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1.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011739

Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Animais , Antivirais/química , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Bufanolídeos/química , Bufanolídeos/farmacologia , Glicosídeos Cardíacos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Digoxina/química , Digoxina/farmacologia , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Fenantrenos/química , Fenantrenos/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
2.
Cell Rep ; 32(13): 108199, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32966801

RESUMO

ACE2 binds the coronavirus SARS-CoV-2 and facilitates its cellular entry. Interferons activate ACE2 expression in pneumocytes, suggesting a critical role of cytokines in SARS-CoV-2 target cells. Viral RNA was detected in breast milk in at least seven studies, raising the possibility that ACE2 is expressed in mammary tissue during lactation. Here, we show that Ace2 expression in mouse mammary tissue is induced during pregnancy and lactation, which coincides with the activation of intronic enhancers. These enhancers are occupied by the prolactin-activated transcription factor STAT5 and additional regulatory factors, including RNA polymerase II. Deletion of Stat5a results in decommissioning of the enhancers and an 83% reduction of Ace2 mRNA. We also demonstrate that Ace2 expression increases during lactation in lung, but not in kidney and intestine. JAK/STAT components are present in a range of SARS-CoV-2 target cells, opening the possibility that cytokines contribute to the viral load and extrapulmonary pathophysiology.


Assuntos
Janus Quinases/metabolismo , Peptidil Dipeptidase A/metabolismo , Gravidez/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Elementos Facilitadores Genéticos , Feminino , Humanos , Mucosa Intestinal/metabolismo , Rim/metabolismo , Lactação/metabolismo , Pulmão/metabolismo , Glândulas Mamárias Humanas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peptidil Dipeptidase A/genética , Fator de Transcrição STAT5/genética , Transdução de Sinais
3.
Life Sci ; 260: 118261, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795539

RESUMO

AIMS: Rheumatoid arthritis is an autoimmune systemic disorder causing pain, swelling, stiffness, and disability in various joints. This work was designed to evaluate the effect of sitagliptin and tofacitinib on Janus kinase (JAK)/signaling transducer and activator of transcription (STAT) and toll like receptor (TLR-4)/nuclear factor kappa B (NF-κB) signaling pathways in adjuvant induced arthritis in rats. MATERIALS AND METHODS: Severity of arthritis was evaluated and serum was analyzed for inflammatory mediators. The mRNA and protein expression level of the most important members of the two signaling pathways were determined. Lipid profile, transaminases and renal function parameters were assessed. KEY FINDINGS: Sitagliptin and tofacitinib significantly decreased the level of inflammatory parameters, the mRNA and protein expression level of the members of JAK/STAT and TLR-4/NF-κB pathways with more prominent effect of sitagliptin on TLR-4/NF-κB pathway and more expected obvious effect of tofacitinib on JAK/STAT pathway. The combination offered additional anti-inflammatory effect by inhibiting the cross talk between these pathways as inhibition of NF-κB activation decreased the serum level of IL-6 preventing the activation of STAT-3 in tibiotarsal tissues. SIGNIFICANCE: The combination of tofacitinib and sitagliptin normalized serum lipids and blood glucose level which could offer protection against cardiovascular diseases and caused partial reversal of serum transaminases and creatinine levels which can protect against tofacitinb's related hepato and nephrotoxicity. We could conclude that the combination of Sitagliptin with tofacitinib can offer synergistic anti-inflammatory effect and more protective action against side effects of tofacitinib.


Assuntos
Artrite Experimental/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios , Glicemia/análise , Sinergismo Farmacológico , Quimioterapia Combinada , Hipoglicemiantes , Interleucina-6/sangue , Janus Quinases/metabolismo , Lipídeos/sangue , Masculino , NF-kappa B/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/metabolismo
4.
Proc Natl Acad Sci U S A ; 117(35): 21420-21431, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817494

RESUMO

One of the emerging hallmarks of cancer illustrates the importance of metabolic reprogramming, necessary to synthesize the building blocks required to fulfill the high demands of rapidly proliferating cells. However, the proliferation-independent instructive role of metabolic enzymes in tumor plasticity is still unclear. Here, we provide evidence that glutathione peroxidase 8 (GPX8), a poorly characterized enzyme that resides in the endoplasmic reticulum, is an essential regulator of tumor aggressiveness. We found that GPX8 expression was induced by the epithelial-mesenchymal transition (EMT) program. Moreover, in breast cancer patients, GPX8 expression significantly correlated with known mesenchymal markers and poor prognosis. Strikingly, GPX8 knockout in mesenchymal-like cells (MDA-MB-231) resulted in an epithelial-like morphology, down-regulation of EMT characteristics, and loss of cancer stemness features. In addition, GPX8 knockout significantly delayed tumor initiation and decreased its growth rate in mice. We found that these GPX8 loss-dependent phenotypes were accompanied by the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). In these cells, IL-6 bound to the soluble receptor (sIL6R), stimulating the JAK/STAT3 signaling pathway by IL-6 trans-signaling mechanisms, so promoting cancer aggressiveness. We observed that in GPX8 knockout cells, this signaling mechanism was impaired as sIL6R failed to activate the JAK/STAT3 signaling pathway. Altogether, we present the GPX8/IL-6/STAT3 axis as a metabolic-inflammatory pathway that acts as a robust regulator of cancer cell aggressiveness.


Assuntos
Neoplasias da Mama/enzimologia , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Peroxidases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fenótipo , Transdução de Sinais
5.
Life Sci ; 258: 118217, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768575

RESUMO

AIMS: Astrocytes expressing the aquaporin-4 (AQP4) water channel are pathogenic, disease specific immunoglobulins (IgG) found in neuromyelitis optica spectrum disorder (NMOSD), referred to as NMO-IgG, which targets astrocytic AQP4. The interleukin-6 (IL-6) signaling when astrocytes were exposed to NMO-IgG present in the serum of NMOSD patients was evaluated. MAIN METHODS: Serum or human-IgG from NMOSD or healthy controls were exposed to astrocytes. The selectivity and immuno-pathological consequences of Ig binding to surface epitopes were measured by confocal microscopy. Astrocytes were exposed to medium, IL-6, soluble IL-6 receptor (sIL-6R), IL-6 + sIL-6R (IL-6/R), NMO-IgG or control-IgG, NMO-IgG + IL-6/R. The expression of key proteins in IL-6 signaling pathway, IL-6 cytokine and mRNA levels were evaluated by western blotting, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. KEY FINDINGS: Serum or NMO-IgG from NMOSD patients both induced the rapid downregulation of AQP4 expression on the surface of astrocytes. Stimulation of astrocytes with NMO-IgG, IL-6/R, and NMO-IgG + IL-6/R resulted in the enhancement of IL-6 mRNA expression. Meanwhile, the exogenous addition of NMO-IgG elicited an inflammatory transcriptional response that involved signaling through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. Inhibition of the IL-6/JAK/STAT3 pathway with the JAK1/2 specific inhibitor, AZD1480, reversed the associated increase of IL-6. SIGNIFICANCE: Our findings suggest that NMO-IgG can stimulate the astrocytic JAK1/2/STAT3-dependent inflammatory response, which represents one of the important events in NMO pathogenesis. Inhibition of the JAK1/2 signaling pathway may be a novel promising therapy for NMOSD.


Assuntos
Astrócitos/metabolismo , Imunoglobulina G/sangue , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neuromielite Óptica/sangue , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Animais , Astrócitos/efeitos dos fármacos , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Células Cultivadas , Feminino , Humanos , Imunoglobulina G/farmacologia , Interleucina-6/agonistas , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Fator de Transcrição STAT3/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Adulto Jovem
6.
Trends Pharmacol Sci ; 41(8): 531-543, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32580895

RESUMO

Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe coronavirus disease 2019 (COVID-19) might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/virologia , Pneumonia Viral/fisiopatologia , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Humanos , Janus Quinases/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/fisiologia
7.
Anticancer Res ; 40(6): 3255-3264, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487620

RESUMO

BACKGROUND/AIM: Rta, a transactivator of Epstein-Barr virus, is associated with progression of nasopharyngel carcinoma (NPC); however, its mechanism of contribution to the pathogenesis of NPC remains unclear. Interleukin-6 (IL-6), a tumor promoter, is detected in NPC. This in vitro study examined whether and how Rta promotes NPC progression by up-regulating IL-6. MATERIALS AND METHODS: Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, ELISA, immunoblotting assays, reporter gene assays, and transwell migration assays were performed. RESULTS: In NPC cells, Rta up-regulated IL-6 expression at the mRNA and protein levels, and the Rta's C-terminus was essential for promoter activation and expression of IL-6. The induction of IL-6 by Rta also required activation of extracellular signal-regulated kinase 1/2 and activator protein-1. Furthermore, IL-6 secreted from Rta-expressing NPC cells promoted migration of Rta-negative NPC cells by activating IL-6 receptor/Janus kinase/signal transducer and activator of transcription 3 pathway. CONCLUSION: Rta contributes to progression of NPC cells through induction of IL-6 in vitro.


Assuntos
Proteínas Imediatamente Precoces/metabolismo , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neoplasias/metabolismo , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Proteínas Imediatamente Precoces/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Neoplasias/genética , Neoplasias/patologia , Neoplasias/virologia , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Transativadores/genética , Fator de Transcrição AP-1/metabolismo , Transfecção , Regulação para Cima
8.
J Biol Chem ; 295(41): 13958-13964, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32587093

RESUMO

The recently emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the devastating COVID-19 lung disease pandemic. Here, we tested the inhibitory activities of the antiviral interferons of type I (IFN-α) and type III (IFN-λ) against SARS-CoV-2 and compared them with those against SARS-CoV-1, which emerged in 2003. Using two mammalian epithelial cell lines (human Calu-3 and simian Vero E6), we found that both IFNs dose-dependently inhibit SARS-CoV-2. In contrast, SARS-CoV-1 was restricted only by IFN-α in these cell lines. SARS-CoV-2 generally exhibited a broader IFN sensitivity than SARS-CoV-1. Moreover, ruxolitinib, an inhibitor of IFN-triggered Janus kinase/signal transducer and activator of transcription signaling, boosted SARS-CoV-2 replication in the IFN-competent Calu-3 cells. We conclude that SARS-CoV-2 is sensitive to exogenously added IFNs. This finding suggests that type I and especially the less adverse effect-prone type III IFN are good candidates for the management of COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Interferon Tipo I/farmacologia , Interferons/farmacologia , Animais , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Janus Quinases/metabolismo , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Pirazóis/farmacologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/fisiologia , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
9.
Environ Toxicol ; 35(9): 991-997, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32401414

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)-1ß is a critical proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL-1ß expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-1ß in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL-1ß. Elevations in IL-1ß mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P1 receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P-promoted IL-1ß expression. Our results indicate that S1P promotes the expression of IL-1ß in osteoblasts via the S1P1 receptor and the JAK and STAT3 signaling pathways.


Assuntos
Interleucina-1beta/genética , Janus Quinases/metabolismo , Lisofosfolipídeos/fisiologia , Osteoblastos/metabolismo , Fator de Transcrição STAT3/metabolismo , Esfingosina/análogos & derivados , Artrite Reumatoide/metabolismo , Células Cultivadas , Humanos , Lisofosfolipídeos/farmacologia , Masculino , Osteoartrite/metabolismo , Osteoblastos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Esfingosina/farmacologia , Esfingosina/fisiologia , Receptores de Esfingosina-1-Fosfato/genética
10.
Life Sci ; 252: 117663, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302624

RESUMO

AIMS: Interleukin-35 (IL-35) is a new member of the interleukin-12 family and is composed of the P35 and EB virus-inducible gene 3 subunits. The aims of this study were to examine the roles of IL-35 in the exhaustion of HBV-specific CTLs, as little as known on the subject. MAIN METHODS: The relative levels of serum HBV markers were detected using automated biochemical techniques. The HBV DNA copies were measured by RT-qPCR. The expression of inhibitory receptors and the cell cytokines on the surface of CTLs were determined by flow cytometry. The pSTAT1-pSTAT4 protein levels expression was determined by flow cytometry, confocal microscopy and Western blot. KEY FINDINGS: Our results showed that IL-35 can activate the Janus kinase 1 (JAK1)/tyrosine kinase 2 (TYK2)/signal transducer and activator of transcription 1 (STAT1)/STAT4 pathway in CTLs in vitro. Interferon-γ and tumor necrosis alpha-α expression increased in CTLs in the presence of a JAK/STAT-pathway blocker. In addition, we evaluated the expression of the exhaustion-associated molecules programmed death-1, cytotoxic T lymphocyte-associated protein-4, and lymphocyte activation gene-3 in CTLs after adding the JAK-STAT inhibitor The results showed that the expression of exhaustion-associated molecules on the CTL surface decreased after blocking the JAK-STAT pathway. IL-35 inhibited the function of HBV-specific CTLs through the JAK1/TYK2/STAT1/STAT4 pathway, and the function of CTLs was recovered after blocking the JAK/STAT pathway. SIGNIFICANCE: These data provide a new experimental basis for immunotherapy for chronic hepatitis B.


Assuntos
Antígenos E da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Interleucinas/imunologia , Linfócitos T Citotóxicos/virologia , Adulto , Citocinas/imunologia , Feminino , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/isolamento & purificação , Humanos , Janus Quinases/metabolismo , Masculino , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia
11.
Life Sci ; 253: 117600, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234492

RESUMO

BACKGROUND: Skin cutaneous melanoma (SKCM) is the most common subtype of skin malignancy, with ever-increasing incidence, mortality, and disease burden. Dysregulation of JAK-STATs signaling pathway is involved in the pathogenesis and progression of cancers, thus affecting the prognosis of cancer patients. The function of JAKs in SKCM is still not clarified. METHODS: A total of five online portal (GEPIA, TIMER, GeneMANIA, LinkedOmics, and GSCALite) is used to mine the expression and gene regulation network JAK2 in SKCM. RESULTS: JAK2 expression was downregulated in SKCM and significantly associated with pathological stage and the prognosis of patients. The functions of JAK2 and associated genes were primarily involved in the DNA recombination, cell cycle checkpoint, metabolic process, NOD-like receptor signaling pathways, p53 signaling pathway and apoptosis. JAK2 level was significantly correlated with the abundance of immune cells and the level of immune biomarkers. Low expression of JAK2 were resistant to QL-VIII-58, TL-1-85, Ruxolitinib, TG101348 and Sunitinib. CONCLUSIONS: Our results reveal the expression and gene regulation network of JAK2 in skin cutaneous melanoma, providing more evidences about the role of JAK2 in carcinogenesis.


Assuntos
Antineoplásicos/farmacologia , Janus Quinases/metabolismo , Melanoma/metabolismo , Pirazóis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sunitinibe/farmacologia , Antineoplásicos/metabolismo , Bases de Dados de Ácidos Nucleicos , Bases de Dados de Proteínas , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Janus Quinases/genética , MicroRNAs/metabolismo , Modelos Biológicos , Prognóstico , Pirazóis/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Sunitinibe/metabolismo
12.
Nucleic Acids Res ; 48(9): 4780-4796, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32232334

RESUMO

Previously, we have shown that human sperm Prohibitin (PHB) expression is significantly negatively correlated with mitochondrial ROS levels but positively correlated with mitochondrial membrane potential and motility. However, the possible role of PHB in mammalian spermatogenesis has not been investigated. Here we document the presence of PHB in spermatocytes and its functional roles in meiosis by generating the first male germ cell-specific Phb-cKO mouse. Loss of PHB in spermatocytes resulted in complete male infertility, associated with not only meiotic pachytene arrest with accompanying apoptosis, but also apoptosis resulting from mitochondrial morphology and function impairment. Our mechanistic studies show that PHB in spermatocytes regulates the expression of STAG3, a key component of the meiotic cohesin complex, via a non-canonical JAK/STAT pathway, and consequently promotes meiotic DSB repair and homologous recombination. Furthermore, the PHB/JAK2 axis was found as a novel mechanism in the maintenance of stabilization of meiotic STAG3 cohesin complex and the modulation of heterochromatin formation in spermatocytes during meiosis. The observed JAK2-mediated epigenetic changes in histone modifications, reflected in a reduction of histone 3 tyrosine 41 phosphorylation (H3Y41ph) and a retention of H3K9me3 at the Stag3 locus, could be responsible for Stag3 dysregulation in spermatocytes with the loss of PHB.


Assuntos
Código das Histonas , Meiose/genética , Proteínas Repressoras/fisiologia , Espermatócitos/metabolismo , Espermatogênese/genética , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Pareamento Cromossômico , Epigenoma , Histonas/metabolismo , Recombinação Homóloga , Infertilidade/genética , Janus Quinase 2/metabolismo , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Estágio Paquíteno , Fosforilação , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Espermatócitos/enzimologia , Espermatócitos/ultraestrutura , Testículo/metabolismo
13.
Exp Mol Pathol ; 115: 104445, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32335083

RESUMO

OBJECTIVE: Since microRNAs (miRNAs) represent as effective therapeutic targets for diabetic retinopathy (DR), we identified aberrantly expressed miRNAs related to cellular dysfunction in DR and further detected their potential targets. This study aimed to explore the synergistic effect of miR-216a, inducible nitric oxide synthase 2 (NOS2) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway on human retinal microvascular endothelial cell (HRMEC) injury in DR. METHODS: The differentially expressed genes in DR were obtained by GEO database, and the downstream signaling pathways and upstream targeted miRNAs were obtained through bioinformatics analysis. Subsequently, a DR model rat was established, and the target miR-216a was overexpressed to observe the pathological and morphological changes of the rat retina and the levels of inflammatory factors. Then, HRMECs were extracted and added with d-Glucose, and then transfected with miR-216a, NOS2 or adding JAK/STAT signaling pathway specific inhibitor to observe changes in cell activity and inflammatory damage. RESULTS: NOS2 was significantly upregulated, and the JAK/STAT signaling pathway was significantly activated in DR. miR-216a targeted NOS2, which played a protective role in the retina of DR rats. Moreover, in cell experiments, overexpression of miR-216a promoted the viability of HRMECs under d-glucose treatment, and inhibited NOS2 expression and the JAK/STAT signaling pathway activation. CONCLUSION: This study suggests that miR-216a protects against HRMECs injury in DR by suppressing the NOS2/JAK/STAT axis.


Assuntos
Retinopatia Diabética/patologia , Células Endoteliais/patologia , Janus Quinases/metabolismo , MicroRNAs/metabolismo , Microvasos/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Retina/patologia , Fatores de Transcrição STAT/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Regulação para Baixo/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Glucose/toxicidade , Humanos , Masculino , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
14.
Biochem Biophys Res Commun ; 525(3): 662-667, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32127173

RESUMO

Insulin resistance (IR) is an important pathological basis of obesity, diabetes and cardiovascular diseases, and emerging evidence demonstrates aerobic exercise as an efficient therapeutical tool in the management of IR and IR-related metabolic disease. Interleukin-4 (IL-4), an important anti-inflammatory cytokine, was recently proved to be involved in regulation of IR, yet the effect of IL-4 on exercise-induced insulin sensitivity and underlying mechanism was less investigated. In this study, using a mouse model of swimming exercise training (60 min/day, 5 days/week for 8 weeks), we found that long-term swimming exercise promoted insulin sensitivity compared with sedentary groups as indexed by the homeostasis model assessment of insulin resistance (HOMA-IR), glucose and insulin tolerance test. Accompanying with increased insulin sensitivity, swimming exercise increased serum IL-4 levels as well as insulin receptor substrate 1 (IRS-1) and protein kinase B (Akt) phosphorylation. Mechanistically, IL-4 treatment increased insulin-stimulated glucose uptake and Akt phosphorylation in skeletal muscle C2C12 cells, and inhibition of IL-4 signaling via ruxolitinib, a Janus kinase (JAK) inhibitor, attenuated IL-4-induced insulin sensitivity. Taken together, our results demonstrated IL-4 as a novel exercise factor contributing to exercise-induced insulin sensitivity, providing a potential therapeutical target of IR and related metabolic disease.


Assuntos
Resistência à Insulina , Interleucina-4/metabolismo , Transdução de Sinais , Regulação para Cima , Animais , Linhagem Celular , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/genética , Interleucina-4/sangue , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
Cancer Biother Radiopharm ; 35(2): 143-152, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32155348

RESUMO

Objective: lncRNA HAND2 antisense RNA 1 (HAND2-AS1) is consistently well recognized to suppress multiple tumors, while its function was uncertified in liver cancer. Materials and Methods: qRT-PCR analysis and TCGA database discovered the expression in liver cancer. CCK-8 and Transwell migration assay demonstrated the impact of HAND2-AS1 on cell proliferation and migration. Bioinformatic analysis and luciferase reporter assay were utilized to monitor the binding between HAND2-AS1 or SOCS5 mRNA and miR-3118. The function of SOCS5 on inactivating the JAK-STAT pathway was confirmed through Western blot assays. Rescue experiments unmasked that HAND2-AS1-mediated SOCS5 affected cell proliferation and migration through the JAK-STAT pathway in liver cancer. Results: The authors discovered the downregulated HAND2-AS1 in liver cancer cells. HAND2-AS1 augmentation apparently impaired the capacity of liver cancer viability, proliferation, and migration. Cytoplasmic HAND2-AS1 directly bound to miR-3118 and released SOCS5, leading to upregulation of SOCS5. Next, the negative regulator role of SOCS5 in the adjusting JAK-STAT pathway was reconfirmed in this study. Conclusions: HAND2-AS1 enhanced inactivation of the JAK-STAT pathway through sponging miR-3118 and facilitating SOCS5 to retard cell proliferation and migration in liver cancer.


Assuntos
Janus Quinases/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Transfecção , Regulação para Cima
16.
Pharmacol Rev ; 72(2): 486-526, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32198236

RESUMO

Before it was molecularly cloned in 1994, acute-phase response factor or signal transducer and activator of transcription (STAT)3 was the focus of intense research into understanding the mammalian response to injury, particularly the acute-phase response. Although known to be essential for liver production of acute-phase reactant proteins, many of which augment innate immune responses, molecular cloning of acute-phase response factor or STAT3 and the research this enabled helped establish the central function of Janus kinase (JAK) family members in cytokine signaling and identified a multitude of cytokines and peptide hormones, beyond interleukin-6 and its family members, that activate JAKs and STAT3, as well as numerous new programs that their activation drives. Many, like the acute-phase response, are adaptive, whereas several are maladaptive and lead to chronic inflammation and adverse consequences, such as cachexia, fibrosis, organ dysfunction, and cancer. Molecular cloning of STAT3 also enabled the identification of other noncanonical roles for STAT3 in normal physiology, including its contribution to the function of the electron transport chain and oxidative phosphorylation, its basal and stress-related adaptive functions in mitochondria, its function as a scaffold in inflammation-enhanced platelet activation, and its contributions to endothelial permeability and calcium efflux from endoplasmic reticulum. In this review, we will summarize the molecular and cellular biology of JAK/STAT3 signaling and its functions under basal and stress conditions, which are adaptive, and then review maladaptive JAK/STAT3 signaling in animals and humans that lead to disease, as well as recent attempts to modulate them to treat these diseases. In addition, we will discuss how consideration of the noncanonical and stress-related functions of STAT3 cannot be ignored in efforts to target the canonical functions of STAT3, if the goal is to develop drugs that are not only effective but safe. SIGNIFICANCE STATEMENT: Key biological functions of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling can be delineated into two broad categories: those essential for normal cell and organ development and those activated in response to stress that are adaptive. Persistent or dysregulated JAK/STAT3 signaling, however, is maladaptive and contributes to many diseases, including diseases characterized by chronic inflammation and fibrosis, and cancer. A comprehensive understanding of JAK/STAT3 signaling in normal development, and in adaptive and maladaptive responses to stress, is essential for the continued development of safe and effective therapies that target this signaling pathway.


Assuntos
Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Fibrose/metabolismo , Humanos , Inflamação/metabolismo , Janus Quinases/genética , Terapia de Alvo Molecular , Neoplasias/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT3/genética
17.
Ann Rheum Dis ; 79(7): 951-959, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32213496

RESUMO

OBJECTIVE: Takayasu's arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK. METHODS: We analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK. RESULTS: Transcriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients. CONCLUSIONS: JAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.


Assuntos
Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Fatores de Transcrição STAT/metabolismo , Arterite de Takayasu/genética , Adulto , Feminino , Humanos , Interferons , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Arterite de Takayasu/tratamento farmacológico , Células Th1 , Células Th17
18.
J Med Chem ; 63(6): 2915-2929, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32134643

RESUMO

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/farmacocinética , Piridinas/farmacologia , Piridinas/farmacocinética , Administração Oral , Animais , Cães , Descoberta de Drogas , Feminino , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/química , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Fosforilação/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/química
19.
Phytother Res ; 34(8): 1745-1760, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32157749

RESUMO

Curcumin is a naturally occurring nutraceutical compound with a number of therapeutic and biological activities such as antioxidant, anti-inflammatory, anti-diabetic, antitumor, and cardioprotective. This plant-derived chemical has demonstrated great potential in targeting various signaling pathways to exert its protective effects. Signal transducers and activator of transcription (STAT) is one of the molecular pathways involved in a variety of biological processes such as cell proliferation and cell apoptosis. Accumulating data demonstrates that the STAT pathway is an important target in treatment of a number of disorders, particularly cancer. Curcumin is capable of affecting STAT signaling pathway in induction of its therapeutic impacts. Curcumin is able to enhance the level of anti-inflammatory cytokines and improve inflammatory disorders such as colitis by targeting STAT signaling pathway. Furthermore, studies show that inhibition of JAK/STAT pathway by curcumin is involved in reduced migration and invasion of cancer cells. Curcumin normalizes the expression of JAK/STAT signaling pathway to exert anti-diabetic, renoprotective, and neuroprotective impacts. At the present review, we provide a comprehensive discussion about the effect of curcumin on JAK/STAT signaling pathway to direct further studies in this field.


Assuntos
Curcumina/uso terapêutico , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Produtos Biológicos , Curcumina/farmacologia , Humanos
20.
Int J Mol Sci ; 21(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046108

RESUMO

Interleukin-27 (IL-27) has shown promise in halting tumor growth and mediating tumor regression in several models, including prostate cancer. We describe our findings on the effects of IL-27 on the gene expression changes of TC2R prostate adenocarcinoma cells. We utilized RNAseq to assess profile differences between empty vector control, vector delivering IL-27 modified at its C-terminus with a non-specific peptide, and IL-27 modified at the C-terminus with a peptide targeting the IL-6-Rα. The targeted IL-27 had higher bioactivity and activity in vivo in a recent study by our group, but the mechanisms underlying this effect had not been characterized in detail at the gene expression level on tumor cells. In the present work, we sought to examine potential mechanisms for targeted IL-27 enhanced activity directly on tumor cells. The targeted IL-27 appeared to modulate several changes that would be consistent with an anti-tumor effect, including upregulation in the Interferon (IFN) and Interferon regulatory factor (IRF), oxidative phosphorylation, Janus kinase/Signal transducers and activators of transcription (JAK/STAT), and eukaryotic initiation factor 2 (EIF2) signaling. Of these signaling changes predicted by ingenuity pathway analyses (IPA), the novel form also with the highest significance (-log(Benjamini-Hochberg (B-H)) p-value) was the EIF2 signaling upregulation. We validated this predicted change by assaying for eukaryotic initiation factor 2 alpha (eIF2α), or phosphorylated eIF2α (p-eIF2α), and caspase-3 levels. We detected an increase in the phosphorylated form of eIF2α and in the cleaved caspase-3 fraction, indicating that the EIF2 signaling pathway was upregulated in these prostate tumor cells following targeted IL-27 gene delivery. This approach of targeting cytokines to enhance their activity against cancer cells is a novel approach to help augment IL-27's bioactivity and efficacy against prostate tumors and could be extended to other conditions where it could help interfere with the EIF2α pathway and promote caspase-3 activation.


Assuntos
Adenocarcinoma/metabolismo , Marcação de Genes/métodos , Terapia Genética/métodos , Interleucina-27/genética , Neoplasias da Próstata/metabolismo , Receptores de Interleucina-6/genética , Transdução de Sinais , Adenocarcinoma/genética , Animais , Linhagem Celular Tumoral , Fator de Iniciação 2 em Eucariotos/metabolismo , Interferons/metabolismo , Interleucina-27/química , Interleucina-27/metabolismo , Janus Quinases/metabolismo , Masculino , Camundongos , Neoplasias da Próstata/genética , Domínios Proteicos , Receptores de Interleucina-6/metabolismo , Fatores de Transcrição STAT/metabolismo
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