RESUMEN
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.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias , Enfermedad de Parkinson , Factores de Transcripción STAT , Transducción de Señal , alfa-Sinucleína , Animales , Ratones , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/inmunología , Humanos , Ratones Transgénicos , Ratones Endogámicos C57BL , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/inmunología , Pirimidinas/farmacologíaAsunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas con Dominio LIM , Neoplasias de la Boca , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas con Dominio LIM/metabolismo , Proteínas con Dominio LIM/antagonistas & inhibidores , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Proliferación Celular/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Progresión de la Enfermedad , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.
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Síndrome de Liberación de Citoquinas , Inhibidores de las Cinasas Janus , Quinasas Janus , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Transducción de Señal/efectos de los fármacos , Citocinas/metabolismo , Animales , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidoresRESUMEN
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.
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Enfermedades Inflamatorias del Intestino , Inhibidores de las Cinasas Janus , Quinasas Janus , Factores de Transcripción STAT , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Animales , Piperidinas/uso terapéutico , Piperidinas/farmacología , Pirimidinas/uso terapéutico , Pirimidinas/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Compuestos Heterocíclicos con 3 AnillosRESUMEN
Cytokines play a crucial role in the pathophysiology of autoimmune and inflammatory diseases, with over 50 cytokines undergoing signal transduction through the Signal Transducers and Activators of Transcription (STAT) signaling pathway. Recent studies have solidly confirmed the pivotal role of STATs in autoimmune and inflammatory diseases. Therefore, this review provides a detailed summary of the immunological functions of STATs, focusing on exploring their mechanisms in various autoimmune and inflammatory diseases. Additionally, with the rapid advancement of structural biology in the field of drug discovery, many STAT inhibitors have been identified using structure-based drug design strategies. In this review, we also examine the structures of STAT proteins and compile the latest research on STAT inhibitors currently being tested in animal models and clinical trials for the treatment of immunological diseases, which emphasizes the feasibility of STATs as promising therapeutic targets and provides insights into the design of the next generation of STAT inhibitors.
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Enfermedades Autoinmunes , Inflamación , Factores de Transcripción STAT , Humanos , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/metabolismo , Animales , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Estructura MolecularRESUMEN
Rosacea is a chronic inflammatory skin disease characterized by facial erythema and telangiectasia. Despite ongoing research, the pathogenesis of rosacea remains incompletely understood, and current therapies are not entirely satisfactory. The JAK/STAT signaling pathway plays an essential role in immunoregulation, inflammation, and neurovascular regulation. Inhibition of the JAK/STAT pathway appears to hold promise as a potential therapy for rosacea. This study aimed to investigate the effects of the JAK inhibitor tofacitinib on rosacea and to preliminarily explore its therapeutic mechanism. To this end, a rosacea-like mouse model was induced using LL37 and treated with a 2% tofacitinib emulsion. The results demonstrated that topical application of tofacitinib significantly ameliorated rosacea-like phenotype, reduced the infiltration of CD4+ T cells and mast cells, and suppressed dermal angiogenesis. RT-qPCR analysis revealed a reduction in mRNA expression levels of STAT1, STAT4, and STAT5a in skin lesions following topical tofacitinib treatment. Additionally, three patients diagnosed with erythematotelangiectatic rosacea (ETR) were included in the study and treated with oral tofacitinib, leading to a significant improvement in erythema and flushing symptoms. These findings collectively suggest that tofacitinib alleviates LL37-induced rosacea-like skin inflammation in mice and rosacea skin lesions by inhibiting the JAK/STAT signaling pathway.
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Piperidinas , Pirimidinas , Rosácea , Transducción de Señal , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Administración Oral , Administración Tópica , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/administración & dosificación , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/metabolismo , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Pirimidinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Pirroles/farmacología , Pirroles/administración & dosificación , Rosácea/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Piel/patología , Piel/efectos de los fármacos , Piel/metabolismo , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factor de Transcripción STAT1/metabolismoRESUMEN
Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.
Asunto(s)
Citocinas , Quinasas Janus , Metabolismo de los Lípidos , Factores de Transcripción STAT , Células Th2 , Humanos , Citocinas/metabolismo , Epidermis/metabolismo , Epidermis/efectos de los fármacos , Ácidos Grasos/metabolismo , Interleucina-4/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Piperidinas/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Células Th2/metabolismo , Células Th2/efectos de los fármacos , Técnicas de Cultivo Tridimensional de CélulasRESUMEN
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.
Asunto(s)
Descubrimiento de Drogas , Quinasas Janus , Factores de Transcripción STAT , Transducción de Señal , Humanos , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Animales , Transducción de Señal/efectos de los fármacos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Terapia Molecular DirigidaRESUMEN
Cancer is indeed considered a hazardous and potentially life-threatening disorder. The JAK/STAT pathway is an important intracellular signaling cascade essential for many physiological functions, such as immune response, cell proliferation, and differentiation. Dysregulation of this pathway aids in the progression and development of cancer. The downstream JAK2/STAT3 signaling cascades are legitimate targets against which newer anticancer drugs can be developed to prevent and treat cancer. Understanding the mechanisms behind JAK2/STAT3 participation in cancer has paved the way for developing innovative targeted medicines with the potential to improve cancer treatment outcomes. This article provides information on the current scenario and recent advancements in the design and development of anticancer drugs targeting JAK2/STAT3, including structural analysis and SAR investigations of synthesized molecules. Numerous preclinical and clinical trials are ongoing on these inhibitors, which are highlighted to gain more insight into the broader development prospects of inhibitors of JAK2/STAT3.
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Antineoplásicos , Inhibidores de las Cinasas Janus , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Transducción de Señal , Factores de Transcripción STAT/antagonistas & inhibidores , Factor de Transcripción STAT3/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Janus kinases (JAK), a group of proteins in the nonreceptor tyrosine kinase (NRTKs) family, play a crucial role in growth, survival, and angiogenesis. They are activated by cytokines through the Janus kinase-signal transducer and activator of a transcription (JAK-STAT) signaling pathway. JAK-STAT signaling pathways have significant roles in the regulation of cell division, apoptosis, and immunity. Identification of the V617F mutation in the Janus homology 2 (JH2) domain of JAK2 leading to myeloproliferative disorders has stimulated great interest in the drug discovery community to develop JAK2-specific inhibitors. However, such inhibitors should be selective toward JAK2 over other JAKs and display an extended residence time. Recently, novel JAK2/STAT5 axis inhibitors (N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives) have displayed extended residence times (hours or longer) on target and adequate selectivity excluding JAK3. To facilitate a deeper understanding of the kinase-inhibitor interactions and advance the development of such inhibitors, we utilize a multiscale Markovian milestoning with Voronoi tessellations (MMVT) approach within the Simulation-Enabled Estimation of Kinetic Rates v.2 (SEEKR2) program to rank order these inhibitors based on their kinetic properties and further explain the selectivity of JAK2 inhibitors over JAK3. Our approach investigates the kinetic and thermodynamic properties of JAK-inhibitor complexes in a user-friendly, fast, efficient, and accurate manner compared to other brute force and hybrid-enhanced sampling approaches.
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Antineoplásicos , Inhibidores de las Cinasas Janus , Citocinas , Janus Quinasa 2 , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Transducción de Señal , Factores de Transcripción STAT/antagonistas & inhibidoresRESUMEN
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in many immunological processes, including cell growth, proliferation, differentiation, apoptosis, and inflammatory responses. Some of these processes can contribute to cancer progression and neurodegeneration. Owing to the complexity of this pathway and its potential crosstalk with alternative pathways, monotherapy as targeted therapy has usually limited long-term efficacy. Currently, the majority of JAK-STAT-targeting drugs are still at preclinical stages. Meanwhile, a variety of plant polyphenols, especially quercetin, exert their inhibitory effects on the JAK-STAT pathway through known and unknown mechanisms. Quercetin has shown prominent inhibitory effects on the JAK-STAT pathway in terms of anti-inflammatory and antitumor activity, as well as control of neurodegenerative diseases. This review discusses the pharmacological effects of quercetin on the JAK-STAT signaling pathway in solid tumors and neurodegenerative diseases.
Asunto(s)
Inhibidores de las Cinasas Janus , Neoplasias , Enfermedades Neurodegenerativas , Humanos , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Quinasas Janus/farmacología , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Quercetina/farmacología , Quercetina/uso terapéutico , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/farmacología , Transducción de SeñalRESUMEN
Canine atopic dermatitis (AD) is a common chronic inflammatory skin disorder resulting from imbalance between T lymphocytes. Current canine AD treatments use immunomodulatory drugs, but some of the dogs have limitations that do not respond to standard treatment, or relapse after a period of time. Thus, the purpose of this study was to evaluate the immunomodulatory effect of mesenchymal stem cells derived from canine adipose tissue (cASCs) and cASCs-derived extracellular vesicles (cASC-EVs) on AD. First, we isolated and characterized cASCs and cASCs-EVs to use for the improvement of canine atopic dermatitis. Here, we investigated the effect of cASCs or cASC-EVs on DNCB-induced AD in mice, before using for canine AD. Interestingly, we found that cASCs and cASC-EVs improved AD-like dermatitis, and markedly decreased levels of serum IgE, (49.6%, p = 0.002 and 32.1%, p = 0.016 respectively) epidermal inflammatory cytokines and chemokines, such as IL-4 (32%, p = 0.197 and 44%, p = 0.094 respectively), IL-13 (47.4%, p = 0.163, and 50.0%, p = 0.039 respectively), IL-31 (64.3%, p = 0.030 and 76.2%, p = 0.016 respectively), RANTES (66.7%, p = 0.002 and 55.6%, p = 0.007) and TARC (64%, p = 0.016 and 86%, p = 0.010 respectively). In addition, cASCs or cASC-EVs promoted skin barrier repair by restoring transepidermal water loss, enhancing stratum corneum hydration and upregulating the expression levels of epidermal differentiation proteins. Moreover, cASCs or cASC-EVs reduced IL-31/TRPA1-mediated pruritus and activation of JAK/STAT signaling pathway. Taken together, these results suggest the potential of cASCs or cASC-EVs for the treatment of chronic inflammation and damaged skin barrier in AD or canine AD.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Dermatitis Atópica , Vesículas Extracelulares , Inflamación , Células Madre Mesenquimatosas , Prurito , Tejido Adiposo/metabolismo , Animales , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Citocinas/metabolismo , Dermatitis Atópica/terapia , Perros , Vesículas Extracelulares/metabolismo , Inflamación/metabolismo , Inflamación/terapia , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/uso terapéutico , Células Madre Mesenquimatosas/metabolismo , Ratones , Prurito/metabolismo , Prurito/terapia , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/uso terapéutico , Transducción de Señal , Piel/metabolismoRESUMEN
The therapeutic benefits of immune checkpoint inhibitors (ICIs), which enable antitumor immune responses, can be tempered by unwanted immune-related adverse events (irAEs). Treatment recommendations stratified by irAE phenotype and immunohistopathological findings have only recently been proposed and are often based on those used in primary autoimmune diseases, including targeting of specific proinflammatory cytokines with monoclonal antibodies. Increasing evidence supports the use of such antibody-based strategies as effective steroid-sparing treatments, although the therapies themselves may be associated with additional drug toxicities and reduced ICI efficacy. Kinases are key contributors to the adaptive and innate responses that drive primary autoimmune diseases and irAEs. The janus kinase/signal transducer and activator of transcription, Bruton's tyrosine kinase, and mitogen-activated protein kinase-interacting serine/threonine protein kinases 1 and 2 pathways are also critical to tumor progression and have important roles in cells of the tumor microenvironment. Herein, we review the histopathological, biological, and clinical evidence to support specific monoclonal antibodies and kinase inhibition as management strategies for irAEs.
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Anticuerpos Monoclonales/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Enfermedades Autoinmunes/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Neoplasias/inmunología , Factores de Transcripción STAT/antagonistas & inhibidores , Microambiente TumoralRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disorder and the treatment involves the use of traditional and biological disease modifying anti-rheumatic drugs (DMARDs). Recent studies have shown JAK/STAT signaling pathway as potential target for the treatment of RA. Novel JAK/STAT inhibitors viz tofacitinib and baricitinib have been recently approved by FDA for RA treatment and have attained substantial importance. However, the discernible risks of thromboembolism, gastrointestinal (GIT) perforations, hepatotoxicity and serious infections including tuberculosis, herpes zoster associated with their administration cannot be overlooked. Furthermore, these are highly expensive which limits their application for a broader use. These limitations provide the basis of exploring novel JAK/STAT inhibitors of natural origin with increased tolerability, safety and cost-effectiveness. In this review we confer an account of various natural compounds/phytochemicals that have proved to be beneficial in attenuating inflammation in RA via modulation of JAK/STAT signaling pathway. Some of these natural compounds including resveratrol have clearly indicated biochemical and clinically significant therapeutic effects in ameliorating RA both in vivo and in clinical settings. We further discuss the physicochemical challenges of poor solubility and absorption coupled with the use of natural JAK/STAT inhibitors. We thereafter discuss and summarize various drug delivery systems (DDS) to confront the physicochemical limitations of natural JAK/STAT inhibitors with the aim to enhance the therapeutic efficacy. Overall the review unveils the potential of natural JAK/STAT inhibitors as a cost-effective approach in ameliorating RA without incorporating the risks of adverse repercussions, thus setting the stage for clinical exploration of these compounds that may possibly complement the present RA therapy.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de las Cinasas Janus/administración & dosificación , Quinasas Janus/antagonistas & inhibidores , Fitoquímicos/administración & dosificación , Factores de Transcripción STAT/antagonistas & inhibidores , Artritis Reumatoide/metabolismo , Predicción , Humanos , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Resultado del TratamientoRESUMEN
Baicalin has distinct therapeutic effects in various skin diseases animal models such as atopic dermatitis (AD) and psoriasis. In this study, we aimed to investigate the anti-atopic dermatitis (AD) effects of baicalin in 2,4-dinitrochlorobenzene (DNCB)-treated mice. Female BALB/c mice treated with DNCB to induce AD-like skin lesions and orally administrated with baicalin daily for 14 consecutive days. Baicalin significantly inhibited dorsal skin thickness and trans-epidermal water loss and epidermal thickness in dorsal skin. In addition, baicalin also significantly up-regulated the protein expressions of filaggrin, involucrin, and loricrin, but inhibited the inflammatory response and the activation of NF-κB and JAK/STAT pathways in the dorsal skin of the DNCB-treated mice. Furthermore, baicalin significantly restored the abundance of probiotics in the gut microbiota of the DNCB-treated mice. Pseudo germ-free (GF) DNCB-treated mice receiving fecal microbiota from baicalin donors reduced the dorsal skin thickness and skin EASI score, and inhibited the release of IgE, histamine, TNF-α and IL-4 in serum of mice. In summary, baicalin ameliorates AD-like skin lesions induced by DNCB in mice via regulation of the Th1/Th2 balance, improvement of skin barrier function and modulation of gut dysbiosis, and inhibition of inflammation through suppressing the activation of NF-κB and JAK/STAT pathways.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Dermatitis Atópica/tratamiento farmacológico , Flavonoides/farmacología , Piel/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Dermatitis Atópica/inducido químicamente , Dinitroclorobenceno , Relación Dosis-Respuesta a Droga , Femenino , Flavonoides/química , Flavonoides/aislamiento & purificación , Microbioma Gastrointestinal/efectos de los fármacos , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Raíces de Plantas/química , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Scutellaria baicalensis/química , Piel/metabolismo , Piel/patología , Relación Estructura-ActividadRESUMEN
Diabetic nephropathy (DN) is a complication of diabetes, which leads to most end-stage kidney diseases and threatens health of patients. Mucin 1 (MUC1) is a heterodimeric oncoprotein, which is abnormally expressed in tumors and hematologic diseases. The aim of this study is to clarify the mechanism and role of MUC1 in DN. The mesangial cells (MCs) suffered from high glucose (HG) treatment to mimic DN in vitro. The cell proliferation was detected by Cell Counting Kit-8 assay and 5-ethynyl-2-deoxyuridine (EdU) staining assay. The expression of MUC1 and fibrosis markers: fibronectin, collagen I, and collagen IV were assessed by western blot. In this study, we demonstrated that HG treatment induced MUC1 expression in MCs. With knockdown of MUC1 or overexpressed MUC1 in MCs, the results indicated that knockdown of MUC1 inhibited MCs proliferation and reduced kidney fibrosis markers expression, including fibronectin, collagen I, and collagen IV, whereas overexpression of MUC1 led to opposite results. Mechanically, MUC1 activated signal transducers and activators of transcription (STAT) and ß-catenin signal pathway. After added AG490 (STAT inhibitor) or FH535 (ß-catenin inhibitor), blocking STAT3 and ß-catenin signal pathway attenuated MUC1-induced cell proliferation and fibronectin production in MCs. Finally, knockdown of MUC1 attenuated DN-induced kidney fibrosis in db/db mice. Therapeutic target for DN. In conclusion, MUC1 promotes MCs proliferation and kidney fibrosis in DN through activating STAT and ß-catenin signal pathway, which can help to provide a novel therapeutic target for DN.
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Proliferación Celular , Nefropatías Diabéticas/metabolismo , Células Mesangiales/metabolismo , Mucina-1/metabolismo , Transducción de Señal , Animales , Células Cultivadas , Fibronectinas/metabolismo , Fibrosis , Riñón/metabolismo , Riñón/patología , Masculino , Células Mesangiales/fisiología , Ratones , Ratones Endogámicos C57BL , Mucina-1/genética , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Sulfonamidas/farmacología , Tirfostinos/farmacología , beta Catenina/antagonistas & inhibidores , beta Catenina/metabolismoRESUMEN
Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.
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Antirreumáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Factor Inhibidor de Leucemia/farmacología , Mutación , Retina/efectos de los fármacos , Retinitis Pigmentosa/tratamiento farmacológico , Rodopsina/genética , Sustitución de Aminoácidos , Animales , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Expresión Génica , Técnicas de Sustitución del Gen , Humanos , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/genética , Quinasas Janus/inmunología , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/patología , FN-kappa B/genética , FN-kappa B/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Retina/inmunología , Retina/patología , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/inmunología , Retinitis Pigmentosa/patología , Rodopsina/deficiencia , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/inmunología , Transducción de Señal , Transgenes , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Janus kinase/signal transduction and transcriptional activator (JAK/STAT) signaling pathway is a transport hub for cytokine secretion and exerts its effects. The activation of JAK/STAT signaling pathway is essential for the regulation of inflammatory responses. Inappropriate activation or deletion of JAK/STAT signaling pathway is the initiator of the inflammatory response. JAK/STAT signaling pathway has been demonstrated to be involved in the process of innate and adaptive immune response to inflammatory bowel disease (IBD). In this review, we discuss the role of the JAK/STAT signaling pathway in the regulation of different cells in IBD, as well as new findings on the involvement of the JAK/STAT signaling pathway in the regulation of the intestinal immune response. The current status of JAK inhibitors in the treatment of IBD is summarized as well. This review highlights natural remedies that can serve as potential JAK inhibitors. These phytochemicals may be useful in the identification of precursor compounds in the process of designing and developing novel JAK inhibitors.
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Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Animales , Productos Biológicos/uso terapéutico , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Factores de Transcripción STAT/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor ß1 (TGF-ß1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders.
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Quinasas Janus/metabolismo , Enfermedades Pulmonares Intersticiales/patología , Factores de Transcripción STAT/metabolismo , Senescencia Celular , Estrés del Retículo Endoplásmico , Humanos , Interleucinas/metabolismo , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/genética , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Transducción de SeñalRESUMEN
Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity. Methods: Primary PsAFLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of Oncostatin M (OSM). pSTAT3 expression in response to OSM was quantified by Western Blot analysis. Pro-inflammatory cytokines/chemokines were quantified by ELISA and cell migration by wound-repair scratch assays. Invasive capacity was examined using Matrigel™ invasion chambers and MMP multiplex MSD assays. PsAFLS bioenergetics was assessed using the Seahorse XFe Extracellular Flux Analyzer, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and oxidative phosphorylation (OCR). In parallel, inflammatory, invasive, and migratory genes were quantified by RT-PCR. Results: OSM induces pSTAT3 expression in PsAFLS. OSM-induced secretion of MCP-1 and IL-6 was inhibited by all JAKi with Peficitinib, Baricitinib and Upadacitinib showing the greatest effect. In contrast, JAKi had no significant impact on IL-8 expression in response to OSM. PsAFLS cell invasion, migratory capacity and MMP1, 3, and 9 were suppressed following JAKi treatment, with Peficitinib showing the greatest effect. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsAFLS, where JAKi significantly decreased glycolysis and the ECAR/OCR, resulting in a shift to a more quiescent phenotype, with Peficitinib demonstrating the most pronounced effect. Conclusion: This study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis. This inhibition shows effective suppression of inflammatory mechanisms that drive pathogenic functions of PsAFLS, further supporting the role of JAKi as a therapeutic target for the treatment of PsA.