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1.
J Med Virol ; 96(3): e29533, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38483048

RESUMO

Cytidine/uridine monophosphate kinase 2 (UMP-CMP kinase 2, CMPK2) has been reported as an antiviral interferon-stimulated gene (ISG). We previously observed that the expression of CMPK2 was significantly upregulated after Zika Virus (ZIKV) infection in A549 cells. However, the association and the underlying mechanisms between CMPK2 induction and ZIKV replication remain to be determined. We investigated the induction of CMPK2 during ZIKV infection and the effect of CMPK2 on ZIKV replication in A549, U251, Vero, IFNAR-deficient U5A and its parental 2fTGH cells, Huh7 and its RIG-I-deficient derivatives Huh7.5.1 cells. The activation status of Jak-STAT signaling pathway was determined by detecting the phosphorylation level of STAT1, the activity of interferon stimulated response element (ISRE) and the expression of several interferon stimulated genes (ISGs). We found that ZIKV infection induced CMPK2 expression through an IFNAR and RIG-I dependent manner. Overexpression of CMPK2 inhibited while CMPK2 knockdown promoted ZIKV replication in A549 and U251 cells. Mechanically, we found that CMPK2 overexpression increased IFNß expression and activated Jak/STAT signaling pathway as shown by the increased level of p-STAT1, enhanced activity of ISRE, and the upregulated expression of downstream ISGs. These findings suggest that ZIKV infection induced CMPK2 expression, which inhibited ZIKV replication and serves as a positive feedback regulator for IFN-Jak/STAT pathway.


Assuntos
Interferon Tipo I , Núcleosídeo-Fosfato Quinase , Infecção por Zika virus , Zika virus , Humanos , Zika virus/metabolismo , Transdução de Sinais , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Interferon Tipo I/genética , Replicação Viral , Receptores Imunológicos
2.
Int J Mol Sci ; 25(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474223

RESUMO

The Janus kinase (JAK) family is a small group of protein tyrosine kinases that represent a central component of intracellular signaling downstream from a myriad of cytokine receptors. The JAK3 family member performs a particularly important role in facilitating signal transduction for a key set of cytokine receptors that are essential for immune cell development and function. Mutations that impact JAK3 activity have been identified in a number of human diseases, including somatic gain-of-function (GOF) mutations associated with immune cell malignancies and germline loss-of-function (LOF) mutations associated with immunodeficiency. The structure, function and impacts of both GOF and LOF mutations of JAK3 are highly conserved, making animal models highly informative. This review details the biology of JAK3 and the impact of its perturbation in immune cell-related diseases, including relevant animal studies.


Assuntos
Síndromes de Imunodeficiência , Neoplasias , Animais , Humanos , Janus Quinase 3/metabolismo , Transdução de Sinais , Janus Quinases/metabolismo , Receptores de Citocinas/metabolismo , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo
3.
Front Immunol ; 15: 1341981, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38464510

RESUMO

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that is characterized by new bone formation in the axial musculoskeletal system, with X-ray discriminating between radiographic and non-radiographic forms. Current therapeutic options include non-steroidal anti-inflammatory drugs in addition to biological disease-modifying anti-rheumatic drugs that specifically target tumor necrosis factor-alpha (TNFα) or interleukin (IL)-17. Pain is the most critical symptom for axSpA patients, significantly contributing to the burden of disease and impacting daily life. While the inflammatory process exerts a major role in determining pain in the early phases of the disease, the symptom may also result from mechanical and neuromuscular causes that require complex, multi-faceted pharmacologic and non-pharmacologic treatment, especially in the later phases. In clinical practice, pain often persists and does not respond further despite the absence of inflammatory disease activity. Cytokines involved in axSpA pathogenesis interact directly/indirectly with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascade, a fundamental component in the origin and development of spondyloarthropathies. The JAK/STAT pathway also plays an important role in nociception, and new-generation JAK inhibitors have demonstrated rapid pain relief. We provide a comprehensive review of the different pain types observed in axSpA and the potential role of JAK/STAT signaling in this context, with specific focus on data from preclinical studies and data from clinical trials with JAK inhibitors.


Assuntos
Espondiloartrite Axial , Inibidores de Janus Quinases , Humanos , Janus Quinases/metabolismo , Transdução de Sinais , Inibidores de Janus Quinases/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Dor
4.
J Drugs Dermatol ; 23(3): 188-190, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38443119

RESUMO

Topical ruxolitinib, a potent Janus kinase (JAK) inhibitor, has shown significant efficacy in treating inflammatory skin conditions. While its use has already been established in atopic dermatitis and vitiligo, recent reports suggest its potential efficacy in treating other dermatoses. Specifically, topical ruxolitinib may be an effective treatment option for refractory dermatological conditions that are inflammation-driven with dysregulated activity of cytokines implicated in the JAK/STAT pathway. In this case series, we present four novel clinical applications of topical ruxolitinib in treatment-resistant dermatological conditions. These cases include pediatric lichen sclerosus et atrophicus, morphea, perioral dermatitis, and notalgia paresthetica. All four patients reported noticeable symptomatic improvement and a significant improvement in the condition of their skin lesions. Our results suggest that ruxolitinib cream can successfully manage these conditions and may serve as supporting evidence for its formal evaluation.   J Drugs Dermatol. 2024;23(3): doi:10.36849/JDD.7696.


Assuntos
Inibidores de Janus Quinases , Janus Quinases , Nitrilas , Pirazóis , Pirimidinas , Humanos , Criança , Fatores de Transcrição STAT , Transdução de Sinais , Citocinas
5.
Front Immunol ; 15: 1341632, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38444845

RESUMO

Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.


Assuntos
Produtos Biológicos , Dermatite Atópica , Inibidores de Janus Quinases , Psoríase , Humanos , Inibidores de Janus Quinases/efeitos adversos , Psoríase/tratamento farmacológico , Janus Quinases
6.
J Orthop Surg Res ; 19(1): 177, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459553

RESUMO

BACKGROUND: Many KOA patients have not reached indications for surgery, thus we need to find effective non-surgical treatments. Acupuncture is thought to have the potential to modulate inflammation and cytokines in KOA through the immune system. However, the mechanisms have not been elucidated, and there is no network Meta-analysis of acupuncture on KOA animals. So we evaluate the effect and mechanism of acupuncture-related therapy in KOA animals. METHODS: A comprehensive search was conducted in multiple databases including PubMed, Web of Science, Embase, CBM, CNKI, WanFang, and VIP Database to identify relevant animal studies focusing on acupuncture therapy for KOA. The included studies were assessed for risk of bias using SYRCLE's Risk of Bias tool. Subsequently, pair-wise meta-analysis and network meta-analysis were performed using Stata 15.0 software, evaluating outcomes such as Lequesne index scale, Mankin score, IL-1ß, TNF-α, MMP3, and MMP13. RESULTS: 56 RCTs with 2394 animals were included. Meta-analysis showed that among the 6 outcomes, there were significant differences between acupuncture and model group; the overall results of network meta-analysis showed that the normal group or sham operation group performed the best, followed by the acupotomy, acupuncture, and medicine group, and the model group had the worst effect, and there were significant differences between 6 interventions. CONCLUSIONS: Acupuncture-related therapy can be a possible treatment for KOA. The mechanism involves many immune-inflammatory pathways, which may be mediated by DAMPs/TLR/NF-κB/MAPK,PI3K/Akt/NF-κB pathway, or IFN-γ/JAK-STAT pathway. It needs to be further confirmed by more high-quality animal experiments or meta-analysis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier: CRD42023377228.


Assuntos
Terapia por Acupuntura , Osteoartrite do Joelho , Animais , Humanos , Osteoartrite do Joelho/terapia , Metanálise em Rede , Janus Quinases , NF-kappa B , Fosfatidilinositol 3-Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Terapia por Acupuntura/métodos , Modelos Animais
7.
Front Immunol ; 15: 1338096, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38495892

RESUMO

Type III interferon (IFN-λ), a new member of the IFN family, was initially considered to possess antiviral functions similar to those of type I interferon, both of which are induced via the JAK/STAT pathway. Nevertheless, recent findings demonstrated that IFN-λ exerts a nonredundant antiviral function at the mucosal surface, preferentially produced in epithelial cells in contrast to type I interferon, and its function cannot be replaced by type I interferon. This review summarizes recent studies showing that IFN-λ inhibits the spread of viruses from the cell surface to the body. Further studies have found that the role of IFN-λ is not only limited to the abovementioned functions, but it can also can exert direct and/or indirect effects on immune cells in virus-induced inflammation. This review focuses on the antiviral activity of IFN-λ in the mucosal epithelial cells and its action on immune cells and summarizes the pathways by which IFN-λ exerts its action and differentiates it from other interferons in terms of mechanism. Finally, we conclude that IFN-λ is a potent epidermal antiviral factor that enhances the respiratory mucosal immune response and has excellent therapeutic potential in combating respiratory viral infections.


Assuntos
Interferon Tipo I , Viroses , Humanos , Interferon lambda , Janus Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Interferon Tipo I/metabolismo , Epitélio/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico
8.
Eur Rev Med Pharmacol Sci ; 28(5): 1864-1872, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38497869

RESUMO

Vasculitis is the inflammation of blood vessels caused by autoimmunity and/or autoinflammation, and its etiology and pathogenesis remain largely unknown. The Janus kinase (JAK) and Signal transduction Transcription Activator (STAT) signal transduction pathways are a group of molecules involved in the major pathways by which many cytokines exert and integrate their functions, and their dysregulation has been implicated in the pathogenesis of a variety of autoimmune diseases. However, current data supporting the role of the JAK/STAT pathway in the development of vasculitis is limited. In terms of treatment, glucocorticoids and immunosuppressants have been the standard therapy. However, because of the huge burden of treatment side effects, people have long waited for new treatment options. JAK inhibitors reduce the production of multiple cytokines and inhibit inflammation by targeting the JAK/STAT pathway, and have the advantage of rapidly acting in oral formulations, reducing glucocorticoid dependence and associated adverse events, especially in refractory cases. Therefore, JAK inhibitors are expected to be a promising drug for the treatment of vasculitis.


Assuntos
Doenças Autoimunes , Inibidores de Janus Quinases , Vasculite , Humanos , Janus Quinases , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Fatores de Transcrição STAT , Transdução de Sinais , Vasculite/tratamento farmacológico , Inflamação/tratamento farmacológico , Citocinas , Glucocorticoides/uso terapêutico , Fatores de Transcrição
9.
Medicine (Baltimore) ; 103(11): e37504, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489696

RESUMO

Immune-related cutaneous adverse events (ircAEs) will undermine the patients' quality of lives, and interrupt the antitumor therapy. A clinical proved recipe for external use of clearing heat and removing dampness (Qing-Re-Li-Shi Formula, hereinafter referred to as "QRLSF") is beneficial to the treatment of ircAEs in clinical practice. Our study will elucidate the mechanism of QRLSF against ircAEs based on network pharmacology and molecular docking. The active components and corresponding targets of QRLSF were collected through traditional Chinese medicine systems pharmacology database. GeneCards, online Mendelian inheritance in man, and pharmacogenomics knowledgebase were used to screen the targets of ircAEs. The intersecting targets between drug and disease were acquired by venn analysis. Cytoscape software was employed to construct "components-targets" network. Search tool for the retrieval of interacting genes/proteins database was applied to establish the protein-protein interaction network and then its core targets were identified. Gene ontology and Kyoto encyclopedia of genes and genomes analysis was performed to predict the mechanism. The molecular docking verification of key targets and related phytomolecules was accomplished by AutoDock Vina software. Thirty-nine intersecting targets related to QRLSF against ircAEs were recognized. The analysis of network clarified 5 core targets (STAT3, RELA, TNF, TP53, and NFKBIA) and 4 key components (quercetin, apigenin, luteolin, and ursolic acid). The activity of QRLSF against ircAEs could be attributed to the regulation of multiple biological effects via multi-pathways (PI3K-Akt pathway, cytokine-cytokine receptor interaction, JAK-STAT pathway, chemokine pathway, Th17 cell differentiation, IL-17 pathway, TNF pathway, and Toll-like receptor pathway). The binding activities were estimated as good level by molecular docking. These discoveries disclosed the multi-component, multi-target, and multi-pathway characteristics of QRLSF against ircAEs, providing a new strategy for such medical problem.


Assuntos
Medicamentos de Ervas Chinesas , Farmacologia em Rede , Humanos , Simulação de Acoplamento Molecular , Temperatura Alta , Janus Quinases , Fosfatidilinositol 3-Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Bases de Dados Genéticas , Medicamentos de Ervas Chinesas/efeitos adversos , Medicina Tradicional Chinesa
10.
Immun Inflamm Dis ; 12(3): e1224, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38517042

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by numerous factors, such as immune system dysfunction and genetic factors. MicroRNAs (miRNAs) play a crucial role in UC pathogenesis, particularly via the JAK-STAT pathway. Our aim was to investigate the association between miRNA-101 and JAK2-STAT3 signaling pathway with inflammatory cytokines in UC patients. METHODS: We enrolled 35 UC patients and 35 healthy individuals as the control group, referred to Shariati Hospital, Tehran, Iran. Patients were diagnosed based on clinical, laboratory, histological, and colonoscopy criteria. RNA and protein extracted from tissue samples. Real-time PCR was used to assess the expression levels of miRNA-101, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and IL-10 genes, while western blot was employed to measure levels of P-STAT3, total STAT3, and JAK2 proteins. RESULTS: Expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 significantly increased, while the expression of IL-10 significantly decreased in the case group versus controls. Additionally, miRNA-101 expression was significantly higher in UC patients. A significant correlation between miRNA-101 and IL-6 expression was observed, indicating their relationship and possible impact on cell signaling pathways, JAK2-STAT3. No significant changes were observed in phosphorylated and total STAT3 and JAK2 protein expression. CONCLUSION: This study provides evidence of increased miRNA-101 expression in UC tissue, suggesting a potential correlation between miRNA-101 and IL-6 expression and their involvement in the JAK2-STAT3 pathway. The study confirms alterations in UC patients' pro-inflammatory cytokines and anti-inflammatory IL-10. However, further investigations are needed to understand the exact role of miRNA-101 in UC pathogenesis fully.


Assuntos
Colite Ulcerativa , MicroRNAs , Humanos , Citocinas/metabolismo , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , MicroRNAs/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/genética , Interleucina-1beta/genética , Janus Quinases/metabolismo , Transdução de Sinais , Irã (Geográfico) , Fatores de Transcrição STAT/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
11.
Eur J Med Res ; 29(1): 191, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38520011

RESUMO

BACKGROUND: Small intestinal monomorphic-epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma originating in the gastrointestinal tract. This study aimed to investigate the clinicopathological features, immunophenotypes, and molecular genetic changes of MEITL. METHODS: The clinicopathological data for three patients with surgically resected MEITL of the small intestine were collected. Next, immunohistochemical labeling, Epstein-Barr virus (EBV) in situ hybridization, assessment of clonal rearrangement of T-cell receptor (TCR) genes, and next-generation sequencing (NGS) were performed. RESULTS: Of the three patients, two were male and one was female, with ages of 61, 67, and 73 years, respectively. Clinical manifestations were predominantly abdominal pain and distension. Histopathology revealed infiltrative growth of small-to-medium-sized lymphocytes with a consistent morphology between the intestinal walls, accompanied by an obvious pro-epithelial phenomenon. The expression of CD3, CD8, CD43, CD56, TIA-1, CD103, H3K36me3, and Bcl-2 was detected, and the Ki-67 proliferation index ranged from 50% to 80%. All three patients tested negative for EBER. However, monoclonal rearrangement of the TCR gene was detected in them. NGS testing showed a JAK3 mutation in all three cases. Further, STAT5B, SETD2, and TP53 mutations were each observed in two cases, and a BCOR mutation was found in one case. All patients were treated with chemotherapy after surgery. Two patients died 7 and 15 month post-operation, and one patient survived for 5 months of follow-up. CONCLUSIONS: Our findings demonstrate that mutations in JAK3 and STAT5B of the JAK/STAT pathway and inactivation of the oncogene SETD2 markedly contribute to the lymphomagenesis of MEITL.


Assuntos
Linfoma de Células T Associado a Enteropatia , Infecções por Vírus Epstein-Barr , Linfoma de Células T , Humanos , Masculino , Feminino , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Janus Quinases , Transdução de Sinais , Herpesvirus Humano 4/genética , Fatores de Transcrição STAT , Linfoma de Células T Associado a Enteropatia/genética , Linfoma de Células T Associado a Enteropatia/complicações , Linfoma de Células T/genética , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Intestino Delgado/patologia , Mutação/genética , Biologia Molecular
12.
Mol Biol Rep ; 51(1): 440, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38520542

RESUMO

Globally, cardiovascular diseases (CVD) are one of the significant causes of death and are considered a major concern of human society. One of the most crucial objectives of scientists is to reveal the mechanisms associated with the pathogenesis of CVD, which has attracted the attention of many scientists. Accumulating evidence showed that the signal transducer and activator of transcription (STAT) signaling pathway is involved in various physiological and pathological processes. According to research on the molecular mechanisms of CVDs, the STAT family of proteins is one of the most crucial players in these diseases. Numerous studies have demonstrated the undeniable relevance of STAT family proteins in various CVDs. The aim of this review is to shed light on how STAT signaling pathways are related to CVD and the potential for using these signaling pathways as therapeutic targets.


Assuntos
Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/terapia , Transdução de Sinais/fisiologia , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo
13.
Sci Adv ; 10(12): eadl0368, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38507500

RESUMO

CCR5 serves as R5-tropic HIV co-receptor. Knocking out CCR5 in HIV patients, which has occurred <10 times, is believed important for cure. JAK/STAT inhibitors tofacitinib and ruxolitinib inhibit CCR5 expression in HIV+ viremic patients. We investigated the association of JAK/STAT signaling pathway with CCR5/CCR2 expression in human primary CD4+ T cells and confirmed its importance. Six of nine JAK/STAT inhibitors that reduced CCR5/CCR2 expression were identified. Inhibitor-treated CD4+ T cells were relatively resistant, specifically to R5-tropic HIV infection. Furthermore, single JAK2, STAT3, STAT5A, and STAT5B knockout and different combinations of JAK/STAT knockout significantly reduced CCR2/CCR5 expression of both RNA and protein levels, indicating that CCR5/CCR2 expression was positively regulated by JAK-STAT pathway in CD4+ T cells. Serum and glucocorticoid-regulated kinase 1 (SGK1) knockout affected CCR2/CCR5 gene expression, suggesting that SGK1 is involved in CCR2/CCR5 regulation. If cell surface CCR5 levels can be specifically and markedly down-regulated without adverse effects, that may have a major impact on the HIV cure agenda.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Linfócitos T/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/metabolismo , Janus Quinases/metabolismo , HIV-1/fisiologia , Receptores CCR5/genética , Receptores CCR5/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Linfócitos T CD4-Positivos/metabolismo
14.
Cell Rep Med ; 5(3): 101472, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38508140

RESUMO

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.


Assuntos
Linfoma Anaplásico de Células Grandes , Transdução de Sinais , Adulto , Criança , Humanos , Transdução de Sinais/genética , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Transformação Celular Neoplásica , Carcinogênese/genética , Fator de Transcrição STAT3/genética
15.
Oncotarget ; 15: 65-75, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319731

RESUMO

Multiple myeloma (MM) is the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. In recent years, new and more effective drugs have become available for the treatment of this B-cell malignancy. These new drugs have often been evaluated together and in combination with older agents. However, even these novel combinations eventually become ineffective; and, thus, novel therapeutic approaches are necessary to help overcome resistance to these treatments. Recently, the Janus Kinase (JAK) family of tyrosine kinases, specifically JAK1 and JAK2, has been shown to have a role in the pathogenesis of MM. Preclinical studies have demonstrated a role for JAK signaling in direct and indirect growth of MM and downregulation of anti-tumor immune responses in these patients. Also, inhibition of JAK proteins enhances the anti-MM effects of other drugs used to treat MM. These findings have been confirmed in clinical studies which have further demonstrated the safety and efficacy of JAK inhibition as a means to overcome resistance to currently available anti-MM therapies. Additional studies will provide further support for this promising new therapeutic approach for treating patients with MM.


Assuntos
Inibidores de Janus Quinases , Mieloma Múltiplo , Pirazóis , Humanos , Mieloma Múltiplo/patologia , Inibidores de Janus Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Nitrilas/uso terapêutico , Janus Quinases/metabolismo , Janus Quinase 2/metabolismo , Janus Quinase 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia
16.
Immunotherapy ; 16(6): 345-357, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38362641

RESUMO

Despite an increasing number of therapies for Crohn's disease (CD), half of patients do not respond to initial treatment or lose response over time, highlighting the need for novel therapies. Inhibition of Janus kinases (JAKs) has emerged as an important therapeutic target for CD. Upadacitinib is an orally administered selective JAK1 inhibitor, which is effective for the induction and maintenance of remission in moderately-to-severely active CD, including in patients with prior failure of biological therapy. Nonselective JAK inhibition has been associated with thromboembolic disease, cardiovascular events and malignancy in patients older than 50 years with rheumatoid arthritis and pre-existing cardiovascular risk factors, which should be considered upon prescription. Upadacitinib is the first and currently only oral advanced therapy for CD.


Not all patients with Crohn's disease (CD) get better with treatment. Blocking Janus kinases (JAKs), enzymes that promote inflammation in the gut, could help these patients. The treatment upadacitinib blocks JAK1 (an enzyme transmitting inflammatory signals) and decreases inflammation in the gut. It eases symptoms. It also resolves gut inflammation in patients with CD. Regarding side effects, JAK inhibitors can cause blood clots in veins, and in the lungs, heart attacks, cancer and infections. Further studies are needed, but caution is advised. Upadacitinib is the first advanced therapy for CD given by mouth.


Assuntos
Artrite Reumatoide , Doença de Crohn , Inibidores de Janus Quinases , Humanos , Doença de Crohn/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases
17.
Mol Biol Rep ; 51(1): 277, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38319443

RESUMO

BACKGROUND: The most widely used food additive monosodium glutamate (MSG) has been linked to immunopathology. Conversely, quercetin (Q), a naturally occurring flavonoid has been demonstrated to have immunomodulatory functions. Therefore, the purpose of the study is to determine if quercetin can mitigate the deleterious effects of MSG on immune cells, and the possible involvement of TLR, if any.  METHODS AND RESULTS: This study was conducted on Q, to determine how it affects the inflammatory response triggered by MSG in primary cultured thymocytes and splenocytes from rats (n = 5). Q shielded cells by augmenting cell survival and decreasing lactate dehydrogenase leakage during MSG treatment. It decreased IL-1ß, IL-6, IL-8, and TNF-α expression and release by hindering NF-kB activation and by inhibiting the JAK/STAT pathway. Moreover, Q prevented NLRP3 activation, lowered IL-1ß production, and promoted an anti-inflammatory response by increasing IL-10 production. Q reduced MSG-induced cellular stress and inflammation by acting as an agonist for PPAR-γ and LXRα, preventing NF-kB activation, and lowering MMP-9 production via increasing TIMP-1. Additionally, Q neutralized free radicals, elevated intracellular antioxidants, and impeded RIPK3, which is involved in inflammation induced by oxidative stress, TNF-α, and TLR agonists in MSG-treated cells. Furthermore, it also modulated TYK2 and the JAK/STAT pathway, which exhibited an anti-inflammatory effect. CONCLUSIONS: MSG exposure is associated with immune cell dysfunction, inflammation, and oxidative stress, and Q modulates TLR to inhibit NF-kB and JAK/STAT pathways, providing therapeutic potential. Further research is warranted to understand Q's downstream effects and explore its potential clinical applications in inflammation.


Assuntos
NF-kappa B , Transdução de Sinais , Animais , Ratos , Anti-Inflamatórios , Inflamação/induzido quimicamente , Janus Quinases , Quercetina/farmacologia , Glutamato de Sódio/toxicidade , Baço , Fatores de Transcrição STAT , Timócitos , Fator de Necrose Tumoral alfa
18.
Cancer Rep (Hoboken) ; 7(2): e1974, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38351535

RESUMO

BACKGROUND: Breast cancer is a highly prevalent disease worldwide, and early diagnosis and treatment could reduce the mortality rate of breast cancer patients. microRNAs (miRNA) have been shown to regulate the occurrences and progression of many types of cancers. Thus, it is crucial to find novel biomarkers in breast cancer. miR-449c-5p acted as a biomarker in non-small cell lung cancer, gastric carcinoma, and so forth. ERBB2 is an ideal target for breast cancer therapy. However, the molecular mechanisms between miR-449c-5p and ERBB2 in breast cancer remain poorly understood. Our study focused on the regulatory role of miR-449c-5p in breast cancer and its targeting relationship with ERBB2. METHODS: The miR-449c-5p expression in breast cancer tissue and normal tissue was searched from the online database (Starbase). The clinical prognosis of miR-449c-5p and ERBB2 was predicted by using the Kaplan-Meier analysis method. The expression of miR-449c-5p mimics and inhibitors was measured by qRT-PCR. T47D cells were transfected with miR-449c-5p mimics and miR-449c-5p inhibitors. After that, CCK-8, colony formation assays and Transwell assays were used to evaluate the cell proliferation ability, migration and invasion. Whether ERBB2 was the target gene of the miR-449c-5p was predicted by Starbase and verified by dual-luciferase activity assay. In addition, protein levels and the relationship between signalling pathways were measured and validated using western blotting analysis. RESULTS: We confirmed that miR-449c-5p was highly expressed in breast cancer tissue, and its downregulation was linked with poor prognosis. Overexpression of miR-449c-5p inhibited the proliferation, migration and invasion of breast cancer cells. ERBB2 was a target of miR-449c-5p. The invasion, migration, and proliferation of breast cancer cells were inhibited by miR-449c-5p/ERBB2 through JAK-STAT. CONCLUSION: This study demonstrated that miR-449c-5p inhibits breast cancer cell proliferation, migration and invasion by targeting ERBB2 via JAK/STAT, which means miR-449c-5p, is a potential biomarker for breast cancer and provides a novel insight for diagnosis.


Assuntos
Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Feminino , Humanos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Janus Quinases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição STAT/metabolismo
19.
J Pharmacol Exp Ther ; 389(1): 40-50, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38336380

RESUMO

B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreΔPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-CreΔPB mice with NAC in drinking water significantly reduced the frequency of CD19+ pre-B-ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by a median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared with control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. SIGNIFICANCE STATEMENT: In a mouse model of precursor B-cell acute lymphoblastic leukemia associated with high levels of reactive oxygen species, treatment with N-acetylcysteine did not delay disease progression but instead selected for leukemic clones with activating R653H mutations in Janus kinase 3.


Assuntos
Água Potável , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Camundongos , Animais , Pré-Escolar , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Janus Quinases , Taxa de Mutação , Espécies Reativas de Oxigênio/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Mutação , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Progressão da Doença
20.
Nat Commun ; 15(1): 1422, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365823

RESUMO

A novel cellular response of midgut progenitors (stem cells and enteroblasts) to Plasmodium berghei infection was investigated in Anopheles stephensi. The presence of developing oocysts triggers proliferation of midgut progenitors that is modulated by the Jak/STAT pathway and is proportional to the number of oocysts on individual midguts. The percentage of parasites in direct contact with enteroblasts increases over time, as progenitors proliferate. Silencing components of key signaling pathways through RNA interference (RNAi) that enhance proliferation of progenitor cells significantly decreased oocyst numbers, while limiting proliferation of progenitors increased oocyst survival. Live imaging revealed that enteroblasts interact directly with oocysts and eliminate them. Midgut progenitors sense the presence of Plasmodium oocysts and mount a cellular defense response that involves extensive proliferation and tissue remodeling, followed by oocysts lysis and phagocytosis of parasite remnants by enteroblasts.


Assuntos
Anopheles , Malária , Parasitos , Plasmodium , Animais , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Malária/parasitologia , Anopheles/parasitologia , Oocistos , Células-Tronco , Plasmodium berghei/fisiologia
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