• Bulletin of the Korean Chemical Society
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• v.33 no.12
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• pp.4207-4210
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• 2012

• BMB Reports
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• v.54 no.12
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• pp.626-631
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• 2021

Janus kinase 2 (JAK2), a non-receptor tyrosine kinase, is a critical component of cytokine and growth factor signaling pathways regulating hematopoietic cell proliferation. JAK2 mutations are associated with multiple myeloproliferative neoplasms. Although physiological and pathological functions of JAK2 in hematopoietic tissues are well-known, such functions of JAK2 in the nervous system are not well studied yet. The present study demonstrated that JAK2 could negatively regulate neuronal differentiation of mouse embryonic stem cells (ESCs). Depletion of JAK2 stimulated neuronal differentiation of mouse ESCs and activated glycogen synthase kinase 3β, Fyn, and cyclin-dependent kinase 5. Knockdown of JAK2 resulted in accumulation of GTP-bound Rac1, a Rho GTPase implicated in the regulation of cytoskeletal dynamics. These findings suggest that JAK2 might negatively regulate neuronal differentiation by suppressing the GSK-3β/Fyn/CDK5 signaling pathway responsible for morphological maturation.

• Biomolecules & Therapeutics
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• v.21 no.2
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• pp.97-106
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• 2013

Chronic hepatitis C virus (HCV) infection is responsible for the development of liver cirrhosis and hepatocellular carcinoma. HCV core protein plays not only a structural role in the virion morphogenesis by encapsidating a virus RNA genome but also a non-structural role in HCV-induced pathogenesis by blocking innate immunity. Especially, it has been shown to regulate JAK-STAT signaling pathway through its direct interaction with Janus kinase (JAK) via its proline-rich JAK-binding motif ($^{79}{\underline{P}}GY{\underline{P}}WP^{84}$). However, little is known about the physiological significance of this HCV core-JAK association in the context of the virus life cycle. In order to gain an insight, a mutant HCV genome (J6/JFH1-79A82A) was constructed to express the mutant core with a defective JAK-binding motif ($^{79}{\underline{A}}GY{\underline{A}}WP^{84}$) using an HCV genotype 2a infectious clone (J6/JFH1). When this mutant HCV genome was introduced into hepatocarcinoma cells, it was found to be severely impaired in its ability to produce infectious viruses in spite of its robust RNA genome replication. Taken together, all these results suggest an essential requirement of HCV core-JAK protein interaction for efficient production of infectious viruses and the potential of using core-JAK blockers as a new anti-HCV therapy.

• Journal of Pathology and Translational Medicine
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• v.52 no.6
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• pp.363-368
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• 2018

Background: Vitiligo is a chronic autoimmune disease in which the destruction of melanocytes causes white spots on the affected skin. Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-signal transducer and activator of transcription pathway. The aim of the present study is to explore the possible role of JAK1 in the pathogenesis of vitiligo using immunohistochemical methods. Methods: The current study was conducted in a sample of 39 patients who presented with vitiligo and 22 healthy individuals who were age and sex matched as a control group. We used immunohistochemistry to evaluate JAK1 status (intensity and distribution) and assess the percentage of residual melanocytes using human melanoma black 45 (HMB45). Results: Intense and diffuse JAK1 expression was significantly more likely to indicate vitiliginous skin compared to normal skin (p<.001). Strong and diffuse JAK1 expression was associated with short disease duration, female sex, and lower percentage of melanocytes (detected by HMB45) (p<.05). Conclusions: JAK1 may be involved in the pathogenesis of vitiligo, as indicated by intense and diffuse expression compared to control and association with lower percentage of melanocytes detected by HMB45 immunostaining.

• The Korean Journal of Physiology and Pharmacology
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• v.11 no.1
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• pp.31-36
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• 2007

To elucidate a potential molecular link between diabetes and atherosclerosis, we investigated the role of Janus tyrosine kinase(JAK) for NAD(P)H oxidase-derived superoxide generation in the enhanced proliferative capacity of vascular smooth muscle cells(VSMC) of Otsuka Long-Evans Tokushima Fatty(OLETF) rat, an animal model of type 2 diabetes. An enhanced proliferative response to 10% fetal bovine serum(FBS) and superoxide generation with an increased NAD(P)H oxidase activity were observed in diabetic(OLETF) VSMC. Both the enhanced proliferation and superoxide generation in diabetic VSMC were significantly attenuated by AG490, JAK2 inhibitor, and PP2, Src kinase inhibitor. Tyrosine phosphorylation of proteins in diabetic VSMC, especially JAK2, was increased compared to control VSMC. Furthermore, the enhanced NAD(P)H oxidase activity in diabetic VSMC was significantly attenuated by AG490 in a dose-dependent manner. Together, these results indicate that the signal pathway which leads to diabetes-associated activation of Src kinase/JAK is critically involved in the diabetic VSMC proliferation through NAD(P)H oxidase activation and superoxide generation.

• Bulletin of the Korean Chemical Society
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• v.35 no.11
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• pp.3377-3380
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• 2014

• Bulletin of the Korean Chemical Society
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• v.35 no.8
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• pp.2581-2584
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• 2014

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.4
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• pp.251-261
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• 2019

Allergic asthma, is a common chronic inflammatory disease of the airway presenting with airway hyperresponsiveness and airway remodelling. T helper cells-derived cytokines are critically associated with asthma pathogenesis. Janus kinase-signal transduction and activation of transcription (JAK/STAT) signaling is found to be involved in asthma. Magnolol is a plant-derived bioactive compound with several pharmacological effects. The study aimed to assess the effects of magnolol in ovalbumin (OVA)-induced asthmatic model. BALB/c mice were sensitized and challenged with OVA. Magnolol (12.5, 25, or 50 mg/kg body weight) was administered to separate groups of animals. Dexamethasone was used as the positive control. Cellular infiltration into the bronchoalveolar lavage fluid (BALF) were reduced on magnolol treatment. The levels of Th2 and Th17 cytokines were reduced with noticeably raised levels of interferon gamma. Lung function was improved effectively along with restoration of bronchial tissue architecture. OVA-specific immunoglobulin E levels in serum and BALF were decreased by magnolol. Magnolol reduced Th17 cell population and effectively modulated the JAK-STAT and Notch 1 signaling. The results suggest the promising use of magnolol in therapy for allergic asthma.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.2
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• pp.131-138
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• 2009

The binding of interleukin-6 (IL-6) cytokine family ligands to the gp130 receptor complex activates the Janus kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3) signal transduction pathway, where STA T3 plays an important role in cell survival and tumorigenesis. Constitutive activation of STAT3 has been frequently observed in many cancer tissues, and thus, blocking of the gp130 signaling pathway, at the JAK level, might be a useful therapeutic approach for the suppression of STAT3 activity, as anticancer therapy. AG490 is a tyrphostin tyrosine kinase inhibitor that has been extensively used for inhibiting JAK2 in vitro and in vivo. In this study, we demonstrate a novel mechanism associated with AG490 that inhibits the JAK/STAT3 pathway. AG490 induced downregulation of gp130, a common receptor for the IL-6 cytokine family compounds, but not JAK2 or STAT3, within three hours of exposure. The downregulation of gp130 was not caused by enhanced degradation of gp130 or by inhibition of mRNA transcription. It most likely occurred by translation inhibition of gp130 in association with phosphorylation of the eukaryotic initiation factor-2 a. The inhibition of protein synthesis of gp130 by AG490 led to immediate loss of mature gp130 in cell membranes, due to its short half-life, thereby resulting in reduction in the STAT3 response to IL-6. Taken together, these results suggest that AG490 blocks the STAT3 activation pathway via a novel pathway.

• Asian-Australasian Journal of Animal Sciences
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• v.14 no.12
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• pp.1785-1793
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• 2001

The interaction of growth hormone with it's receptor results in dimerization of receptor, a feature known in action of certain cytokines. The interaction results in generation of number of signalling molecules. The involvement of Janus kinases, mitogen activated kinases, signal transduction and activator of transcription proteins, insulin like substrate, phosphatidylinositol 3-kinase, phospholipase C, protein kinase C is almost established in growth hormone action. There are still many missing links in explaining diversified activities of growth hormone. Amino acid sequence data for growth hormones and growth hormone receptors from a number of species have proved useful in understanding species specific effects of growth hormone. Complete understanding of growth hormone action can have implications in designing drugs for obtaining desired effects of growth hormone.