ABSTRACT
Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.
Subject(s)
Humans , Carcinoma, Squamous Cell/pathology , DNA , Down-Regulation , Flap Endonucleases/metabolism , Head and Neck Neoplasms , Interferon-gamma/metabolism , Mouth Neoplasms/pathology , Phenotype , Squamous Cell Carcinoma of Head and Neck , Tumor Microenvironment , Janus Kinases/metabolismABSTRACT
Purpose: To investigate the role of cyanidin-3-O-glucoside (C3G) in renal ischemia/reperfusion (I/R) injury and the potential mechanisms. Methods: Mouse models were established by clamping the left renal vessels, and in vitro cellular models were established by hypoxic reoxygenation. Results: Renal dysfunction and tissue structural damage were significantly higher in the I/R group. After treatment with different concentrations of C3G, the levels of renal dysfunction and tissue structural damage decreased at different levels. And its protective effect was most pronounced at 200 mg/kg. The use of C3G reduced apoptosis as well as the expression of endoplasmic reticulum stress (ERS)-related proteins. Hypoxia/reoxygenation (H/R)-induced apoptosis and ERS are dependent on oxidative stress in vitro. In addition, both AG490 and C3G inhibited the activation of JAK/STAT pathway and attenuated oxidative stress, ischemia-induced apoptosis and ERS. Conclusions: The results demonstrated that C3G blocked renal apoptosis and ERS protein expression by preventing reactive oxygen species (ROS) production after I/R via the JAK/STAT pathway, suggesting that C3G may be a potential therapeutic agent for renal I/R injury.
Subject(s)
Animals , Mice , Reperfusion Injury , MAP Kinase Signaling System , Janus Kinases , Acute Kidney Injury/physiopathology , Ischemia , Anthocyanins/analysisABSTRACT
CONTEXTO: Mielofibrose é uma neoplasia maligna rara que pode se desenvolver como doença primária, sendo uma doença mieloproliferativa crônica caracterizada pela falha da medula óssea e proliferação clonal de células mieloides associada com excesso de fibras de reticulina e/ou colágeno, e algum grau de atipia no megacariócito. O quadro clínico pode evoluir com esplenomegalia, anemia, sintomas constitucional (fadiga, sudorese noturna, febre), caquexia, dor óssea, infarto esplênico, prurido, trombose e sangramentos. A incidência na União Europeia e EUA é de 0,3 casos por 100.000 habitantes. Não há dados epidemiológicos robustos no Brasil. Ruxolitinibe é um inibidor seletivo das Janus Quinases associadas (JAKs) JAK1 e JAK2. A desregulação da via JAK-STAT tem sido associada a vários tipos de câncer e aumento da proliferação e sobrevida de células malignas. TECNOLOGIA: Ruxolitinibe. PERGUNTA: O uso de ruxolitinibe no tratamento da mielofibrose risco intermediário-2 ou alto (classificação IPSS), em adultos, com contagem plaquetária acima de 100.000/mm3 é eficaz e seguro quando comprado ao
Subject(s)
Humans , Janus Kinases/antagonists & inhibitors , Primary Myelofibrosis/drug therapy , Unified Health System , Brazil , Cost-Benefit Analysis/economicsABSTRACT
INTRODUÇÃO: O baricitinbe, um imunomodulador que atua sobre a atividade da IL-6 (citocina pró-inflamatória), pode representar uma estratégia para o tratamento de pacientes com COVID-19 que tiveram comprometimento pulmonar devido a resposta hiperinflamátoria desencadeada pela tempestade de citocinas característica na infecção causada pelo vírus SARS-COV2. TECNOLOGIA: Baricitinibe (Olumiant®). EVIDÊNCIAS CLÍNICAS: Para seleção das evidências clínicas foi conduzida uma revisão sistemática da literatura em busca de ensaios clínicos randomizados (ECR), estudos observacionais (mundo real) e revisões sistemáticas que avaliassem os efeitos do baricitinibe como monoterapia ou associado aos cuidados usuais - definidos aqui como 'terapia padrão' (corticoesteróides sistêmicos, anticoagulantes, antimicrobianos/antivirais) no tratamento de pacientes adultos com COVID-19, hospitalizados e que necessitam de suplementação de oxigênio (máscara ou cateter nasal, alto fluxo de oxigênio ou ventilação não invasiva). As buscas eletrônicas foram realizadas nas bases de dados: the Cochrane Library, MEDLINE via Pubmed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), EMBASE e Centre for Reviews and Dissemination (CRD). O risco de viés dos estudos primários incluídos foi avaliado pelas ferramentas Risk of Bias versão 2 da Cochrane (para ECR) ou ROBINS-I (para estudos observacionais), e a qualidade metodológica das revisões sistemáticas foi avaliada pela ferramenta AMSTAR-2. A qualidade da evidência foi avaliada pelo sistema GRADE. Seis artigos foram incluídos na presente revisão, sendo dois deles referentes a um ensaio clínico randomizado (ECR), um estudo observacional e três revisões sistemáticas com meta-análise (RSMA), sendo uma
Subject(s)
Humans , Oxygen Inhalation Therapy/instrumentation , Janus Kinases/antagonists & inhibitors , Noninvasive Ventilation/instrumentation , SARS-CoV-2/drug effects , COVID-19/drug therapy , Immunosuppressive Agents/antagonists & inhibitors , Unified Health System , Brazil , Cost-Benefit Analysis/economics , InpatientsABSTRACT
Tofacitinib is a Janus kinase inhibitor and can block the Janus kinase-signal transducer and activator of transcription signal transduction pathway and reduce the production and release of a variety of cytokines. It has great potential in the treatment of various rheumatic diseases with a rapid onset of action and can reduce corticosteroid dependence and related adverse events. The therapeutic effect of tofacitinib in adult patients has been confirmed, and it has been increasingly used in pediatric patients in recent years. This article reviews the clinical application of tofacitinib in the treatment of pediatric autoimmune diseases.
Subject(s)
Adult , Child , Humans , Janus Kinases/metabolism , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Rheumatic Diseases/drug therapyABSTRACT
OBJECTIVES: TTP488, an antagonist of the receptor for advanced glycation end-products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). However, the mechanism underlying the protective action of TTP488 against AD has not yet been fully explored. METHODS: Healthy male rats were exposed to aberrant amyloid β (Aβ) 1-42. Lipopolysaccharide (LPS) and the NOD-like receptor family pyrin domain containing 1 (NLRP1) overexpression lentivirus were injected to activate the NLRP1 inflammasome and exacerbate AD. TTP488 was administered to reverse AD injury. Finally, tofacitinib and fludarabine were used to inhibit the activity of Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) to prove the relationship between the JAK/STAT signaling pathway and TTP488. RESULTS: LPS and NLRP1 overexpression significantly increased the NLRP1 levels, reduced neurological function, and aggravated neuronal damage, as demonstrated by the impact latency time of, time spent by, and length of the platform covered by, the mice in the Morris water maze assay, Nissl staining, and immunofluorescence staining in rats with AD. CONCLUSIONS: TTP488 administration successfully reduced AD injury and reversed the aforementioned processes. Additionally, tofacitinib and fludarabine administration could further reverse AD injury after the TTP488 intervention. These results suggest a new potential mechanism underlying the TTP488-mediated alleviation of AD injury.
Subject(s)
Animals , Male , Mice , Rats , Janus Kinases/metabolism , Alzheimer Disease/drug therapy , Tyrosine , Transducers , Signal Transduction , Amyloid beta-Peptides , Janus Kinase 2 , Receptor for Advanced Glycation End Products , ImidazolesABSTRACT
BACKGROUND: Kidney ischemia-reperfusion injury is a common pathophysiological phenomenon in the clinic. A large number of studies have found that the tyrosine protein kinase/signal transducer and activator of transcription (JAK/STAT) pathway is involved in the development of a variety of kidney diseases and renal protection associated with multiple drugs. Edaravone (EDA) is an effective free radical scavenger that has been used clinically for the treatment of postischemic neuronal injury. This study aimed to identify whether EDA improved kidney function in rats with ischemia-reperfusion injury by regulating the JAK/STAT pathway and clarify the underlying mechanism. METHODS: Histomorphological analysis was used to assess pathological kidney injury, and mitochondrial damage was observed by transmission electron microscopy. Terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) staining was performed to detect tubular epithelial cell apoptosis. The expression of JAK2, P-JAK2, STAT3, P-STAT3, STAT1, P-STAT1, BAX and Bcl-2 was assessed by western blotting. Mitochondrial function in the kidney was assessed by mitochondrial membrane potential (ΔψM) measurement. RESULTS: The results showed that EDA inhibited the expression of p-JAK2, p-STAT3 and p-STAT1, accompanied by downregulation of the expression of Bax and caspase-3, and significantly ameliorated kidney damage caused by ischemia-reperfusion injury (IRI). Furthermore, the JC-1 dye assay showed that edaravone attenuated ischemia-reperfusion-induced loss of kidney (ΔψM). CONCLUSION: Our findings indicate that EDA protects against kidney damage caused by ischemia-reperfusion through JAK/STAT signaling, inhibiting apoptosis and improving mitochondrial injury.
Subject(s)
Animals , Male , Rats , Reperfusion Injury/drug therapy , Free Radical Scavengers/pharmacology , Edaravone/pharmacology , Signal Transduction/drug effects , Rats, Sprague-Dawley , Apoptosis , STAT Transcription Factors/drug effects , Janus Kinases/drug effects , MitochondriaABSTRACT
RESUMEN La artritis reumatoide (AR) es una enfermedad sistémica que en las últimas décadas ha tenido múltiples opciones terapéuticas. Con la información disponible en la literatura no se recomienda el uso de terapia biológica en pacientes con enfermedad pulmonar difusa, dado que estos medicamentos pueden exacerbar el compromiso pulmonar. Un medicamento de más reciente aparición es el inhibidor de la enzima Janus quinasa, el cual es una opción terapéutica en monoterapia o combinado para pacientes con AR en moderada y alta actividad de la enfermedad, con contraindicación al uso de FARME sintéticos o biológicos, y en pacientes con fallo terapéutico, no obstante, su seguridad a nivel pulmonar no ha sido evaluada en ensayos clínicos y la información disponible es escasa. Describimos el tratamiento, seguimiento y resultados del uso de tofacitinib en 4 pacientes con enfermedad pulmonar secundaria a AR en una serie de casos.
ABSTRACT Rheumatoid arthritis (RA) is a systemic disease for which multiple therapeutic options have been developed in the last decades. Based on the information available in the literature, the use of biological therapy in patients with diffuse lung disease is not recommended because these medications can exacerbate the lung disease. A newer drug is the Janus kinase enzyme inhibitor, which can be used as monotherapy or in combination in patients with moderate to high activity RA, in whom the use of synthetic or biological DMARDs is contraindicated, as well as in patients with therapeutic failure. However, the pulmonary safety of the drug has not been evaluated in clinical trials and the information available is limited. This article discusses the treatment, follow-up, and outcomes of the use of tofacitinib in a series of 4 patients with lung disease secondary to RA.
Subject(s)
Humans , Middle Aged , Aged , Arthritis, Rheumatoid , Biological Therapy , Janus Kinases , Lung DiseasesABSTRACT
Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is one of the downstream pathways of cytokine signaling transduction. It regulates cell development, differentiation, proliferation, apoptosis and so on. The pathway is not only involved in the regulation of normal physiological processes, but also significant in the development of tumors, especially in hematologic malignancies. In recent years, with the further research of JAK/STAT signaling pathway, it has been found that the pathway also plays a key role in the development of solid tumors. Here we reviewed the research advances of JAK/STAT signaling pathway in lung cancer, especially the mechanisms of development, metastasis and drug resistance, and the application of inhibitors which targeting JAK/STAT signaling pathway in the treatment of lung cancer. .
Subject(s)
Animals , Humans , Antineoplastic Agents , Therapeutic Uses , Biomedical Research , Methods , Janus Kinases , Metabolism , Lung Neoplasms , Drug Therapy , Metabolism , Pathology , Neoplasm Metastasis , STAT Transcription Factors , Metabolism , Signal TransductionABSTRACT
<p><b>OBJECTIVES</b>To investigate the mechanism of Liuwei Dihuang Pill (, LDP) in treating postmenopausal osteoporosis (PMOP) with Shen (Kidney) yin deficiency.</p><p><b>METHODS</b>In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group (Group A), PMOP Shen-yang deficiency group (Group B), PMOP without Shen deficiency group (Group C), and control group (Group N). Real-time polymerase chain reaction (RT-PCR) and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 (CLCF1), ankyrin repeat and SOCS box containing 1 (ASB1), and prokineticin 2 (PROK2) genes and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway.</p><p><b>RESULTS</b>The mRNA (P<0.05) and protein (P<0.01) expression levels of the CLCF1 gene in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gene were obviously up-regulated (P<0.01). After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated (both P<0.01), and the average bone density of the top femur had significantly increased (P<0.05). In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3.</p><p><b>CONCLUSIONS</b>The CLCF1 gene is an important gene associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gene expression and activation of the JAK/STAT signaling pathway.</p>
Subject(s)
Female , Humans , Middle Aged , Cytokines , Genetics , Metabolism , Drugs, Chinese Herbal , Pharmacology , Therapeutic Uses , Gene Expression Regulation , Janus Kinases , Metabolism , Osteoporosis, Postmenopausal , Drug Therapy , Genetics , RNA, Messenger , Genetics , Metabolism , STAT Transcription Factors , Metabolism , Signal Transduction , Up-Regulation , Yin Deficiency , Drug Therapy , GeneticsABSTRACT
Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects the joints. This chronic inflammatory condition causes joint destruction and functional disability, and reduces the quality of life of patients. Therefore, the aims of RA treatment are to control a patient's symptoms by decreasing the inflammation, to prevent joint damage, and to maintain the patient's quality of life while minimizing the progress of the disease. In recent years, the early initiation of disease-modifying anti-rheumatic drugs (DMARDs) has been emphasized because a window of opportunity is thought to exist in early RA, when the disease is more responsive to treatment. Recently, the treat-to-target strategy for RA treatment has also been suggested. This strategy involves setting a goal such as remission or low disease state, implementing strict monitoring, and switching the medication regimen promptly as needed. Currently, several DMARDs are available to manage RA. DMARDs form two major classes: synthetic chemical compounds (sDMARDs) and biological agents (bDMARDs), which target specific pro-inflammatory cytokines to prevent inflammation. This review summarizes the effectiveness and safety of the current DMARDs available for RA treatment. Tumor necrosis factor inhibitors, T cell costimulation inhibitor, an anti-B cell agent, and the interleukin 6 receptor-blocking monoclonal antibody are classified as bDMARDs. Tofacitinib, a new sDMARD specifically designed to target janus kinases, is also discussed in this article.
Subject(s)
Humans , Antirheumatic Agents , Arthritis, Rheumatoid , Biological Factors , Cytokines , Drug Therapy , Inflammation , Interleukin-6 , Janus Kinases , Joints , Quality of Life , Tumor Necrosis Factor-alphaABSTRACT
Although there have been substantial advances in confirming diagnoses and defining the molecular characteristics of polycythemia vera (PV) and essential thrombocythemia (ET), treatments for these conditions remain elementary. The main goal is still mainly focused on reducing the risk of thrombosis. The prevention of hemorrhage, leukemia transformation, and progression to myelofibrosis has yet to be established. To reduce the risk of thrombosis, risk-adapted treatment is recommended. Phlebotomy is the most important and effective treatment modality for patients with erythrocytosis, while cytoreduction using hydroxyurea, busulfan, or interferon-α is an ancillary treatment for patients at high risk for thrombosis. Anagrelide is used to decrease platelet counts in patients with thrombocytosis by inhibiting the maturation of platelets from megakaryocytes. Recent trials have shown that ruxolitinib, a Janus kinase (JAK) inhibitor, has clinical benefits in patients with polycythemia vera who show an inadequate response, or unacceptable side effects, to therapeutic doses of hydroxyurea. Theoretically, JAK inhibitors may also delay the progression of leukemia transformation and myelofibrosis but there is still no evidence of this. The cost of JAK inhibitors for the treatment of patients with PV/ET is a difficult hurdle for its use as a first-line treatment.
Subject(s)
Humans , Busulfan , Diagnosis , Hemorrhage , Hydroxyurea , Janus Kinases , Leukemia , Megakaryocytes , Phlebotomy , Phosphotransferases , Platelet Count , Polycythemia Vera , Polycythemia , Primary Myelofibrosis , Thrombocythemia, Essential , Thrombocytosis , ThrombosisABSTRACT
Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of clonal expansion of cytotoxic T- or NK-cells in blood and bone marrow, and often associated with autoimmune disorders. According to the current WHO classification of the hematopoietic and lymphoid tissue tumors, the clonal LGL expansions are further classified as T-cell large granular lymphocytic leukemia (T-LGLL), chronic lymphoproliferative disorders of NK cells (CLPD-NK) and aggressive NK cell leukemia. Since there is a general lack of awareness of this disease, some patients may be misdiagnosed or some cases may be missed when diagnosis was done. At present, the pathogenesis of LGLL remains incomplete and unclear, and the therapeutic effects are unsatisfactory. For this reason, it is necessary to find prognostic marks and therapeutic targets of this disease. The constitutive activation of JAK/STAT pathway has been claimed to be involved in the development of LGLL. Recently, the somatic mutations in the SH2 domain of STAT3 in LGLL are frequently observed, which lead to the activation of JAK/STAT pathway. STAT3 is the first molecular markers that are highly specific for LGLL, and STAT3 mutations have been rarely detected in other tumor types studied, thus the STAT3 mutations can be used as molecular markers for LGLL diagnosis and can provide a novel therapeutic target for patients with LGLL.
Subject(s)
Humans , Janus Kinases , Genetics , Metabolism , Leukemia, Large Granular Lymphocytic , Genetics , Metabolism , Mutation , STAT3 Transcription Factor , Genetics , Metabolism , Signal TransductionABSTRACT
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaive, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.
Subject(s)
Humans , Administration, Oral , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/diagnosis , Biological Products/administration & dosage , Disability Evaluation , Drug Administration Schedule , Janus Kinases/antagonists & inhibitors , Molecular Targeted Therapy , Predictive Value of Tests , Protein Kinase Inhibitors/administration & dosage , Recovery of Function , Remission Induction , Signal Transduction/drug effects , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are being investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are being used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage.
Subject(s)
Humans , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Biological Factors/therapeutic use , Cell Adhesion Molecules/antagonists & inhibitors , Colitis, Ulcerative/drug therapy , Janus Kinases/antagonists & inhibitors , Piperidines/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic useABSTRACT
BACKGROUND: Carbon tetrachloride (CCl4) induces hepatotoxicity in animal models, including the increased blood flow and cytokine accumulation that are characteristic of tissue inflammation. The present study investigates the hepato-protective effect of rutin on CCl4-induced hepatotoxicity in rats. RESULTS: Forty male Wistar rats were divided into four groups. Group I (control group) received 1 mL/kg of dimethyl sulfoxide intragastrically and 3 mL/kg olive oil intraperitoneally twice a week for 4 weeks. Group II received 70 mg/ kg rutin intragastrically. Groups III and IV received CCl4 (3 mL/kg, 30 % in olive oil) intraperitoneally twice a week for 4 weeks. Group IV received 70 mg/kg rutin intragastrically after 48 h of CCl4 treatment. Liver enzyme levels were determined in all studied groups. Expression of the following genes were monitored with real-time PCR: interleukin-6 (IL-6), dual-specificity protein kinase 5 (MEK5), Fas-associated death domain protein (FADD), epidermal growth factor (EGF), signal transducer and activator of transcription 3 (STAT3), Janus kinase (JAK), B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra-large (Bcl-XL). The CCl4 groups showed significant increases in biochemical markers of hepatotoxicity and up-regulation of expression levels of IL-6, Bcl-XL, MEK5, FADD, EGF, STAT3 and JAK compared with the control group. However, CCl4 administration resulted in significant down-regulation of Bcl2 expression compared with the control group. Interestingly, rutin supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. CONCLUSION: CCl4 administration causes alteration in expression of IL-6/STAT3 pathway genes, resulting in hepatotoxicity. Rutin protects against CCl4-induced hepatotoxicity by reversing these expression changes.
Subject(s)
Animals , Male , Rats , Rutin/pharmacology , Signal Transduction/drug effects , Interleukin-6/metabolism , STAT3 Transcription Factor/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Aspartate Aminotransferases/blood , Carbon Tetrachloride , Biomarkers , Gene Expression/drug effects , Rats, Wistar , Proto-Oncogene Proteins c-bcl-2/metabolism , Protective Agents/pharmacology , MAP Kinase Kinase 5/metabolism , Alanine Transaminase/blood , Epidermal Growth Factor/metabolism , bcl-X Protein/metabolism , Janus Kinases/metabolism , Fas-Associated Death Domain Protein/metabolism , Real-Time Polymerase Chain Reaction , Liver/drug effectsABSTRACT
Inflammation is a part of the complex biological responses of a tissue to injury that protect the organ by removing injurious stimuli and initiating the healing process, and is considered as a mechanism of innate immunity. To identify biologically active compounds against pathogenic inflammatory and immune responses, we fractionated water, aqueous methanol and n-hexane layers from nine kinds of leguminosae and examined anti-inflammatory activity of the fractions in human keratinocytes and mouse skin. Among the fractions, rf3 and rf4, isolated from the aqueous methanol layer of Astragalus sinicus L., exhibited the strongest reactive oxygen species (ROS)-scavenging and anti-inflammatory activities as measured by inhibition of the intracellular ROS production, nuclear factor-kappaB (NF-kappaB), janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphatidylinositol 3-kinase/Akt signaling in cytokine-stimulated human keratinocytes, as well as by effects on T-cell differentiation in mouse CD4+ T cells. In addition, topical application of rf3 and rf4 suppressed the progression of psoriasis-like dermatitis and expression of pro-inflammatory mediators in interleukin (IL)-23-injected mouse ears. Our results suggest that Astragalus sinicus L. may ameliorate chronic inflammatory skin diseases due to its antioxidant and anti-inflammatory activities via regulation of the intracellular ROS production, NF-kappaB, JAK/STAT and PI3/Akt signaling cascades as well as immune responses, and these results are the first report that Astragalus sinicus L. exhibits pharmacological activity.
Subject(s)
Animals , Humans , Mice , Anti-Inflammatory Agents/isolation & purification , Astragalus Plant/chemistry , Cell Line , Dermatitis/drug therapy , Interleukin-23/pharmacology , Janus Kinases/metabolism , Keratinocytes/drug effects , Mice, Inbred C57BL , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Plant Extracts/isolation & purification , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , STAT Transcription Factors/metabolism , Skin/drug effectsABSTRACT
BACKGROUND/AIMS: The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). METHODS: A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. RESULTS: Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. CONCLUSIONS: Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile.
Subject(s)
Humans , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Janus Kinases/antagonists & inhibitors , Methotrexate/therapeutic use , Piperidines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Pyrroles/administration & dosage , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
Myeloproliferative neoplasms ( MPN ) is a class of clonal hematopoietic stem cell disease. Studies found that the JAK-STAT signaling pathway is closely related to the pathogenesis of MPN. The lymphocyte-specific adaptor protein (LNK) gene negatively regulates Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling and may play an important role in the pathogenesis of MPN. Especially in JAK2 mutation-negative MPN, LNK gene specific mutations may be the key to cause MPN subtypes. Certain single nucleotide polymorphism of LNK gene regulation of hematopoietic cells in different directions may also be important influence factors of MPN performance for different subtypes. LNK gene functional changes lead to abnormal activation of the JAK-STAT signaling pathway, and may be a new mechanism of MPN. In this review, the role of LNK gene in MPN pathogenesis is briefly summarized.
Subject(s)
Humans , Janus Kinases , Metabolism , Mutation , Myeloproliferative Disorders , Genetics , Proteins , Genetics , STAT Transcription Factors , Metabolism , Signal TransductionABSTRACT
<p><b>BACKGROUND</b>Traumatic brain injury (TBI) is a major cause of death and disability in children and young adults worldwide. Therefore, we investigated the role of AG490 in regulating brain oedema, expression of CD40 and neurological function after TBI.</p><p><b>METHODS</b>Sprague Dawley rats (n = 240) were randomly divided into a sham operation group, TBI+saline group and TBI+AG490 (JAK/STAT inhibitor) group. Members of each group were euthanized at 6, 12, 24 or 72 hours after injury. Neurological severity score (NSS) was used to evaluate the severity of neurological damage. Brain water was quantitated by wet/dry weight method. The expression of CD40 was assessed by flow cytometry.</p><p><b>RESULTS</b>In both the TBI+saline group and the TBI+AG490 group, the brain water content was elevated after TBI, reached a peak at 24-hour and remained high for the rest of the period investigated; the expression of CD40 reached a peak 24 hours after TBI; the NSS was elevated after TBI and then decreased after 6 hours. Elevations in the level of CD40, degree of brain edema and NSS after TBI were significantly reduced in TBI+AG490 group.</p><p><b>CONCLUSION</b>Inhibition of the JAK/STAT signalling pathway reduces brain oedema, decreases the expression of CD40 and exerts neuroprotective effects after TBI.</p>