RESUMEN
Inflammation is emerging as one of the hallmarks of cancer, yet its role in most tumors remains unclear. Whereas a minority of solid tumors are associated with overt inflammation, long-term treatment with non-steroidal anti-inflammatory drugs is remarkably effective in reducing cancer rate and death. This indicates that inflammation might have many as-yet-unrecognized facets, among which an indolent course might be far more prevalent than previously appreciated. In this Review, we explore the various inflammatory processes underlying the development and progression of colorectal cancer and discuss anti-inflammatory means for its prevention and treatment.
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Adenocarcinoma/inmunología , Adenoma/inmunología , Carcinogénesis/inmunología , Neoplasias Colorrectales/inmunología , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Inflamación , Enfermedades Inflamatorias del Intestino/inmunología , Mucosa Intestinal/inmunología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/prevención & control , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/prevención & control , Daño del ADN/inmunología , Progresión de la Enfermedad , Humanos , Inmunidad Innata/inmunología , Inmunidad Mucosa/inmunología , Interleucina-1beta/antagonistas & inhibidores , Quinasas Janus/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores de Interleucina-6/antagonistas & inhibidores , Factores de Transcripción STAT/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
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.
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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
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
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
Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.
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Proteínas Potenciadoras de Unión a CCAAT/genética , Inhibidores Enzimáticos/administración & dosificación , Histona Demetilasas/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores del Factor Estimulante de Colonias/genética , Factores de Transcripción STAT/metabolismo , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Femenino , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos BALB C , Receptores del Factor Estimulante de Colonias/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Transducción de Señal/efectos de los fármacosRESUMEN
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
Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC50) by â¼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.
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Inmunidad Innata/efectos de los fármacos , Inmunogenicidad Vacunal , Biosíntesis de Proteínas/efectos de los fármacos , Vacunas Sintéticas/farmacología , Proteínas del Envoltorio Viral/administración & dosificación , Animales , Línea Celular , Virus de la Encefalitis Equina Venezolana/efectos de los fármacos , Virus de la Encefalitis Equina Venezolana/inmunología , Virus de la Encefalitis Equina Venezolana/patogenicidad , Fibroblastos , Regulación de la Expresión Génica , Células HeLa , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunoglobulina G/biosíntesis , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/inmunología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/genética , Quinasas Janus/inmunología , Ratones , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , FN-kappa B/genética , FN-kappa B/inmunología , Nitrilos , Virus de la Parainfluenza 5/efectos de los fármacos , Virus de la Parainfluenza 5/inmunología , Virus de la Parainfluenza 5/patogenicidad , Pirazoles/farmacología , Pirimidinas , Conejos , Virus de la Rabia/efectos de los fármacos , Virus de la Rabia/inmunología , Virus de la Rabia/patogenicidad , Ratas , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/inmunología , Transducción de Señal , Vacunas Sintéticas/biosíntesis , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Vacunas de ARNmRESUMEN
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.
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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.
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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
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
Inflammation is not only a defense mechanism of the innate immune system against invaders, but it is also involved in the pathogenesis of many diseases such as atherosclerosis, thrombosis, diabetes, epilepsy, and many neurodegenerative disorders. The World Health Organization (WHO) reports worldwide estimates of people (9.6% in males and 18.0% in females) aged over 60 years, suffering from symptomatic osteoarthritis, and around 339 million suffering from asthma. Other chronic inflammatory diseases, such as ulcerative colitis and Crohn's disease are also highly prevalent. The existing anti-inflammatory agents, both non-steroidal and steroidal, are highly effective; however, their prolonged use is marred by the severity of associated side effects. A holistic approach to ensure patient compliance requires understanding the pathophysiology of inflammation and exploring new targets for drug development. In this regard, various intracellular cell signaling pathways and their signaling molecules have been identified to be associated with inflammation. Therefore, chemical inhibitors of these pathways may be potential candidates for novel anti-inflammatory drug approaches. This review focuses on the anti-inflammatory effect of these inhibitors (for JAK/STAT, MAPK, and mTOR pathways) describing their mechanism of action through literature search, current patents, and molecules under clinical trials.
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Acrilonitrilo/análogos & derivados , Compuestos de Anilina/uso terapéutico , Antiinflamatorios/uso terapéutico , Líquido Intracelular/efectos de los fármacos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores mTOR/uso terapéutico , Transducción de Señal/efectos de los fármacos , Acrilonitrilo/farmacología , Acrilonitrilo/uso terapéutico , Compuestos de Anilina/farmacología , Animales , Antiinflamatorios/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Líquido Intracelular/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Inhibidores mTOR/farmacología , Factores de Transcripción STAT/antagonistas & inhibidores , Transducción de Señal/fisiologíaRESUMEN
Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.
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Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Antiinflamatorios/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Mediadores de Inflamación/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Terapia Molecular Dirigida , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismoRESUMEN
Coronavirus disease 2019 (SARS-CoV2) is an active global health threat for which treatments are desperately being sought. Even though most people infected experience mild to moderate respiratory symptoms and recover with supportive care, certain vulnerable hosts develop severe clinical deterioration. While several drugs are currently being investigated in clinical trials, there are currently no approved treatments or vaccines for COVID-19 and hence there is an unmet need to explore additional therapeutic options. At least three inflammatory disorders or syndromes associated with immune dysfunction have been described in the context of cellular therapy. Specifically, Cytokine Release Syndrome (CRS), Immune Reconstitution Inflammatory Syndrome (IRIS), and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) all have clinical and laboratory characteristics in common with COVID19 and associated therapies that could be worth testing in the context of clinical trials. Here we discuss these diseases, their management, and potential applications of these treatment in the context of COVID-19. We also discuss current cellular therapies that are being evaluated for the treatment of COVID-19 and/or its associated symptoms.
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Infecciones por Coronavirus/etiología , Neumonía Viral/etiología , Corticoesteroides/uso terapéutico , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/fisiopatología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/terapia , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/etiología , Síndrome Inflamatorio de Reconstitución Inmune/terapia , Inmunización Pasiva , Interleucina-1/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Células Asesinas Naturales/inmunología , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/terapia , Pandemias , Plasmaféresis , Neumonía Viral/fisiopatología , Factores de Transcripción STAT/antagonistas & inhibidores , Tratamiento Farmacológico de COVID-19RESUMEN
After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1-7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.
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Angiotensina I/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antivirales/uso terapéutico , Azetidinas/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Quinasas Janus/genética , Metotrexato/uso terapéutico , Pandemias , Fragmentos de Péptidos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Enzima Convertidora de Angiotensina 2 , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Progresión de la Enfermedad , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/inmunología , Terapia Molecular Dirigida/métodos , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/inmunología , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , Purinas , Pirazoles , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/inmunología , SARS-CoV-2 , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: This study aimed to investigate the role of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in protection by peritoneal resuscitation (PR) using pyruvate-peritoneal dialysis solution (PY-PDS) against intestinal injury from hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Sixty-four rats were assigned to eight groups: group SHAM; group intravenous resuscitation (VR); groups NS, LA, and PY in which the rats were subjected to HS and PR with normal saline (NS), lactate-peritoneal dialysis solution (LA-PDS), and PY-PDS, respectively, combined with VR; and groups DMSO, RPM, and AG490 in which the rats were subjected to HS and VR with pretreatment of dimethyl sulfoxide (DMSO), rapamycin (RPM), and tyrphostin B42 (AG490). RESULTS: At 2 h after HS and resuscitation, the levels of diamine oxidase, 15-F2t-isoprostane, thromboxane B2, and endothelin-1, in the blood and the intestinal mucosal apoptotic index and caspase-3 were lower in groups PY, RPM, and AG490 than in groups VR, NS, LA, and DMSO. Group PY showed lower levels of malondialdehyde and myeloperoxidase and a higher level of superoxide dismutase than groups VR, NS, and LA. Phosphorylated JAK2 and phosphorylated STAT3 levels were lower in groups PY, RPM, AG490, and LA than in groups VR, NS, and DMSO. CONCLUSIONS: The protection mechanism of PR with PY-PDS combined with VR was related to the inhibition of the JAK/STAT signaling pathway during HS and resuscitation. The process might include suppression of oxidative stress, reduction of neutrophil infiltration, regulation of microcirculation, and inhibition of apoptosis.
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Enfermedades Intestinales/prevención & control , Ácido Pirúvico/uso terapéutico , Resucitación/métodos , Choque Hemorrágico/terapia , Animales , Soluciones para Diálisis , Evaluación Preclínica de Medicamentos , Enfermedades Intestinales/etiología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Masculino , Ácido Pirúvico/farmacología , Ratas , Ratas Sprague-Dawley , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/metabolismo , Choque Hemorrágico/complicaciones , Transducción de Señal/efectos de los fármacosRESUMEN
PROTACs have recently emerged as a novel paradigm in drug discovery. They can hijack existing biological machinery to selectively degrade proteins of interest, in a catalytic fashion. Here we describe the design, optimisation and biological activity of a set of novel PROTACs targeting the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) of proximal membrane-bound proteins. The JAK family proteins display membrane localisation by virtue of their association with cytoplasmic tails of cytokine receptors, and there are no reports of a successful PROTAC strategy being deployed against this class of proteins. JAK PROTACs from two distinct JAK chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing JAK1 and JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets. A number of known ligase binders were explored, and it was found that PROTACs bearing an inhibitor of apoptosis protein (IAP) ligand induced significantly more JAK degradation over Von Hippel-Lindau (VHL) and Cereblon (CRBN) PROTACs. In addition, the mechanism of action of the JAK PROTACs was elucidated, and it was confirmed that JAK degradation was both IAP- and proteasome-dependent.
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Quinasas Janus/antagonistas & inhibidores , Proteolisis/efectos de los fármacos , Pirimidinas/farmacología , Quinoxalinas/farmacología , Factores de Transcripción STAT/antagonistas & inhibidores , Ubiquitina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Quinasas Janus/metabolismo , Ligandos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Quinoxalinas/síntesis química , Quinoxalinas/química , Factores de Transcripción STAT/metabolismo , Relación Estructura-Actividad , Células THP-1 , Ubiquitina/metabolismoRESUMEN
Fucoidan has been reported to have a variety of biological activities. However, different algae species, extraction methods, harvesting seasons, and growth regions lead to the structural variation of fucoidan, which would affect the bioactivities of fucoidan. To date, the anti-inflammatory properties and the underlying mechanism of fucoidan from brown alga Saccharina japonica (S. japonica) remain limited. The aims of the present study were to investigate the structure, the anti-inflammatory properties, and the potential molecular mechanisms of fucoidan isolated from S. japonica (SF6) against lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. SF6 was characterized using high performance liquid gel permeation chromatography (HPGPC), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR), and observed to be rich in fucose, galactose, and sulfate. Additionally, results showed that SF6 remarkably inhibited LPS-induced production of various inflammatory mediators and pro-inflammation cytokines, including nitric oxide (NO), NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-ß (IL-ß), and interleukin-6 (IL-6). A mechanism study showed that SF6 could effectively inhibit inflammatory responses through blocking LPS-induced inflammation pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)-2 and signal transducer and activator of transcription (STAT)-1/3 pathways. These results suggested that SF6 has the potential to be developed as an anti-inflammatory agent applied in functional food.
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Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Janus Quinasa 2/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Polisacáridos/farmacología , Factores de Transcripción STAT/antagonistas & inhibidores , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas , Macrófagos/efectos de los fármacos , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Phaeophyceae/química , Células RAW 264.7 , Factores de Transcripción STAT/metabolismoRESUMEN
Myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive and negative. The JAK2 V617F is the most common mutation in Philadelphia negative patients and results in a constitutive activation of the JAK/STAT pathway, conferring a proliferative advantage and apoptosis inhibition. Recent studies identified a functional crosstalk between the JAK/STAT and mTOR pathways. The identification of an effective therapy is often difficult, so the availability of new therapeutic approaches might be attractive. Previous studies showed that curcumin, the active principle of the Curcuma longa, can suppress JAK2/STAT pathways in different type of cancer and injuries. In this study, we investigated the anti-proliferative and pro-apoptotic effects of curcumin in JAK2 V617F-mutated cells. HEL cell line and cells from patients JAK2 V617F mutated have been incubated with increasing concentrations of curcumin for different time. Apoptosis and proliferation were evaluated. Subsequently, JAK2/STAT and AKT/mTOR pathways were investigated at both RNA and protein levels. We found that curcumin induces apoptosis and inhibition of proliferation in HEL cells. Furthermore, we showed that curcumin inhibits JAK2/STAT and mTORC1 pathways in JAK2 V617F-mutated cells. This inhibition suggests that curcumin could represent an alternative strategy to be explored for the treatment of patients with myeloproliferative neoplasms.