart failure (HF) is one of the most serious diseases worldwide. Astragaloside IV (ASI) is widely used for the treatment of cardiovascular disease in China. OBJECTIVE: To evaluate the protective effect of ASI on the HF in a Sprague-Dawley rat model of left coronary artery ligation, and investigate the angiogenesis-related mechanisms. MATERIALS AND METHODS: Left coronary artery was ligated to induce a rat model of HF, and the rats were treated with vehicle (saline) or different doses of ASI (0.1, 0.3 and 1 mg/kg/day) by oral gavage for 6 weeks. Cardiac function was evaluated by echocardiography. Infarct size was determined by triphenyltetrazolium chloride staining. Cardiac vascular density was analyzed by microangiography. Real-time PCR, Western blot and chromatin immunoprecipitation were performed to investigate the mechanisms. RESULTS: ASI treatment improved the body weight and survival rate of HF rats, as well as the cardiac function of HF rats, with significantly improved ejection fraction (75.27 ± 5.75% vs. 36.26 ± 4.14%) and fractional shortening (45.39 ± 3.66% vs. 17.88 ± 1.32%). ASI reduced the infarct size of the HF rats by 47%. ASI promoted angiogenesis, with increased vascular density (2.08-fold) and induced mRNA expression of CD31 (1.81-fold) and VEGF (2.70-fold) in the ischemic heart. Furthermore, ASI induced the phosphorylation of JAK (1.89-fold) and STAT3 (2.95-fold), as well as the activity of VEGF promoter which was regulated by STAT3. DISCUSSION AND CONCLUSIONS: ASI alleviated HF by promoting angiogenesis through JAK-STAT3 pathway, providing novel alternative strategies to prevent HF in the future.


Assuntos
Indutores da Angiogênese/farmacologia , Vasos Coronários/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Janus Quinases/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Estimativa de Kaplan-Meier , Masculino , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miocárdio/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3 , Transdução de Sinais/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
13.
Int J Mol Sci ; 20(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901970

RESUMO

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.


Assuntos
Interferon Tipo I/metabolismo , Interferons/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Ativação Enzimática , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo
14.
Int Immunopharmacol ; 70: 88-100, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30797172

RESUMO

BACKGROUND AND AIM: AZD8055, a new immunosuppressive reagent, a dual TORC1/2 inhibitor, had been used successfully in animal models for heart transplantation. The aim of this study was to evaluate the effects and mechanisms of AZD8055 on chronic intestinal inflammation. METHODS: Dextran sulfate sodium (DSS) - induced chronic colitis was used to investigate the effects of AZD8055 on the development of colitis. Colitis activity was monitored by body weight assessment, colon length, histology and cytokine profile analysis. RESULTS: AZD8055 treatment significantly alleviated the severity of colitis, as assessed by colonic length and colonic damage. In addition, AZD8055 treatment decreased the colonic CD4+ T cell numbers and reduced both Th1 and Th17 cell activation and cytokine production. The percentages of Treg cells in the colon were also expanded by AZD8055 treatment. Furthermore, AZD8055 effectively inhibited mTOR downstream proteins and signal transducer and activator of transcription related proteins in CD4+ T cells of intestinal lamina propria. CONCLUSIONS: These findings increased our understanding of DSS-induced colitis and shed new lights on mechanisms of digestive tract chronic inflammation. Dual TORC1/2 inhibition showed potent anti-inflammatory and immune regulation effects by targeting critical signaling pathways. The results supported the strategy of using dual mTOR inhibitor to treat inflammatory bowel disease.


Assuntos
Colite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Morfolinas/uso terapêutico , Trifosfato de Adenosina/metabolismo , Animais , Doença Crônica , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Transplante de Coração , Humanos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
15.
Exerc Immunol Rev ; 25: 50-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785869

RESUMO

BACKGROUND: Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study evaluated the participation of SOCS-JAK-STAT signaling in the effects of AT on airway inflammation, remodeling and hyperresponsiveness in a model of allergic airway inflammation. METHODS: C57Bl/6 mice were divided into Control (Co), Exercise (Ex), HDM (HDM), and HDM+Exercise (HDM+ Ex). Dermatophagoides pteronyssinus (100ug/mouse) were administered oro-tracheally on days 0, 7, 14, 21, 28, 35, 42 and 49. AT was performed in a treadmill during 4 weeks in moderate intensity, from day 24 until day 52. RESULTS: AT inhibited HDM-induced total cells (p<0.001), eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in BAL, and eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in peribronchial space. AT also reduced BAL levels of IL-4 (p<0.001), IL-5 (p<0.001), IL-13 (p<0.001), CXCL1 (p<0.01), IL-17 (p<0.01), IL-23 (p<0.05), IL-33 (p<0.05), while increased IL- 10 (p<0.05). Airway collagen fibers (p<0.01), elastic fibers p<0.01) and mucin (p<0.01) were also reduced by AT. AT also inhibited HDM-induced airway hyperresponsiveness (AHR) to methacholine 6,25mg/ml (p<0.01), 12,5mg/mL (p<0.01), 25mg/mL (p<0.01) and 50mg/mL (p<0.01). Mechanistically, AT reduced the expression of STAT6 (p<0.05), STAT3 (p<0.001), STAT5 (p<0.01) and JAK2 (p<0.001), similarly by peribronchial leukocytes and by airway epithelial cells. SOCS1 expression (p<0.001) was upregulated in leukocytes and in epithelial cells, SOCS2 (p<0.01) was upregulated in leukocytes and SOCS3 down-regulated in leukocytes (p<0.05) and in epithelial cells (p<0.001). CONCLUSIONS: AT reduces asthma phenotype involving SOCSJAK- STAT signaling.


Assuntos
Asma/metabolismo , Janus Quinases/metabolismo , Condicionamento Físico Animal , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Modelos Animais de Doenças , Eosinófilos/citologia , Interleucinas/metabolismo , Linfócitos/citologia , Cloreto de Metacolina , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Hipersensibilidade Respiratória/metabolismo
16.
Oncol Rep ; 41(3): 1779-1788, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30747218

RESUMO

Gallic acid (3,4,5­trihydroxybenzoic acid; GA), a plant­derived natural phenolic compound, has been reported to prevent the development and progression of various types of cancers. However, there has been little elaboration of the anticancer effects and underlying mechanisms of GA alone and/or in combination with cisplatin in non­small cell lung cancer (NSCLC). The aim of the present study was to investigate the anticancer effects of GA on NSCLC A549 cells and its auxiliary effects on the anticancer activity of cisplatin. The results revealed that GA inhibited the proliferation and induced the apoptosis of NSCLC A549 cells in dose­ and time­dependent manners, which was associated with upregulated B­cell lymphoma 2 (Bcl­2)­associated X protein (Bax) and downregulated Bcl­2. Notably, the results also indicated that GA enhanced the anticancer effects of cisplatin in the inhibition of cancer cell proliferation and the induction of cell apoptosis following elevated Bax expression and suppressed Bcl­2 expression. Furthermore, the results of the present study also demonstrated that GA exerted independent anticancer effects on NSCLC A549 cells, and facilitated the anticancer effects of cisplatin by modulating the JAK/STAT3 signaling pathway and downstream apoptotic molecules. These results may serve as a rationale for further basic studies and preclinical investigations on the anticancer effects of GA and its auxiliary effects on cisplatin function in human NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Ácido Gálico/farmacologia , Janus Quinases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
J Environ Pathol Toxicol Oncol ; 38(1): 51-59, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806290

RESUMO

The eukaryotic cell cycle via mitogen-activated protein kinase (MAPK) has been considered as an effective signaling cascade pathway for anticancer therapy. In addition to the MAPK signaling pathway, the Rat Sarcoma Virus (Ras)/Rapidly Accelerated Fibrosarcoma (Raf)/MAPK-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway is a signaling cascade that has a crucial role to play in cell survival and development of cancer, especially breast cancer. Novel drugs and clinical trials need to be investigated, taking into consideration the already studied genetic defects related to genesis of tumors in certain populations. The present review provides novel insights into current anticancer treatments involving the MAPK pathway.


Assuntos
Neoplasias da Mama/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias da Mama/patologia , Humanos , Janus Quinases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Serina-Treonina Quinases TOR/metabolismo
19.
PLoS One ; 14(2): e0209587, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30759154

RESUMO

The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN-α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN-α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN-α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design.


Assuntos
Fatores Imunológicos/farmacologia , Interferon-alfa/farmacologia , Células Cultivadas , Simulação por Computador , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fatores Imunológicos/farmacocinética , Interferon-alfa/farmacocinética , Janus Quinases/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Modelos Biológicos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
20.
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
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