RESUMO
Graveoline exhibits various biological activities. However, only limited studies have focused on its hepatoprotective properties. This study evaluated the anti-inflammatory and hepatoprotective activities of graveoline, a minor 2-phenylquinolin-4-one alkaloid isolated from Ruta graveolens L., in a liver injury model in vitro and in vivo. A network pharmacology approach was used to investigate the potential signaling pathway associated with the hepatoprotective activity of graveoline. Subsequently, biological experiments were conducted to validate the findings. Topological analysis of the KEGG pathway enrichment revealed that graveoline mediates its hepatoprotective activity through genes associated with the hepatitis B viral infection pathway. Biological experiments demonstrated that graveoline effectively reduced the levels of alanine transaminase and aspartate transaminase in lipopolysaccharide (LPS)-induced HepG2 cells. Graveoline exerted antihepatitic activity by inhibiting the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and elevated the anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) in vitro and in vivo. Additionally, graveoline exerted its hepatoprotective activity by inhibiting JAK1 and STAT3 phosphorylation both in vitro and in vivo. In summary, graveoline can attenuate acute liver injury by inhibiting the TNF-α inflammasome, activating IL-4 and IL-10, and suppressing the JAK1/STAT3 signaling pathway. This study sheds light on the potential of graveoline as a promising therapeutic agent for treating liver injury.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Galactosamina , Janus Quinase 1 , Lipopolissacarídeos , Fator de Transcrição STAT3 , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Janus Quinase 1/metabolismo , Janus Quinase 1/antagonistas & inibidores , Animais , Humanos , Lipopolissacarídeos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Masculino , Células Hep G2 , Galactosamina/toxicidade , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Citocinas/metabolismo , Quinolinas/farmacologiaAssuntos
Síndrome Hipereosinofílica , Janus Quinase 1 , Mutação , Nitrilas , Pirazóis , Pirimidinas , Humanos , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/patologia , Janus Quinase 1/genética , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/antagonistas & inibidores , Leucemia , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Feminino , IdosoRESUMO
Introduction: Conventional rosacea treatments are not uniformly pervasive, and the adverse reactions can potentially constrain their utility. The clinical use of JAK1 inhibitors upadacitinib and abrocitinib in the treatment of refractory rosacea has rarely been explored. Case report: We presented two cases of patients who received the JAK1 inhibitor upadacitinib and four cases of patients who received the JAK1 inhibitor abrocitinib for the treatment of refractory rosacea. Discussion: The JAK1 inhibitors upadacitinib and abrocitinib may be promising medical options for patients with refractory rosacea. However, the long-term safety and efficacy of upadacitinib and abrocitinib require prospective controlled studies to assess them more comprehensively.
Assuntos
Compostos Heterocíclicos com 3 Anéis , Inibidores de Janus Quinases , Rosácea , Humanos , Rosácea/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Feminino , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Sulfonamidas/uso terapêutico , Masculino , Resultado do Tratamento , Adulto , Janus Quinase 1/antagonistas & inibidoresRESUMO
Studies conducted on animal models have identified several therapeutic targets for myelofibrosis, the most severe of the myeloproliferative neoplasms. Unfortunately, many of the drugs which were effective in pre-clinical settings had modest efficacy when tested in the clinic. This discrepancy suggests that treatment for this disease requires combination therapies. To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-ß (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-ß) signaling and TGF-ß trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). The comparison was carried out by expressing the endpoints, which had either already been published or had been retrospectively obtained for this study, as the fold change of the values in the corresponding vehicles. In this model, only Ruxolitinib was found to decrease spleen size, only Aplidin and SB431542/AVID200 increased platelet counts, and with the exception of AVID200, all the inhibitors reduced fibrosis and microvessel density. The greatest effects were exerted by Reparixin, which also reduced TGF-ß content. None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-ß or CXCL1).
Assuntos
Janus Quinase 1 , Selectina-P , Mielofibrose Primária , Pirimidinas , Receptores de Interleucina-8B , Fator de Crescimento Transformador beta , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Selectina-P/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8A/metabolismo , Camundongos , Janus Quinase 2/metabolismo , Janus Quinase 2/antagonistas & inibidores , Nitrilas/uso terapêutico , Nitrilas/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Fator de Transcrição GATA1/metabolismo , Fator de Transcrição GATA1/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , HumanosRESUMO
Histone deacetylase inhibitors (HDACis) show beneficial effects on different hematological malignancy subtypes. However, their impacts on treating solid tumors are still limited due to diverse resistance mechanisms. Recent studies have found that the feedback activation of BRD4-LIFR-JAK1-STAT3 pathway after HDACi incubation is a vital mechanism inducing resistance of specific solid tumor cells to HDACis. This review summarizes the recent development of multi-target HDACis that can concurrently block BRD4-LIFR-JAK1-STAT3 pathway. Moreover, our findings hope to shed novel lights on developing novel multi-target HDACis with reduced BRD4-LIFR-JAK1-STAT3-mediated drug resistance in some tumors.
Assuntos
Inibidores de Histona Desacetilases , Janus Quinase 1 , Neoplasias , Fator de Transcrição STAT3 , Transdução de Sinais , Fatores de Transcrição , Humanos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Proteínas que Contêm BromodomínioRESUMO
This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo.
Assuntos
Janus Quinase 1 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais , Raízes de Plantas , Vitiligo , Vitiligo/tratamento farmacológico , Vitiligo/metabolismo , Humanos , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Janus Quinase 1/química , Janus Quinase 1/metabolismo , Janus Quinase 1/antagonistas & inibidoresRESUMO
Ruxolitinib {RUX; systematic name: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, C17H18N6} is an orally bioavailable JAK1/2 inhibitor approved for treating intermediate- or high-risk myelofibrosis (MF) and high-risk polycythemia vera (PV). Recent patents claim that RUX can exist in many different forms, information for which is important for the clinical utilization of RUX, especially for the formulation and bioavailability of the drug. But there has been no detailed study on its forms so far. Herein crystals of RUX and its dihydrate (RUX-2H; C17H18N6·2H2O) and phosphate (RUX-P; systematic name: 4-{1-[(1R)-2-cyano-1-cyclopentylethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-3-ium dihydrogen phosphate, C17H19N6+·H2PO4-) were prepared successfully and their structures studied in detail for the first time. Our study shows that the three crystals of RUX differ in the orientation of the pyrimidine ring relative to the pyrazole ring of the RUX molecule, and in their hydrogen-bond interactions. The water molecules in RUX-2H and the dihydrogen phosphate anion in RUX-P enrich the hydrogen-bond networks in these forms. The expected proton transfer occurs in RUX phosphate and the protonated N atom is engaged in a charge-assisted hydrogen bond with the counter-anion. Hydrogen-bonding interactions dominate in the crystal packing of the three forms. The detailed conformations and packing of the three forms were compared through the calculation of both Hirshfeld surfaces and fingerprint plots.
Assuntos
Ligação de Hidrogênio , Janus Quinase 1 , Janus Quinase 2 , Nitrilas , Fosfatos , Pirazóis , Pirimidinas , Pirimidinas/química , Pirimidinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Nitrilas/química , Cristalografia por Raios X , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/química , Janus Quinase 2/metabolismo , Fosfatos/química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/química , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , HumanosRESUMO
OBJECTIVE: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models. METHODS: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly. RESULTS: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. CONCLUSION: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.
Assuntos
Modelos Animais de Doenças , Janus Quinase 1 , Janus Quinase 3 , Proteínas Serina-Treonina Quinases , Sulfonamidas , Animais , Camundongos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 3/antagonistas & inibidores , Sulfonamidas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Feminino , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Purinas/farmacologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/imunologia , Azetidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/patologia , Psoríase/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , PirazóisRESUMO
Cervical cancer (CC) remains among the most frequent cancers worldwide despite advances in screening and the development of vaccines against human papillomavirus (HPV), involved in virtually all cases of CC. In mid-income countries, a substantial proportion of the cases are diagnosed in advanced stages, and around 40% of them are diagnosed in women under 49 years, just below the global median age. This suggests that members of this age group share common risk factors, such as chronic inflammation. In this work, we studied samples from 46 patients below 45 years old, searching for a miRNA profile regulating cancer pathways. We found 615 differentially expressed miRNAs between tumor samples and healthy tissues. Through bioinformatic analysis, we found that several of them targeted elements of the JAK/STAT pathway and other inflammation-related pathways. We validated the interactions of miR-30a and miR-34c with JAK1 and STAT3, respectively, through dual-luciferase and expression assays in cervical carcinoma-derived cell lines. Finally, through knockdown experiments, we observed that these miRNAs decreased viability and promoted proliferation in HeLa cells. This work contributes to understanding the mechanisms through which HPV regulates inflammation, in addition to its canonical oncogenic function, and brings attention to the JAK/STAT signaling pathway as a possible diagnostic marker for CC patients younger than 45 years. To our knowledge to date, there has been no previous description of a panel of miRNAs or even ncRNAs in young women with locally advanced cervical cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , Inflamação , MicroRNAs , Fator de Transcrição STAT3 , Transdução de Sinais , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais/genética , Adulto , Inflamação/genética , Inflamação/patologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Células HeLa , Janus Quinase 1/metabolismo , Janus Quinase 1/genética , Proliferação de Células/genética , Linhagem Celular Tumoral , Pessoa de Meia-IdadeRESUMO
Janus kinases (JAKs), a kind of non-receptor tyrosine kinases, the function has been implicated in the regulation of cell proliferation, differentiation and apoptosis, immune, inflammatory response and malignancies. Among them, JAK1 represents an essential target for modulating cytokines involved in inflammation and immune function. Rheumatoid arthritis, atopic dermatitis, ulcerative colitis and psoriatic arthritis are areas where approved JAK1 drugs have been applied for the treatment. In the review, we provided a brief introduction to JAK1 inhibitors in market and clinical trials. The structures of high active JAK1 compounds (IC50 ≤ 0.1 nM) were highlighted, with primary focus on structure-activity relationship and selectivity. Moreover, the druggability processes of approved drugs and high active compounds were analyzed. In addition, the issues involved in JAK1 compounds clinical application as well as strategies to surmount these challenges, were discussed.
Assuntos
Janus Quinase 1 , Inibidores de Proteínas Quinases , Relação Estrutura-Atividade , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Estrutura Molecular , Animais , Relação Dose-Resposta a DrogaRESUMO
Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.
Assuntos
Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Janus Quinase 1 , Inibidores de Janus Quinases , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Animais , Feminino , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Linfócitos T CD8-Positivos/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-ß-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.
Assuntos
Autoimunidade , Citocinas , Lúpus Eritematoso Sistêmico , Transdução de Sinais , Espermina , Animais , Espermina/metabolismo , Espermina/farmacologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Camundongos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Citocinas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Janus Quinase 1/metabolismo , Fosforilação , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Psoríase/imunologia , Psoríase/metabolismo , Camundongos Endogâmicos C57BL , Janus Quinases/metabolismo , Feminino , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismoRESUMO
Keratoconjunctivitis sicca (KCS) is an ocular condition characterized by insufficient tear production and inflammatory irritation, with Sjögren's syndrome (SS) being a major causative factor. This study aimed to extract patient transcriptomic data from the GEO database to identify signature genes associated with the diagnosis and treatment of KCS and the expression of three key genes were experimentally verified. We performed a difference analysis on the SS patient dataset and performed a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on the resulting genes. Additionally, a Weighted Gene Co-expression Network Analysis (WGCNA) was constructed. Machine learning techniques were employed to analyze the most strongly correlated gene modules with SS traits. These findings were further validated using KCS immune-correlation microarrays as a validation set. The correlation of the three identified genes with 22 immune cells was assessed through immune infiltration analysis. Subsequently, a rat model of desiccated keratoconjunctivitis was established, and the modeling situation and expression of characteristic genes were analyzed at the morphological, tissue, and molecular levels. Bioinformatic prediction revealed that the expression of JAK1, SKI, ZBTB16 not only differed in the machine learning validation set, but also correlated with some immune cells in the immune infiltration analysis. The results of animal experiments showed that the transcription and expression levels of these three genes were significantly different in rat KCS tissues and normal tissues, and there were also differences in the expression of JAK1 and SKI in rat peripheral blood, as well as significant up-regulation of the expression of related inflammatory factors in KCS tissues. Through bioinformatics prediction and animal experimental validation, this study identified three differentially expressed genes in SS mediated KCS patients, which provide new potential biological targets for the diagnosis and treatment of KCS.
Assuntos
Biomarcadores , Janus Quinase 1 , Ceratoconjuntivite Seca , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Animais , Humanos , Ratos , Ceratoconjuntivite Seca/genética , Ceratoconjuntivite Seca/metabolismo , Biomarcadores/metabolismo , Síndrome de Sjogren/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Redes Reguladoras de Genes , Inflamação/genética , Masculino , Perfilação da Expressão Gênica/métodos , Feminino , Modelos Animais de Doenças , Transcriptoma , Aprendizado de Máquina , Biologia Computacional/métodosRESUMO
BACKGROUND: APLNR is a G protein-coupled receptor and our previous study had revealed that APLNR could inhibit nasopharyngeal carcinoma (NPC) growth and metastasis. However, the role of APLNR in regulating PD-L1 expression and immune escape in NPC is unknown. METHODS: We analyzed the expression and correlation of APLNR and PD-L1 in NPC tissues and cells. We investigated the effect of APLNR on PD-L1 expression and the underlying mechanism in vitro and in vivo. We also evaluated the therapeutic potential of targeting APLNR in combination with PD-L1 antibody in a nude mouse xenograft model. RESULTS: We found that APLNR was negatively correlated with PD-L1 in NPC tissues and cells. APLNR could inhibit PD-L1 expression by binding to the FERM domain of JAK1 and blocking the interaction between JAK1 and IFNGR1, thus suppressing IFN-γ-mediated activation of the JAK1/STAT1 pathway. APLNR could also inhibit NPC immune escape by enhancing IFN-γ secretion and CD8+ T-cell infiltration and reducing CD8+ T-cell apoptosis and dysfunction. Moreover, the best effect was achieved in inhibiting NPC growth in nude mice when APLNR combined with PD-L1 antibody. CONCLUSIONS: Our study revealed a novel mechanism of APLNR regulating PD-L1 expression and immune escape in NPC and suggested that APLNR maybe a potential therapeutic target for NPC immunotherapy.
Assuntos
Antígeno B7-H1 , Camundongos Nus , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Evasão Tumoral , Animais , Feminino , Humanos , Masculino , Camundongos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Janus Quinase 1/metabolismo , Camundongos Endogâmicos BALB C , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1/metabolismo , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFß, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.
Assuntos
Astrócitos , Encefalomielite Autoimune Experimental , Janus Quinase 1 , Glicoproteína Mielina-Oligodendrócito , Receptores de Citocinas , Células Th17 , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Animais , Astrócitos/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Camundongos , Receptores de Citocinas/metabolismo , Receptores de Citocinas/genética , Janus Quinase 1/metabolismo , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Reprogramação Celular , Feminino , Células CultivadasRESUMO
INTRODUCTION: Vitiligo is a chronic, autoimmune condition characterized by skin depigmentation caused by inflammatory-mediated melanocyte degradation. Treatment of vitiligo is challenging due to the chronic nature of the condition. Ruxolitinib cream 1.5% was recently approved by the Food and Drug Administration (FDA) as a Janus kinase 1 and 2 inhibitor for use in nonsegmental vitiligo for those 12 years and older. AREAS COVERED: The purpose of this review is to describe the role of ruxolitinib in treating nonsegmental vitiligo.We searched PubMed using search terms nonsegmental vitiligo, jak inhibitor, and ruxolitinib. Clinicaltrials.gov was used to identify clinical trial data including efficacy, pharmacodynamics, pharmacokinetics, safety, and tolerability. EXPERT OPINION: In both phase II and phase III (TRuE-V1 and TRuE-V2) trials, ruxolitinib cream 1.5% improved repigmentation with minimal adverse effects. Topical ruxolitinib is a much needed new vitiligo treatment option. Real life efficacy may not match that seen in clinical trials if the hurdle of poor adherence to topical treatment is not surmounted.
Assuntos
Nitrilas , Pirazóis , Pirimidinas , Vitiligo , Humanos , Vitiligo/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , Janus Quinase 1/antagonistas & inibidores , Creme para a Pele/uso terapêutico , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêuticoAssuntos
Janus Quinase 1 , Pneumonia , Humanos , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/tratamento farmacológico , Hipersensibilidade/genética , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Animais , Asma/genética , Asma/tratamento farmacológico , Asma/imunologiaRESUMO
AIMS: The extent of perihematomal edema following intracerebral hemorrhage (ICH) significantly impacts patient prognosis, and disruption of the blood-brain barrier (BBB) exacerbates perihematomal edema. However, the role of peripheral IL-10 in mitigating BBB disruption through pathways that link peripheral and central nervous system signals remains poorly understood. METHODS: Recombinant IL-10 was administered to ICH model mice via caudal vein injection, an IL-10-inhibiting adeno-associated virus and an IL-10 receptor knockout plasmid were delivered intraventricularly, and neurobehavioral deficits, perihematomal edema, BBB disruption, and the expression of JAK1 and STAT3 were evaluated. RESULTS: Our study demonstrated that the peripheral cytokine IL-10 mitigated BBB breakdown, perihematomal edema, and neurobehavioral deficits after ICH and that IL-10 deficiency reversed these effects, likely through the IL-10R/JAK1/STAT3 signaling pathway. CONCLUSIONS: Peripheral IL-10 has the potential to reduce BBB damage and perihematomal edema following ICH and improve patient prognosis.
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Edema Encefálico , Hemorragia Cerebral , Interleucina-10 , Janus Quinase 1 , Receptores de Interleucina-10 , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Fator de Transcrição STAT3/metabolismo , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Edema Encefálico/etiologia , Edema Encefálico/tratamento farmacológico , Janus Quinase 1/metabolismo , Janus Quinase 1/antagonistas & inibidores , Interleucina-10/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismoRESUMO
Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery.
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Antineoplásicos , Proliferação de Células , Janus Quinase 1 , Proteólise , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proteólise/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Descoberta de Drogas , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Dose-Resposta a Droga , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value.