375 results on '"janus kinase 1"'
Search Results
2. The underrepresentation of older adults in clinical trials of Janus kinase inhibitors in the treatment of atopic dermatitis
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Shreya A, Sreekantaswamy, Janell, Tully, Linda S, Edelman, Mark A, Supiano, and Daniel, Butler
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Clinical Trials as Topic ,Humans ,Janus Kinase Inhibitors ,Janus Kinase 1 ,Dermatology ,Aged ,Dermatitis, Atopic - Published
- 2022
3. The anti-neoplastic activities of aloperine in HeLa cervical cancer cells are associated with inhibition of the IL-6-JAK1-STAT3 feedback loop
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Wen-Wen Fan, Kun Xu, Fang-Yu Cai, Hui Zhang, Yao-Dong Chen, Yu-Ze Mao, Xiaofang Liu, Feng-Qi Jiang, Yongsheng Yang, and Wu Chen
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STAT3 Transcription Factor ,Quinolizidines ,Mice, Nude ,Uterine Cervical Neoplasms ,Apoptosis ,Feedback ,Flow cytometry ,HeLa ,Mice ,Western blot ,Cell Movement ,In vivo ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,MTT assay ,Epithelial–mesenchymal transition ,STAT3 ,Cell Proliferation ,medicine.diagnostic_test ,biology ,Interleukin-6 ,Chemistry ,Janus Kinase 1 ,General Medicine ,biology.organism_classification ,Complementary and alternative medicine ,Cancer research ,biology.protein ,Female ,HeLa Cells ,Signal Transduction - Abstract
Cervical cancer (CC) is recognized as the most common neoplasm in the female reproductive system worldwide. The lack of chemotherapeutic agents with outstanding effectiveness and safety severely compromises the anti-cipated prognosis of patients. Aloperine (ALO) is a natural quinolizidine alkaloid with marked anti-cancer effects on multiple malignancies as well as favorable activity in relieving inflammation, allergies and infection. However, its therapeutic efficacy and underlying mechanism in CC are still unclear. In the current study, MTT assay was employed to evaluate the viability of HeLa cells exposed to ALO to preliminarily estimate the effectiveness of ALO in CC. Then, the effects of ALO on the proliferation and apoptosis of HeLa cells were further investigated by plate colony formation and flow cytometry, respectively, while the migration and invasion of ALO-treated HeLa cells were evaluated using Transwell assay. Moreover, nude mice were subcutaneously inoculated with HeLa cells to demonstrate the anti-CC properties of ALO in vivo. The molecular mechanisms underlying these effects of ALO were evaluated by Western blot and immunohistochemical analysis. This study experimentally demonstrated that ALO inhibited the proliferation of HeLa cells via G2 phase cell cycle arrest. Simultaneously, ALO promoted an increase in the percentage of apoptotic HeLa cells by increasing the Bax/Bcl-2 ratio. Additionally, the migration and invasion of HeLa cells were attenuated by ALO treatment, which was considered to result from inhibition of epithelial-to-mesenchymal transition. For molecular mechanisms, the expression and activation of the IL-6-JAK1-STAT3 feedback loop were markedly suppressed by ALO treatment. This study indicated that ALO markedly suppresses the proliferation, migration and invasion and enhances the apoptosis of HeLa cells. In addition, these prominent anti-CC properties of ALO are associated with repression of the IL-6-JAK1-STAT3 feedback loop.
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- 2021
4. Selective JAK1 inhibitors for the treatment of inflammatory bowel disease
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Nielsen, Ole Haagen, Boye, Theresa Louise, Gubatan, John, Chakravarti, Deepavali, Jaquith, James B., and LaCasse, Eric C.
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Janus kinase 1 ,Pharmacology ,Crohn's disease ,Ulcerative colitis ,Small molecules ,Pharmacology (medical) ,Signal transducers and activators of transcription ,Therapy - Abstract
Janus kinase (JAK) inhibitors, also known as jakinibs, are third-generation oral small molecules that have expanded the therapeutic options for the management of chronic inflammatory diseases, including inflammatory bowel disease (IBD). Tofacitinib, a pan-JAK inhibitor, has spearheaded the new JAK class for IBD treatment. Unfortunately, serious adverse effects, including cardiovascular complications such as pulmonary embolism and venous thromboembolism or even death from any cause, have been reported for tofacitinib. However, it is anticipated that next-generation selective JAK inhibitors may limit the development of serious adverse events, leading to a safer treatment course with these novel targeted therapies. Nevertheless, although this drug class was recently introduced, following the launch of second-generation biologics in the late 1990s, it is breaking new ground and has been shown to efficiently modulate complex cytokine-driven inflammation in both preclinical models and human studies. Herein, we review the clinical opportunities for targeting JAK1 signaling in the pathophysiology of IBD, the biology and chemistry underpinning these target-selective compounds, and their mechanisms of actions. We also discuss the potential for these inhibitors in efforts to balance their benefits and harms.
- Published
- 2023
5. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial
- Author
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Thomas Bieber, Alvina D. Chu, Barbara A. Hendrickson, Xiaofei Hu, Xiaohong Huang, Weily Soong, Jiewei Zeng, Marjolein S. de Bruin-Weller, Jonathan I. Silverberg, Thomas Werfel, Barry Ladizinski, Henrique D. Teixeira, Kenji Kabashima, and Kristian Reich
- Subjects
Adult ,Male ,medicine.medical_specialty ,Internationality ,Combination therapy ,Population ,030204 cardiovascular system & hematology ,Placebo ,Severity of Illness Index ,Eczema Area and Severity Index ,Dermatitis, Atopic ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,Adrenal Cortex Hormones ,law ,Internal medicine ,Severity of illness ,medicine ,Humans ,Janus Kinase Inhibitors ,030212 general & internal medicine ,education ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Janus Kinase 1 ,General Medicine ,Atopic dermatitis ,medicine.disease ,Clinical trial ,Drug Therapy, Combination ,Female ,business ,Heterocyclic Compounds, 3-Ring - Abstract
Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group.Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.AbbVie.
- Published
- 2021
6. Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib
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Alice Wang, Richard A. Flavell, Brett A. King, William Damsky, Meaghan K. McGeary, Marcus Bosenberg, Danielle Peterson, Michael J. Murphy, Austin McHenry, and Nur-Taz Rahman
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CD4-Positive T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Inflammation ,Proinflammatory cytokine ,Granuloma Annulare ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Piperidines ,medicine ,Humans ,Janus Kinase Inhibitors ,Immunology and Allergy ,Aged ,Skin ,Tofacitinib ,biology ,Janus kinase 1 ,Sequence Analysis, RNA ,business.industry ,Macrophages ,Oncostatin M ,Fibroblasts ,Middle Aged ,Pyrimidines ,Cytokine ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,STAT protein ,Cytokines ,medicine.symptom ,Janus kinase ,business - Abstract
Background Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. The potential health implications of severe GA are unknown. Objective We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. Methods We used single-cell RNA sequencing to study the immunopathogenesis of GA and also evaluated the efficacy of tofacitinib (a Janus kinase 1/3 inhibitor) in 5 patients with severe, long-standing GA in an open-label clinical trial. Results Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. Treatment of 5 patients with recalcitrant GA with tofacitinib inhibited IFN-γ and oncostatin M, as well as IL-15 and IL-21, activity and resulted in clinical and histologic disease remission in 3 patients and marked improvement in the other 2. Inhibition of these effects at the molecular level paralleled the clinical improvement. Evidence of systemic inflammation is also present in some patients with severe GA and is mitigated by tofacitinib. Conclusions The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN-γ and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.
- Published
- 2021
7. IL-10 derived from Hepatocarcinoma cells improves human induced regulatory T cells function via JAK1/STAT5 pathway in tumor microenvironment
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Yaqing Zhu, Ji Gao, Zheng Ju, Jinren Zhou, Chengyu Shi, Xiaojie Gan, Zhang Li, Jiannan Qiu, and Shaopeng Zhang
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Adenoma ,0301 basic medicine ,Lung Neoplasms ,medicine.medical_treatment ,T cell ,Immunology ,Apoptosis ,Adenocarcinoma ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,STAT5 Transcription Factor ,Tumor Microenvironment ,medicine ,Humans ,Receptors, Interleukin-10 ,IL-2 receptor ,Molecular Biology ,Tumor microenvironment ,Chemistry ,Tumor Suppressor Proteins ,Liver Neoplasms ,FOXP3 ,Forkhead Transcription Factors ,Hep G2 Cells ,Janus Kinase 1 ,Immunotherapy ,Coculture Techniques ,Interleukin-10 ,Pancreatic Neoplasms ,Interleukin 10 ,030104 developmental biology ,medicine.anatomical_structure ,Culture Media, Conditioned ,Cancer cell ,Hepatocytes ,Cancer research ,030215 immunology - Abstract
Forkhead box P3 (Foxp3) expressing CD4+CD25+ regulatory T cells (Tregs), an essential subset of immune T cells for maintaining immune homeostasis is implicated as a negative regulator in an anti-tumor immune response. Current researches suggest that reducing tumor-infiltrating Tregs contribute to enhanced anti-cancer effect. However, the mechanism of infiltration of a large number of Tregs into tumor tissues is still unclear. In this study, human induced Tregs (iTregs) were co-cultured with human hepatocytes and various types of cancer cells (HepG2, NSCLC, and AsPC-1) supernatants. Foxp3, multiple cytokines, levels of apoptosis and suppressive ability of iTregs were detected by FACS. Western blot was employed to test of proteins. Impact of HepG2 supernatants on T cell subpopulations differentiation, cytokines in supernatants were examed by FACS and ELISA respectively. Anti-IL-10R antibody and JAK1 inhibitor were used to reconfirm the role of tumor-derived IL-10 play in the regulation on iTregs. Hepatocarcinoma cells (HCC) supernatants treatment increases Foxp3 stability and reduces apoptosis level in human iTregs without influencing its differentiation trend. Furthermore, IL-10 was found to be extremely higher in HCC supernatants than other groups, IL-10R blockade neutralize the effect of HCC supernatants on iTregs in vitro obviously. HCC supernatants also reversed IL-1β/6 triggered decline on Foxp3 which may be related to higher expression of JAK1 and elevated phosphorylation level of STAT5 induced by IL-10. Our results suggest that improved stability and abnormal accumulation of Tregs in tumor microenvironment is IL-10/JAK1/STAT5 signal pathway-dependent and provide a novel approach for improving the efficiency of anti-tumor immunotherapy.
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- 2021
8. PIM Kinases Promote Survival and Immune Escape in Primary Mediastinal Large B-Cell Lymphoma through Modulation of JAK-STAT and NF-κB Activity
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Monika Prochorec-Sobieszek, Przemyslaw Juszczynski, Anna Szumera-Ciećkiewicz, Sonia Dębek, Andrea Massimiliano Tomirotti, Małgorzata Szołkowska, and Maciej Szydlowski
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,Chemokine ,Apoptosis ,Mediastinal Neoplasms ,Pathology and Forensic Medicine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Proto-Oncogene Proteins c-pim-1 ,hemic and lymphatic diseases ,Murine leukemia virus ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Humans ,Cell Proliferation ,biology ,Kinase ,NF-kappa B ,JAK-STAT signaling pathway ,NF-κB ,Janus Kinase 1 ,biology.organism_classification ,medicine.disease ,Lymphoma ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Tumor Escape ,Lymphoma, Large B-Cell, Diffuse ,BCL2-related protein A1 - Abstract
Primary mediastinal large B-cell lymphoma (PMBL) cells depend on the constitutive activity of NF-κB and STAT transcription factors, which drive expression of multiple molecules essential for their survival. In a molecularly related B-cell malignant tumor (classic Hodgkin lymphoma), tumor Reed-Sternberg cells overexpress oncogenic (proviral integration site for Moloney murine leukemia virus (PIM) 1, 2, and 3 kinases in a NF-κB- and STAT-dependent manner and PIMs enhance survival and expression of immunomodulatory molecules. Given the multiple overlapping characteristics of Reed-Sternberg and PMBL cells, we hypothesized that PIM kinases may be overexpressed in PMBL and involved in PMBL pathogenesis. The expression of PIM kinases in PMBL diagnostic biopsy specimens was assessed and their role in survival and immune escape of the tumor cells was determined. PIMs were abundantly expressed in primary tumors and PMBL cell lines. Inhibition of PIM kinases was toxic to PMBL cells, attenuated protein translation, and down-regulated NF-κB- and STAT-dependent transcription of prosurvival factors BCL2A1, BCL2L1, and FCER2. Furthermore, PIM inhibition decreased expression of molecules engaged in shaping the immunosuppressive microenvironment, including programmed death ligand 1/2 and chemokine (C-C motif) ligand 17. Taken together, our data indicate that PIMs support PMBL cell survival and immune escape and identify PIMs as promising therapeutic targets for PMBL.
- Published
- 2021
9. Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression
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Yinghao Sun, Zhe-Xu Cao, Shancheng Ren, Wei Zhang, Guang-An Xiao, Shihong Peng, Yaoming Li, Xiaolei Shi, Rui Chen, Lin Zhao, Guang Liu, Ziyu Fang, Yifan Chang, Xinwen Nian, and Yasheng Zhu
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Male ,STAT3 Transcription Factor ,Leukemia Inhibitory Factor Receptor alpha Subunit ,Leukemia inhibitory factor receptor ,medicine.disease_cause ,Leukemia Inhibitory Factor ,Metastasis ,Immunomodulation ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,Drug Discovery ,Gene expression ,Genetics ,medicine ,Humans ,Neoplasm Metastasis ,Molecular Biology ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Competing endogenous RNA ,business.industry ,Prostatic Neoplasms ,Janus Kinase 1 ,medicine.disease ,Long non-coding RNA ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,RNA, Long Noncoding ,Original Article ,Carcinogenesis ,business ,Signal Transduction - Abstract
Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both in vitro and in vivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.
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- 2020
10. miR-515–5p suppresses HCC migration and invasion via targeting IL6/JAK/STAT3 pathway
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Hao Zheng, Yuan-ping Tao, Weiping Zhou, Zhen-guang Wang, Jun-sheng Ni, Yang-liu Ou, Li-hua Song, and Hong-Li Yan
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Male ,STAT3 Transcription Factor ,0301 basic medicine ,Carcinoma, Hepatocellular ,Mice, Nude ,Apoptosis ,Stat3 Signaling Pathway ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,microRNA ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Medicine ,Interleukin 6 ,STAT3 ,Cell Proliferation ,Gene knockdown ,biology ,Interleukin-6 ,business.industry ,Liver Neoplasms ,Cell migration ,Janus Kinase 1 ,Middle Aged ,Prognosis ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Survival Rate ,MicroRNAs ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Surgery ,Signal transduction ,Janus kinase ,business - Abstract
MicroRNAs (miRNAs) have been identified as critical modulators of cell migration and invasion, which are the major causes of cancer progression including hepatocellular carcinoma (HCC). However, the accurate role of miR-515–5p in HCC is still uncertain. Here, we report that miR-515–5p expression is down-regulated in HCC tissues and cell lines, and associated with absence of capsule formation (p = 0.015)﹑microvascular invasion(p = 0.003)﹑and advantange TNM stage (II-III) (p = 0.014) in HCC patients. Overexpression of miR-515–5p inhibited migration and invasion of HCC cells in vitro and in vivo, while miR-515–5p knockdown has the inverse effect. Moreover, using miRNA databases and dual-luciferase report assay, we find miR-515–5p directly binds to the 3′-untranslated region (3′-UTR) of interleukin 6 (IL6). In addition, the regulatory association between miR-515–5p and the IL-6/Janus kinase (JNK)/signal transducer and activator of transcription-3 (STAT3) signaling pathway was explored. Furthermore, overexpression of miR-515–5p inhibited the activation of the JAK/STAT3 signaling pathway, which was rescued by overexpression of IL-6. The results of the current study indicate that miR-515–5p overexpression may serve an important role in inhibiting migration and invasion of HCC cells via suppression of IL-6/JAK/STAT3 signaling pathway activation. MiR-515–5p may serve as a potential therapeutic target for HCC.
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- 2020
11. The potential of JAK/STAT pathway inhibition by ruxolitinib in the treatment of COVID-19
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Cigir Biray Avci and Bakiye Goker Bagca
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0301 basic medicine ,Ruxolitinib ,Cell signaling ,Coronavirus disease 2019 (COVID-19) ,Endocrinology, Diabetes and Metabolism ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Inflammatory response ,Pneumonia, Viral ,Immunology ,Cytokine storm ,Antiviral Agents ,Article ,General Biochemistry, Genetics and Molecular Biology ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Nitriles ,JAK/STAT pathway ,medicine ,Humans ,Janus Kinase Inhibitors ,Immunology and Allergy ,Stat signaling ,Pandemics ,ComputingMethodologies_COMPUTERGRAPHICS ,SARS-CoV-2 ,business.industry ,COVID-19 ,JAK-STAT signaling pathway ,Janus Kinase 1 ,Janus Kinase 2 ,medicine.disease ,STAT Transcription Factors ,Pyrimidines ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Pyrazoles ,Coronavirus Infections ,Cytokine Release Syndrome ,business ,Signal Transduction ,medicine.drug - Abstract
Graphical abstract, Highlights • The most important cause of COVID-19 deaths is the development of complications. • Dysregulated immune response and cytokine storm are the most important complications. • The JAK / STAT pathway is the main signal pathway that controls cytokine production. • The JAK1 and JAK2 inhibitor ruxolitinib may be a choice to prevent cytokine storm. • However, the disadvantages of ruxolitinib should also be considered., Ruxolitinib is the first approved JAK1 and JAK2 inhibitor, and is known to interfere with the JAK / STAT signaling pathway, one of the critical cellular signaling pathways involved in the inflammatory response. This review presents an overview of SARS-CoV-2 and the COVID-19 pandemic, and then focuses on the potential efficacy of ruxolitinib in this infection. The potential targets of ruxolitinib were determined by using genetic alterations that have been reported in COVID-19 patients. The potential effectiveness of ruxolitinib is suggested by evaluating the interactions of these potential targets with ruxolitinib or JAK/STAT pathway.
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- 2020
12. Molecular cloning and functional characterization of duck Janus kinase 1
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Yaqian Li, Hui Jin, Huijun Zheng, Peng Zhou, Dejian Liu, and Rui Luo
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0301 basic medicine ,Small interfering RNA ,animal structures ,biology ,Janus kinase 1 ,Activator (genetics) ,viruses ,Immunology ,Janus Kinase 1 ,biology.organism_classification ,Protein kinase R ,Molecular biology ,Immunity, Innate ,Sendai virus ,Avian Proteins ,03 medical and health sciences ,Ducks ,030104 developmental biology ,0302 clinical medicine ,Transcription (biology) ,Viperin ,Animals ,Signal transduction ,Molecular Biology ,030215 immunology - Abstract
Janus kinase 1 (JAK1) is a member of JAK family of non-receptor protein tyrosine kinases that plays critical roles in transducing cytokine signals via JAK-signal transducer and activator of transcription (STAT) signaling pathway. The importance of JAK1 in innate immunity has been well-studied in mammals and fish, yet in avian remains largely unknown. Here, we cloned the full-length of the duck JAK1 (duJAK1) gene for the first time. DuJAK1 encoded a protein of 1152 amino acids and possessed high amino acid identity with goose and budgerigar JAK1s. The duJAK1 was expressed in all detected tissues, especially high in the thymus and bursa of Fabricius. Overexpression of duJAK1 significantly activated ISRE promoter activity and induced duck viperin, 2', 5'-OAS, MX, PKR and ZAP expression. Knockdown of duJAK1 by small interfering RNA significantly inhibited duck Tembusu virus (DTMUV)-, duck Enteritis virus (DEV)-, poly (I:C)-, poly (dA:dT)- or Sendai virus (SeV)-induced ISRE promoter activation. Furthermore, duJAK1 exhibited antiviral activity against DTMUV infection. These results will help us understand the function of JAK family proteins in duck antiviral immunity.
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- 2020
13. Inhibition of JAK1 mitigates postoperative ileus in mice
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Zhilin Hong, Hongying Shi, Pan Chi, and Yafeng Sun
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Male ,Pyridines ,Inflammation ,Pharmacology ,Proinflammatory cytokine ,Mice ,Ileus ,Postoperative Complications ,Downregulation and upregulation ,Western blot ,Preoperative Care ,Gene expression ,Animals ,Humans ,Medicine ,Intestinal Mucosa ,Peroxidase ,Janus kinase 1 ,medicine.diagnostic_test ,business.industry ,Muscle, Smooth ,Janus Kinase 1 ,Smooth muscle contraction ,Triazoles ,Up-Regulation ,Disease Models, Animal ,Jejunum ,Immunohistochemistry ,Surgery ,Inflammation Mediators ,medicine.symptom ,Gastrointestinal Motility ,business ,Muscle Contraction ,Signal Transduction - Abstract
Background Intestinal inflammation is the predominant contributor to the genesis of postoperative ileus. Janus kinase 1 plays an important role during inflammation. Here, we investigated the role of Janus kinase 1 in postoperative ileus and whether inhibition of Janus kinase 1 could mitigate postoperative ileus. Methods A mouse model of postoperative ileus was induced by intestinal manipulation. Janus kinase 1 inhibitor GLPG0634 or placebo was administered orally before intestinal manipulation. At the indicated time points post operation, neutrophil infiltration was assessed by immunohistochemistry and enzyme-linked immunosorbent assay; proinflammatory gene expression was quantified by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay; and Janus kinase 1 activation was detected by Western blot. Functional studies were conducted to evaluate intestinal motility. Results We found that intestinal manipulation led to marked activation of Janus kinase 1, with increased proinflammatory gene expression and upregulated myeloperoxidase level. Moreover, intestinal manipulation resulted in an impairment of intestinal transit in vivo and inhibition of smooth muscle contractility in vitro. Preoperative administration of GLPG0634 markedly lowered the expression of proinflammatory cytokines, the myeloperoxidase level in the muscularis layer after bowel manipulation, and significantly ameliorated smooth muscle contractile function and intestinal transit ability. Conclusion Our data showed that Janus kinase 1 activation mediated intestinal manipulation-induced resident macrophage activation after intestinal manipulation, and subsequent complex inflammatory cascade and gut dysmotility. Janus kinase 1 inhibition appears to be a prospective and convenient approach for the prevention of postoperative ileus.
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- 2019
14. CircUBXN7 suppresses cell proliferation and facilitates cell apoptosis in lipopolysaccharide-induced cell injury by sponging miR-622 and regulating the IL6ST/JAK1/STAT3 axis
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Fan Xu, Runnan Chen, Yue Shen, Hanhan Liu, Lijuan Hu, and Lei Zhu
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Lipopolysaccharides ,STAT3 Transcription Factor ,MicroRNAs ,Respiratory Distress Syndrome ,Cytokine Receptor gp130 ,Humans ,Apoptosis ,Janus Kinase 1 ,RNA, Circular ,Cell Biology ,Biochemistry ,Cell Proliferation ,Adaptor Proteins, Signal Transducing - Abstract
Acute respiratory distress syndrome (ARDS) is a common and serious respiratory illness with substantial morbidity and mortality. Circular RNAs have been demonstrated to participate in various diseases processes. However, the biological function and mechanism of most circular RNAs have not been elucidated in ARDS. In this study, we found that circUBXN7 was significantly increased in lipopolysaccharide (LPS)-induced A549 and Beas-2B cell injury. Inhibition of circUBXN7 significantly promoted cell proliferation and reduced cell apoptosis, while overexpression of circUBXN7 suppressed cell proliferation and accelerated cell apoptosis in LPS-induced A549 and Beas-2B cells. CircUBXN7 acted as a sponge for miR-622, and miR-622 rescued the effect of circUBXN7 on cell proliferation and apoptosis. We also found that IL6ST was a target gene of miR-622, and the expression of IL6ST was indirectly regulated by circUBXN7. Furthermore, western blotting indicated that the JAK1/STAT3 signaling pathway was involved in the circUBXN7/miR-622/IL6ST axis in LPS-induced A549 and Beas-2B cell injury. Overall, our study suggested that circUBXN7 suppressed cell proliferation and facilitated cell apoptosis by sponging miR-622 and regulating IL6ST, to activate the JAK1/STAT3 signaling pathway in LPS-induced A549 and Beas-2B cell injury. CircUBXN7 might therefore be a potential biomarker for ARDS, and dysregulation of circUBXN7 may be involved in the pathogenesis of ARDS.
- Published
- 2022
15. OAS1, OAS2, and OAS3 Contribute to Epidermal Keratinocyte Proliferation by Regulating Cell Cycle and Augmenting IFN-1‒Induced Jak1‒Signal Transducer and Activator of Transcription 1 Phosphorylation in Psoriasis
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Yan-Zhou Huang, Yu-Xin Zheng, Yuan Zhou, Fan Xu, Ying-Zhe Cui, Xue-Yan Chen, Zhao-Yuan Wang, Bing-Xi Yan, Min Zheng, and Xiao-Yong Man
- Subjects
Keratinocytes ,Biological Products ,Cell Cycle ,Interleukin-17 ,Janus Kinase 1 ,Cell Biology ,Dermatology ,Antiviral Agents ,Interleukin-23 ,Biochemistry ,Ligases ,STAT1 Transcription Factor ,2',5'-Oligoadenylate Synthetase ,Humans ,Psoriasis ,Epidermis ,Phosphorylation ,Molecular Biology ,Biomarkers ,Cell Proliferation - Abstract
Psoriasis is a systemic immune‒mediated inflammatory disease characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes. Recent studies have identified IL-17 and IL-23 as key drivers of psoriasis pathogenesis, but the underlying molecular mechanisms remain unclear. The 2'-5'-oligoadenylate synthetases (OASs), namely, OAS1, OAS2, OAS3, and OASL, are a family of IFN-induced enzymes with multiple antiviral activities, but their role in psoriasis is unknown. In this study, we identified the overexpression of OAS1, OAS2, and OAS3 in human lesional psoriatic skin and serum and found that their expression was downregulated by biologics. Moreover, OASs were highly expressed in epidermal keratinocytes, epidermal dendritic cells, epidermal CD3
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- 2022
16. IFNγ-induced PD-L1 expression in ovarian cancer cells is regulated by JAK1, STAT1 and IRF1 signaling
- Author
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Sveta, Padmanabhan, Bijaya, Gaire, Yue, Zou, Mohammad M, Uddin, and Ivana, Vancurova
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Gene Expression Regulation, Neoplastic ,Ovarian Neoplasms ,Interferon-gamma ,STAT1 Transcription Factor ,Cell Line, Tumor ,Humans ,Female ,Janus Kinase 1 ,Cell Biology ,Carcinoma, Ovarian Epithelial ,B7-H1 Antigen ,Interferon Regulatory Factor-1 - Abstract
Expression of the immune checkpoint programmed death ligand-1 (PD-L1) is increased in ovarian cancer (OC) and correlates with poor prognosis. Interferon-γ (IFNγ) induces PD-L1 expression in OC cells, resulting in their increased proliferation and tumor growth, but the mechanisms that regulate the PD-L1 expression in OC remain unclear. Here, we show that the IFNγ-induced PD-L1 expression in OC cells is associated with increased levels of STAT1, Tyr-701 pSTAT1 and Ser-727 pSTAT1. Suppression of JAK1 and STAT1 significantly decreases the IFNγ-induced PD-L1 expression in OC cells, and STAT1 overexpression increases the IFNγ-induced PD-L1 expression. In addition, IFNγ induces expression of the transcription factor interferon regulatory factor 1 (IRF1) and IRF1 suppression attenuates the IFNγ-induced gene and protein levels of PD-L1. Chromatin immunoprecipitation results show that IFNγ induces PD-L1 promoter acetylation and recruitment of STAT1, Ser-727 pSTAT1 and IRF1 in OC cells. Together, these findings demonstrate that the IFNγ-induced PD-L1 expression in OC cells is regulated by JAK1, STAT1, and IRF1 signaling, and suggest that targeting the JAK1/ STAT1/IRF1 pathway may provide a leverage to regulate the PD-L1 levels in ovarian cancer.
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- 2022
17. Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders
- Author
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Robert, Roskoski
- Subjects
Arthritis, Rheumatoid ,Pharmacology ,Primary Myelofibrosis ,COVID-19 ,Humans ,Janus Kinase Inhibitors ,Janus Kinase 1 ,Janus Kinase 2 ,Polycythemia Vera ,Protein Kinase Inhibitors ,Janus Kinases - Abstract
The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.
- Published
- 2022
18. Down-regulation of circPTTG1IP induces hepatocellular carcinoma development via miR-16-5p/RNF125/JAK1 axis
- Author
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Rui Peng, Jun Cao, Bing-Bing Su, Xue-song Bai, Xin Jin, Ao-qing Wang, Qian Wang, Ren-jie Liu, Guo-qing Jiang, Sheng-jie Jin, Chi Zhang, and Dou-sheng Bai
- Subjects
Gene Expression Regulation, Neoplastic ,MicroRNAs ,Cancer Research ,Carcinoma, Hepatocellular ,Oncology ,Cell Line, Tumor ,Liver Neoplasms ,Down-Regulation ,Humans ,Janus Kinase 1 ,RNA, Circular ,In Situ Hybridization, Fluorescence ,Cell Proliferation - Abstract
Circular RNAs are known to regulate the biological processes of hepatocellular carcinoma (HCC), and humans with Down syndrome are at low risk of developing solid tumors due to the amplification of several tumor suppressor genes on human chromosome 21 (HSA21). Here, we aimed to investigate the potential role of circRNAs originating from HSA21 in the progression of HCC. CircRNA-sequencing was performed to analyze differentially expressed circRNAs in 4 HCC and peritumor tissues, and circRNAs originating from HSA21 were further analyzed. Circ_0061984 (circPTTG1IP) was chosen for further study because it showed the lowest expression in HCC tissues, and qRT-PCR was used to confirm the expression of circPTTG1IP in HCC patient tissues. The biological function of circPTTG1IP was detected in HCC cells both in vivo and in vitro. Moreover, luciferase reporter assays, circRNA immunoprecipitation, and fluorescence in situ hybridization (FISH) were used to investigate the potential mechanism of circPTTG1IP. Finally, the possible mechanisms of filgotinib in circPTTG1IP-driven HCC were assessed. CircPTTG1IP expression was decreased in HCC compared to peritumoral tissues. Moreover, low circPTTG1IP expression was revealed to be associated with a poor prognosis of HCC patients. Elevation of circPTTG1IP was revealed to inhibit HCC development both in vitro and in vivo. Mechanistically, circPTTG1IP was shown to function as a competing endogenous RNA (ceRNA) of RNF125 by binding miR-16-5p to increase the level of the E3 ubiquitin ligase RNF125, which further ubiquitinated and degraded JAK1 protein. Finally, we demonstrated that administration of filgotinib, a JAK1 inhibitor, restricted HCC progression induced by low circPTTG1IP expression. Thus, we revealed that circPTTG1IP is a novel tumor suppresser circRNA in HCC and that a low circPTTG1IP level promotes HCC development via the miR-16-5p/RNF125/JAK1 axis. Patients with low circPTTG1IP may benefit from filgotinib treatment.
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- 2022
19. Nonylphenol exacerbates ovalbumin-induced allergic rhinitis via the TSLP-TSLPR/IL-7R pathway and JAK1/2-STAT3 signaling in a mouse model
- Author
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Yunxiu, Wang, Zhiwei, Cao, He, Zhao, and Zhaowei, Gu
- Subjects
Mice, Inbred BALB C ,Receptors, Interleukin-7 ,Ovalbumin ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Immunoglobulins ,Janus Kinase 1 ,General Medicine ,Rhinitis, Allergic ,Pollution ,Disease Models, Animal ,Mice ,STAT Transcription Factors ,Th2 Cells ,Phenols ,Thymic Stromal Lymphopoietin ,Animals ,Cytokines ,RNA, Messenger ,Receptors, Cytokine ,Signal Transduction - Abstract
Nonylphenol (NP) can be widely used as a plasticizer, surfactant, antioxidant, textile printing, dyeing additive, and pesticide emulsifier. Animal studies have shown that NP aggravates ovalbumin (OVA)-induced allergic rhinitis (AR); however, the exact mechanism underlying its action has not yet been detailed. This study aimed to explore the aggravation of the AR inflammatory response following NP exposure and its possible mechanism. The AR mouse model was constructed using OVA. Under NP exposure, allergic nasal symptoms were observed, eosinophil infiltration was assessed by Sirius red staining, and the levels of IL-4, IL-5, and IL-13 in nasal mucosa samples were detected using cytometric bead array. The mRNA levels of OX40/OX40L and GATA3 in nasal mucosa were detected by qPCR, and the expression levels of the TSLP and JAK1/2-STAT3 signaling pathway components were also identified. Our results suggest that NP exposure exacerbated allergic nasal symptoms and that eosinophils accumulated in nasal mucosa after OVA challenge. The levels of the typical T helper 2 cytokines, as well as the mRNA levels of OX40/OX40L and GATA3, were elevated in the nasal mucosa of OVA-challenged mice exposed to NP. In addition, NP exposure elevated the TSLP, TSLPR, IL-7R, p-JAK1, p-JAK2, and p-STAT3 levels in the nasal mucosa after OVA stimulation. Overall, the present study suggests NP can exacerbate OVA-induced AR inflammatory responses; furthermore, this aggravating effect of NP may be related to the TSLP-TSLPR/IL-7R and JAK1/2-STAT3 signaling pathways.
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- 2022
20. Contributions of intestine and liver to the absorption and disposition of FZJ-003, a selective JAK1 inhibitor with structure modification of filgotinib
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Yu Zhuang, Qiushuang Sun, Tian Jing, Jia Liu, Haitao Meng, Yaqi Cao, Zhixia Qiu, Junen Sun, and Ning Li
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Pyridines ,Pharmaceutical Science ,Janus Kinase 1 ,Triazoles ,Amides ,Rats ,Intestines ,Intestinal Absorption ,Liver ,Microsomes, Liver ,Animals ,Humans ,Janus Kinase Inhibitors ,Caco-2 Cells - Abstract
FZJ-003 is a selective Janus kinase 1 (JAK1) inhibitor with structural modification of filgotinib for rheumatoid arthritis (RA) treatment. In this study, a series of in vivo and in vitro experiments were conducted to investigate the specific contribution of the intestine and liver to the disposition of FZJ-003 compared with filgotinib. Results showed that FZJ-003 exhibited over 2-fold higher systemic exposure and lower clearance than those of filgotinib, after intravenous or intragastric administration at the equivalent mole dose level to conscious rats. In anesthetized rats treated with different dosing routes, FZJ-003 exhibited higher intestinal bioavailability (F
- Published
- 2022
21. Special editorial: When prescribing Janus kinase inhibitors for dermatologic conditions, be mindful of the Food and Drug Administration's September 1, 2021, data safety communication
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Timothy Druso, Morgan Murphrey, Jane M. Grant-Kels, and Reid A. Waldman
- Subjects
Ruxolitinib ,medicine.medical_specialty ,Tofacitinib ,Alopecia Areata ,United States Food and Drug Administration ,business.industry ,Communication ,Janus Kinase 1 ,Dermatology ,Atopic dermatitis ,Alopecia areata ,medicine.disease ,United States ,Food and drug administration ,Psoriasis ,Humans ,Janus Kinase Inhibitors ,Medicine ,business ,Janus kinase ,Janus Kinases ,Janus kinase inhibitor ,medicine.drug - Published
- 2022
22. Inhibition of protein nitration prevents cisplatin-induced inactivation of STAT3 and promotes anti-apoptotic signaling in organ of Corti cells
- Author
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Monazza Shahab, Rita Rosati, Samson Jamesdaniel, and William L. Neumann
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,Antineoplastic Agents ,Apoptosis ,Biology ,Nitric Oxide ,Catalysis ,Article ,Cell Line ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Phosphorylation ,STAT3 ,Organ of Corti ,Cisplatin ,JAK-STAT signaling pathway ,Janus Kinase 1 ,Cell Biology ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Tyrosine ,Signal transduction ,Peroxynitrite ,Signal Transduction ,medicine.drug - Abstract
JAK/STAT pathway is one among the several oxidative stress-responsive signaling pathways that play a critical role in facilitating cisplatin-induced ototoxicity. Cisplatin treatment decreases the levels of cochlear LMO4, which acts as a scaffold for IL6-GP130 protein complex. Cisplatin-induced nitration and degradation of LMO4 could destabilize this protein complex, which in turn could compromise the downstream STAT3-mediated cellular defense mechanism. Here, we investigated the link between cisplatin-induced nitrative stress and STAT3-mediated apoptosis by using organ of Corti cell cultures. SRI110, a peroxynitrite decomposition catalyst that prevented cisplatin-induced decrease in LMO4 levels and ototoxicity, was used to inhibit nitrative stress. Immunoblotting and immunostaining indicated that cisplatin treatment decreased the expression levels, phosphorylation, and nuclear localization of STAT3 in UB/OC1 cells. Inhibition of nitration by SRI110 co-treatment prevented cisplatin-induced inactivation of STAT3 and promoted its nuclear localization. SRI110 co-treatment reversed the cisplatin-induced changes in the expression levels of Bcl2l1, Ccnd1, Jak2, Jak3, and Src and significantly attenuated the changes in the expression levels of Cdkn1a, Egfr, Fas, Il6st, Jak1, Stat3, and Tyk2. Collectively, these results suggest that the inhibition of cisplatin-induced nitration prevents the inactivation of STAT3, which in turn enables the transcription of anti-apoptotic genes and thereby helps to mitigate cisplatin-induced toxicity.
- Published
- 2019
23. Differential effect of inhibitory strategies of the V617 mutant of JAK2 on cytokine receptor signaling
- Author
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Stefan N. Constantinescu, Andrew K. Shiau, Thomas Balligand, Alexandra Dusa, Didier Colau, Emilie Leroy, Christian Pecquet, Céline Mouton, UCL - SSS/DDUV/SIGN - Cell signalling, and UCL - (SLuc) Service d'hématologie
- Subjects
IFNGR ,0301 basic medicine ,Immunology ,Cell Line ,Cytokine receptor signaling ,JAK2 V617F ,Mice ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Animals ,Humans ,Immunology and Allergy ,IL-2 receptor ,Receptors, Cytokine ,Receptor ,Janus Kinases ,Janus kinase 1 ,Chemistry ,Janus Kinase 2 ,Cell biology ,Erythropoietin receptor ,Myeloproliferative disorders ,JAK1 ,kinases ,030104 developmental biology ,Tyrosine kinase 2 ,030220 oncology & carcinogenesis ,Mutation ,STAT protein ,Cytokine receptor ,Janus kinase ,Signal Transduction - Abstract
Background Janus kinase (JAK) 2 plays pivotal roles in signaling by several cytokine receptors. The mutant JAK2 V617F is the most common molecular event associated with myeloproliferative neoplasms. Selective targeting of the mutant would be ideal for treating these pathologies by sparing essential JAK2 functions. Objective We characterize inhibitory strategies for JAK2 V617F and assess their effect on physiologic signaling by distinct cytokine receptors. Methods Through structure-guided mutagenesis, we assessed the role of key residues around F617 and used a combination of cellular and biochemical assays to measure the activity of JAKs in reconstituted cells. We also assessed the effect of several specific JAK2 V617F inhibitory mutations on receptor dimerization using the NanoBiT protein complementation approach. Results We identified a novel Janus kinase homology 2 (JH2) αC mutation, A598F, which is suggested to inhibit the aromatic stacking between F617 with F594 and F595. Like other JAK2 V617F inhibitory mutations, A598F decreased oncogenic activation and spared cytokine activation while preventing JAK2 V617F–promoted erythropoietin receptor dimerization. Surprisingly, A598F and other V617F-inhibiting mutations (F595A, E596R, and F537A) significantly impaired IFN-γ signaling. This was specific for IFN-γ because the inhibitory mutations preserved responses to ligands of a series of receptor complexes. Similarly, homologous mutations in JAK1 prevented signaling by IFN-γ. Conclusions The JH2 αC region, which is required for JAK2 V617F hyperactivation, is crucial for relaying cytokine-induced signaling of the IFN-γ receptor. We discuss how strategies aiming to inhibit JAK2 V617F could be used for identifying inhibitors of IFN-γ signaling.
- Published
- 2019
24. RETRACTED: Geniposide alleviates hypoxia-induced injury by down-regulation of lncRNA THRIL in rat cardiomyocytes derived H9c2 cells
- Author
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Lianhe Wu, Cunjian Sheng, and Fang Hu
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,Myocardial Infarction ,Down-Regulation ,Apoptosis ,Pharmacology ,Cell Line ,Flow cytometry ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Iridoids ,Myocytes, Cardiac ,Gene Silencing ,Viability assay ,Protein kinase B ,Cell damage ,PI3K/AKT/mTOR pathway ,medicine.diagnostic_test ,Chemistry ,Heart ,Janus Kinase 1 ,Transfection ,Cell cycle ,medicine.disease ,Cell Hypoxia ,Rats ,030104 developmental biology ,Cytoprotection ,cardiovascular system ,RNA, Long Noncoding ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Geniposide (GEN) is an iridoid glycoside extracts from Gardenia jasminoides Ellis with antioxidant and anti-inflammarory properties. The objective of this study was to explore the effects of GEN on a cell model of myocardial infarction (MI). After transfection, hypoxia-stimulated H9c2 cells were treated with GEN. Cell viability and apoptosis were detected by Cell Counting kit-8 assay and flow cytometry, respectively. Cell cycle-, apoptosis- and signal pathway related proteins were examined by Western blot. The expression of THRIL was determined by qRT-PCR. In addition, in vivo experiments were performed in rats. Then the infarct size and the left ventricular (LV) end diastolic diameter (LVEDD), LV ejection fraction (LVEF) and LV fractional shortening (LVFS) were monitored. Results showed that treating H9c2 cells with GEN attenuated hypoxia-induced cell damage as cell viability was increased, and cell apoptosis was repressed. Meanwhile, THRIL was found to be down-regulated by GEN. The cardioprotective effects of GEN on H9c2 cells were attenuated when THRIL was overexpressed. Besides this, the phosphorylation of PI3K, AKT, JAK1 and STAT3 were up-regulated by GEN while down-regulated by THRIL overexpression. Moreover, GEN decreased infarct size and LVEDD, while increased LVEF and LVFS. Taken together, this study demonstrated that GEN alleviated cardiomyocytes damage and cardiac dysfunction possible through down-regulation of THRIL.
- Published
- 2019
25. Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling
- Author
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Xingrong Liu, Nico Ghilardi, Simon Charles Goodacre, Michael Siu, Jim Nonomiya, G. Buckley, Adam R. Johnson, Yun-Xing Cheng, F.A. Romero, Nick Ray, Rohan Mendonca, C. Robinson, Yuen Po-Wai, Jane R. Kenny, Marya Liimatta, Terry Kellar, Mark Zak, Gary Salmon, J. Lloyd, D.G. Brown, Neville James Mclean, Joseph P. Lyssikatos, Emily J. Hanan, Patrick J. Lupardus, Pawan Bir Kohli, Christopher A. Hurley, Guiling Zhao, Paul Gibbons, and Peter H. Crackett
- Subjects
Receptor complex ,Clinical Biochemistry ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,Dermatitis, Atopic ,Allergic inflammation ,Drug Discovery ,Humans ,Molecular Biology ,Interleukin-13 ,Janus kinase 1 ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Janus Kinase 1 ,Janus Kinase 2 ,Small molecule ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Tyrosine kinase 2 ,Interleukin 13 ,Cancer research ,Molecular Medicine ,Janus kinase ,Signal Transduction ,Janus Kinase Family - Abstract
Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).
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- 2019
26. Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling pathway in Takayasu's arteritis
- Author
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Lindi Jiang, Rongyi Chen, Lili Ma, Qingrong Huang, Xiaomeng Cui, Si Zhang, Xiaoming Dai, Ying Sun, Sifan Wu, Xiufang Kong, and Zongfei Ji
- Subjects
Male ,0301 basic medicine ,Adventitia ,Immunology ,Inflammation ,Models, Biological ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Western blot ,Fibrosis ,Autophagy ,medicine ,Humans ,Immunology and Allergy ,Interleukin 6 ,Aorta ,030203 arthritis & rheumatology ,biology ,medicine.diagnostic_test ,Interleukin-6 ,business.industry ,Autophagosomes ,Janus Kinase 1 ,medicine.disease ,Immunohistochemistry ,Takayasu Arteritis ,Collagen, type I, alpha 1 ,030104 developmental biology ,biology.protein ,Cancer research ,Female ,medicine.symptom ,Signal transduction ,business ,Signal Transduction - Abstract
Background Autophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6. Methods Autophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA. Results The expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway. Conclusions IL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA.
- Published
- 2019
27. A novel HBx genotype serves as a preoperative predictor and fails to activate the JAK1/STATs pathway in hepatocellular carcinoma
- Author
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Shuhan Sun, Fu Yang, Kongying Lin, Weiping Zhou, Qing‐guo Xu, Zhen-guang Wang, Qi-fei Tao, De-shu Dai, Fangming Gu, Hui Liu, Guo Xinggang, Jin-zhao Ma, Jingfeng Liu, Le-Qun Li, Ling-Hao Zhao, Yuan Yang, Shengxian Yuan, Yun-jin Zang, Jian Yu, and Jie Cai
- Subjects
0301 basic medicine ,Carcinoma, Hepatocellular ,Genotype ,viruses ,medicine.medical_treatment ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Viral Regulatory and Accessory Proteins ,Neoplasm Staging ,Hepatitis B virus ,Hepatology ,business.industry ,Liver Neoplasms ,Janus Kinase 1 ,Hepatitis B ,Prognosis ,medicine.disease ,digestive system diseases ,BCLC Stage ,STAT Transcription Factors ,HBx ,030104 developmental biology ,Hepatocellular carcinoma ,Trans-Activators ,Cancer research ,030211 gastroenterology & hepatology ,Hepatectomy ,Liver cancer ,business ,Signal Transduction - Abstract
Background & Aims Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. Methods We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. Results In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. Conclusion Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. Lay summary We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.
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- 2019
28. Janus kinase-1 and 3 in ankylosing spondylitis
- Author
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Chien Chih Lai, Tzu Hao Li, Wei Sheng Chen, Chun Hsiung Chen, Hsien-Tzung Liao, Hung An Chen, Chang-Youh Tsai, and Chung Tei Chou
- Subjects
Adult ,Male ,CD3 ,CD14 ,Taiwan ,Severity of Illness Index ,Peripheral blood mononuclear cell ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Spondylitis, Ankylosing ,BASDAI ,lcsh:R5-920 ,Ankylosing spondylitis ,biology ,Janus kinase 1 ,business.industry ,Acute-phase protein ,Janus Kinase 3 ,Janus Kinase 1 ,General Medicine ,Middle Aged ,medicine.disease ,C-Reactive Protein ,ROC Curve ,Case-Control Studies ,030220 oncology & carcinogenesis ,Immunology ,Leukocytes, Mononuclear ,biology.protein ,Female ,030211 gastroenterology & hepatology ,lcsh:Medicine (General) ,business ,BASFI ,Biomarkers - Abstract
Background/purpose: To investigate the Janus kinase-1 and 3 (JAK-1 and 3) expression in peripheral blood mononuclear cells (PBMCs) in ankylosing spondylitis (AS). Methods: The levels of JAK-1 and JAK-3 mRNA in PBMCs, CD3+ T cells and CD14+ monocytes were measured by RT-PCR in 52 AS patients and 31 healthy controls (HCs). The demographic features, BASDAI, BASFI, HLA-B27, ESR, CRP and serum immunoglobulin A (IgA) level were recorded and correlated with the JAK-1 & JAK-3 transcripts in patients and HCs as appropriate. Results: JAK-1 and JAK-3 expression in PB CD3+ T cells plus CD14+ monocytes was significantly higher in AS patients than in HCs (p 4) and BASFI (>4) than ESR or CRP in AS patients. Conclusion: In AS, JAK-1 expression in PB cells rather than ESR or CRP might be regarded as a bio-marker for monitoring disease activity and functional index in AS. These findings have also suggested that JAK-1 and JAK-3 expression may play a role in the inflammatory processes in patients with AS. Keywords: Ankylosing spondylitis, Janus kinase (JAK), Acute-phase reactant
- Published
- 2019
29. Identification of galangin as the bioactive compound from Alpinia calcarata (Haw.) Roscoe rhizomes to inhibit IRAK-1/ MAPK/ NF-κB p65 and JAK-1 signaling in LPS stimulated RAW 264.7 cells
- Author
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Thamizharasi Erusappan, Sivasakthi Paramasivam, and Sanmuga Priya Ekambaram
- Subjects
Flavonoids ,Inflammation ,Lipopolysaccharides ,Pharmacology ,Dose-Response Relationship, Drug ,Plant Extracts ,Anti-Inflammatory Agents ,Transcription Factor RelA ,Janus Kinase 1 ,Mice ,Interleukin-1 Receptor-Associated Kinases ,RAW 264.7 Cells ,Drug Discovery ,Alpinia ,Animals ,Mitogen-Activated Protein Kinases ,Rhizome - Abstract
Alpinia calcarata (Haw.) Roscoe rhizomes are used to treat diabetes, rheumatism, gastrointestinal problems, inflammatory diseases, cough and respiratory problems in traditional practices. The primary objective of the study is to identify and isolate anti-inflammatory bioactive compounds from A.calcarata rhizomes and to assess its molecular mechanism.The bioassay-guided fractionation of methanolic extract of A. calcarata rhizomes yielded chloroform fraction as the effective fraction and galangin as the bioactive compound identified by NMR studies. The anti-inflammatory action of galangin was evaluated by determining NO and cytokine production in LPS stimulated RAW264.7 cells. Further, its mechanism was studied on the expression levels of mRNA and protein targets by qPCR and Western blot analysis.Based on the MTT assay, the concentration of 3.1-25 μM of galangin was selected for further studies. Galangin reduced the levels of NO and proinflammatory cytokines (TNF-α, IL-1β and IL-6) production in LPS induced RAW 264.7 cells in a dose-dependent manner. In addition, the qPCR analysis revealed a reduction in the mRNA expression levels of COX-2, IRAK 1 and JAK 1 in galangin treated LPS stimulated RAW 264.7 cells in a dose-dependent manner. Western blot analysis implicated that galangin has markedly reduced the protein expression levels of cell signaling regulators (JAK-1, IRAK-1, MyD88, MAPK (p38 and ERK) and NF-κB p65).From the results, it is evident that the inhibition of these cell signaling regulators has contributed to the anti-inflammatory effects of galangin. To our knowledge, we are the first to report IRAK-1 and JAK-1 as therapeutic targets of galangin for its anti-inflammatory effect.
- Published
- 2022
30. RETRACTED: Angelica sinensis polysaccharide protects rat cardiomyocytes H9c2 from hypoxia-induced injury by down-regulation of microRNA-22
- Author
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Hui Pan and Linlin Zhu
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STAT3 Transcription Factor ,0301 basic medicine ,Time Factors ,Angelica sinensis ,Cell Survival ,Myocardial Infarction ,Down-Regulation ,Apoptosis ,Pharmacology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Western blot ,Polysaccharides ,medicine ,Animals ,Myocytes, Cardiac ,Viability assay ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Plants, Medicinal ,Dose-Response Relationship, Drug ,biology ,medicine.diagnostic_test ,Plant Extracts ,Cell growth ,Chemistry ,Janus Kinase 1 ,General Medicine ,biology.organism_classification ,Cell Hypoxia ,Rats ,MicroRNAs ,030104 developmental biology ,Cytoprotection ,Cell culture ,030220 oncology & carcinogenesis ,Phosphatidylinositol 3-Kinase ,Proto-Oncogene Proteins c-akt ,Phytotherapy ,Signal Transduction - Abstract
Background The cardioprotective role of Angelica sinensis has been proven in previous studies. However, the effects of Angelica sinensis polysaccharide (ASP, major bioactive component of Angelica sinensis) on myocardial infarction (MI) remain unclear. This study aimed to investigate the effects of ASP on hypoxia-induced H9c2 cell injury as well as the underlying mechanisms. Methods We constructed in vitro hypoxic model to mimic MI. Cell viability, proliferation and apoptosis were respectively measured by using CCK-8 assay, Western blot analysis, and flow cytometry assay/Western blot analysis, to evaluate cell injury after treatments. The effects of ASP pretreatment on hypoxia-induced injury were explored. Expression of miR-22 after treatments was determined by stem-loop RT-PCR, and whether ASP affected H9c2 cells via miR-22 was studied. Involvements of the PI3K/AKT and JAK1/STAT3 pathways were finally explored. Results Hypoxia-induced decreases of cell viability and proliferation as well as increase of apoptosis were attenuated by ASP pretreatments. Hypoxia treatment up-regulated miR-22 expression, and the up-regulation was mitigated by ASP pretreatment. Effects of ASP pretreatment on hypoxia-treated H9c2 cells were mitigated by miR-22 overexpression while were augmented by miR-22 inhibition. Phosphorylation levels of PI3K, AKT, JAK1 and STAT3 were increased by ASP through down-regulating miR-22 in hypoxia-treated H9c2 cells. Conclusion ASP pretreatment attenuated hypoxia-induced H9c2 cell injury, possibly through down-regulating miR-22 expression. The PI3K/AKT and JAK1/STAT3 pathways were activated by ASP pretreatment via miR-22 in hypoxia-treated cells.
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- 2018
31. Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages
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Marah C. Runtsch, Stefano Angiari, Alexander Hooftman, Ridhima Wadhwa, Yanling Zhang, Yunan Zheng, Joseph S. Spina, Melanie C. Ruzek, Maria A. Argiriadi, Anne F. McGettrick, Rui Santalla Mendez, Alessia Zotta, Christian G. Peace, Aoife Walsh, Roberta Chirillo, Emily Hams, Padraic G. Fallon, Ranjith Jayaraman, Kamal Dua, Alexandra C. Brown, Richard Y. Kim, Jay C. Horvat, Philip M. Hansbro, Chu Wang, and Luke A.J. O’Neill
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Endocrinology & Metabolism ,Physiology ,Macrophages ,Succinates ,Janus Kinase 1 ,Cell Biology ,Macrophage Activation ,Molecular Biology ,0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics ,Signal Transduction - Abstract
The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling. Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI. JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity. Finally, OI treatment suppressed M2 macrophage polarization and JAK1 phosphorylation in vivo. We therefore identify itaconate and OI as JAK1 inhibitors, suggesting a new strategy to inhibit JAK1 in M2 macrophage-driven diseases.
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- 2022
32. Synthesis and structure-activity relationship studies of 1,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 1 (JAK1) inhibitors
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Jae-Hoon Jung, Woochan Kim, Yong-Chul Kim, Sun-Mi Lee, and Pyeonghwa Jeong
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Models, Molecular ,Clinical Biochemistry ,Triazole ,Pharmaceutical Science ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,Isozyme ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,JAK1 Inhibitor ,Humans ,Janus Kinase Inhibitors ,Structure–activity relationship ,Pyrroles ,Molecular Biology ,IC50 ,Dose-Response Relationship, Drug ,Molecular Structure ,Janus kinase 1 ,biology ,Chemistry ,Organic Chemistry ,Janus Kinase 1 ,Triazoles ,In vitro ,Enzyme assay ,Pyrimidines ,biology.protein ,Molecular Medicine - Abstract
JAK inhibitors have been considered as useful targets for the treatment of related diseases. However, first-generation JAK inhibitors have side effects such as anemia, thrombocytopenia, neutropenia and headaches which have been suggested to result from high JAK2 inhibition. Second-generation JAK inhibitors with more specific JAK isozyme inhibition have been studied to eliminate these adverse effects. In this study, novel 4-(1,5- or 2,5-triazole)-pyrrolopyrimidine derivatives with aromatic moieties were synthesized as JAK1 inhibitors, and an in vitro enzyme assay was used to evaluate the JAK inhibitory effects. Among these JAK1 inhibitors, the compound 23a showed an IC50 level of 72 nM, as well as being selective against other JAKs by 12 times or more: the results of molecular docking studies suggested that the high JAK1 selectivity resulted from a key interaction between the iodine atom of compound 23a and His-885 of hJAK1
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- 2022
33. Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19
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Ji Zhang, Zhigang Qi, Weizhen Qiao, Yan Zhang, and Xiuhong Zhang
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0301 basic medicine ,animal diseases ,Cytokine storm ,Severity of Illness Index ,JAK-STAT ,0302 clinical medicine ,Baricitinib ,Immunology and Allergy ,Clinical Trials as Topic ,Sulfonamides ,biology ,JAK-STAT signaling pathway ,Treatment Outcome ,030220 oncology & carcinogenesis ,Rheumatoid arthritis ,Cytokines ,Angiotensin-Converting Enzyme 2 ,Coronavirus Infections ,Cytokine Release Syndrome ,Signal Transduction ,Pneumonia, Viral ,Immunology ,Peptidyl-Dipeptidase A ,Article ,Proinflammatory cytokine ,Betacoronavirus ,03 medical and health sciences ,Pharmaceutical care ,Viral entry ,medicine ,Humans ,Pandemics ,Pharmacology ,SARS-CoV-2 ,business.industry ,Virus Assembly ,C-reactive protein ,COVID-19 ,Janus Kinase 1 ,Janus Kinase 2 ,Virus Internalization ,medicine.disease ,COVID-19 Drug Treatment ,Pneumonia ,030104 developmental biology ,Purines ,biology.protein ,Azetidines ,Pyrazoles ,business ,Janus kinase - Abstract
Highlights • Cytokine storm is a key factor in the rapid deterioration of COVID-19. • Baricitinib could interrupt the passage of SARS-CoV-2 into the cells and treat cytokine storm. • The key points of pharmaceutical care have been elaborated in this article., In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1–2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.
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- 2020
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34. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
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Svitlana Tatulych, Thomas Bieber, Claire Feeney, Catherine Maari, Rodney Sinclair, Andreas Wollenberg, Michael J. Cork, Pinaki Biswas, Eric L. Simpson, Roland Aschoff, Carsten Flohr, Seth Forman, Hernan Valdez, Ricardo Rojo, Jacob P. Thyssen, Nina Magnolo, and Gil Yosipovitch
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Adult ,Male ,Canada ,medicine.medical_specialty ,Adolescent ,Eczema ,Administration, Oral ,030204 cardiovascular system & hematology ,Placebo ,Severity of Illness Index ,Eczema Area and Severity Index ,Dermatitis, Atopic ,law.invention ,Placebos ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Severity of illness ,Ethnicity ,medicine ,Humans ,030212 general & internal medicine ,Child ,Protein Kinase Inhibitors ,Aged ,Asthma ,Body surface area ,Sulfonamides ,business.industry ,Australia ,Janus Kinase 1 ,General Medicine ,Atopic dermatitis ,Middle Aged ,medicine.disease ,United States ,Europe ,Clinical trial ,Pyrimidines ,Treatment Outcome ,Case-Control Studies ,Female ,Safety ,business - Abstract
Background\ud \ud Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.\ud \ud \ud Methods\ud \ud In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.\ud \ud \ud Findings\ud \ud Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p
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- 2020
35. Intestinal epithelial cells express immunomodulatory ISG15 during active ulcerative colitis and Crohn's disease
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Wahida Afroz, Helene Kolstad Skovdahl, Gunnar Andreas Walaas, Tarjei Dahl Svendsen, Ingunn Bakke, Torunn Bruland, Berit Doseth, Bjorn I. Gustafsson, Silje Thorsvik, Arne K. Sandvik, Ann Elisabet Østvik, Tom Eirik Mollnes, and Atle van Beelen Granlund
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Chemokine ,ISG15 ,medicine.medical_treatment ,Biopsy ,Gene Expression ,Crohn Disease ,CD11a Antigen ,innate immunity ,biology ,Gastroenterology ,General Medicine ,Interleukin-12 ,Lymphocyte Function-Associated Antigen-1 ,VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710 ,Up-Regulation ,Organoids ,STAT Transcription Factors ,Cytokine ,Receptors, Pattern Recognition ,Interferon Type I ,Cytokines ,HT29 Cells ,Signal Transduction ,Colon ,digestive system ,Proinflammatory cytokine ,medicine ,Humans ,Interleukin 8 ,RNA, Messenger ,Ubiquitins ,AcademicSubjects/MED00260 ,Human intestinal organoids ,Innate immune system ,business.industry ,Sequence Analysis, RNA ,Tumor Necrosis Factor-alpha ,Epithelial Cells ,VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710 ,Original Articles ,Janus Kinase 1 ,Immunity, Innate ,digestive system diseases ,Toll-Like Receptor 3 ,CCL20 ,TLR3 ,Cancer research ,biology.protein ,Leukocytes, Mononuclear ,Colitis, Ulcerative ,business - Abstract
Background and Aims Intestinal epithelial cells [IECs] secrete cytokines that recruit immune cells to the mucosa and regulate immune responses that drive inflammation in inflammatory bowel disease [IBD]. However, experiments in patient-derived IEC models are still scarce. Here, we aimed to investigate how innate immunity and IEC-specific pattern recognition receptor [PRR] signalling can be involved in an enhanced type I interferon [IFN] gene signature observed in colon epithelium of patients with active IBD, with a special focus on secreted ubiquitin-like protein ISG15. Methods Gene and protein expression in whole mucosa biopsies and in microdissected human colonic epithelial lining, in HT29 human intestinal epithelial cells and primary 3D colonoids treated with PRR-ligands and cytokines, were detected by transcriptomics, in situ hybridisation, immunohistochemistry, western blots, and enzyme-linked immunosorbent assay [ELISA]. Effects of IEC-secreted cytokines were examined in human peripheral blood mononuclear cells [PBMCs] by multiplex chemokine profiling and ELISA. Results The type I IFN gene signature in human mucosal biopsies was mimicked in Toll-like receptor TLR3 and to some extent tumour necrosis factor [TNF]-treated human IECs. In intestinal biopsies, ISG15 expression correlated with expression of the newly identified receptor for extracellular ISG15, LFA-1 integrin. ISG15 was expressed and secreted from HT29 cells and primary 3D colonoids through both JAK1-pSTAT-IRF9-dependent and independent pathways. In experiments using PBMCs, we show that ISG15 releases IBD-relevant proinflammatory cytokines such as CXCL1, CXCL5, CXCL8, CCL20, IL1, IL6, TNF, and IFNγ. Conclusions ISG15 is secreted from primary IECs upon extracellular stimulation, and mucosal ISG15 emerges as an intriguing candidate for immunotherapy in IBD.
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- 2020
36. Transcriptome of porcine alveolar macrophages activated by interferon-gamma and lipopolysaccharide
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Xijun He, Yong-Li Zhang, Xuehui Cai, Zhuo Zhang, Wei Hu, Shouping Hu, and Qiang Liu
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Lipopolysaccharides ,0301 basic medicine ,Lipopolysaccharide ,Swine ,Primary Cell Culture ,Biophysics ,Immunoglobulins ,Argininosuccinate Synthase ,Biology ,Virus Replication ,Biochemistry ,Proinflammatory cytokine ,Transcriptome ,Interferon-gamma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Macrophages, Alveolar ,medicine ,Animals ,Cell Lineage ,Porcine respiratory and reproductive syndrome virus ,Interferon gamma ,Receptors, Cytokine ,Molecular Biology ,Cell Differentiation ,Molecular Sequence Annotation ,Janus Kinase 1 ,Cell Biology ,Porcine reproductive and respiratory syndrome virus ,biology.organism_classification ,Phenotype ,Cell biology ,STAT Transcription Factors ,Gene Ontology ,030104 developmental biology ,chemistry ,Viral replication ,030215 immunology ,medicine.drug - Abstract
The molecular repertoire of porcine alveolar macrophages (PAMs) is greatly affected by the microenvironment they are exposed to, and specifically by inflammatory cytokines, such as interferon gamma (IFN-γ) released by activated lymphocytes, and microbial products, such as lipopolysaccharide (LPS). In our previous study, we found that IFN-γ- and LPS-activated PAMs (M1) could inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication. In this study, comprehensive analysis of the expression profiles of the genes associated with the polarization of M0-type PAMs (resting) toward M1 phenotypes (activated by IFN-γ and LPS) led to the following main results: 1) 1551 and 1823 genes were upregulated or downregulated in M1-type PAMs, respectively, compared with M0-type PAMs; 2) Among these, genes encoding ASS1 and CRTAM were the most upregulated and downregulated, respectively; 3) Genes involved in cytokine-cytokine receptor interaction and the JAK/STAT signaling pathway were significantly upregulated, suggesting their critical role in cellular activation; and 4) Genes involved in antigen proteolysis and presentation (immunoproteasome subunits), and inhibition of virus replication (host restriction factors) were significantly upregulated, emphasizing the critical role of these cytokines in immunity. Thus, our results provide important information for future studies on the role of PAM polarization in modulation of infection.
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- 2018
37. JAK1-mediated Sirt1 phosphorylation functions as a negative feedback of the JAK1-STAT3 pathway
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Fei Li, Juncheng Wei, Beixue Gao, Guohua Yu, Deyu Fang, Yuanming Xu, Yana Zhang, Wenhui Wang, and Heeyoung Yang
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STAT3 Transcription Factor ,0301 basic medicine ,endocrine system diseases ,environment and public health ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Sirtuin 1 ,Humans ,Phosphorylation ,Molecular Biology ,Transcription factor ,Feedback, Physiological ,biology ,Janus kinase 1 ,Chemistry ,Janus Kinase 1 ,Cell Biology ,Cell biology ,Enzyme Activation ,enzymes and coenzymes (carbohydrates) ,HEK293 Cells ,030104 developmental biology ,Histone ,Acetylation ,030220 oncology & carcinogenesis ,biology.protein ,Tyrosine ,Histone deacetylase ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Tyrosine kinase ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
The type III NAD–dependent histone deacetylase Sirt1 plays important roles in a variety of pathobiological functions through targeting either the acetylated histones or transcription factors. However, the molecular mechanisms underlying how the Sirt1 functions are regulated remain vague. Herein we identified that the Janus kinase 1 (JAK1) interacts with Sirt1 and catalyzes its phosphorylation at the tyrosine residues of 280 and 301, both of which are highly conserved and located in the histone deacetylase catalytic domain of Sirt1. IL-6 stimulation enhanced Sirt1 interaction with JAK1 and JAK1-mediated Sirt1 phosphorylation. Interestingly, JAK1-mediated Sirt1 phosphorylation did not alter Sirt1 deacetylase catalytic activity, but instead it is required for Sirt1 interaction with the downstream transcription factor STAT3. JAK1-mediated phosphorylation enhanced Sirt1 suppression of STAT3 acetylation and transcriptional activity. As a consequence, Sirt1 activation attenuates IL-6 activity in protecting cancer cells from chemotherapeutic drug–induced apoptosis. Our studies identify JAK1 as a previously unappreciated tyrosine kinase of Sirt1 and reveal a novel negative feedback of the JAK1-STAT3 pathway.
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- 2018
38. Development of selective inhibitors for the treatment of rheumatoid arthritis: (R)-3-(3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor
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Chieyeon Chough, Sunmin Lee, Misuk Joung, Jonghoon Kim, Lee Jae-Min, and B. Moon Kim
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Male ,0301 basic medicine ,Pyrrolidines ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Arthritis, Rheumatoid ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,In vivo ,Oral administration ,Drug Discovery ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Molecular Biology ,IC50 ,030203 arthritis & rheumatology ,Mice, Inbred ICR ,Tofacitinib ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,Janus Kinase 1 ,medicine.disease ,Enzyme assay ,Rats ,Pyrimidines ,030104 developmental biology ,Mice, Inbred DBA ,Rheumatoid arthritis ,Microsomes, Liver ,biology.protein ,Microsome ,Molecular Medicine ,Selectivity - Abstract
A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib’s core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC50 11, 2.4 × 102, 2.8 × 103, and 1.1 × 102 nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.
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- 2018
39. Enhanced perforin expression associated with dasatinib therapy in natural killer cells
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Yoshihiro Hatta, Masami Takei, Noriyoshi Iriyama, Hiromichi Takahashi, Masaru Nakagawa, Katsuhiro Miura, and Yoshihito Uchino
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Adult ,Male ,STAT3 Transcription Factor ,Cancer Research ,medicine.drug_class ,medicine.medical_treatment ,Dasatinib ,Antineoplastic Agents ,Tyrosine-kinase inhibitor ,Interferon-gamma ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Humans ,STAT3 ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,biology ,Perforin ,business.industry ,Janus Kinase 1 ,Hematology ,Middle Aged ,Killer Cells, Natural ,Pyrimidines ,STAT1 Transcription Factor ,Cytokine ,Oncology ,Nilotinib ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,biology.protein ,Cancer research ,Interleukin-2 ,Female ,Janus kinase ,business ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
We investigated the effects of dasatinib on natural killer (NK) cell-induced signaling protein and perforin expression as well as plasma cytokine levels by analyzing blood samples from patients with well-controlled chronic myeloid leukemia receiving tyrosine kinase inhibitor (TKI) therapy. Perforin expression and phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, Janus kinase (JAK) 1, and JAK2 in NK cells were evaluated by flow cytometry, and the levels of plasma cytokines, including interferon (IFN)-γ and interleukin (IL)-2, were determined by enzyme-linked immunosorbent assays in 40 patients (dasatinib, n = 23; imatinib, n = 11; and nilotinib, n = 6). Perforin levels in NK cells were higher in dasatinib-treated patients before TKI treatment; phospho (p)-STAT1 levels were closely correlated with pJAK1 and perforin levels, and pSTAT3 levels were correlated with pJAK2 and perforin levels. The correlation between pJAK1 and pSTAT1 was apparent in dasatinib-treated patients but not in other TKI-treated patients, and the correlation between pJAK2 and pSTAT3 was apparent in patients treated with other TKIs. Constitutive expression of IFN-γ was higher in patients treated with dasatinib or with other TKIs than in those who were in treatment-free remission (TFR). In contrast, constitutive expression of IL-2 was lower in patients treated with other TKIs than in those treated with dasatinib or in those who were in TFR. These results provided insights into the effects of dasatinib on JAK/STAT signaling in NK cells in vivo and the mechanisms underlying NK cell activation induced by dasatinib therapy.
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- 2018
40. African swine fever virus protein MGF-505-7R promotes virulence and pathogenesis by inhibiting JAK1- and JAK2-mediated signaling
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Li Dan, Weifang Kang, Lulu Li, Jing Zhang, Yong Ran, Wenping Yang, Li Pan, Yi Ru, and Haixue Zheng
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RNF125 ,MAP Kinase Signaling System ,Swine ,Virulence Factors ,Virulence ,Biology ,Biochemistry ,African swine fever virus ,Cell Line ,Proinflammatory cytokine ,Viral Proteins ,Immune system ,CAAS, Chinese Academy of Agricultural Sciences ,Macrophages, Alveolar ,IRF1, IFN-regulatory factor 1 ,Animals ,Humans ,ASFV, African swine fever virus ,African Swine Fever ,HAD, hemadsorption ,Molecular Biology ,Innate immune system ,Attenuated vaccine ,PAM, porcine alveolar macrophage ,DNA virus ,Janus Kinase 1 ,Cell Biology ,Janus Kinase 2 ,biology.organism_classification ,African Swine Fever Virus ,Virology ,Ubiquitin ligase ,JAK1 ,JAK2 ,biology.protein ,FMDV, foot-and-mouth disease virus ,LVRI, Lanzhou Veterinary Research Institute ,ASFV ,Hes5 ,MGF-505-7R ,Research Article - Abstract
African swine fever virus (ASFV) is a large DNA virus that is highly contagious and pathogenic in domestic pigs with a mortality rate up to 100%. However, how ASFV suppresses JAK-STAT1 signaling to evade the immune response remains unclear. In this study, we found that the ASFV-encoded protein MGF-505-7R inhibited proinflammatory IFN-γ-mediated JAK-STAT1 signaling. Mechanistically, MGF-505-7R was found to interact with JAK1 and JAK2 and mediate their degradation. Further study indicated that MGF-505-7R promoted degradation of JAK1 and JAK2 by upregulating the E3 ubiquitin ligase RNF125 expression and inhibiting expression of Hes5, respectively. Consistently, MGF-505-7R-deficient ASFV induced high levels of IRF1 expression and displayed compromised replication both in primary porcine alveolar macrophages and pigs compared with wild-type ASFV. Furthermore, MGF-505-7R deficiency attenuated the virulence of the ASFV and pathogenesis of ASF in pigs. These findings suggest that the JAK-STAT1 axis mediates the innate immune response to the ASFV and that MGF-505-7R plays a critical role in the virulence of the ASFV and pathogenesis of ASF by antagonizing this axis. Thus, we conclude that deletion of MGF-505-7R may serve as a strategy to develop attenuated vaccines against the ASFV.
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- 2021
41. Multicentric Castleman disease revealing complete signal transducer and activator of transcription 1 deficiency treated by JAK1/2 inhibition
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Jean-Jacques De Bruycker, Camille Beaufils, Jean-François Soucy, Philippe Ovetchkine, Luc L. Oligny, Marie-Paule Morin, Sonia Cellot, Isabel Fernandez, Elie Haddad, Lorie Marchitto, and Fabien Touzot
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STAT3 Transcription Factor ,Hemophagocytic lymphohistiocytosis ,Ruxolitinib ,business.industry ,Castleman Disease ,Janus Kinase 1 ,medicine.disease ,STAT1 Transcription Factor ,Cancer research ,medicine ,STAT protein ,Primary immunodeficiency ,Humans ,Immunology and Allergy ,Multicentric Castleman Disease ,business ,medicine.drug - Published
- 2021
42. The JAK inhibitor Tofacitinib inhibits structural damage in osteoarthritis by modulating JAK1/TNF-alpha/IL-6 signaling through Mir-149-5p
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Wei Hwa Lee, Chih Cheng Lin, Oluwaseun Adebayo Bamodu, Yen Shuo Chiu, Iat Hang Fong, Chen Hsu Lu, and Chi Tai Yeh
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0301 basic medicine ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Arthritis ,030209 endocrinology & metabolism ,Chondrocyte hypertrophy ,Inflammation ,Proinflammatory cytokine ,Muscle hypertrophy ,Mice ,03 medical and health sciences ,Chondrocytes ,0302 clinical medicine ,Piperidines ,Osteoarthritis ,medicine ,Animals ,Janus Kinase Inhibitors ,Tofacitinib ,biology ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Janus Kinase 1 ,medicine.disease ,MicroRNAs ,Pyrimidines ,030104 developmental biology ,RANKL ,biology.protein ,Cancer research ,Tumor necrosis factor alpha ,medicine.symptom ,business - Abstract
Background Osteoarthritis (OA), a common articular bone degenerative disease, is exacerbated by proinflammatory cytokine signaling. Mounting evidence suggests that epigenetic modifiers, namely microRNAs (miRs), are dysregulated in articular chondrocytes (ACs) during OA. Methods An initial database search led to the identification of miR-149-5p, which was downregulated in clinical OA samples and contributed to chronic inflammation, by increasing TNF-α/IL-6 signaling within the synovium, and OA progression. Results We overexpressed miR-149-5p in the human chondrocyte cell lines C20A4 and C28/I2 to examine its role in chondrocyte hypertrophy and osteoclastogenesis and found a significant decrease in IL-6 expression, an increase in SOX9 expression, and a reduction in chondrocyte hypertrophy. We evaluated the therapeutic effects of tofacitinib (JAK inhibitor) by suppressing inflammation and restoring miR-149-5p expression. Tofacitinib-treated C20A4 and C28/I2 cells had a significantly lower expression of JAK/IL-6/TNF-α and an increased level of miR-149-5p. Notably, tofacitinib treatment reduced AC hypertrophy and secretion of RANKL and IL-6. Finally, an OA mouse model was used to evaluate the therapeutic potential of tofacitinib. Intra-articular injection of tofacitinib significantly lowered arthritis scores and bone degradation in treated mice compared with their control counterparts. Conclusion We show for the first time that tofacitinib suppresses the expression level of JAK1/TNF-α/IL-6 by upregulating miR-149-5p level. Our findings revealed the functional association between proinflammatory JAK1/TNF-α/IL-6 signaling and ACs development and highlight the therapeutic potential of tofacitinib in OA.
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- 2021
43. The JAK1/2 inhibitor baricitinib suppresses eosinophil effector function and restricts allergen-induced airway eosinophilia
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Akos Heinemann, Johannes Pilic, Petra Luschnig, David Roula, Melanie Kienzl, Reham Atallah, and Eva M. Sturm
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Adult ,Male ,Biochemistry ,Mice ,Young Adult ,Eosinophilia ,Animals ,Humans ,Janus Kinase Inhibitors ,Medicine ,Cells, Cultured ,Pharmacology ,Mice, Inbred BALB C ,Sulfonamides ,Eosinophil differentiation ,Tofacitinib ,business.industry ,Effector ,Pyroglyphidae ,JAK-STAT signaling pathway ,Janus Kinase 1 ,Janus Kinase 2 ,respiratory system ,Eosinophil ,respiratory tract diseases ,Respiratory burst ,Eosinophils ,medicine.anatomical_structure ,Purines ,Immunology ,Eosinophil chemotaxis ,Azetidines ,Pyrazoles ,Female ,medicine.symptom ,business - Abstract
Background Eosinophilic asthma is increasingly recognized as one of the most severe and difficult-to-treat asthma subtypes. The JAK/STAT pathway is the principal signaling mechanism for a variety of cytokines and growth factors involved in asthma. However, the direct effect of JAK inhibitors on eosinophil effector function has not been addressed thus far. Objective Here we compared the effects of the JAK1/2 inhibitor baricitinib and the JAK3 inhibitor tofacitinib on eosinophil effector function in vitro and in vivo. Methods Differentiation of murine bone marrow-derived eosinophils. Migratory responsiveness, respiratory burst, phagocytosis and apoptosis of human peripheral blood eosinophils were assessed in vitro. In vivo effects were investigated in a mouse model of acute house dust mite-induced airway inflammation in BALB/c mice. Results Baricitinib more potently induced apoptosis and inhibited eosinophil chemotaxis and respiratory burst, while baricitinib and tofacitinib similarly affected eosinophil differentiation and phagocytosis. Of the JAK inhibitors, oral application of baricitinib more potently prevented lung eosinophilia in mice following allergen challenge. However, both JAK inhibitors neither affected airway resistance nor compliance. Conclusion Our data suggest that the JAK1/2 inhibitor baricitinib is even more potent than the JAK3 inhibitor tofacitinib in suppressing eosinophil effector function. Thus, targeting the JAK1/2 pathway represents a promising therapeutic strategy for eosinophilic inflammation as observed in severe eosinophilic asthma.
- Published
- 2021
44. 26237 Baricitinib, an oral, reversible Janus kinase-1 and -2 inhibitor, for atopic dermatitis: Head and neck response from BREEZE-AD5
- Author
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Neil J. Korman, Yves Poulin, Jose Luis Rueda, Benjamin Lockshin, Na Lu, Orin Goldblum, Robert Bissonnette, and Yun-Fei Chen
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medicine.medical_specialty ,Janus kinase 1 ,business.industry ,Baricitinib ,Medicine ,Dermatology ,Atopic dermatitis ,business ,Head and neck ,medicine.disease - Published
- 2021
45. Berberine suppresses bladder cancer cell proliferation by inhibiting JAK1-STAT3 signaling via upregulation of miR-17-5p
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Jiangxia Li, Shuna Sun, Shouzhen Chen, Yangli Shen, Li Gong, Yongxin Zou, Yaofeng Zhu, Yong Wang, Yangyang Xia, Xuewen Jiang, Wenfu Wang, Xiaochen Liu, Benkang Shi, and Jianfeng Cui
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,Cell cycle checkpoint ,Berberine ,Cell ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cytotoxic T cell ,skin and connective tissue diseases ,STAT3 ,Cell Line, Transformed ,Cell Proliferation ,Pharmacology ,Mice, Inbred BALB C ,biology ,Janus kinase 1 ,Chemistry ,Janus Kinase 1 ,Xenograft Model Antitumor Assays ,Up-Regulation ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Urinary Bladder Neoplasms ,Apoptosis ,030220 oncology & carcinogenesis ,STAT protein ,biology.protein ,Cancer research ,Female ,Signal Transduction - Abstract
Background: Berberine (BBR), an active component extracted from Coptis chinensis, has shown anti-tumor effects in multiple tumors. However, the underlying mechanisms haven’t been fully elucidated. In this study, the effects of BBR on bladder cancer (BCa) cells and the underlying mechanisms were investigated both in vivo and vitro. Methods: MTT, colony formation, EdU incorporation assays and xenograft tumor models were performed to evaluate the anti-proliferation effects of BBR on BCa cells in vivo and vitro. The roles of BRR in migration and invasion of BCa cells were investigated by wound-healing, transwell migration and invasion assays. The apoptosis and senescence induced by BBR were determined by flow cytometry, tunel assay and senescence-associated β-galactosidase (SA-β-gal) activity assay. Potential candidate targets were screened using western blot. The relationships between miR-17-5p and JAK1-STAT3 pathway were then predicted using in-silico analysis and identified by dual-luciferase reporter assay. The regulatory mechanism of miR-17-5p mediated suppression of JAK1-STAT3 pathway caused by BBR treatment was validated by qRT-PCR and western blot.Results: We found that BBR showed significant cytotoxic effects against bladder cancer (BCa) cell lines both in vivo and vitro, with much lower cytotoxic effects on human normal urothelial cell line SV-HUC-1. BBR treatment induced DNA replication defects and cycle cell arrest, resulting in apoptosis or cell senescence, depending on p53 status, in BCa cells. Mechanically, BBR exerted anti-tumor effects on BCa cells through inhibiting JAK1-STAT3 signaling via promoting expression of miR-17-5p, which directly bound to 3’ UTR of JAK1 and STAT3 and downregulated their expressions. Conclusion: Our results demonstrate that BBR exerts anti-tumor effects through perturbing JAK1-STAT3 signaling via upregulating expression of miR-17-5p in BCa cells, and BBR may serve as a potential therapeutic option for BCa treatment.
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- 2021
46. JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis
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Nicole Leib, Thomas Bieber, Nadine Herrmann, Joerg Wenzel, Anna Sophie Klaeschen, Tim Joachim Nümm, Takashi Sakai, and Laura Maintz
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0301 basic medicine ,Cellular differentiation ,Immunology ,Gene Expression ,Dermatitis, Atopic ,Proinflammatory cytokine ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Immunology and Allergy ,Medicine ,Protein Kinase Inhibitors ,Interleukin 4 ,business.industry ,Cell Differentiation ,Janus Kinase 1 ,Dendritic cell ,Janus Kinase 2 ,030104 developmental biology ,Epidermal Cells ,Interleukin 13 ,STAT protein ,Cancer research ,Cytokines ,business ,Janus kinase ,Tyrosine kinase - Abstract
Background Janus kinase (JAK) inhibitors are a new class of therapeutic compounds for dermatological diseases. In atopic dermatitis (AD), data of clinical phase III trials show rapid improvement of pruritus and significant reduction of inflammation within the first weeks with a favorable safety profile. However, their mode of action in AD is not fully understood. Objectives In our study, we investigate the effect of different JAK inhibitors on cell differentiation, phenotype, and function of inflammatory dendritic epidermal cells (IDECs). Methods We analyzed the JAK expression in IDEC from ex vivo skin and in vitro generated IDECs using flow cytometry and PCR. Further, we studied in vitro the effect of different JAK inhibitors on IDEC cell differentiation, phenotype, and maturation. Results IDECs express JAK1 and JAK2 ex vivo and in vitro. We found that JAK1 and JAK2 were upregulated during the differentiation from monocytes to IDECs. Conversely, JAK2 inhibition by ruxolitinib (JAK1/2 inhibitor) or BMS-911543 (JAK2 inhibitor) abrogated the differentiation from monocytes into IDECs. Differentiated IDECs can redifferentiate into a more monocyte-like phenotype in the presence of ruxolitinib or BMS-911543. Furthermore, we showed that concomitant inhibition of JAK1/2 rather than blocking JAK1 or JAK2 alone, impaired maturation and the release of proinflammatory cytokines on lipopolysaccharide stimulation. Conclusions Our results suggest that inhibition of JAK1/2 impairs IDEC differentiation and function. We provide new insight into the mode of action of JAK inhibitors in AD and highlight the role of JAK1/2 inhibitors for the treatment of patients with AD.
- Published
- 2021
47. A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia
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Yan Xin, Carrie Baker Brachmann, Srdan Verstovsek, Lixin Shao, Stephane Courby, Ashish Bajel, Julia D. Maltzman, Ruben A. Mesa, Daniel Huang, Martin Griesshammer, and Jun Kawashima
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Adult ,Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Nausea ,Phases of clinical research ,Essential thrombocythemia ,Hematocrit ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Polycythemia vera ,White blood cell ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Phase 2 study ,Janus Kinase 1 ,Hematology ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,Surgery ,Pyrimidines ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Benzamides ,Female ,medicine.symptom ,business ,Momelotinib ,Thrombocythemia, Essential - Abstract
Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100 mg and 200 mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit < 45%, white blood cell count < 10 × 109/L, platelet count ≤400 × 109/L, and resolution of palpable splenomegaly, each lasting ≥4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving ≥12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200 mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET).
- Published
- 2017
48. JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics
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Thomas A. Waldmann
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STAT3 Transcription Factor ,0301 basic medicine ,T-Lymphocytes ,medicine.medical_treatment ,T-cell leukemia ,Antineoplastic Agents ,Biology ,Biochemistry ,Article ,stat ,03 medical and health sciences ,Endocrinology ,Antineoplastic Combined Chemotherapy Protocols ,STAT5 Transcription Factor ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Phosphorylation ,STAT3 ,Protein Kinase Inhibitors ,Molecular Biology ,Cell Proliferation ,Sulfonamides ,Aniline Compounds ,Janus Kinase 3 ,JAK-STAT signaling pathway ,Janus Kinase 1 ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cytokine ,Cancer research ,biology.protein ,Signal transduction ,Janus kinase ,Signal Transduction - Abstract
Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals. Functional cytokine receptors were required for pSTAT expression. Combining a JAK1/2 inhibitor with a Bcl-xL inhibitor navitoclax provided additive/synergistic activity with IL-2 dependent ATLL cell lines and in a mouse model of human IL-2 dependent ATLL. The insight that disorders of the γc/JAK/STAT system are pervasive suggests approaches including those that target gamma cytokines, their receptors or that use JAK kinase inhibitors may be of value in multicomponent therapy for T-cell malignancies.
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- 2017
49. Defective IL-4 signaling in T cells defines severe common variable immunodeficiency
- Author
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June Helen Myklebust, Vera Hilden, Børre Fevang, Johanna Olweus, Kjetil Taskén, Pål Aukrust, Eli Taraldsrud, Silje F. Jørgensen, and Kristine Moltu
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Adult ,Male ,0301 basic medicine ,T-Lymphocytes ,T cell ,Programmed Cell Death 1 Receptor ,Immunology ,Gene Expression ,Biology ,medicine.disease_cause ,Severity of Illness Index ,Immunophenotyping ,Autoimmunity ,Hypogammaglobulinemia ,03 medical and health sciences ,Th2 Cells ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Interleukin 4 ,STAT6 ,Common variable immunodeficiency ,Interleukin ,Janus Kinase 1 ,Middle Aged ,Th1 Cells ,medicine.disease ,Common Variable Immunodeficiency ,030104 developmental biology ,medicine.anatomical_structure ,Female ,Interleukin-4 ,STAT6 Transcription Factor ,Biomarkers ,Signal Transduction - Abstract
Common variable immunodeficiency (CVID) is defined by hypogammaglobulinemia and B-cell dysfunction, with significant clinical and immunological heterogeneity. Severe non-infectious complications, such as autoimmunity, granulomatous disease and splenomegaly, constitute a major cause of morbidity in CVID patients. T cells are generally regarded important for development of these clinical features. However, while T-cell abnormalities have been found in CVID patients, functional characteristics of T cells corresponding to well-defined clinical subtypes have not been identified. As common γ-chain cytokines play important roles in survival and differentiation of T cells, characterization of their signaling pathways could reveal functional differences of clinical relevance. We characterized CVID T cells functionally by studies of cytokine-induced signaling, and correlated the findings to defined clinical subtypes. Peripheral blood T cells from 29 CVID patients and 19 healthy donors were analyzed for i) phenotype, ii) cytokine-induced (interleukin (IL)-2, IL-4, IL-7 and IL-21) phosphorylation of signal transducer and activator of transcription (STAT) 3, STAT5 and STAT6, and iii) T-helper (Th)1/Th2 polarization. Expression of IL-4 receptor and downstream signaling molecules was measured. A subgroup of CVID patients (n = 7) was identified by impaired IL-4-induced p-STAT6 in naive and memory CD4 and CD8 T cells. This corresponded to patients with the largest accumulation of severe (non-infectious) complications. The signaling defect persisted over years and was not due to constitutively activated p-STAT6. The CD4 T cells were strongly Th1-skewed, but IL-4 signaling was impaired independently of Th status. However, IL-4Rα and Janus kinase (JAK) 1 mRNA levels were significantly lower than in normal donors, providing a likely mechanism for the defective IL-4-induced p-STAT6 and Th1-bias. In conclusion, we identified a subgroup of CVID patients with defective IL-4 signaling in T cells, with severe clinical features of inflammation and autoimmunity.
- Published
- 2017
50. Enterovirus 71 suppresses interferon responses by blocking Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling through inducing karyopherin-α1 degradation
- Author
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Carol J. Cardona, Yu Jin, Lianfu Ji, Xinhui Yuan, Zheng Xing, Menghuai Sun, and Chunyang Wang
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alpha Karyopherins ,0301 basic medicine ,Recombinant Fusion Proteins ,030106 microbiology ,Active Transport, Cell Nucleus ,Virus Replication ,Microbiology ,Biochemistry ,stat ,Virus ,03 medical and health sciences ,Interferon ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,STAT1 ,Phosphorylation ,Vero Cells ,Molecular Biology ,Cytopathic effect ,biology ,Caspase 3 ,STAT2 Transcription Factor ,Interferon-beta ,Janus Kinase 1 ,Cell Biology ,Virology ,Enterovirus A, Human ,Enterocytes ,STAT1 Transcription Factor ,030104 developmental biology ,Viral replication ,Proteolysis ,STAT protein ,biology.protein ,RNA Interference ,Janus kinase ,HT29 Cells ,Protein Processing, Post-Translational ,HeLa Cells ,Signal Transduction ,medicine.drug - Abstract
Enterovirus 71 (EV71) has emerged as one of the most important enteroviruses since the eradication of poliovirus, and it causes severe neurological symptoms for which no effective antiviral drugs are available. Type I interferons (IFN) α/β have been used clinically as antiviral therapy as the first line of defense against virus infections successfully for decades. However, treatment with type I interferons has not been effective in patients with EV71 infection. In this study, we found that in cells pretreated with IFN-β, EV71 infection could still lead to a cytopathic effect, and the viral replication was not affected. The mechanism by which EV71 antagonizes interferon signaling, however, has been controversial. Our study indicated that EV71 infection did not inhibit phosphorylation of STAT1/2 induced by IFN-β stimulation, but p-STAT1/2 transport into the nucleus was significantly blocked. We showed that EV71 infection reduced the formation of STAT/karyopherin-α1 (KPNA1) complex upon interferon stimulation and that the virus down-regulated the expression of KPNA1, a nuclear localization signal receptor for p-STAT1. Using specific caspase inhibitors and siRNA for caspase-3, we demonstrated that EV71 infection induced degradation of cellular KPNA1 in a caspase-3-dependent manner, which led to decreased induction of interferon-inducible genes and IFN response. Viral 2A and 3C proteases did not degrade KPNA1, inhibit the activity of ISRE or suppress the transcription of interferon-inducible genes induced by IFN-β. Our study demonstrates a novel mechanism by which antiviral signaling is suppressed through degradation of KPNA1 by activated caspase-3 induced in an enteroviral infection.
- Published
- 2017
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