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jak-janus-kinase

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Meeting Abstracts
Journal: Diabetes
Diabetes 2019;68(Supplement_1):112-OR
Published: 01 June 2019
... risk. One such candidate gene is a member of the JAK (Janus Kinase) family of tyrosine kinases, TYK2, which plays a critical role in intracellular signaling stimulated by cytokines through STATs. Loss-of-function variants of TYK2 are associated with protection against T1D. In line with this, silencing...
Images
Heat map of KEGG pathway enrichment analysis. Normalized counts/pseudocount...
Published: 30 May 2017
Figure 3 Heat map of KEGG pathway enrichment analysis. Normalized counts/pseudocounts of the DE genes were subjected to GAGE analysis by using the Bioconductor package gage. Pathways with adjusted P values (Benjamini-Hochberg procedure) of <0.05 are indicated by asterisks. The Stat.mean values represent the averaged magnitude and direction of fold changes at the gene set level corresponding to the color-coded upregulated (red) and downregulated (blue) changes. KEGG pathway maps were used to perform classifications. Akt, protein kinase B; ECM, extracellular matrix; HIF-1, hypoxia-inducible factor 1; Jak, Janus kinase; MAPK, mitogen-activated kinase; PI3K, phosphatidylinositol 3-kinase; TGF, transforming growth factor; tRNA, transfer RNA. Figure 3. Heat map of KEGG pathway enrichment analysis. Normalized counts/pseudocounts of the DE genes were subjected to GAGE analysis by using the Bioconductor package gage. Pathways with adjusted P values (Benjamini-Hochberg procedure) of <0.05 are indicated by asterisks. The Stat.mean values represent the averaged magnitude and direction of fold changes at the gene set level corresponding to the color-coded upregulated (red) and downregulated (blue) changes. KEGG pathway maps were used to perform classifications. Akt, protein kinase B; ECM, extracellular matrix; HIF-1, hypoxia-inducible factor 1; Jak, Janus kinase; MAPK, mitogen-activated kinase; PI3K, phosphatidylinositol 3-kinase; TGF, transforming growth factor; tRNA, transfer RNA. More
Images
Activation of inflammatory mediators in pancreatic β-cells in type 1 diabet...
Published: 23 April 2011
FIG. 3. Activation of inflammatory mediators in pancreatic β-cells in type 1 diabetes. Tumor necrosis factor-α (TNF-α), IL-1β, and interferon-γ (IFN-γ) are the most likely cytokines acting in synergy during inflammation of pancreatic β-cells, leading to the activation of a final common pathway, such as nuclear factor-κB (NF-κB) and, ultimately, to β-cell destruction. NF-κB can be activated by a variety of stimuli, including TNF-α, IL-1, receptor for advanced glycation end products (RAGE), and Toll-like receptors (TLRs). IL-1β is an inflammatory cytokine that plays a major role in immune-mediated β-cell destruction. Interestingly, in patients with type 2 diabetes, the IL-1 pathway blockade with an IL-1 receptor antagonist (Anakinra) improved glycemic control and β-cell secretory function and resulted in a significant reduction marker of systemic inflammation, namely, C-reactive protein and IL-6 ( 56 ). A recent clinical study indicated that the blockade of the IL-1β pathway in type 1 diabetes resulted in the reduced ability of mononuclear cells to traffic to sites of inflammation ( 57 ). The latter observations provide evidence for a possible mechanistic link between type 1 and type 2 diabetes, and additional studies are necessary to unravel the common inflammatory pathways involved in the pathologic etiology of these two diseases. Compelling evidence indicates that cytokines influence the expression of inducible NO synthase (iNOS) leading to NO production. IL-1β and IFNγ, by NO synthesis, were reported to markedly decrease sarco(endo)plasmic reticulum Ca2+ ATPase 2b (SERCA2b) protein expression, deplete Ca2+ stores, and activate ER stress pathway, which is a potential contributing mechanism to β-cell death. Furthermore, cytokine-induced (IL-1β + IFN-γ) apoptosis of INS-1 cells appears to depend on NO production, as demonstrated by the use of the NO dioxygenase blocker NG-methyl-l-arginine. NO also contributes to cytokine-induced apoptosis through potentiation of Jun NH2-terminal kinase (JNK) activity and suppression of Akt/protein kinase B. Although whether oxidative stress plays a key role in the pathogenesis of type 1 diabetes is still being discussed, a reduced antioxidant capacity has been demonstrated in patients with type 1 diabetes compared with healthy control subjects. To summarize the cytokine signaling, TNF-α signals through trimerized p60 receptors that interact with the TNF receptor type 1–associated death domain protein (TRADD). Fas-associated protein with death domain (FADD) is then recruited by TRADD, thus allowing binding of receptor-interacting protein (RIP) and TNF receptor–associated factor 2 (TRAF2) to the receptor complex. TRAF2 activates NF-κB through NF-κB–inducing kinase (NIK)–inhibitor of κB kinase (IKK) and activates the JNK/p38 pathways. TNF-α is an inflammatory cytokine that appears to be associated with a number of autoimmune disorders, including type 1 diabetes. TNF-α may activate intraislet resident macrophages, resulting in the release of IL-1β, which generates iNOS expression and the overproduction of NO in β-cells. Alterations in the number and function of CD4+CD25+ T-cells may be an additional mechanism by which TNF-α may cause type 1 diabetes in NOD mice. The role of RAGE mediated by NF-κB has not been entirely elucidated, although RAGE may be an important intermediary in causing monocyte production of inflammatory mediators such as TNF-α. It is possible that increased expression of RAGE in response to hyperglycemia may lead to activation of innate and even adaptive immune responses and enhance β-cell destruction. After IL-1β binding to IL-1βR1, MyD88 is recruited to the receptor complex. MyD88 interacts with IL-1 receptor–associated kinase (IRAK), allowing the binding of TRAF6 to IRAK. TRAF6 causes activation of mitogen-activated protein kinase/stress-activated protein kinase and activation of the NF-κB pathway by transforming growth factor-β–activated kinase 1 (TAK1)–mediated activation of IKK. IL-1β also stimulates activation of protein kinase C-δ (PKC-δ), possibly through phospholipase C generation of diacylglycerol. ERK, extracellular signal–regulated kinase; Jak, Janus kinase; STAT1, signal transducer and activator of transcription-1. FIG. 3. Activation of inflammatory mediators in pancreatic β-cells in type 1 diabetes. Tumor necrosis factor-α (TNF-α), IL-1β, and interferon-γ (IFN-γ) are the most likely cytokines acting in synergy during inflammation of pancreatic β-cells, leading to the activation of a final common pathway, such as nuclear factor-κB (NF-κB) and, ultimately, to β-cell destruction. NF-κB can be activated by a variety of stimuli, including TNF-α, IL-1, receptor for advanced glycation end products (RAGE), and Toll-like receptors (TLRs). IL-1β is an inflammatory cytokine that plays a major role in immune-mediated β-cell destruction. Interestingly, in patients with type 2 diabetes, the IL-1 pathway blockade with an IL-1 receptor antagonist (Anakinra) improved glycemic control and β-cell secretory function and resulted in a significant reduction marker of systemic inflammation, namely, C-reactive protein and IL-6 (56). A recent clinical study indicated that the blockade of the IL-1β pathway in type 1 diabetes resulted in the reduced ability of mononuclear cells to traffic to sites of inflammation (57). The latter observations provide evidence for a possible mechanistic link between type 1 and type 2 diabetes, and additional studies are necessary to unravel the common inflammatory pathways involved in the pathologic etiology of these two diseases. Compelling evidence indicates that cytokines influence the expression of inducible NO synthase (iNOS) leading to NO production. IL-1β and IFNγ, by NO synthesis, were reported to markedly decrease sarco(endo)plasmic reticulum Ca2+ ATPase 2b (SERCA2b) protein expression, deplete Ca2+ stores, and activate ER stress pathway, which is a potential contributing mechanism to β-cell death. Furthermore, cytokine-induced (IL-1β + IFN-γ) apoptosis of INS-1 cells appears to depend on NO production, as demonstrated by the use of the NO dioxygenase blocker NG-methyl-l-arginine. NO also contributes to cytokine-induced apoptosis through potentiation of Jun NH2-terminal kinase (JNK) activity and suppression of Akt/protein kinase B. Although whether oxidative stress plays a key role in the pathogenesis of type 1 diabetes is still being discussed, a reduced antioxidant capacity has been demonstrated in patients with type 1 diabetes compared with healthy control subjects. To summarize the cytokine signaling, TNF-α signals through trimerized p60 receptors that interact with the TNF receptor type 1–associated death domain protein (TRADD). Fas-associated protein with death domain (FADD) is then recruited by TRADD, thus allowing binding of receptor-interacting protein (RIP) and TNF receptor–associated factor 2 (TRAF2) to the receptor complex. TRAF2 activates NF-κB through NF-κB–inducing kinase (NIK)–inhibitor of κB kinase (IKK) and activates the JNK/p38 pathways. TNF-α is an inflammatory cytokine that appears to be associated with a number of autoimmune disorders, including type 1 diabetes. TNF-α may activate intraislet resident macrophages, resulting in the release of IL-1β, which generates iNOS expression and the overproduction of NO in β-cells. Alterations in the number and function of CD4+CD25+ T-cells may be an additional mechanism by which TNF-α may cause type 1 diabetes in NOD mice. The role of RAGE mediated by NF-κB has not been entirely elucidated, although RAGE may be an important intermediary in causing monocyte production of inflammatory mediators such as TNF-α. It is possible that increased expression of RAGE in response to hyperglycemia may lead to activation of innate and even adaptive immune responses and enhance β-cell destruction. After IL-1β binding to IL-1βR1, MyD88 is recruited to the receptor complex. MyD88 interacts with IL-1 receptor–associated kinase (IRAK), allowing the binding of TRAF6 to IRAK. TRAF6 causes activation of mitogen-activated protein kinase/stress-activated protein kinase and activation of the NF-κB pathway by transforming growth factor-β–activated kinase 1 (TAK1)–mediated activation of IKK. IL-1β also stimulates activation of protein kinase C-δ (PKC-δ), possibly through phospholipase C generation of diacylglycerol. ERK, extracellular signal–regulated kinase; Jak, Janus kinase; STAT1, signal transducer and activator of transcription-1. More
Images
Signal transduction pathways of metabolic hormones that stimulate GLP-1 sec...
Published: 01 December 2006
FIG. 5. Signal transduction pathways of metabolic hormones that stimulate GLP-1 secretion. Insulin receptor activation results in phosphorylation of insulin receptor substrate (IRS) molecules and subsequent activation of Akt and p44/42 MAPK through phosphatidylinositol 3-kinase (PI3K) and mitogen-... More
Journal Articles
Journal: Diabetes
Diabetes 2005;54(12):3410–3417
Published: 01 December 2005
.... In this study, we analyzed leptin-mediated signal transduction and preproinsulin gene regulation at the molecular level in pancreatic β-cells. Leptin stimulation led to janus kinase (JAK)2-dependent phosphorylation and nuclear translocation of the transcription factors signal transducer and activator...
Journal Articles
Journal: Diabetes
Diabetes 2006;55(4):942–951
Published: 01 April 2006
...Ana C.P. Thirone; Lellean JeBailey; Philip J. Bilan; Amira Klip Many cytokines increase their receptor affinity for Janus kinases (JAKs). Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. Intriguingly, insulin acting through its...
Meeting Abstracts
Journal: Diabetes
Diabetes 2001;50(suppl_1):S40
Published: 01 February 2001
... of a single tyro- sine residue by receptor-associated Janus kinases (JAKs). tor (6) (provided by Dr. Wollheim, Switzerland), was trans- The phosphorylated STAT proteins dimerize and translocate to the nucleus, where they bind speci c DNA elements and fected with the pTRE-vector containing the cDNA encoding...
Journal Articles
Journal: Diabetes
Diabetes 2003;52(11):2696–2700
Published: 01 November 2003
..., The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: noras@scripps.edu 30 7 2003 12 6 2003 DIABETES 2003 H-E, hematoxylin-eosin IFN, interferon IL, interleukin JAK, Janus kinase SOCS, suppressors of cytokine signaling STAT, signal transducers...
Journal Articles
Journal: Diabetes
Diabetes 2007;56(10):2561–2568
Published: 01 October 2007
...−/− neonatal pancreata were not destroyed when grafted into diabetic NOD/BDC2.5 mice that developed CD4+ T-cell–dependent islet cell death. In NOD/STAT1−/− mice, autoreactive T-cell priming was not impaired, but Th1 differentiation was impaired. A janus kinase (JAK) 2 inhibitor...
Includes: Supplementary data
Journal Articles
Journal: Diabetes
Diabetes 2007;56(1):72–79
Published: 01 January 2007
... (>139-fold) and Trp-tRNA synthase (WARS) (>17-fold) along with 975 other transcripts more than threefold, notably the downstream effectors janus kinase (JAK)2, signal transducer and activator of transcription (STAT)1, IFN-γ regulatory factor-1, and several chemokines (CXCL9/MIG, CXCL10/IP10, CXCL11/1...
Meeting Abstracts
Journal: Diabetes
Diabetes 2019;68(Supplement_1):310-LB
Published: 01 June 2019
... kinase/signal transducer and activator of transcription (JAK/STAT) signaling initiated by the leptin receptor (ObR). Leptin resistance arises in part from the inhibition of leptin-initiated JAK/STAT signaling by SOCS3 binding to the phosphorylated Tyr-985 of ObR. We developed a cell-permeable, trans...
Journal Articles
Journal: Diabetes
Diabetes 2009;58(2):469–477
Published: 01 February 2009
...-induced DBA/2J mice, commonly studied murine models of diabetic nephropathy, were analyzed. RESULTS— In human glomeruli and tubulointerstitial samples, the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway was highly and significantly regulated. Jak-1, -2, and -3 as well...
Includes: Supplementary data
Meeting Abstracts
Journal: Diabetes
Diabetes 1999;48(2):426–429
Published: 01 February 1999
..., horseradish peroxidase; Ig, immunoglobulin; JAK, Janus kinase; Ob- ually compared with that from the PPP. R, leptin receptor; Ob-Ra, short form of the leptin receptor; Ob-Rb, long form of the leptin receptor; PPP, platelet-poor plasma; PRP, platelet-rich plasma; RESULTS STAT, signal transducer and activator...
Journal Articles
Journal: Diabetes
Diabetes 2017;66(6):1650–1660
Published: 14 March 2017
... in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development...
Includes: Multimedia, Supplementary data
Journal Articles
Journal: Diabetes
Diabetes 2005;54(2):394–401
Published: 01 February 2005
... on Ang II–mediated activation of Janus-activated kinase (JAK)-2, a tyrosine kinase related with myocyte hypertrophy and cytokine and fibrogenetic growth factor overexpression, in ventricular myocytes isolated from nonfailing human hearts (n = 5) and failing human hearts (n = 8...
Journal Articles
Journal: Diabetes
Diabetes 2013;62(1):299–308
Published: 13 December 2012
... complications, such as elements of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and vascular endothelial growth factor receptor (VEGFR) signaling pathways. In addition, novel pathways not previously associated with DN and cross-species gene nodes...
Includes: Supplementary data
Journal Articles
Journal: Diabetes
Diabetes 2012;61(1):61–73
Published: 12 December 2011
..., a deacetylation inhibitor, and an acetylated mutant of STAT3 were used to examine the effect of ER stress on hepatic STAT3 action. ER stress inhibited STAT3-dependent suppression of gluconeogenic enzyme gene expression by suppressing hepatic Janus kinase (JAK)2 and STAT3 phosphorylation. A tyrosine phosphatase...
Includes: Supplementary data
Meeting Abstracts
Journal: Diabetes
Diabetes 1999;48(11):2204–2209
Published: 01 November 1999
... in the ity and are activated by ligand-induced receptor homo- or het- hypothalamus, is not required for the observed in vivo erodimerization and activation of receptor-associated mem- effects of the peptide on energy balance. LEP- bers of the Janus kinase (JAK) family (10,11). Activated JAK (116 130...
Journal Articles
Journal: Diabetes
Diabetes 2007;56(2):541–548
Published: 01 February 2007
... and leptin resistance ( 2 , 3 ), and cytokines have also been suggested to contribute to β-cell failure of type 2 diabetes ( 4 ). The SOCS proteins were identified in 1997 and were characterized as a family of proteins capable of inhibiting Janus kinase (JAK)–signal transducers and activators...
Journal Articles
Journal: Diabetes
Diabetes 2006;55(9):2554–2561
Published: 01 September 2006
... IL, interleukin IRS, insulin receptor substrate JAK, janus kinase PI, phosphatidylinositol STAT, signal transducer and activator of transcription Prolonged exercise of medium to high intensity is known to profoundly affect energy balance ( 1 – 3 ). Studies of individuals who have maintained...