RESUMO
Recent advancements in the treatment landscape of ulcerative colitis (UC) have ushered in a new era of possibilities, particularly with the introduction of Janus kinase (JAK)-signal transducer and activator of transcription inhibitors. These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes. With approved JAK inhibitors (JAKis), such as tofacitinib, filgotinib, and upadacitinib, clinicians now have powerful tools to modulate immune responses and gene expression, potentially revolutionizing the treatment algorithm for UC. Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission, presenting viable options for patients who have failed conventional therapies. Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy, particularly in patients with aggressive disease phenotypes or refractory to biologic agents. The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC, offering timely relief for patients with active disease and facilitating personalized treatment approaches. Despite safety concerns, including cardiovascular risks and infections, ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.
Assuntos
Colite Ulcerativa , Inibidores de Janus Quinases , Janus Quinases , Piperidinas , Transdução de Sinais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Colite Ulcerativa/diagnóstico , Humanos , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Resultado do Tratamento , Pirimidinas/uso terapêutico , Indução de Remissão/métodos , Pirróis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes , Piridinas , TriazóisRESUMO
New biomarkers for early diagnosis of gastric cancer (GC), the second leading cause of cancer-related death, are urgently needed. IGFBP7, known to play various roles in multiple tumours, is complexly regulated across diverse cancer types, as evidenced by our pancancer analysis. Bioinformatics analysis revealed that IGFBP7 expression was related to patient prognosis, tumour clinicopathological characteristics, tumour stemness, microsatellite instability and immune cell infiltration, as well as the expression of oncogenes and immune checkpoints. GSEA links IGFBP7 to several cancer-related pathways. IGFBP7 deficiency inhibited GC cell proliferation and migration in vitro. Furthermore, an in vivo nude mouse model revealed that IGFBP7 downregulation suppressed the tumorigenesis of GC cells. Western blotting analysis showed that the JAK1/2-specific inhibitor ruxolitinib could rescue alterations induced by IGFBP7 overexpression in GC cells. Additionally, our bioinformatics analysis and in vitro assays suggested that IGFBP7 is regulated by DNA methylation at the genetic level and that the RNA m6A demethylase FTO modulates it at the posttranscriptional level. This study emphasizes the clinical relevance of IGFBP7 in GC and its influence on cell proliferation and migration via the JAK/STAT signalling pathway. This study also highlights the regulation of IGFBP7 in GC by DNA and m6A RNA methylation.
Assuntos
Movimento Celular , Proliferação de Células , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Fatores de Transcrição STAT , Transdução de Sinais , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Humanos , Movimento Celular/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Animais , Camundongos , Linhagem Celular Tumoral , Fatores de Transcrição STAT/metabolismo , Camundongos Nus , Janus Quinases/metabolismo , Feminino , Masculino , Metilação de RNARESUMO
Immune checkpoint inhibitors (ICIs) immunotherapy facilitates new approaches to achieve precision cancer treatment. A growing number of patients with non-small cell lung cancer (NSCLC) have benefited from treatment with neoadjuvant ICIs combined with chemotherapy. However, the mechanisms and associations between the therapeutic efficacy of neoadjuvant pembrolizumab and chemotherapy (NAPC) and macrophage subsets are still unclear. We performed single-cell RNA sequencing (scRNA-seq) and identified a novel FABP4+C1q+ macrophage subtype, which exhibited stronger proinflammatory cytokine production and phagocytic ability. This subtype was found to be more abundant in tumor tissues and lymph nodes of major pathological response (MPR) patients compared to non-MPR patients, and was associated with a good efficacy of NAPC. Multiplex fluorescent immunohistochemical (mIHC) staining was subsequently used to verify our findings. Further mechanistic studies indicated that FABP4 and C1q regulate the expression of proinflammatory cytokines synergistically. In addition, FABP4 and C1q promote fatty acid synthesis, enhance anti-apoptosis ability and phagocytic ability of macrophage via the interaction of AMPK/JAK/STAT axis. This study provides novel insights into the underlying mechanisms and predictive biomarkers of NAPC. Our findings contribute to improving the prognosis of patients with NSCLC by potentially guiding more precise patient selection and treatment strategies. NOVELTY & IMPACT STATEMENTS: We identified a group of macrophages (FABP4+C1q+ macrophages) related to the therapeutic efficacy of neoadjuvant chemoimmunotherapy. FABP4+C1q+ macrophages highly expressed proinflammatory cytokines-related genes and had a strong cytokine production and phagocytic ability. We believe that our study provides a novel insight into the synergistic mechanism of neoadjuvant ICI combined with chemotherapy and may lead to improved clinical outcomes in patients with NSCLC in the future.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Proteínas de Ligação a Ácido Graxo , Neoplasias Pulmonares , Macrófagos , Terapia Neoadjuvante , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Janus Quinases/metabolismo , Camundongos , Feminino , Masculino , Fatores de Transcrição STAT/metabolismo , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacosRESUMO
Cytokines function as communication tools of the immune system, serving critical functions in many biological responses and shaping the immune response. When cytokine production or their biological activity goes awry, the homeostatic balance of the immune response is altered, leading to the development of several pathologies such as autoimmune and inflammatory disorders. Cytokines bind to specific receptors on cells, triggering the activation of intracellular enzymes known as Janus kinases (JAKs). The JAK family comprises four members, JAK1, JAK2, JAK3 and tyrosine kinase 2, which are critical for intracellular cytokine signalling. Since the mid-2010s multiple JAK inhibitors have been approved for inflammatory and haematological indications. Currently, approved JAK inhibitors have demonstrated clinical efficacy; however, improved selectivity for specific JAKs is likely to enhance safety profiles, and different strategies have been used to accomplish enhanced JAK selectivity. In this update, we discuss the background of JAK inhibitors, current approved indications and adverse effects, along with new developments in this field. We address the issue of JAK selectivity and its relevance in terms of efficacy, and describe new modalities of JAK targeting, as well as new aspects of JAK inhibitor action.
Assuntos
Inibidores de Janus Quinases , Humanos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Citocinas/metabolismoRESUMO
Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are implicated in the development and progression of various tumors. The aim of this study was to investigate the effects of circ_SMA4 in Gastrointestinal Stromal Tumors (GISTs) malignant progression. Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in GISTs. The effect of circ_SMA4 on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo settings. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_SMA4/miR-494-3p/ KIT axis. The results revealed that circ_SMA4 was significantly upregulated in GISTs, and exhibited high diagnostic efficiency with an AUC of 0.9824 (P < 0.01). circ_SMA4 promoted cell proliferation, invasion, migration, while inhibiting apoptosis in GISTs cells, both in vitro and in vivo. Silencing circ_SMA4 partially inhibited GISTs malignant progression. Additionally, circ_SMA4 acted as a competing endogenous RNA (ceRNA) by targeting miR-494-3p, and KIT was identified as a functional gene for miR-494-3p in GISTs. Furthermore, the results confirmed that circ_SMA4/miR-494-3p/ KIT axis plays a role in activating the JAK/STAT signaling pathway in GISTs. Therefore, for the first time, we have identified and emphasized that circ_SMA4 is significantly upregulated and plays an oncogenic role in GISTs by sponging miR-494-3p to activate the KIT/JAK/STAT pathway. These findings underscore circ_SMA4 may serve as a novel diagnostic biomarker and therapeutic target for GISTs.
Assuntos
Proliferação de Células , Progressão da Doença , Tumores do Estroma Gastrointestinal , Regulação Neoplásica da Expressão Gênica , Janus Quinases , MicroRNAs , RNA Circular , Fatores de Transcrição STAT , Transdução de Sinais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Proliferação de Células/genética , Janus Quinases/metabolismo , Janus Quinases/genética , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/genética , Linhagem Celular Tumoral , Animais , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Movimento Celular/genética , Masculino , Camundongos , Feminino , Apoptose/genética , Pessoa de Meia-Idade , Camundongos NusRESUMO
Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable growth inhibition. Due to the lack of tumor suppressor agonists, this hypothesis and the mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor offering a promising avenue for this investigation. Spatial genomics suggests that the molecular portrait of AR-expressing BC cells in tumor microenvironment corresponds to better overall patient survival, clinically confirming AR's role as a tumor suppressor. Ligand activation of AR in ER-positive BC xenografts reprograms cistromes, inhibits oncogenic pathways, and promotes cellular elasticity toward a more differentiated state. Sustained AR activation results in cistrome rearrangement toward transcription factor PROP paired-like homeobox 1, transformation of AR into oncogene, and activation of the Janus kinase/signal transducer (JAK/STAT) pathway, all culminating in lineage plasticity to an aggressive resistant subtype. While the molecular profile of AR agonist-sensitive tumors corresponds to better patient survival, the profile represented in the resistant phenotype corresponds to shorter survival. Inhibition of activated oncogenes in resistant tumors reduces growth and resensitizes them to AR agonists. These findings indicate that persistent activation of a context-dependent tumor suppressor may lead to resistance through lineage plasticity-driven tumor metamorphosis. Our work provides a framework to explore the above phenomenon across multiple cancer types and underscores the importance of factoring sensitization of tumor suppressor targets while developing agonist-like drugs.
Assuntos
Neoplasias da Mama , Receptores Androgênicos , Receptores de Estrogênio , Fatores de Transcrição STAT , Humanos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/genética , Animais , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética , Oncogenes , Janus Quinases/metabolismo , Camundongos , Transdução de Sinais , Linhagem Celular Tumoral , Microambiente Tumoral , Regulação Neoplásica da Expressão GênicaRESUMO
Mesenchymal stromal/stem cells (MSC) play a crucial role in promoting neovascularization, which is essential for wound healing. They are commonly utilized as an autologous source of progenitor cells in various stem cell-based therapies. However, incomplete MSC differentiation towards a vascular endothelial cell phenotype questions their involvement in an alternative process to angiogenesis, namely vasculogenic mimicry (VM), and the signal transducing events that regulate their in vitro priming into capillary-like structures. Here, human MSC were primed on top of Cultrex matrix to recapitulate an in vitro phenotype of VM. Total RNA was extracted, and differential gene expression assessed through RNA-Seq analysis and RT-qPCR. Transient gene silencing was achieved using specific siRNA. AG490, Tofacitinib, and PP2 pharmacological effects on VM structures were analyzed using the Wimasis software. In vitro VM occurred within 4 h and was prevented by the JAK/STAT3 inhibitors AG490 and Tofacitinib, as well as by the Src inhibitor PP2. RNA-Seq highlighted STAT3 as a signaling hub contributing to VM when transcripts from capillary-like structures were compared to those from cell monolayers. Concomitant increases in IL6, IL1b, CSF1, CSF2, STAT3, FOXC2, RPSA, FN1, and SNAI1 transcript levels suggest the acquisition of a combined angiogenic, inflammatory and epithelial-to-mesenchymal transition phenotype in VM cultures. Increases in STAT3, FOXC2, RPSA, Fibronectin, and Snail protein expression were confirmed during VM. STAT3 and RPSA gene silencing abrogated in vitro VM. In conclusion, in vitro priming of MSC into VM structures requires Src/JAK/STAT3 signaling. This molecular evidence indicates that a clinically viable MSC-mediated pseudo-vasculature process could temporarily support grafts through VM, allowing time for the host vasculature to infiltrate and remodel the injured tissues.
Assuntos
Janus Quinases , Células-Tronco Mesenquimais , Neovascularização Fisiológica , Fator de Transcrição STAT3 , Transdução de Sinais , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Fator de Transcrição STAT3/metabolismo , Janus Quinases/metabolismo , Quinases da Família src/metabolismo , Células Cultivadas , Diferenciação CelularRESUMO
Rationale: Food allergy is a prevalent disease in the U.S., affecting nearly 30 million people. The primary management strategy for this condition is food avoidance, as limited treatment options are available. The elevation of pathologic IgE and over-reactive mast cells/basophils is a central factor in food allergy anaphylaxis. This study aims to comprehensively evaluate the potential therapeutic mechanisms of a small molecule compound called formononetin in regulating IgE and mast cell activation. Methods: In this study, we determined the inhibitory effect of formononetin on the production of human IgE from peripheral blood mononuclear cells of food-allergic patients using ELISA. We also measured formononetin's effect on preventing mast cell degranulation in RBL-2H3 and KU812 cells using beta-hexosaminidase assay. To identify potential targets of formononetin in IgE-mediated diseases, mast cell disorders, and food allergies, we utilized computational modeling to analyze mechanistic targets of formononetin from various databases, including SEA, Swiss Target Prediction, PubChem, Gene Cards, and Mala Cards. We generated a KEGG pathway, Gene Ontology, and Compound Target Pathway Disease Network using these targets. Finally, we used qRT-PCR to measure the gene expression of selected targets in KU812 and U266 cell lines. Results: Formononetin significantly decreased IgE production in IgE-producing human myeloma cells and PBMCs from food-allergic patients in a dose-dependent manner without cytotoxicity. Formononetin decreased beta-hexosaminidase release in RBL-2H3 cells and KU812 cells. Formononetin regulates 25 targets in food allergy, 51 in IgE diseases, and 19 in mast cell diseases. KEGG pathway and gene ontology analysis of targets showed that formononetin regulated disease pathways, primary immunodeficiency, Epstein-Barr Virus, and pathways in cancer. The biological processes regulated by formononetin include B cell proliferation, differentiation, immune response, and activation processes. Compound target pathway disease network identified NFKB1, NFKBIA, STAT1, STAT3, CCND1, TP53, TYK2, and CASP8 as the top targets regulated at a high degree by formononetin. TP53, STAT3, PTPRC, IL2, and CD19 were identified as the proteins mostly targeted by formononetin. qPCR validated genes of Formononetin molecular targets of IgE regulation in U266 cells and KU812 cells. In U266 cells, formononetin was found to significantly increase the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. In basophils KU812 cells, formononetin significantly increased the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK, TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. Conclusion: These findings comprehensively present formononetin's mechanisms in regulating IgE production in plasma cells and degranulation in mast cells.
Assuntos
Hipersensibilidade Alimentar , Imunoglobulina E , Isoflavonas , Janus Quinases , Leucócitos Mononucleares , Mastócitos , Fatores de Transcrição STAT , Transdução de Sinais , Isoflavonas/farmacologia , Humanos , Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Mastócitos/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Adulto , Degranulação Celular/efeitos dos fármacos , Animais , Pessoa de Meia-IdadeAssuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas com Domínio LIM , Neoplasias Bucais , Transdução de Sinais , Humanos , Transdução de Sinais/efeitos dos fármacos , Proteínas com Domínio LIM/metabolismo , Proteínas com Domínio LIM/antagonistas & inibidores , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas do Citoesqueleto/metabolismo , Proteínas do Citoesqueleto/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Progressão da Doença , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Parkinson's disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.
Assuntos
Modelos Animais de Doenças , Doenças Neuroinflamatórias , Doença de Parkinson , Fatores de Transcrição STAT , Transdução de Sinais , alfa-Sinucleína , Animais , Camundongos , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/imunologia , Humanos , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Janus Quinases/metabolismo , Janus Quinases/antagonistas & inibidores , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/imunologia , Pirimidinas/farmacologiaRESUMO
Inflammatory bowel disease (IBD) encompasses a group of non-specific chronic intestinal inflammatory conditions of unclear etiology. The current treatment and long-term management primarily involve biologics. Nevertheless, some patients experience treatment failure or intolerance to biologics [1], making these patients a primary focus of IBD research. The Janus kinase (JAK)-Signal Transducers and Activator of Transcription (STAT) signal transduction pathway is crucial to the regulation of immune and inflammatory responses [2], and plays an important role in the pathogenesis of IBD. JAK inhibitors alleviate IBD by suppressing the transmission of JAK-STAT signaling pathway. As the first small-molecule oral inhibitor for IBD, JAK inhibitors greatly improved the treatment of IBD and have demonstrated significant efficacy, with tofacitinib and upadacitinib being approved for the treatment of ulcerative colitis (UC) [3]. JAK inhibitors can effectively alleviate intestinal inflammation in IBD patients who have failed to receive biologics, which may bring new treatment opportunities for refractory IBD patients. This review aims to elucidate the crucial roles of JAK-STAT signal transduction pathway in IBD pathogenesis, examine its role in various cell types within IBD, and explore the research progress of JAK inhibitors as therapeutic agents, paving the road for new IBD treatment strategies.
Assuntos
Doenças Inflamatórias Intestinais , Inibidores de Janus Quinases , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Humanos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Animais , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Colite Ulcerativa/tratamento farmacológico , Compostos Heterocíclicos com 3 AnéisRESUMO
Canine gastrointestinal lymphoma is known to be of T-cell origin in most cases, but the molecular biological aberrations have not been clarified. In human intestinal T-cell lymphoma, the mutations in the genes associated with Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway have been frequently observed. In this study, the gene mutations were investigated in 31 dogs with large cell gastrointestinal lymphoma (LCGIL) by focusing on the genes involved in JAK-STAT pathway. Next-generation sequencing analysis to examine the mutations in STAT3, STAT5B, and JAK1 genes throughout the exon regions revealed the mutations in STAT3 gene in two dogs and JAK1 gene in one dog. In conclusion, this study could not indicate the associations of gene mutations in JAK-STAT pathway with LCGIL in most canine cases.
Assuntos
Doenças do Cão , Neoplasias Gastrointestinais , Mutação , Fator de Transcrição STAT3 , Cães , Animais , Doenças do Cão/genética , Doenças do Cão/metabolismo , Neoplasias Gastrointestinais/veterinária , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Transdução de Sinais , Janus Quinases/metabolismo , Janus Quinases/genética , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Masculino , Feminino , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismoRESUMO
Immune factors such as interferonɣ and interleukin 4 belong to the group of cytokines that are dependent on type I/II receptors for their signal transmission. Upon activation, these receptors transmit their signal to the cell nucleus and, thus, modulate gene transcription via a signaling cascade consisting of Janus kinases (JAK). This family of four kinases (JAK 1, JAK 2, JAK 3, and tyrosine kinase 2 (TYK2)) subsequently activate members of the signal transducer and activator of transcription (STAT). This finding turned the JAK/STAT signaling pathway into a pharmacological target for the treatment of inflammatory diseases in which cytokines using type I/II receptors play a pathogenic role. In 2018, the European Medicines Agency (EMA) approved tofacitinib for the treatment of psoriatic arthritis. This was the first approval of a JAK/STAT pathway inhibitor for patients treated by dermatologists and rheumatologists. Since then, several new JAK inhibitors have been approved for dermatologic diseases such as atopic dermatitis, alopecia areata, vitiligo, and plaque-type psoriasis. In addition, JAK inhibitors are being investigated for the treatment of many other skin diseases. Thus, systemic JAK inhibitors complete the spectrum of immunotherapeutics with a broader immunological approach compared to monoclonal antibodies. The low molecular weight of JAK inhibitors enables the preparation of these drugs for both systemic and topical administration. Their utilization could represent a valuable alternative to topical steroids. The safety profile of JAK inhibitors must be taken into account. Possible long-term effects may become apparent in the next few years. This article describes both approved JAK inhibitors and relevant new JAK inhibitors that are promising candidates for approval as therapeutics in dermatology.
Assuntos
Inibidores de Janus Quinases , Dermatopatias , Humanos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Dermatopatias/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Pirróis/uso terapêutico , Pirróis/farmacologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismoRESUMO
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway serves as a paradigm for signal transduction from the extracellular environment to the nucleus. It plays a pivotal role in physiological functions, such as hematopoiesis, immune balance, tissue homeostasis, and surveillance against tumors. Dysregulation of this pathway may lead to various disease conditions such as immune deficiencies, autoimmune diseases, hematologic disorders, and cancer. Due to its critical role in maintaining human health and involvement in disease, extensive studies have been conducted on this pathway, ranging from basic research to medical applications. Advances in the structural biology of this pathway have enabled us to gain insights into how the signaling cascade operates at the molecular level, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced comprehension of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed us to engineer cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. In this review, we outline the structural basis that governs key nodes in this pathway, offering a comprehensive overview of the signal transduction process. Furthermore, we explore recent advances in cytokine engineering for therapeutic development in this pathway.
Assuntos
Citocinas , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Janus Quinases/química , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/química , Transdução de Sinais/genética , Citocinas/genética , Citocinas/metabolismo , Engenharia de ProteínasRESUMO
Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-ß triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.
Assuntos
Inibidores de Checkpoint Imunológico , Interferon Tipo I , Melanoma , Receptor de Morte Celular Programada 1 , Receptor de Interferon alfa e beta , Transdução de Sinais , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/genética , Melanoma/metabolismo , Humanos , Receptor de Interferon alfa e beta/metabolismo , Receptor de Interferon alfa e beta/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Camundongos , Interferon Tipo I/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/metabolismo , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/genética , Interferon beta/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Janus Quinases/metabolismo , Camundongos Endogâmicos C57BL , Interferon-alfa/farmacologia , Interferon-alfa/metabolismo , FemininoRESUMO
BACKGROUND: The pathogenesis of psoriasis involves the interaction between keratinocytes and immune cells, leading to immune imbalance. While most current clinical treatment regimens offer rapid symptom relief, they often come with significant side effects. Tetrastigma hemsleyanum polysaccharides (THP), which are naturally nontoxic, possess remarkable immunomodulatory and anti-inflammatory properties. METHODS: In this study, we utilized an imiquimod (IMQ)-induced psoriasis mouse model and a LPS/IL-6-stimulated HaCaT model. The potential and mechanism of action of THP in psoriasis treatment were assessed through methods including Psoriasis Area Severity Index (PASI) scoring, histopathology, flow cytometry, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Percutaneous administration of THP significantly alleviated symptoms and manifestations in IMQ-induced psoriatic mice, including improvements in psoriatic skin appearance (erythema, folds, scales), histopathological changes, decreased PASI scores, and spleen index. Additionally, THP suppressed abnormal proliferation of Th17 cells and excessive proliferation and inflammation of keratinocytes. Furthermore, THP exhibited the ability to regulate the JAK/STAT3 signaling pathway. CONCLUSION: Findings from in vivo and in vitro studies suggest that THP can inhibit abnormal cell proliferation and excessive inflammation in lesional skin, balance Th17 immune cells, and disrupt the interaction between keratinocytes and Th17 cells. This mechanism of action may involve the modulation of the JAK/STAT3 signaling pathway, offering potential implications for psoriasis treatment.
Assuntos
Modelos Animais de Doenças , Imiquimode , Polissacarídeos , Psoríase , Fator de Transcrição STAT3 , Transdução de Sinais , Vitaceae , Animais , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Fator de Transcrição STAT3/metabolismo , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Camundongos , Humanos , Vitaceae/química , Janus Quinases/metabolismo , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células HaCaT , Queratinócitos/efeitos dos fármacos , Masculino , Pele/efeitos dos fármacos , Pele/patologia , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer that is fatal and has a dismal prognosis. Obovatol (Ob), a novel lignan derived from the leaf and stem bark of Magnolia obovata Thunb, has exhibited anti-tumor effect on diverse tumors. However, its effect and mechanisms on HCC remain to be further explored. METHODS: Huh7 and Hep3B cells, as well as BALB/c nude mice were used to determine the function and mechanisms of Ob on growth, invasion and immune escape by cell counting kit-8, transwell, enzyme-linked immunosorbent assay (ELISA) and western blot experiments. RESULTS: Ob reduced the cell viability of Huh7 and Hep3B cells, with a IC50 value of 57.41 µM and 62.86 µM, respectively. Ob declined the invasion ability, the protein expression of N-cadherin and the concentrations of IL-10 and TGF-ß, whereas increased the E-cadherin expression and the contents of IFN-γ and IL-2 in Hep3B and Huh7 cells. Mechanically, Ob decreased the protein level of p-JAK/JAK, p-STAT3/STAT3 and PD-L1, which was partly restored with the treatment of RO8191, an activator of JAK/STAT3 axis. The effect of Ob on the cell viability, the invasion ability, the protein level of N-cadherin and E-cadherin, and the concentrations of IL-10, TGF-ß, IFN-γ and IL-2 in both Hep3B and Huh7 cells was reversed with the management of RO8191. In vivo, Ob reduced tumor volume and weight, the level of N-cadherin, PD-L1, p-JAK/JAK, and p-STAT3/STAT3, with an elevated expression of E-cadherin and IFN-γ. CONCLUSION: Ob downregulated the JAK/STST3/PD-L1 pathway to attenuate the growth, invasion and immune escape of HCC.
Assuntos
Antígeno B7-H1 , Carcinoma Hepatocelular , Proliferação de Células , Janus Quinases , Neoplasias Hepáticas , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais , Humanos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Janus Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Camundongos , Invasividade Neoplásica , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Éteres Fenílicos/farmacologia , Éteres Fenílicos/uso terapêutico , Movimento Celular/efeitos dos fármacos , Compostos de BifeniloRESUMO
Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.
Assuntos
Inibidores de Janus Quinases , Contração Muscular , Músculo Esquelético , Piperidinas , Pirimidinas , Humanos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Inibidores de Janus Quinases/farmacologia , Masculino , Pirróis/farmacologia , Feminino , Adulto , Transdução de Sinais/efeitos dos fármacos , Pessoa de Meia-Idade , Janus Quinases/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismoRESUMO
The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure-activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.