931 results on '"Janus Kinase 1 metabolism"'
Search Results
2. Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.
- Author
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Huang H, Chen H, Yao Y, and Lou X
- Subjects
- Animals, Mice, Male, Janus Kinase 1 metabolism, Diet, High-Fat adverse effects, Adipose Tissue metabolism, Cytokines metabolism, Dietary Supplements, Inflammation metabolism, Disease Models, Animal, Amino Acids, Branched-Chain metabolism, Amino Acids, Branched-Chain administration & dosage, Insulin Resistance, Macrophages metabolism, Signal Transduction, Obesity metabolism, Obesity etiology, STAT1 Transcription Factor metabolism
- Abstract
Background: Obesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes., Methods: In vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings., Results: We found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization., Conclusions: The obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients., (© 2024. The Author(s).)
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- 2024
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3. Genetic and Pharmacologic Inhibition of JAK1/2 Antagonizes Cardiac Fibrosis.
- Author
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Meng Q, Yang B, Qiao Y, Wu Y, Chen J, Lin X, and Molkentin JD
- Subjects
- Animals, Mice, Myocardium pathology, Myocardium metabolism, Humans, Mice, Knockout, Janus Kinase 2 genetics, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 genetics, Janus Kinase 1 metabolism, Fibrosis
- Abstract
Competing Interests: None.
- Published
- 2024
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4. Key subdomains of mesencephalic astrocyte-derived neurotrophic factor attenuate myocardial ischemia/reperfusion injury by JAK1/STAT1/NF-κB signaling pathway.
- Author
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Dong H, Jia W, Wang C, Teng D, Xu B, Ding X, Yang J, Zhong L, and Gong L
- Subjects
- Animals, Mice, Humans, Male, Endoplasmic Reticulum Stress, Cell Line, Disease Models, Animal, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury genetics, Signal Transduction, NF-kappa B metabolism, Nerve Growth Factors metabolism, Nerve Growth Factors genetics, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, Myocytes, Cardiac metabolism, STAT1 Transcription Factor metabolism, Apoptosis
- Abstract
Background: Myocardial ischemia/reperfusion (I/R) injury is a common pathological process in clinical practice. Developing effective therapeutic strategies to reduce or prevent this injury is crucial. The article aimed to investigate the role and mechanism of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its key subdomains in modulating myocardial I/R-induced cardiomyocyte apoptosis., Methods: MANF stable knockout cell line and MANF mutant overexpression plasmids were constructed. The effects of MANF and mutants on apoptosis and endoplasmic reticulum (ER) stress related proteins were evaluated in hypoxia/reoxygenation-induced HL-1 cardiomyocytes by western blot, immunofluorescence, Tunel and flow cytometry. Echocardiography, ELISA, TTC and Masson were used to observe the effects of recombinant MANF protein (rMANF) on cardiac function in myocardial I/R mice., Results: This study observed increased expression of MANF in both myocardial infarction patients and I/R mice. MANF overexpression in cardiomyocytes decreased ER stress-induced apoptosis, while MANF knockout exacerbated it. rMANF improved cardiac function in I/R mice by reducing injury and inflammation. This study specifically demonstrates that mutations in the α-helix of MANF were more effective in reducing ER stress and cardiomyocyte apoptosis. Mechanistically, MANF and the α-helix mutant attenuated I/R injury by inhibiting the JAK1/STAT1/NF-κB signaling pathway in addition to reducing ER stress-induced apoptosis., Conclusion: These findings highlight MANF and its subdomains as critical regulators of myocardial I/R injury, offering promising therapeutic targets with significant clinical implications for I/R-related diseases., (© 2024. The Author(s).)
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- 2024
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5. Nicorandil mitigates arsenic trioxide-induced lung injury via modulating vital signalling pathways SIRT1/PGC-1α/TFAM, JAK1/STAT3, and miRNA-132 expression.
- Author
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Abdel-Wahab BA, Zafaar D, Habeeb MS, and El-Shoura EAM
- Subjects
- Animals, Male, Rats, Transcription Factors metabolism, DNA-Binding Proteins metabolism, DNA-Binding Proteins genetics, Rats, Wistar, Rats, Sprague-Dawley, Oxidative Stress drug effects, Nicorandil pharmacology, STAT3 Transcription Factor metabolism, Sirtuin 1 metabolism, Sirtuin 1 genetics, Signal Transduction drug effects, Arsenic Trioxide pharmacology, Arsenic Trioxide toxicity, MicroRNAs metabolism, MicroRNAs genetics, Janus Kinase 1 metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Lung Injury chemically induced, Lung Injury metabolism, Lung Injury drug therapy, Lung Injury pathology, Lung Injury prevention & control
- Abstract
Background and Purpose: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug-induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)-induced lung injury and to elucidate the underlying mechanistic pathways., Experimental Approach: We assessed the effects of nicorandil (15 mg·kg
-1 , p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg-1 , i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin-1, sirtuin-3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted., Key Results: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti-inflammatory actions. On a molecular level, treatment with nicorandil down-regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro-RNA 132 while up-regulating Sirt1, 3, TFAM, AMPK, and ERR-α in lung tissue., Conclusions and Implications: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings., (© 2024 British Pharmacological Society.)- Published
- 2024
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6. Inhibition of the Janus kinase protein (JAK1) by the A. Pyrethrum Root Extract for the treatment of Vitiligo pathology. Design, Molecular Docking, ADME-Tox, MD Simulation, and in-silico investigation.
- Author
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Ouabane M, Zaki K, Zaki H, Guendouzi A, Sbai A, Sekkate C, Lakhlifi T, and Bouachrine M
- Subjects
- Humans, Molecular Docking Simulation, Vitiligo drug therapy, Vitiligo metabolism, Plant Extracts chemistry, Plant Extracts therapeutic use, Molecular Dynamics Simulation, Plant Roots chemistry, Janus Kinase 1 chemistry, Janus Kinase 1 metabolism, Janus Kinase 1 antagonists & inhibitors
- Abstract
This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)
- Published
- 2024
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7. Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities.
- Author
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Zhang X, Wang W, Dong G, Song Y, Zhai X, and Sheng C
- Subjects
- Humans, Structure-Activity Relationship, Cell Line, Tumor, Drug Screening Assays, Antitumor, Drug Discovery, Molecular Structure, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Dose-Response Relationship, Drug, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Proteasome Endopeptidase Complex metabolism, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Proteolysis drug effects, Cell Proliferation drug effects
- Abstract
Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor-momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC
50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)- Published
- 2024
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8. APLNR inhibited nasopharyngeal carcinoma growth and immune escape by downregulating PD-L1.
- Author
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Liu Y, Li N, Guo Y, Zhou Q, Yang Y, Lu J, Tian Z, Zhou J, Yan S, Li X, Shi L, Jiang S, Ge J, Feng R, Huang D, Zeng Z, Fan S, Xiong W, Li G, and Zhang W
- Subjects
- Animals, Female, Humans, Male, Mice, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Down-Regulation, Gene Expression Regulation, Neoplastic drug effects, Interferon-gamma metabolism, Janus Kinase 1 metabolism, Mice, Inbred BALB C, Receptors, G-Protein-Coupled metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled immunology, Receptors, Interferon genetics, Receptors, Interferon metabolism, STAT1 Transcription Factor metabolism, Xenograft Model Antitumor Assays, B7-H1 Antigen metabolism, B7-H1 Antigen immunology, Mice, Nude, Nasopharyngeal Carcinoma immunology, Nasopharyngeal Carcinoma pathology, Nasopharyngeal Neoplasms immunology, Nasopharyngeal Neoplasms pathology, Tumor Escape drug effects
- Abstract
Background: APLNR is a G protein-coupled receptor and our previous study had revealed that APLNR could inhibit nasopharyngeal carcinoma (NPC) growth and metastasis. However, the role of APLNR in regulating PD-L1 expression and immune escape in NPC is unknown., Methods: We analyzed the expression and correlation of APLNR and PD-L1 in NPC tissues and cells. We investigated the effect of APLNR on PD-L1 expression and the underlying mechanism in vitro and in vivo. We also evaluated the therapeutic potential of targeting APLNR in combination with PD-L1 antibody in a nude mouse xenograft model., Results: We found that APLNR was negatively correlated with PD-L1 in NPC tissues and cells. APLNR could inhibit PD-L1 expression by binding to the FERM domain of JAK1 and blocking the interaction between JAK1 and IFNGR1, thus suppressing IFN-γ-mediated activation of the JAK1/STAT1 pathway. APLNR could also inhibit NPC immune escape by enhancing IFN-γ secretion and CD8
+ T-cell infiltration and reducing CD8+ T-cell apoptosis and dysfunction. Moreover, the best effect was achieved in inhibiting NPC growth in nude mice when APLNR combined with PD-L1 antibody., Conclusions: Our study revealed a novel mechanism of APLNR regulating PD-L1 expression and immune escape in NPC and suggested that APLNR maybe a potential therapeutic target for NPC immunotherapy., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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9. Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity.
- Author
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Xu H, Zhang X, Wang X, Li B, Yu H, Quan Y, Jiang Y, You Y, Wang Y, Wen M, Liu J, Wang M, Zhang B, Li Y, Zhang X, Lu Q, Yu CY, and Cao X
- Subjects
- Animals, Humans, Mice, Macrophages immunology, Macrophages metabolism, Janus Kinase 1 metabolism, Phosphorylation, Interferon Type I metabolism, Interferon Type I immunology, Psoriasis immunology, Psoriasis metabolism, Mice, Inbred C57BL, Janus Kinases metabolism, Female, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Spermine metabolism, Spermine pharmacology, Signal Transduction drug effects, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic metabolism, Autoimmunity, Cytokines metabolism
- Abstract
Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-β-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease., Competing Interests: Declaration of interests X.C. is a member of the advisory board of Immunity. X.C., H.X., and X.Z. have applied a patent entitled “USE OF SPERMINE IN PREVENTION AND TREATMENT OF INFLAMMATORY DISEASES” (International Application No. PCT/CN2022/141371). X.C. and H.X. have applied a patent entitled “Spermine derivatives and their uses for the treatment of diseases” (International Application No. PCT/CN2022/141364)., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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10. The JAK1/JAK2 inhibitor ruxolitinib inhibits mediator release from human basophils and mast cells.
- Author
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Poto R, Cristinziano L, Criscuolo G, Strisciuglio C, Palestra F, Lagnese G, Di Salvatore A, Marone G, Spadaro G, Loffredo S, and Varricchi G
- Subjects
- Humans, Cells, Cultured, Janus Kinase Inhibitors pharmacology, Cytokines metabolism, Immunoglobulin E immunology, Immunoglobulin E metabolism, Protein Kinase Inhibitors pharmacology, Basophils drug effects, Basophils immunology, Basophils metabolism, Pyrimidines pharmacology, Nitriles pharmacology, Mast Cells drug effects, Mast Cells immunology, Mast Cells metabolism, Pyrazoles pharmacology, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Janus Kinase 2 metabolism, Janus Kinase 2 antagonists & inhibitors
- Abstract
Introduction: The Janus kinase (JAK) family includes four cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) constitutively bound to several cytokine receptors. JAKs phosphorylate downstream signal transducers and activators of transcription (STAT). JAK-STAT5 pathways play a critical role in basophil and mast cell activation. Previous studies have demonstrated that inhibitors of JAK-STAT pathway blocked the activation of mast cells and basophils., Methods: In this study, we investigated the in vitro effects of ruxolitinib, a JAK1/2 inhibitor, on IgE- and IL-3-mediated release of mediators from human basophils, as well as substance P-induced mediator release from skin mast cells (HSMCs)., Results: Ruxolitinib concentration-dependently inhibited IgE-mediated release of preformed (histamine) and de novo synthesized mediators (leukotriene C
4 ) from human basophils. Ruxolitinib also inhibited anti-IgE- and IL-3-mediated cytokine (IL-4 and IL-13) release from basophils, as well as the secretion of preformed mediators (histamine, tryptase, and chymase) from substance P-activated HSMCs., Discussion: These results indicate that ruxolitinib, inhibiting the release of several mediators from human basophils and mast cells, is a potential candidate for the treatment of inflammatory disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Poto, Cristinziano, Criscuolo, Strisciuglio, Palestra, Lagnese, Di Salvatore, Marone, Spadaro, Loffredo and Varricchi.)- Published
- 2024
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11. Leonurus japonicus Houtt. modulates neuronal apoptosis in intracerebral hemorrhage: Insights from network pharmacology and molecular docking.
- Author
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Wu JW, Gao W, Shen LP, Chen YL, Du SQ, Du ZY, Zhao XD, and Lu XJ
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- Animals, Mice, Male, Neuroprotective Agents pharmacology, Neuroprotective Agents chemistry, Neuroprotective Agents isolation & purification, Plant Extracts pharmacology, Plant Extracts chemistry, Janus Kinase 1 metabolism, STAT1 Transcription Factor metabolism, Disease Models, Animal, Molecular Docking Simulation, Apoptosis drug effects, Network Pharmacology, Leonurus chemistry, Neurons drug effects, Neurons metabolism, Cerebral Hemorrhage drug therapy
- Abstract
Ethnopharmacological Relevance: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear., Aims of the Study: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH., Materials and Methods: The study employed network pharmacology, UPLC-Q-TOF-MS technique, molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms., Results: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression., Conclusion: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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12. Research progress of multi-target HDAC inhibitors blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway in the treatment of cancer.
- Author
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Jia S, Jia Y, Liang S, and Wu L
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- Humans, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Bromodomain Containing Proteins, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors chemical synthesis, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism
- Abstract
Histone deacetylase inhibitors (HDACis) show beneficial effects on different hematological malignancy subtypes. However, their impacts on treating solid tumors are still limited due to diverse resistance mechanisms. Recent studies have found that the feedback activation of BRD4-LIFR-JAK1-STAT3 pathway after HDACi incubation is a vital mechanism inducing resistance of specific solid tumor cells to HDACis. This review summarizes the recent development of multi-target HDACis that can concurrently block BRD4-LIFR-JAK1-STAT3 pathway. Moreover, our findings hope to shed novel lights on developing novel multi-target HDACis with reduced BRD4-LIFR-JAK1-STAT3-mediated drug resistance in some tumors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)
- Published
- 2024
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13. Dexamethasone relieves the inflammatory response caused by inguinal hernia meshes through miR-155.
- Author
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Li Y, Lv Y, Li J, Ling P, Guo X, Zhang L, Ni J, and Long Y
- Subjects
- Animals, Rats, Male, Anti-Inflammatory Agents pharmacology, Rats, Sprague-Dawley, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics, Interleukin-1beta metabolism, Interleukin-1beta genetics, Interleukin-6 metabolism, Interleukin-6 genetics, Caspase 1 metabolism, Caspase 1 genetics, Interleukin-18 metabolism, Herniorrhaphy adverse effects, Herniorrhaphy methods, Random Allocation, MicroRNAs metabolism, Dexamethasone therapeutic use, Dexamethasone pharmacology, Hernia, Inguinal surgery, Surgical Mesh adverse effects, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, Inflammation metabolism
- Abstract
Background: Inguinal hernia is a relatively common condition. Most patients with inguinal hernia require surgery. At present, mesh repair is one of the most effective methods to treat inguinal hernia, but insertion of the mesh can cause inflammation. Dexamethasone (DEX) can treat inflammation, but the mechanism by which DEX alleviates inflammation caused by inguinal hernia mesh placement remains unclear., Method: We randomly divided rats into groups: negative control (NC), inguinal hernia (IH), polypropylene mesh (PM), DEX treatment, and miR-155 treatment groups. RT-qPCR was performed to determine the expression of miR-155. ELISA was implemented to determine the secretion of IL-1β, IL-6, and IL-18. Western blotting was used to detect caspase-1, JAK1, p-JAK1, STAT3, and p-STAT3 expression. A dual-luciferase reporter gene array identified a connection between miR-155 and JAK1., Results: The results revealed that the expression of miR-155, IL-1β, IL-6, and IL-18 was upregulated in the PM group. After DEX treatment, the secretion of miR-155, caspase-1, IL-1β, IL-6, and IL-18 decreased. Dual luciferase results confirmed that miR-155 induced the targeted downregulation of JAK1, while a miR-155 mimic reversed the therapeutic effect of DEX, and the expression levels of p-JAK1 and p-STAT3 increased., Conclusion: DEX regulates the JAK1/STAT3 signaling pathway through miR-155 to relieve inflammation caused by inguinal hernia meshes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)
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- 2024
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14. Revisiting Structure-activity Relationships: Unleashing the potential of selective Janus kinase 1 inhibitors.
- Author
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Shan M, Zhao X, Sun P, Qu X, Cheng G, and Qin LP
- Subjects
- Structure-Activity Relationship, Humans, Molecular Structure, Animals, Dose-Response Relationship, Drug, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis
- Abstract
Janus kinases (JAKs), a kind of non-receptor tyrosine kinases, the function has been implicated in the regulation of cell proliferation, differentiation and apoptosis, immune, inflammatory response and malignancies. Among them, JAK1 represents an essential target for modulating cytokines involved in inflammation and immune function. Rheumatoid arthritis, atopic dermatitis, ulcerative colitis and psoriatic arthritis are areas where approved JAK1 drugs have been applied for the treatment. In the review, we provided a brief introduction to JAK1 inhibitors in market and clinical trials. The structures of high active JAK1 compounds (IC
50 ≤ 0.1 nM) were highlighted, with primary focus on structure-activity relationship and selectivity. Moreover, the druggability processes of approved drugs and high active compounds were analyzed. In addition, the issues involved in JAK1 compounds clinical application as well as strategies to surmount these challenges, were discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
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15. Enhancement of vincristine sensitivity in retinoblastoma through Janus kinase inhibition by ruxolitinib.
- Author
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Ke F, Wang N, Zhang X, Liu R, Ren T, Ke J, Yang J, Yan H, and Ma J
- Subjects
- Animals, Humans, Mice, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Janus Kinase Inhibitors pharmacology, Xenograft Model Antitumor Assays, Cell Line, Tumor, Retinal Neoplasms drug therapy, Retinal Neoplasms pathology, Drug Synergism, Cell Proliferation drug effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Retinoblastoma drug therapy, Retinoblastoma pathology, Nitriles pharmacology, Pyrimidines pharmacology, Vincristine pharmacology, Pyrazoles pharmacology, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Drug Resistance, Neoplasm drug effects
- Abstract
Chemotherapy remains the main approach conserving vision during the treatment of retinoblastoma, the most prevalent eye cancer in children. Unfortunately, the development of chemoresistance stands as the primary reason for treatment failure. Within this study, we showed that prolonged exposure to vincristine led to heightened expression of JAK1 and JAK2 in retinoblastoma cells, while the other members of the JAK family exhibited no such changes. Employing a genetic intervention, we demonstrated the efficacy of depleting either JAK1 or JAK2 in countering vincristine-resistant retinoblastoma cells. In addition, the dual depletion of both JAK1 and JAK2 produced a more potent inhibitory outcome compared to the depletion of either gene alone. We further demonstrated that ruxolitinib, a small molecular inhibitor of JAK1/2, effectively reduced viability and colony formation in vincristine-resistant retinoblastoma cells. It also acts synergistically with vincristine in retinoblastoma cells regardless of inherent cellular and genetic heterogeneity. The effectiveness of ruxolitinib as standalone treatment against chemoresistant retinoblastoma, as well as its combination with vincristine, was validated in multiple retinoblastoma mouse models. Importantly, mice exhibited favorable tolerance to ruxolitinib administration. We confirmed that the underlying mechanism of ruxolitinib's action in chemoresistant retinoblastoma cells is the inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Our study reveals that the underlying mechanism driving ruxolitinib's impact on chemoresistant retinoblastoma cells is the inhibition of JAK/STAT signaling. This study reveals the contribution of JAK1/2 to the development of chemoresistance in retinoblastoma and underscores the effectiveness of targeting JAK1/2 as a strategy to sensitize retinoblastoma to chemotherapy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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16. Edaravone and obeticholic acid protect against cisplatin-induced heart toxicity by suppressing oxidative stress and inflammation and modulating Nrf2, TLR4/p38MAPK, and JAK1/STAT3/NF-κB signals.
- Author
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El-Shoura EAM, Hassanein EHM, Taha HH, Shalkami AS, Hassanein MMH, Ali FEM, and Bakr AG
- Subjects
- Animals, Male, Rats, Cardiotoxicity prevention & control, Rats, Wistar, Antioxidants pharmacology, Antineoplastic Agents toxicity, Antineoplastic Agents pharmacology, Inflammation drug therapy, Inflammation chemically induced, Inflammation metabolism, Inflammation prevention & control, Inflammation pathology, Cardiotonic Agents pharmacology, Cardiotonic Agents therapeutic use, Oxidative Stress drug effects, NF-kappa B metabolism, Cisplatin toxicity, NF-E2-Related Factor 2 metabolism, Toll-Like Receptor 4 metabolism, Janus Kinase 1 metabolism, STAT3 Transcription Factor metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Signal Transduction drug effects, Chenodeoxycholic Acid analogs & derivatives, Chenodeoxycholic Acid pharmacology, Edaravone pharmacology
- Abstract
Cardiotoxicity is a significant adverse effect of cisplatin (CIS) that necessitates extensive medical care. The current study examines the cardioprotective effects of edaravone (EDV), obeticholic acid (OCA), and their combinations on CIS-induced cardiac damage. Rats were allocated into five groups: the normal control group, the remaining four groups received CIS (7.5 mg/kg, i.p.) as a single dose on the fifth day and were assigned to CIS, OCA (10 mg/kg/day) + CIS, EDV (20 mg/kg/day) + CIS, and the (EDV + OCA) + CIS group. Compared to the CIS-treated group, co-treating rats with EDV, OCA, or their combinations significantly decreased ALP, AST, LDH, CK-MB, and troponin-I serum levels and alleviated histopathological heart abnormalities. Biochemically, EDV, OCA, and EDV plus OCA administration mitigated cardiac oxidative stress as indicated by a marked decrease in heart MDA content with a rise in cardiac antioxidants SOD and GSH associated with upregulating Nrf2, PPARγ, and SIRT1 expression. Besides, it dampened inflammation by decreasing cardiac levels of TNF-α, IL-1β, and IL-6, mediated by suppressing NF-κB, JAK1/STAT3, and TLR4/p38MAPK signal activation. Notably, rats co-administered with EDV plus OCA showed noticeable protection that exceeded that of EDV and OCA alone. In conclusion, our study provided that EDV, OCA, and their combinations effectively attenuated CIS-induced cardiac intoxication by activating Nrf2, PPARγ, and SIRT1 signals and downregulating NF-κB, JAK1/STAT3, and TLR4/p38MAPK signals., (© 2024. The Author(s).)
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- 2024
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17. Graveoline attenuates D-GalN/LPS-induced acute liver injury via inhibition of JAK1/STAT3 signaling pathway.
- Author
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He J, Feng X, Liu Y, Wang Y, Ge C, Liu S, and Jiang Y
- Subjects
- Animals, Humans, Male, Hep G2 Cells, Mice, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents isolation & purification, Cytokines metabolism, Quinolines pharmacology, STAT3 Transcription Factor metabolism, Janus Kinase 1 metabolism, Janus Kinase 1 antagonists & inhibitors, Lipopolysaccharides toxicity, Signal Transduction drug effects, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury prevention & control, Chemical and Drug Induced Liver Injury drug therapy, Galactosamine toxicity
- Abstract
Graveoline exhibits various biological activities. However, only limited studies have focused on its hepatoprotective properties. This study evaluated the anti-inflammatory and hepatoprotective activities of graveoline, a minor 2-phenylquinolin-4-one alkaloid isolated from Ruta graveolens L., in a liver injury model in vitro and in vivo. A network pharmacology approach was used to investigate the potential signaling pathway associated with the hepatoprotective activity of graveoline. Subsequently, biological experiments were conducted to validate the findings. Topological analysis of the KEGG pathway enrichment revealed that graveoline mediates its hepatoprotective activity through genes associated with the hepatitis B viral infection pathway. Biological experiments demonstrated that graveoline effectively reduced the levels of alanine transaminase and aspartate transaminase in lipopolysaccharide (LPS)-induced HepG2 cells. Graveoline exerted antihepatitic activity by inhibiting the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and elevated the anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) in vitro and in vivo. Additionally, graveoline exerted its hepatoprotective activity by inhibiting JAK1 and STAT3 phosphorylation both in vitro and in vivo. In summary, graveoline can attenuate acute liver injury by inhibiting the TNF-α inflammasome, activating IL-4 and IL-10, and suppressing the JAK1/STAT3 signaling pathway. This study sheds light on the potential of graveoline as a promising therapeutic agent for treating liver injury., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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- 2024
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18. Momelotinib: Mechanism of action, clinical, and translational science.
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Vlasakakis G, McCabe MT, Ho YL, Ferron-Brady G, Martin P, Bentley D, Ellis C, Antonysamy M, and Visser SAG
- Subjects
- Humans, Primary Myelofibrosis drug therapy, Primary Myelofibrosis metabolism, Benzamides pharmacology, Benzamides pharmacokinetics, Benzamides adverse effects, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Pyrimidines therapeutic use, Pyrimidines administration & dosage, Pyrimidines adverse effects, Animals, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Signal Transduction drug effects, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors administration & dosage, Bridged-Ring Compounds, Translational Research, Biomedical
- Abstract
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK-STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady-state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUC
tau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite-to-parent AUC ratio of 1.4-2.1. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2024
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19. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, attenuates autoimmune dermatoses in murine models.
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Li D, Shan S, Mao X, Zhao Y, Chen B, Xiong Q, Pan D, and Huang S
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- Animals, Mice, Female, Autoimmune Diseases drug therapy, Autoimmune Diseases pathology, Purines pharmacology, Dermatitis, Atopic drug therapy, Dermatitis, Atopic pathology, Dermatitis, Atopic chemically induced, Dermatitis, Atopic immunology, Azetidines pharmacology, Protein Kinase Inhibitors pharmacology, Psoriasis drug therapy, Psoriasis immunology, Psoriasis pathology, Psoriasis chemically induced, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic pathology, Pyrazoles, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Janus Kinase 3 antagonists & inhibitors, Disease Models, Animal, Sulfonamides pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Objective: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models., Methods: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly., Results: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor., Conclusion: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.
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- 2024
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20. Fluoxetine attenuates chlorpyrifos-induced neuronal injury through the PPARγ, SIRT1, NF-κB, and JAK1/STAT3 signals.
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Althagafy HS and Hassanein EHM
- Subjects
- Animals, Male, Rats, Neurons drug effects, Neurons pathology, Oxidative Stress drug effects, Insecticides toxicity, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Rats, Sprague-Dawley, Hippocampus drug effects, Hippocampus metabolism, Hippocampus pathology, Neurotoxicity Syndromes drug therapy, Neurotoxicity Syndromes pathology, STAT3 Transcription Factor metabolism, Sirtuin 1 metabolism, NF-kappa B metabolism, PPAR gamma metabolism, Janus Kinase 1 metabolism, Fluoxetine pharmacology, Fluoxetine therapeutic use, Signal Transduction drug effects, Chlorpyrifos toxicity, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use
- Abstract
Chlorpyrifos (CPF) is a widely used organophosphate insecticide in agriculture and homes. Exposure to organophosphates is associated with neurotoxicity. Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) that is widely prescribed for depression and anxiety disorders. Studies have shown that FLX has neuroprotective, anti-inflammatory, antioxidant, and antiapoptotic effects. The molecular mechanisms underlying FLX are not fully understood. This work aimed to investigate the potential neuroprotective effect of FLX on CPF-induced neurotoxicity and the underlying molecular mechanisms involved. Thirty-two rats were randomly divided into four groups: (I) the vehicle control group; (II) the FLX-treated group (10 mg/kg/day for 28 days, p.o); (III) the CPF-treated group (10 mg/kg for 28 days); and (IV) the FLX+CPF group. FLX attenuated CPF-induced neuronal injury, as evidenced by a significant decrease in Aβ and p-Tau levels and attenuation of cerebral and hippocampal histological abrasion injury induced by CPF. FLX ameliorated neuronal oxidative stress, effectively reduced MDA production, and restored SOD and GSH levels through the coactivation of the PPARγ and SIRT1 proteins. FLX counteracted the neuronal inflammation induced by CPF by decreasing MPO, NO, TNF-α, IL-1β, and IL-6 levels by suppressing NF-κB and JAK1/STAT3 activation. The antioxidant and anti-inflammatory properties of FLX help to prevent CPF-induced neuronal intoxication., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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21. Anti-inflammatory and anti-rheumatic effects of Phoenix dactylifera L. (date palm) seed by controlling cytokines and inhibiting JAK1/STAT3 pathway on CFA-induced arthritis rat and its phytochemical profiling.
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El-Gendy ZA, Abdelazeem S, Abdel Jaleel GA, Ali ME, Mohamed A, Salah A, and Raslan MA
- Subjects
- Animals, Male, Antirheumatic Agents pharmacology, Antirheumatic Agents isolation & purification, Rats, Phytochemicals analysis, Phytochemicals pharmacology, Signal Transduction drug effects, Rats, Wistar, Rats, Sprague-Dawley, Antioxidants pharmacology, Phoeniceae chemistry, STAT3 Transcription Factor metabolism, Arthritis, Experimental drug therapy, Arthritis, Experimental pathology, Freund's Adjuvant, Plant Extracts pharmacology, Plant Extracts chemistry, Janus Kinase 1 metabolism, Anti-Inflammatory Agents pharmacology, Cytokines metabolism, Seeds chemistry
- Abstract
Ethnopharmacological Relevance: Phoenix dactylifera L. (date palm) seed is widely used in Arabian traditional medicine to alleviate several health problems including inflammatory conditions. The herbal tea of date palm seed has been consumed by rheumatoid patients to relief their symptoms., Aim of the Study: The purpose of this study was to investigate the claimed beneficial use of P. dactylifera L. (Sewy variety) seed (PDS) in the treatment of rheumatoid arthritis (RA) and its mechanism of action as well as to study its phytoconstituents., Materials and Methods: The anti-inflammatory and anti-oxidative properties of the non-polar and the polar extracts of PDS were studied using Complete Freund's adjuvant (CFA)-induced arthritis rat model. Paw edema, body weight, total nitrate/nitrite NO
X content and cytokine markers were evaluated to monitor the progress of arthritis. Also, histological examination and thermal analysis were conducted. The phytoconstituent profiles of non-polar and polar extracts of PDS were investigated using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The multiple reactions monitoring mode (MRM) of liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) was used to quantify phenolic phytoconstituents in both extracts., Results: According to the findings, the polar and non-polar PDS extracts kept body weight comparable to those of healthy individuals while considerably lowering paw swelling, edema, and neutrophil infiltration. It also reduced the levels of Nuclear Factor Kappa B (NF-κB), Tumor Necrosis Factor Alpha (TNF-α), Interleukin 22, Interleukin 23, Interferon (IFN), Interleukin 17, Interleukin 1β, Interleukin 6, Interleukin 36, Janus Kinase 1 (JAK1), and Signal Transducer and Activator of Transcription 3 (STAT3). They also reduced the degenerative alterations caused by RA. Thermal research gave additional support for these findings. 83 phytoconstituents were identified in the non-polar PDS extract and 86 phytoconstituents were identified in the polar PDS extract. 74 of the identified phytoconstituents were common in both extracts. 33 phytoconstituents were identified here from P. dactylifera for the first time as far as we know. In MRM-LC-ESI-MS/MS analysis, the major phenolics in both extracts were chlorogenic acid, naringenin, and vanillin. Catechin was only detected in the non-polar PDS extract. On the other hand, apigenin, kaempferol, and hesperetin were only detected in the polar PDS extract. Generally, the polar PDS extract showed higher concentrations of the identified phenolics than the non-polar extract., Conclusions: The PDS extracts especially the non-polar extract showed significant anti-inflammatory and anti-oxidative properties in the CFA-induced arthritis rat model. PDS might be used to produce RA medicines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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22. The Variation in the Traits Ameliorated by Inhibitors of JAK1/2, TGF-β, P-Selectin, and CXCR1/CXCR2 in the Gata1 low Model Suggests That Myelofibrosis Should Be Treated by These Drugs in Combination.
- Author
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Gobbo F, Martelli F, Di Virgilio A, Demaria E, Sarli G, and Migliaccio AR
- Subjects
- Animals, Receptors, Interleukin-8A antagonists & inhibitors, Receptors, Interleukin-8A metabolism, Mice, Janus Kinase 2 metabolism, Janus Kinase 2 antagonists & inhibitors, Nitriles therapeutic use, Nitriles pharmacology, Disease Models, Animal, Drug Therapy, Combination, GATA1 Transcription Factor metabolism, GATA1 Transcription Factor genetics, Pyrazoles pharmacology, Pyrazoles therapeutic use, Humans, Primary Myelofibrosis drug therapy, Primary Myelofibrosis metabolism, Primary Myelofibrosis pathology, Transforming Growth Factor beta metabolism, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, P-Selectin metabolism, Receptors, Interleukin-8B antagonists & inhibitors, Receptors, Interleukin-8B metabolism, Pyrimidines pharmacology, Pyrimidines therapeutic use
- Abstract
Studies conducted on animal models have identified several therapeutic targets for myelofibrosis, the most severe of the myeloproliferative neoplasms. Unfortunately, many of the drugs which were effective in pre-clinical settings had modest efficacy when tested in the clinic. This discrepancy suggests that treatment for this disease requires combination therapies. To rationalize possible combinations, the efficacy in the Gata1
low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-β (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-β) signaling and TGF-β trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). The comparison was carried out by expressing the endpoints, which had either already been published or had been retrospectively obtained for this study, as the fold change of the values in the corresponding vehicles. In this model, only Ruxolitinib was found to decrease spleen size, only Aplidin and SB431542/AVID200 increased platelet counts, and with the exception of AVID200, all the inhibitors reduced fibrosis and microvessel density. The greatest effects were exerted by Reparixin, which also reduced TGF-β content. None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-β or CXCL1).- Published
- 2024
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23. Baricitinib protects ICIs-related myocarditis by targeting JAK1/STAT3 to regulate Macrophage polarization.
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Wang X, Chen J, Shen Y, Zhang H, Xu Y, Zhang J, and Cheng L
- Subjects
- Animals, Male, Mice, Immune Checkpoint Inhibitors pharmacology, Macrophage Activation drug effects, RAW 264.7 Cells, Signal Transduction drug effects, Troponin I metabolism, Azetidines pharmacology, Janus Kinase 1 metabolism, Macrophages metabolism, Macrophages drug effects, Mice, Inbred BALB C, Myocarditis chemically induced, Myocarditis drug therapy, Myocarditis pathology, Myocarditis metabolism, Purines pharmacology, Pyrazoles pharmacology, STAT3 Transcription Factor metabolism, Sulfonamides pharmacology
- Abstract
Purpose: The emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis., Methods: To establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis., Results: Baricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings., Conclusion: Baricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related myocarditis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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24. JAK1, SKI, ZBTB16 as potential biomarkers mediate the inflammatory response in keratoconjunctivitis sicca.
- Author
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Dong Z, Wang C, Dou S, Yang X, Wang D, Shi K, and Wu N
- Subjects
- Animals, Humans, Rats, Sjogren's Syndrome genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Gene Regulatory Networks, Inflammation genetics, Male, Gene Expression Profiling methods, Female, Disease Models, Animal, Transcriptome, Machine Learning, Computational Biology methods, Janus Kinase 1 genetics, Janus Kinase 1 metabolism, Keratoconjunctivitis Sicca genetics, Keratoconjunctivitis Sicca metabolism, Biomarkers metabolism
- Abstract
Keratoconjunctivitis sicca (KCS) is an ocular condition characterized by insufficient tear production and inflammatory irritation, with Sjögren's syndrome (SS) being a major causative factor. This study aimed to extract patient transcriptomic data from the GEO database to identify signature genes associated with the diagnosis and treatment of KCS and the expression of three key genes were experimentally verified. We performed a difference analysis on the SS patient dataset and performed a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on the resulting genes. Additionally, a Weighted Gene Co-expression Network Analysis (WGCNA) was constructed. Machine learning techniques were employed to analyze the most strongly correlated gene modules with SS traits. These findings were further validated using KCS immune-correlation microarrays as a validation set. The correlation of the three identified genes with 22 immune cells was assessed through immune infiltration analysis. Subsequently, a rat model of desiccated keratoconjunctivitis was established, and the modeling situation and expression of characteristic genes were analyzed at the morphological, tissue, and molecular levels. Bioinformatic prediction revealed that the expression of JAK1, SKI, ZBTB16 not only differed in the machine learning validation set, but also correlated with some immune cells in the immune infiltration analysis. The results of animal experiments showed that the transcription and expression levels of these three genes were significantly different in rat KCS tissues and normal tissues, and there were also differences in the expression of JAK1 and SKI in rat peripheral blood, as well as significant up-regulation of the expression of related inflammatory factors in KCS tissues. Through bioinformatics prediction and animal experimental validation, this study identified three differentially expressed genes in SS mediated KCS patients, which provide new potential biological targets for the diagnosis and treatment of KCS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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25. Maternal administration of APAP induces angiogenesis disorders in mouse placenta via SOCS3/JAK1/STAT3 pathway.
- Author
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Dai Y, He J, Chen X, Geng Y, Chen Z, Liu F, Li F, Wang Y, and Mu X
- Subjects
- Animals, Female, Pregnancy, Humans, Mice, Analgesics, Non-Narcotic toxicity, Mice, Inbred C57BL, Neovascularization, Pathologic chemically induced, Angiogenesis, STAT3 Transcription Factor metabolism, Placenta blood supply, Placenta drug effects, Placenta metabolism, Suppressor of Cytokine Signaling 3 Protein metabolism, Janus Kinase 1 metabolism, Human Umbilical Vein Endothelial Cells, Signal Transduction drug effects, Acetaminophen toxicity
- Abstract
Acetaminophen (APAP, also known as paracetamol) is a commonly used antipyretic and analgesic that is considered safe to use during pregnancy. However, a growing body of research indicates that gestational administration of APAP increased the risk of neurodevelopmental, reproductive and genitourinary disorders in offspring, alongside impairments in placental development. Notably, over-dosed APAP exhibits direct toxicity to endothelial cells, but there is very limited research investigating the impact of APAP on placental angiogenesis, a gap we aim to address in this study. Pregnant mice were gavaged with APAP (15, 50 and 150 mg/kg/d) from embryonic day 11.5 (E11.5) to E13.5. Administration of 150 mg/kg/d APAP leads to low birth weight (LBW) of the offspring and disordered vascular structures within the labyrinthine (Lab) layer of the placenta. This disruption is accompanied by a significant increase in Suppressor of Cytokine Signaling 3 (SOCS3) level, a negative regulator of the Janus kinase signal transducer 1 and activator of the transcription 3 (JAK1/STAT3) signaling. Meanwhile, Human umbilical vein endothelial Cells (HUVECs) with the treatment of 3 mM APAP exhibited reduced cell viability, whereas 1 mM APAP significantly affected the proliferation, migration, invasion and angiogenic capacities of HUVECs. Further, SOCS3 was up-regulated in HUVECs, accompanied by inhibition of JAK1/STAT3 pathways. Knocking-down SOCS3 in HUVECs restored the nuclear translocation of STAT3 and efficiently promoted cellular capacity of tube formation. Overall, short-term maternal administration of overdosed APAP impairs angiogenic capacities of fetal endothelial cells via SOCS3/JAK1/STAT3 pathway in the mouse placenta. This study reveals that overdose of APAP during pregnancy may adversely affect placental angiogenesis, emphasizing the importance of adhering to the safe principles of smallest effective dose for the shortest required durations., Competing Interests: Declaration of Competing Interest All authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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26. Therapeutic targeting of siRNA/anti-cancer drug delivery system for non-melanoma skin cancer. Part I: Development and gene silencing of JAK1siRNA/5-FU loaded liposome nanocomplexes.
- Author
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Aslan M, Ozturk S, Shahbazi R, Bozdemir Ö, Dilara Zeybek N, Vargel İ, Eroğlu İ, and Ulubayram K
- Subjects
- Humans, Cell Line, Tumor, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Nanoparticles chemistry, Cell Survival drug effects, Drug Liberation, RNA Interference, Liposomes, RNA, Small Interfering administration & dosage, RNA, Small Interfering genetics, RNA, Small Interfering pharmacology, Fluorouracil administration & dosage, Fluorouracil pharmacology, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms pathology, Janus Kinase 1 genetics, Janus Kinase 1 metabolism, Gene Silencing drug effects, Drug Delivery Systems methods
- Abstract
Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 10
1 µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p < 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene in vitro, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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27. Vitamin D3 attenuates autoimmune thyroiditis by regulating Th17/Treg cell differentiation via YAP/JAK1/STAT1 axis.
- Author
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Zhang Q, He X, Chen W, Jiu J, Gao C, and Gao T
- Subjects
- Animals, Mice, Female, Adaptor Proteins, Signal Transducing metabolism, Cytokines metabolism, Th17 Cells immunology, Th17 Cells metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Thyroiditis, Autoimmune metabolism, Thyroiditis, Autoimmune immunology, Thyroiditis, Autoimmune etiology, STAT1 Transcription Factor metabolism, Cell Differentiation drug effects, Cholecalciferol pharmacology, Cholecalciferol administration & dosage, Signal Transduction drug effects, Disease Models, Animal, Janus Kinase 1 metabolism, YAP-Signaling Proteins metabolism
- Abstract
Background: Autoimmune thyroiditis (AITD) is an organ-specific autoimmune disease. Substantial evidence suggests that Vitamin D (VitD) deficiency is closely associated with an increased risk of AITD. However, the effects of VitD3 on immune cells, especially Th17/Treg cell subsets, and the underlying molecular mechanism in AITD have not yet been investigated., Methods: An experimental autoimmune thyroiditis (EAT) mouse model was established with a high-iodine diet. After 8 weeks, thyroid injury was assessed using hematoxylin and eosin (H&E) staining. ELISA was employed to measure serum levels of thyroxine (T3 and T4), thyroid autoimmune antibodies (Tg-Ab and TPO-Ab), and inflammatory cytokines. Flow cytometry and multiplex fluorescence immunohistochemical (mIHC) assays were used to analyze Th17/Treg cell subsets. The CCK-8 and flow cytometry assays were used to determine cell viability and apoptosis., Results: Administration of VitD3 reduced thyroid follicle destruction, decreased lymphocyte infiltration, and lowered T3, T4, Tg-Ab, and TPO-Ab serum levels in EAT mice. VitD3 treatment also reduced the frequency of Th17 cells while promoting the Treg cell subset both in the thyroid tissue and in the splenocytes cultured in vitro. Furthermore, VitD3 administration suppressed the production of inflammatory cytokines in EAT mice. VitD3 was also found to regulate Treg cells' differentiation, viability, and apoptosis. Mechanistically, we discovered that VitD3 treatment upregulated YAP expression and activated the JAK/STAT pathway. Rescue assays confirmed that depletion of YAP counteracted the effects of VitD3 on Treg cell differentiation and function., Conclusion: Vitamin D3 attenuates AITD by modulating Th17/Treg cell balance via regulating the YAP/JAK1/STAT1 axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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28. In vitro effect of diazoxon on cell signaling and second messengers in Nile tilapia (Oreochromis niloticus) leukocytes.
- Author
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Camacho-Pérez MR, Díaz-Resendiz KJG, Ortiz-Butrón R, Covantes-Rosales CE, Benitez-Trinidad AB, Girón-Pérez DA, Toledo-Ibarra GA, Pavón L, and Girón-Pérez MI
- Subjects
- Animals, STAT3 Transcription Factor metabolism, Cyclic AMP metabolism, Tetradecanoylphorbol Acetate pharmacology, Janus Kinase 1 metabolism, Phosphorylation drug effects, Ionomycin pharmacology, Insecticides toxicity, Insecticides pharmacology, Organophosphorus Compounds, Leukocytes drug effects, Leukocytes metabolism, Signal Transduction drug effects, Second Messenger Systems drug effects
- Abstract
The physiological and molecular responses of leukocytes are altered by organophosphate pesticides. Some reports have shown that diazinon causes immunotoxic effects; diazoxon, the oxon metabolite of diazinon, is attributed to influence the immune response by affecting the leukocyte cholinergic system. In this study, the in vitro effects of diazoxon on molecules involved in cell signaling (cAMP, IP3, DAG, JAK1, and STAT3), which play a crucial role in the activation, differentiation, and survival of leukocytes, were evaluated. Data indicate that diazoxon leads to a decrease in cAMP concentration and an increase in basal IP3 levels. However, diazoxon does not affect basal levels of JAK1 and STAT3 phosphorylation. Instead, diazoxon inhibits leukocyte responsiveness to phorbol myristate acetate and ionomycin, substances that, under normal conditions, enhance JAK/STAT signaling. These findings demonstrate that diazoxon significantly affects key molecular parameters related to cell signaling., Competing Interests: Conflict of interest statement. The authors declare no conflict of interest., (© Crown copyright 2024.)
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- 2024
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29. Double-negative T cells utilize a TNFα-JAK1-ICAM-1 cytotoxic axis against acute myeloid leukemia.
- Author
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Tin E, Lee JB, Khatri I, Na Y, Minden MD, and Zhang L
- Subjects
- Humans, Cytotoxicity, Immunologic, Signal Transduction, Cell Line, Tumor, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets immunology, Leukemia, Myeloid, Acute metabolism, Intercellular Adhesion Molecule-1 metabolism, Tumor Necrosis Factor-alpha metabolism, Janus Kinase 1 metabolism
- Abstract
Abstract: Allogeneic double-negative T cells (DNTs) are a rare T-cell subset that effectively target acute myeloid leukemia (AML) without inducing graft-versus-host disease in an allogeneic setting. A phase 1 clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy among patients with relapsed AML. However, the molecular mechanisms of DNT-mediated cytotoxicity against AML remain elusive. Thus, we used a flow cytometry-based high throughput screening to compare the surface molecule expression profile on DNTs during their interaction with DNT-susceptible or -resistant AML cells and identified a tumor necrosis factor α (TNFα)-dependent cytotoxic pathway in DNT-AML interaction. TNFα secreted by DNTs, upon encountering susceptible AML targets, sensitized AML cells to DNT-mediated killing, including those otherwise resistant to DNTs. Mechanistically, TNFα upregulated ICAM-1 on AML cells through a noncanonical JAK1-dependent pathway. DNTs then engaged with AML cells more effectively through an ICAM-1 receptor, lymphocyte function-associated antigen 1, leading to enhanced killing. These results reveal a TNFα-JAK1-ICAM-1 axis in DNT-mediated cytotoxicity against AML to improve therapeutic efficacy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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30. Subcutaneous administration of Stattic alleviates neuropathic pain by relieving inflammation in a mouse model of postherpetic neuralgia.
- Author
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Li D, Pan S, Jiang W, and Gao H
- Subjects
- Animals, Mice, Male, Neuralgia metabolism, Inflammation metabolism, Janus Kinase 1 metabolism, Janus Kinase 1 antagonists & inhibitors, Mice, Inbred C57BL, Injections, Subcutaneous, Signal Transduction, Cyclic S-Oxides, Diterpenes, Neuralgia, Postherpetic metabolism, STAT3 Transcription Factor metabolism, Ganglia, Spinal metabolism, Disease Models, Animal
- Abstract
Stattic, a commercial inhibitor of STAT3, can drive the development of neuropathic pain. Exploring the connection between Stattic and JAK1/STAT3 signaling may facilitate the understanding of neuropathic pain caused by postherpetic neuralgia (PHN). In the current study, as crucial regulators of inflammation, STAT3 and its associated JAK1/STAT3 pathway were found to be upregulated and activated in the L4-L6 dorsal root ganglion (DRG) of mice in response to resiniferatoxin (RTX)-induced PHN, while subcutaneous administration of Stattic was found to downregulate STAT3 expression and phosphorylation in a PHN model. Stattic administration further attenuated hypersensitivity to mechanical and thermal stimuli in PHN mice, and alleviated inflammation and cell death in the L4-L6 DRG of mice. Overexpression of STAT3 via microinjection of a lentiviral-STAT3 overexpression vector reversed the abnormal decrease of STAT3 at both the mRNA and protein levels in the L4-6 DRGs of PHN mice and significantly promoted hypersensitivity to mechanical stimuli in the mice. Collectively, we found that subcutaneous static administration alleviated RTX-induced neuropathic pain by deactivating JAK1/STAT3 in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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31. Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma.
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Yu L, Deng Y, Wang X, Santos C, Davis IJ, Earp HS, and Liu P
- Subjects
- Humans, Cell Line, Tumor, Animals, Mice, Axl Receptor Tyrosine Kinase, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins antagonists & inhibitors, Bone Neoplasms drug therapy, Bone Neoplasms metabolism, Bone Neoplasms pathology, Bone Neoplasms genetics, Xenograft Model Antitumor Assays, c-Mer Tyrosine Kinase metabolism, c-Mer Tyrosine Kinase genetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Phosphorylation drug effects, Female, STAT6 Transcription Factor, Sarcoma, Ewing drug therapy, Sarcoma, Ewing metabolism, Sarcoma, Ewing pathology, Sarcoma, Ewing genetics, Janus Kinase 1 metabolism, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 genetics, Signal Transduction drug effects, Receptor Protein-Tyrosine Kinases metabolism, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Intercellular Signaling Peptides and Proteins metabolism
- Abstract
Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value., (© 2024. The Author(s).)
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- 2024
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32. The Metabolism and Disposition of Brepocitinib in Humans and Characterization of the Formation Mechanism of an Aminopyridine Metabolite.
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Dowty ME, Qiu R, Dantonio A, Niosi M, Doran A, Balesano A, Wright SW, Walker GS, and Sharma R
- Subjects
- Humans, Male, Adult, Young Adult, Pyrazoles pharmacokinetics, Pyrazoles metabolism, Pyrazoles blood, Pyrazoles administration & dosage, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Administration, Oral, Cytochrome P-450 CYP3A metabolism, Healthy Volunteers, Microsomes, Liver metabolism, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 metabolism, Feces chemistry, Hydroxylation, Cytochrome P-450 CYP1A2 metabolism, Middle Aged, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors metabolism
- Abstract
Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of
14 C-brepocitinib (∼300 nCi). The average mass balance recovery was 96.7% ± 6.3%, with the majority of dose (88.0% ± 8.0%) recovered in urine and 8.7% ± 2.1% of the dose recovered in feces. Absorption of brepocitinib was rapid, with maximal plasma concentrations of total radioactivity and brepocitinib achieved within 0.5 hours after dosing. Circulating radioactivity consisted primarily of brepocitinib (47.8%) and metabolite M1 (37.1%) derived from hydroxylation at the C5' position of the pyrazole ring. Fractional contributions to metabolism via cytochrome P450 enzymes were determined to be 0.77 for CYP3A4/5 and 0.14 for CYP1A2 based on phenotyping studies in human liver microsomes. However, additional clinical studies are required to understand the potential contribution of CYP1A1. Approximately 83% of the dose was eliminated as N-methylpyrazolyl oxidative metabolites, with 52.1% of the dose excreted as M1 alone. Notably, M1 was not observed as a circulating metabolite in earlier metabolic profiling of human plasma from a multiple ascending dose study with unlabeled brepocitinib. Mechanistic studies revealed that M1 was highly unstable in human plasma and phosphate buffer, undergoing chemical oxidation leading to loss of the 5-hydroxy-1-methylpyrazole moiety and formation of aminopyrimidine cleavage product M2. Time-dependent inhibition and trapping studies with M1 yielded insights into the mechanism of this unusual and unexpected instability. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of brepocitinib, a JAK1/TYK2 inhibitor for atopic dermatitis, in humans as well as characterization of clearance pathways and pharmacokinetics of brepocitinib and its metabolites., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2024
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33. Myelin oligodendrocyte glycoprotein reactive Th17 cells drive Janus Kinase 1 dependent transcriptional reprogramming in astrocytes and alter cell surface cytokine receptor profiles during experimental autoimmune encephalomyelitis.
- Author
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Milne SM, Lahiri A, Sanchez CL, Marshall MJ, Jahan I, and Meares GP
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Cytokines metabolism, Cellular Reprogramming, Female, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Astrocytes metabolism, Th17 Cells immunology, Th17 Cells metabolism, Myelin-Oligodendrocyte Glycoprotein, Receptors, Cytokine metabolism, Receptors, Cytokine genetics, Janus Kinase 1 metabolism
- Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFβ, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation., (© 2024. The Author(s).)
- Published
- 2024
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34. Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis.
- Author
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Keenan C, Albeituni S, Oak N, Stroh A, Tillman HS, Wang Y, Freeman BB 3rd, Alemán-Arteaga S, Meyer LK, Woods R, Verbist KC, Zhou Y, Cheng C, and Nichols KE
- Subjects
- Animals, Mice, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, Pyrroles pharmacology, Pyrroles therapeutic use, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Mice, Inbred C57BL, Sulfonamides pharmacology, Sulfonamides therapeutic use, STAT1 Transcription Factor metabolism, STAT1 Transcription Factor genetics, Janus Kinase Inhibitors pharmacology, Janus Kinase Inhibitors therapeutic use, Piperidines pharmacology, Humans, Benzenesulfonamides, Bridged-Ring Compounds, Pyrrolidines, Nitriles, Pyrimidines pharmacology, Lymphohistiocytosis, Hemophagocytic drug therapy, Lymphohistiocytosis, Hemophagocytic chemically induced, Lymphohistiocytosis, Hemophagocytic pathology, Pyrazoles pharmacology, Pyrazoles therapeutic use, Disease Models, Animal
- Abstract
Abstract: Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in preclinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, JAK2 inhibitor fedratinib, and JAK1/2 inhibitor ruxolitinib. All 3 drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFN-γ)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, in which perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib, and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, whereas fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent proinflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
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35. Peripheral cytokine interleukin-10 alleviates perihematomal edema after intracerebral hemorrhage via interleukin-10 receptor/JAK1/STAT3 signaling.
- Author
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Xu Y, Wang K, Dai Y, Yang W, Ru X, Li W, Feng H, Zhu G, Hu Q, and Chen Y
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, STAT3 Transcription Factor metabolism, Cerebral Hemorrhage complications, Cerebral Hemorrhage drug therapy, Cerebral Hemorrhage metabolism, Brain Edema etiology, Brain Edema drug therapy, Janus Kinase 1 metabolism, Janus Kinase 1 antagonists & inhibitors, Interleukin-10 metabolism, Signal Transduction drug effects, Signal Transduction physiology, Receptors, Interleukin-10
- Abstract
Aims: The extent of perihematomal edema following intracerebral hemorrhage (ICH) significantly impacts patient prognosis, and disruption of the blood-brain barrier (BBB) exacerbates perihematomal edema. However, the role of peripheral IL-10 in mitigating BBB disruption through pathways that link peripheral and central nervous system signals remains poorly understood., Methods: Recombinant IL-10 was administered to ICH model mice via caudal vein injection, an IL-10-inhibiting adeno-associated virus and an IL-10 receptor knockout plasmid were delivered intraventricularly, and neurobehavioral deficits, perihematomal edema, BBB disruption, and the expression of JAK1 and STAT3 were evaluated., Results: Our study demonstrated that the peripheral cytokine IL-10 mitigated BBB breakdown, perihematomal edema, and neurobehavioral deficits after ICH and that IL-10 deficiency reversed these effects, likely through the IL-10R/JAK1/STAT3 signaling pathway., Conclusions: Peripheral IL-10 has the potential to reduce BBB damage and perihematomal edema following ICH and improve patient prognosis., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)
- Published
- 2024
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36. Nifuroxazide attenuates indomethacin-induced renal injury by upregulating Nrf2/HO-1 and cytoglobin and suppressing NADPH-oxidase, NF-κB, and JAK-1/STAT3 signals.
- Author
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Hassanein EHM, Abdel-Reheim MA, Althagafy HS, Hemeda MS, Gad RA, and Abdel-Sattar AR
- Subjects
- Animals, Male, Rats, Oxidative Stress drug effects, Kidney drug effects, Kidney pathology, Kidney metabolism, Rats, Wistar, Nitrofurans pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Kidney Diseases chemically induced, Kidney Diseases prevention & control, Kidney Diseases pathology, Kidney Diseases metabolism, Rats, Sprague-Dawley, Acute Kidney Injury chemically induced, Acute Kidney Injury prevention & control, Acute Kidney Injury pathology, Acute Kidney Injury metabolism, Acute Kidney Injury drug therapy, STAT3 Transcription Factor metabolism, NF-kappa B metabolism, NF-E2-Related Factor 2 metabolism, Up-Regulation drug effects, Indomethacin toxicity, Janus Kinase 1 metabolism, Hydroxybenzoates pharmacology, Heme Oxygenase (Decyclizing) metabolism, Signal Transduction drug effects, NADPH Oxidases metabolism
- Abstract
Indomethacin (INDO) is an NSAID with remarkable efficacy and widespread utilization for alleviating pain. Nevertheless, renal function impairment is an adverse reaction linked to INDO usage. Nifuroxazide (NFX), an oral nitrofuran antibiotic, is frequently employed as an intestinal anti-infective agent. Our study aimed to investigate the renoprotective effects of NFX against INDO-induced nephrotoxicity and explore the protection mechanisms. Four groups of rats were allocated to (I) the normal control, (II) the NFX-treated (50 mg/kg), (III) INDO control (20 mg/kg), and (IV) NFX + INDO. NFX attenuates renal impairment in INDO-induced renal injury, proved by decreasing serum levels of urea, creatinine, uric acid, and NGAL while the albumin was elevated. NFX mitigates renal oxidative stress by decreasing MDA levels and restoring the antioxidants' GSH and SOD levels mediated by upregulating Nrf2, HO-1, and cytoglobin pathways. NFX mitigated renal inflammation and effectively decreased MPO, IL-1β, and TNF-α levels in the rat's kidney mediated by significant downregulation of NADPH-oxidase and NF-κB expression and suppression of JAK-1 and STAT3 phosphorylation. NFX mitigates renal apoptosis by decreasing the expression of cleaved caspase-3 expression. In conclusion, NFX treatment prevents INDO nephrotoxicity by regulating Nrf2/HO-1, cytoglobin, NADPH-oxidase, NF-κB, and JAK-1/STAT3 signals., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2024
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37. Hair growth-promoting effects of Enz_MoriL on human dermal papilla cells through modulation of the Wnt/β-Catenin and JAK-STAT signaling pathways.
- Author
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Chang B, Bae J, Lee DS, and Kim S
- Subjects
- Humans, Cells, Cultured, Glycogen Synthase Kinase 3 beta metabolism, Intercellular Signaling Peptides and Proteins metabolism, Janus Kinases metabolism, Dermis cytology, Dermis drug effects, Phosphorylation drug effects, STAT3 Transcription Factor metabolism, Hair drug effects, Hair growth & development, Wnt-5a Protein metabolism, Janus Kinase 1 metabolism, Signal Transduction drug effects, STAT Transcription Factors metabolism, Hair Follicle drug effects, Hair Follicle cytology, Hair Follicle metabolism, Cell Proliferation drug effects, Wnt Signaling Pathway drug effects, Interferon-gamma metabolism, beta Catenin metabolism, Alopecia Areata metabolism, Alopecia Areata drug therapy, Alopecia Areata pathology
- Abstract
Enz_MoriL is a naturally occurring substance extracted from the leaves of Morus alba L. through enzymatic conversion. Historically, M. alba L. has been recognized for its potential to promote hair regrowth. However, the precise mechanism by which Enz_MoriL affects human hair follicle dermal papilla cells (hDPCs) remains unclear. The aim of this study was to investigate the molecular basis of Enz_MoriL's effect on hair growth in hDPCs. Interferon-gamma (IFN-γ) was used to examine the effects of Enz_MoriL on hDPCs during the anagen and catagen phases, as well as under conditions mimicking alopecia areata (AA). Enz_MoriL demonstrated the ability to promote cell proliferation in both anagen and catagen stages. It increased the levels of active β-catenin in the catagen stage induced by IFN-γ, leading to its nuclear translocation. This effect was achieved by increasing the phosphorylation of GSK3β and decreasing the expression of DKK-1. This stimulation induced proliferation in hDPCs and upregulated the expression of the Wnt family members 3a, 5a, and 7a at the transcript level. Additionally, Enz_MoriL suppressed JAK1 and STAT3 phosphorylation, contrasting with IFN-γ, which induced them in the catagen stage. In conclusion, Enz_MoriL directly induced signals for anagen re-entry into hDPCs by affecting the Wnt/β-catenin pathway and enhancing the production of growth factors. Furthermore, Enz_MoriL attenuated and reversed the interferon-induced AA-like environment by blocking the JAK-STAT pathway in hDPCs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2024
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38. The Janus kinase 1 is critical for pancreatic cancer initiation and progression.
- Author
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Shrestha H, Rädler PD, Dennaoui R, Wicker MN, Rajbhandari N, Sun Y, Peck AR, Vistisen K, Triplett AA, Beydoun R, Sterneck E, Saur D, Rui H, and Wagner KU
- Subjects
- Animals, Humans, Mice, CCAAT-Enhancer-Binding Protein-delta metabolism, CCAAT-Enhancer-Binding Protein-delta genetics, Disease Progression, Signal Transduction, Cell Line, Tumor, Mice, Knockout, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, STAT3 Transcription Factor metabolism
- Abstract
Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRAS
G12D -induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant downstream target of JAK1 signaling, which is upregulated in human PDAC. Reinstating the expression of C/EBPδ was sufficient to restore the growth of JAK1-deficient cancer cells as tumorspheres and in xenografted mice. Collectively, the findings of this study suggest that JAK1 executes important functions of inflammatory cytokines through C/EBPδ and may serve as a molecular target for PDAC prevention and treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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39. Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2.
- Author
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Schiefer S and Hale BG
- Subjects
- Humans, HEK293 Cells, Interferon-Stimulated Gene Factor 3, gamma Subunit metabolism, Interferon-Stimulated Gene Factor 3, gamma Subunit genetics, Phosphorylation, Proteome metabolism, STAT1 Transcription Factor metabolism, Ubiquitin-Protein Ligases metabolism, Interferon Type I metabolism, Janus Kinase 1 metabolism, Receptor, Interferon alpha-beta metabolism, Signal Transduction, STAT2 Transcription Factor metabolism, TYK2 Kinase metabolism, Ubiquitination
- Abstract
Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leverage TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal human proteomes of all seven canonical type I IFN signaling cascade members under basal and IFN-stimulated conditions. This uncovers a network of 103 high-confidence proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9, and validates several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identifies PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits the activating phosphorylation of TYK2 thereby restraining downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities., (© 2024. The Author(s).)
- Published
- 2024
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40. Synthesis, Antiproliferative Activity and Molecular Docking Analysis of Both Enantiomerically Pure Decursin Derivatives as Anticancer Agents.
- Author
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Ahn J, Hwang HH, Jung SY, Lee JY, Kim C, Choi HM, Gwon MJ, Kim MJ, Kwon Y, Woo J, Park B, Ko SG, and Lee JY
- Subjects
- Humans, A549 Cells, Stereoisomerism, Dose-Response Relationship, Drug, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Structure-Activity Relationship, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Molecular Structure, Angelica chemistry, Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents, Phytogenic chemical synthesis, Antineoplastic Agents, Phytogenic chemistry, Cell Proliferation drug effects, Molecular Docking Simulation, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor metabolism, Drug Screening Assays, Antitumor, Benzopyrans pharmacology, Benzopyrans chemistry, Benzopyrans chemical synthesis, Butyrates pharmacology, Butyrates chemistry, Butyrates chemical synthesis, Apoptosis drug effects
- Abstract
Using (S)-decursinol isolated from root of Angelica gigas Nakai (AGN), we semi-synthesized and evaluated a series of both enantiomerically pure decursin derivatives for their antiproliferative activities against A549 human lung cancer cells. All synthesized compounds showed a broad spectrum of inhibitory activities against the growth of A549 cells. Especially, compound (S)-2d with (E)-(furan-3-yl)acryloyl group showed the most potent activity (IC
50 : 14.03 µM) against A549 cancer cells as compared with the reference compound, decursin (IC50 : 43.55 µM) and its enantiomer, (R)-2d (IC50 : 151.59 µM). Western blotting assays indicated that (S)-2d more strongly inhibited Janus kinase 1 (JAK1) and signal transducer and activator of transcription activation 3 (STAT3) phosphorylation than decursin in a dose-dependent manner, while having no effect on CXCR7 overexpression and total STAT3 level. In addition, (S)-2d induced cell cycle arrest at G1 phase and subsequent apoptotic cell death in A549 cancer cells. Our combined analysis of molecular docking studies and biological data suggests that the inhibition of JAK1 with (S)-2d resulted in loss of STAT3 phosphorylation and inhibition of cell growth in A549 cancer cells. These overall results strongly suggest that (S)-2d (MRC-D-004) as a novel JAK1 inhibitor may have therapeutic potential in the treatment of A549 human lung cancers by targeting the JAK1/STAT3 signaling pathway.- Published
- 2024
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41. A microRNA Profile Regulates Inflammation-Related Signaling Pathways in Young Women with Locally Advanced Cervical Cancer.
- Author
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Millan-Catalan O, Pérez-Yépez EA, Martínez-Gutiérrez AD, Rodríguez-Morales M, López-Urrutia E, Coronel-Martínez J, Cantú de León D, Jacobo-Herrera N, Peralta-Zaragoza O, López-Camarillo C, Rodríguez-Dorantes M, and Pérez-Plasencia C
- Subjects
- Humans, Female, Adult, HeLa Cells, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, Cell Proliferation genetics, Cell Line, Tumor, Middle Aged, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms virology, MicroRNAs genetics, MicroRNAs metabolism, Signal Transduction genetics, Inflammation genetics, Inflammation pathology, Gene Expression Regulation, Neoplastic, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics
- Abstract
Cervical cancer (CC) remains among the most frequent cancers worldwide despite advances in screening and the development of vaccines against human papillomavirus (HPV), involved in virtually all cases of CC. In mid-income countries, a substantial proportion of the cases are diagnosed in advanced stages, and around 40% of them are diagnosed in women under 49 years, just below the global median age. This suggests that members of this age group share common risk factors, such as chronic inflammation. In this work, we studied samples from 46 patients below 45 years old, searching for a miRNA profile regulating cancer pathways. We found 615 differentially expressed miRNAs between tumor samples and healthy tissues. Through bioinformatic analysis, we found that several of them targeted elements of the JAK/STAT pathway and other inflammation-related pathways. We validated the interactions of miR-30a and miR-34c with JAK1 and STAT3, respectively, through dual-luciferase and expression assays in cervical carcinoma-derived cell lines. Finally, through knockdown experiments, we observed that these miRNAs decreased viability and promoted proliferation in HeLa cells. This work contributes to understanding the mechanisms through which HPV regulates inflammation, in addition to its canonical oncogenic function, and brings attention to the JAK/STAT signaling pathway as a possible diagnostic marker for CC patients younger than 45 years. To our knowledge to date, there has been no previous description of a panel of miRNAs or even ncRNAs in young women with locally advanced cervical cancer.
- Published
- 2024
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42. Annona squamosa Fruit Extract Ameliorates Lead Acetate-Induced Testicular Injury by Modulating JAK-1/STAT-3/SOCS-1 Signaling in Male Rats.
- Author
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Mobasher MA, Alsirhani AM, Alwaili MA, Baakdah F, Eid TM, Alshanbari FA, Alzahri RY, Alkhodair SA, and El-Said KS
- Subjects
- Animals, Male, Rats, Janus Kinase 1 metabolism, Molecular Docking Simulation, Oxidative Stress drug effects, Rats, Sprague-Dawley, STAT3 Transcription Factor metabolism, Annona chemistry, Fruit chemistry, Organometallic Compounds, Plant Extracts pharmacology, Plant Extracts chemistry, Signal Transduction drug effects, Testis drug effects, Testis metabolism, Testis pathology
- Abstract
Lead (Pb) is a common pollutant that is not biodegradable and gravely endangers the environment and human health. Annona squamosa fruit has a wide range of medicinal uses owing to its phytochemical constituents. This study evaluated the effect of treatment with A. squamosa fruit extract (ASFE) on testicular toxicity induced in male rats by lead acetate. The metal-chelating capacity and phytochemical composition of ASFE were determined. The LD
50 of ASFE was evaluated by probit analysis. Molecular docking simulations were performed using Auto Dock Vina. Forty male Sprague Dawley rats were equally divided into the following groups: Gp1, a negative control group; Gp2, given ASFE (350 mg/kg body weight (b. wt.)) (1/10 of LD50 ); Gp3, given lead acetate (PbAc) solution (100 mg/kg b. wt.); and Gp4, given PbAc as in Gp3 and ASFE as in Gp2. All treatments were given by oro-gastric intubation daily for 30 days. Body weight changes, spermatological parameters, reproductive hormone levels, oxidative stress parameters, and inflammatory biomarkers were evaluated, and molecular and histopathological investigations were performed. The results showed that ASFE had promising metal-chelating activity and phytochemical composition. The LD50 of ASFE was 3500 mg/kg b. wt. The docking analysis showed that quercetin demonstrated a high binding affinity for JAK-1 and STAT-3 proteins, and this could make it a more promising candidate for targeting the JAK-1/STAT-3 pathway than others. The rats given lead acetate had defective testicular tissues, with altered molecular, biochemical, and histological features, as well as impaired spermatological characteristics. Treatment with ASFE led to a significant mitigation of these dysfunctions and modulated the JAK-1/STAT-3/SOCS-1 axis in the rats.- Published
- 2024
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43. Reversible effects on female rat fertility with abrocitinib, a Janus kinase 1 inhibitor.
- Author
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Bowman CJ, Campion SN, Catlin NR, Nowland WS, Stethem CM, Radi ZA, and Cappon GD
- Subjects
- Female, Animals, Pregnancy, Rats, Rats, Sprague-Dawley, Embryo Implantation drug effects, Janus Kinase Inhibitors pharmacology, Pregnancy Rate, Fertility drug effects, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Pyrimidines pharmacology, Sulfonamides pharmacology
- Abstract
Background: Abrocitinib is a Janus kinase (JAK) 1 selective inhibitor approved for the treatment of atopic dermatitis. Female reproductive tissues were unaffected in general toxicity studies, but an initial female rat fertility study resulted in adverse effects at all doses evaluated. A second rat fertility study was conducted to evaluate lower doses and potential for recovery., Methods: This second study had 4 groups of 20 females each administered abrocitinib (0, 3, 10, or 70 mg/kg/day) 2 weeks prior to cohabitation through gestation day (GD) 7. In addition, 2 groups of 20 rats (0 or 70 mg/kg/day) were dosed for 3 weeks followed by a 4-week recovery period before mating. All mated females were evaluated on GD 14., Results: No effects were observed at ≤10 mg/kg/day. At 70 mg/kg/day (29x human exposure), decreased pregnancy rate, implantation sites, and viable embryos were observed. All these effects reversed 4 weeks after the last dose., Conclusions: Based on these data and literature on the potential role of JAK signaling in implantation, we hypothesize that these effects may be related to JAK1 inhibition and, generally, that peri-implantation effects such as these, in the absence of cycling or microscopic changes in nonpregnant female reproductive tissues, are anticipated to be reversible., (© 2024 Wiley Periodicals LLC.)
- Published
- 2024
- Full Text
- View/download PDF
44. Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.
- Author
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Amaral JL, Lucredi NC, França VLB, Santos SJM, Maia FF Jr, Morais PA, Souza PFN, Comar JF, and Freire VN
- Subjects
- Humans, Quantum Theory, Autoimmune Diseases drug therapy, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Hydrogen Bonding, Janus Kinase Inhibitors chemistry, Janus Kinase Inhibitors therapeutic use, Janus Kinase Inhibitors pharmacology, Adamantane chemistry, Pyrroles chemistry, Pyrroles pharmacology, Molecular Docking Simulation, Pyrimidines chemistry, Pyrimidines pharmacology, Piperidines chemistry, Piperidines pharmacology, Piperidines therapeutic use, Niacinamide chemistry, Niacinamide analogs & derivatives, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Janus Kinase 1 chemistry, Adamantane analogs & derivatives
- Abstract
Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.
- Published
- 2024
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45. Janus Kinase Inhibitors Differentially Inhibit Specific Cytokine Signals in the Mesenteric Lymph Node Cells of Inflammatory Bowel Disease Patients.
- Author
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Hindmarch DC, Malashanka S, Shows DM, Clarke AS, and Lord JD
- Subjects
- Humans, Crohn Disease drug therapy, Crohn Disease pathology, Signal Transduction drug effects, Pyrrolidines pharmacology, Pyrrolidines therapeutic use, Male, Colitis, Ulcerative drug therapy, Colitis, Ulcerative pathology, Colitis, Ulcerative immunology, Adult, Mesentery, Female, Janus Kinase 3 antagonists & inhibitors, Janus Kinase 3 metabolism, Heterocyclic Compounds, 3-Ring pharmacology, Heterocyclic Compounds, 3-Ring therapeutic use, Middle Aged, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases pathology, Quinazolinones pharmacology, Quinazolinones therapeutic use, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Benzamides pharmacology, Benzamides therapeutic use, Janus Kinase Inhibitors pharmacology, Janus Kinase Inhibitors therapeutic use, Piperidines pharmacology, Piperidines therapeutic use, Pyrimidines pharmacology, Pyrimidines therapeutic use, Cytokines metabolism, Lymph Nodes pathology, Lymph Nodes drug effects, Pyrroles pharmacology, Pyrroles therapeutic use, Pyridines, Triazoles
- Abstract
Background: Janus kinase [JAK] inhibitors [JAKinibs] are effective small molecule therapies for treating Crohn's disease [CD] and ulcerative colitis [UC], collectively known as inflammatory bowel disease [IBD]. By preventing JAKs from phosphorylating signal transducer and activator of transcription proteins, JAKinibs disrupt cytokine signalling pathways that promote inflammation. Despite considerable overlap in the JAKs they target, first- and second-generation JAKinibs display different clinical efficacies in CD and UC., Methods: We conducted a comparative phosflow study of four JAKinibs [filgotinib, upadacitinib, tofacitinib, and deucravacitinib] to observe subtle mechanistic differences that may dictate their clinical behaviour. Resected mesenteric lymph node [MLN] cells from 19 patients [9 CD, 10 UC] were analysed by flow cytometry in the presence or absence of different cytokine stimuli and titrated JAKinibs., Results: We found a higher potency of the JAK 1/3-preferential inhibitor, tofacitinib, for JAK 3-dependent cytokine signalling pathways in comparison to filgotinib, but a higher potency of the JAK 1-preferential inhibitors, filgotinib and upadacitinib, for JAK 3-independent cytokine signalling pathways. Deucravacitinib, a TYK2-preferential inhibitor, demonstrated a much narrower selectivity by inhibiting only IL-10 and IFN-β pathways, albeit more potently than the other JAKinibs. Additionally, we found some differences in the sensitivity of immune cells from CD versus UC, and patients with versus without a CD-associated NOD2 polymorphism, to phosphorylate signal transducer and activator of transcriptions in response to specific cytokine stimulation., Conclusions: Despite their similarities, differences exist in the relative potencies of different JAKinibs against distinct cytokine families, to explain their clinical efficacy., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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- View/download PDF
46. Novel JAK Inhibitors to Reduce Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in a Preclinical Mouse Model.
- Author
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Kim S, Ruminski P, Singh M, Staser K, Ashami K, Ritchey J, Lim S, DiPersio JF, and Choi J
- Subjects
- Animals, Mice, Antigen-Presenting Cells immunology, Antigen-Presenting Cells drug effects, Antigen-Presenting Cells metabolism, Azetidines pharmacology, Disease Models, Animal, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Janus Kinase 2 metabolism, Janus Kinase 2 antagonists & inhibitors, Janus Kinase Inhibitors pharmacology, Mice, Inbred C57BL, Purines pharmacology, Sulfonamides pharmacology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory drug effects, Graft vs Host Disease prevention & control, Graft vs Host Disease drug therapy, Hematopoietic Stem Cell Transplantation adverse effects, Pyrazoles pharmacology, Transplantation, Homologous
- Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib.
- Published
- 2024
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47. Integration of fingerprint-based similarity searching and kernel-based partial least squares analysis to predict inhibitory activity against CSK, HER2, JAK1, JAK2, and JAK3.
- Author
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Deokar H, Deokar M, and Buolamwini JK
- Subjects
- Humans, CSK Tyrosine-Protein Kinase antagonists & inhibitors, Drug Discovery methods, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 chemistry, Janus Kinase 2 metabolism, Janus Kinase 3 antagonists & inhibitors, Janus Kinase 3 metabolism, Least-Squares Analysis, Receptor, ErbB-2 antagonists & inhibitors, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 chemistry, Janus Kinase 1 metabolism, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology
- Abstract
Fingerprint-based similarity searching is an important strategy for virtual screening in drug discovery. In the present study, we carried out a systematic virtual screening study, followed by the establishment of kernel-based partial least square (KPLS) analysis prediction models for five tyrosine kinase drug targets, C-terminal SRC kinase (CSK), human epidermal growth factor 2 (HER2), and Janus kinases 1, 2, and 3 (JAK1, JAK2, and JAK3), using a dataset of 3688 compounds. These kinases are important drug discovery targets, particularly as HER2 has been validated for the treatment of metastatic breast cancer, JAK inhibitors have been validated for the clinical management of arthritis and autoimmune diseases, and CSK has been found to play an important role in bone remodeling in arthritis. We conducted similarity screenings with the most active molecule for each target in the dataset as a query using eight (8) types of two-dimensional (2D) molecular fingerprints, comprising seven Hashed fingerprints, Linear, Dendritic, Radial, Pairwise, Triplet, Torsion, and MOLSPRINT2D, and one Structural keys fingerprint, MACCS. The top ranked 1% of compounds from each target's similarity screening results was used to set up kernel-based partial least square (KPLS) prediction models, with q
2 values up to 0.8. The best KPLS model for each target was selected based on its predictive ability and boot strapping results and used for prediction. This integrated study approach combining similarity screening with KPLS analysis has a high potential to enhance the accuracy and efficiency of virtual screening and thus improve the drug discovery process., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2024
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- View/download PDF
48. [Protective effect of salidroside on renal damage in diabetic nephropathy mice by regulating RAGE/JAK1/STAT signaling pathway].
- Author
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Leng CL, Lin K, Zhou M, Ye XS, Shu XJ, and Liu W
- Subjects
- Animals, Mice, Male, Protective Agents pharmacology, Protective Agents administration & dosage, Humans, Mice, Inbred C57BL, Blood Glucose metabolism, Blood Glucose drug effects, Diabetic Nephropathies drug therapy, Diabetic Nephropathies metabolism, Glucosides pharmacology, Glucosides administration & dosage, Receptor for Advanced Glycation End Products metabolism, Receptor for Advanced Glycation End Products genetics, Signal Transduction drug effects, Kidney drug effects, Kidney metabolism, Kidney pathology, Phenols pharmacology, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics
- Abstract
This study aims to investigate the protective effect of salidroside(SAL) on renal damage in diabetic nephropathy(DN) mice based on the receptor for advanced glycation end products/janus activated kinase 1/signal transduction and activator of transcription 3(RAGE/JAK1/STAT3) signaling pathway. The mouse DN model was established by high-fat/high-sucrose diets combined with intraperitoneal injection of streptozocin(STZ). Mice were randomly divided into normal group, model group, low-dose SAL group(20 mg·kg~(-1)), high-dose SAL group(100 mg·kg~(-1)), and metformin group(140 mg·kg~(-1)), with 12 mice in each group. After establishing the DN model, mice were given drugs or solvent intragastrically, once a day for consecutive 10 weeks. Body weight, daily water intake, and fasting blood glucose(FBG) were measured every two weeks. After the last dose, the glucose tolerance test was performed, and the samples of 24-hour urine, serum, and kidney tissue were collected. The levels of 24 hours urinary total protein(24 h-UTP), serum creatinine(Scr), blood urea nitrogen(BUN), triglyceride(TG), total cholesterol(TC), low density lipoprotein cholesterol(LDL-C), and high density lipoprotein cholesterol(HDL-C) were detected by biochemical tests. Periodic acid-schiff(PAS) staining was used to observe the pathological changes in the kidney tissue. The protein expressions of α-smooth muscle actin(α-SMA), vimentin, and advanced glycation end products(AGEs) in kidneys were detected by immunohistochemical staining. The activities of superoxide dismutase(SOD), catalase(CAT), glutathione peroxidase(GSH-PX), and the level of malondialdehyde(MDA) in kidneys were detected by using a corresponding detection kit. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of AGEs, carboxymethyllysine(CML), and carboxyethyllysine(CEL) in serum. The protein expressions of RAGE and the phosphorylation level of JAK1 and STAT3 in kidneys were detected by Western blot. Compared with the normal group, the levels of FBG, the area under the curve of glucose(AUCG), water intake, kidney index, 24 h-UTP, tubular injury score, extracellular matrix deposition ratio of the renal glomerulus, the serum levels of Scr, BUN, TG, LDL-C, AGEs, CEL, and CML, the level of MDA, the protein expressions of α-SMA, vimentin, AGEs, and RAGE, and the phosphorylation level of JAK1 and STAT3 in kidney tissue were increased significantly(P<0.01), while the level of HDL-C in serum and the activity of SOD, CAT, and GSH-PX in kidney tissue were decreased significantly(P<0.01). Compared with the model group, the above indexes of the high-dose SAL group were reversed significantly(P<0.05 or P<0.01). In conclusion, this study suggests that SAL can alleviate oxidative stress and renal fibrosis by inhibiting the activation of AGEs-mediated RAGE/JAK1/STAT3 signaling axis, thus playing a potential role in the treatment of DN.
- Published
- 2024
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- View/download PDF
49. N-Acetylcysteine Alters Disease Progression and Increases Janus Kinase Mutation Frequency in a Mouse Model of Precursor B-Cell Acute Lymphoblastic Leukemia.
- Author
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Sams MP, Iansavitchous J, Astridge M, Rysan H, Xu LS, Rodrigues de Oliveira B, and DeKoter RP
- Subjects
- Child, Humans, Mice, Animals, Child, Preschool, Acetylcysteine pharmacology, Acetylcysteine therapeutic use, Janus Kinases, Mutation Rate, Reactive Oxygen Species metabolism, Precursor Cells, B-Lymphoid metabolism, Janus Kinase 1 genetics, Janus Kinase 1 metabolism, Mutation, Janus Kinase 3 genetics, Janus Kinase 3 metabolism, Disease Progression, Drinking Water, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreΔPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-CreΔPB mice with NAC in drinking water significantly reduced the frequency of CD19
+ pre-B-ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by a median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared with control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. SIGNIFICANCE STATEMENT: In a mouse model of precursor B-cell acute lymphoblastic leukemia associated with high levels of reactive oxygen species, treatment with N-acetylcysteine did not delay disease progression but instead selected for leukemic clones with activating R653H mutations in Janus kinase 3., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2024
- Full Text
- View/download PDF
50. Design, synthesis and evaluation of C-5 substituted pyrrolopyridine derivatives as potent Janus Kinase 1 inhibitors with excellent selectivity.
- Author
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Chen L, Tang Y, Lang JJ, Lin Y, Yu Z, Li X, Zheng X, Mi P, Lv Y, and Lin YW
- Subjects
- Humans, Structure-Activity Relationship, Janus Kinase 1 metabolism, Protein Kinase Inhibitors pharmacology, Janus Kinase 2 metabolism, Heterocyclic Compounds, Autoimmune Diseases
- Abstract
The development of highly selective Janus Kinase 1 (JAK1) inhibitors is crucial for improving efficacy and minimizing adverse effects in the clinical treatment of autoimmune diseases. In a prior study, we designed a series of C-5 4-pyrazol substituted pyrrolopyridine derivatives that demonstrated significant potency against JAK1, with a 10 ∼ 20-fold selectivity over Janus Kinase 2 (JAK2). Building on this foundation, we adopted orthogonal strategy by modifying the C-5 position with 3-pyrazol/4-pyrazol/3-pyrrol groups and tail with substituted benzyl groups on the pyrrolopyridine head to enhance both potency and selectivity. In this endeavor, we have identified several compounds that exhibit excellent potency and selectivity for JAK1. Notably, compounds 12b and 12e, which combined 4-pyrazol group at C-5 site and meta-substituted benzyl tails, displayed IC
50 value with 2.4/2.2 nM and high 352-/253-fold selectivity for JAK1 over JAK2 in enzyme assays. Additionally, both compounds showed good JAK1-selective in Ba/F3-TEL-JAK1/2 cell-based assays. These findings mark a substantial improvement, as these compounds are 10-fold more potent and over 10-fold more selective than the best compound identified in our previous study. The noteworthy potency and selectivity properties of compounds 12b and 12e suggest their potential utility in furthering the development of drugs for autoimmune diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
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