427 research outputs found
The role of c-Jun in controlling the EPAC1-dependent induction of the SOCS3 gene in HUVECs
The cyclic AMP sensor, EPAC1, activates AP1-mediated transcription in HUVECs. Correspondingly, induction of the SOCS3 minimal promoter by EPAC1 requires a single AP1 site that constitutively binds phosphorylated (Ser63) c-Jun in DNA-pull-down assays. c-Jun (Ser63) becomes further phosphorylated following cyclic AMP stimulation and specific activation of protein kinase A (PKA), but not through selective activation of EPAC1. Moreover, despite a requirement for c-Jun for SOCS3 induction in fibroblasts, phospho-null c-Jun (Ser63/73Ala) had little effect on SOCS3 induction by cyclic AMP in HUVECs. AP1 activation and SOCS3 induction by EPAC1 in HUVECs therefore occur independently of c-Jun phosphorylation on Ser63
Endoscopic full-thickness resection of a nonlifting adenoma in an ileal pouch using an over-the-scope full-thickness resection device.
HyperISGylation of Old World Monkey ISG15 in Human Cells
BACKGROUND: ISG15 is an Ubiquitin-like protein, highly induced by Type I Interferons. Upon the cooperative activity of specific Ubiquitinating enzymes, ISG15 can be conjugated to its substrates. Increasing evidence points to a role for protein ISGylation in anti-viral and anti-tumoral defense. PRINCIPAL FINDINGS: We identified ISG15 from Old World Monkeys (OWm) as a hyper-efficient protein modifier. Western blot analysis visualized more efficient conjugation of OWmISG15 relative to HuISG15 in human (Hu), monkey and mouse (Mo) cell-lines. Moreover, the substrates of OWmISG15 identified upon Tandem Affinity Purification followed by LC-MS/MS identification largely outnumbered these of HuISG15 itself. Several Ubiquitin-Conjugating enzymes were identified as novel ISGylated substrates. Introduction of a N89D mutation in HuISG15 improved its ISGylation capacity, and additional Q31K/T33A/D133N mutations yielded a HuISG15 variant with an ISGylation efficiency comparable to OWmISG15. Homology modeling and structural superposition situate N89 in the interaction interface with the Activating enzyme. Analysis of the UbE1L residues in this interface revealed a striking homology between OWmUbE1L and HuUbE1, the Activating enzyme of Ubiquitin. In line with this observation, we found efficient activation of AgmISG15, but not HuISG15 or MoISG15, by HuUbE1, thus providing a likely explanation for OWm hyperISGylation. CONCLUSIONS: This study discloses the poor conjugation competence of HuISG15 compared to OWmISG15 and maps the critical determinants for efficient conjugation. HyperISGylation may greatly assist ISGylation studies and may enhance its function as positive regulator of Interferon-related immune responses or as anti-tumoral modulator
Stepwise radical endoscopic resection for eradication of Barrett's oesophagus with early neoplasia in a cohort of 169 patients
Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production
Suppressor of cytokine signalingâ3 (SOCS3) has multiple functions including inhibition of Janus kinase (Jak) activity, regulation of protein degradation, and suppression of cytokine signaling. SOCS3 modulates macrophage response to cytokines such as ILâ6 and leptin that are systemically induced in obesity. Obesity is a suspected risk factor for SOCS3ârelated pathology such as rheumatoid arthritis and Crohn's disease as well as zoledronic acid (ZA)âinduced osteonecrosis of the jaw (ONJ). Thus, understanding the ability of bisphosphonates to modulate SOCS3 is necessary to qualify their contribution to these disorders. ONJ occurs in up to 10% of patients using intravenous bisphosphonates and has an unknown pathogenesis that may be linked to decreased bone turnover, altered vascularity, bacterial invasion, and compromised wound healing. Given the increased risk of ONJ with obesity and importance of macrophages in wound healing, we hypothesized that aminoâbisphosphonates could contribute to the pathogenesis of ONJ by regulating macrophage responses to cytokines such as leptin and ILâ6. We report that ZA is a novel inhibitor of SOCS3 in primary macrophages and human ONJ biopsy specimens. Inhibition of SOCS3 by ZA resulted in significant increases in ILâ6 production. SOCS3 transcription is regulated by nuclear accumulation of phosphorylatedâStat3 (PâStat3). We found that ZA decreased phosphorylation of Stat3 in a mevalonateâpathway dependent manner. However, restoration of PâStat3 was not sufficient to correct SOCS3 inhibition. We propose that disruption of macrophage SOCS3 expression by aminoâbisphosphonates such as ZA may be a novel contributor to inflammatory phenotypes in obesity and the pathogenesis of ONJ. J. Cell. Biochem. 112: 3364â3372, 2011. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87102/1/23267_ftp.pd
Management of supragastric belching with cognitive behavioural therapy: factors determining success and follow-up outcomes at 6-12 months post-therapy
Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer
Gastroparesis: Current Concepts and Management
Delayed gastric emptying in the absence of mechanical obstruction is referred to as gastroparesis. Symptoms that are often attributed to gastroparesis include postprandial fullness, nausea, and vomiting. Although tests of gastric motor function may aid diagnostic labeling, their contribution to determining the treatment approach is often limited. Although clinical suspicion of gastroparesis warrants the exclusion of mechanical causes and serum electrolyte imbalances, followed by empirical treatment with a gastroprokinetic such as domperidone or metoclopramide, evidence that these drugs are effective for patients with gastroparesis is far from overwhelming. In refractory cases with severe weight loss, invasive therapeutics such as inserting a feeding jejunostomy tube, intrapyloric injection of botulinum toxin, surgical (partial) gastrectomy, and implantable gastric electrical stimulation are occasionally considered
SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function
Suppressor of cytokine signaling 2 (SOCS2) is known as a feedback inhibitor of cytokine signaling and is highly expressed in primary bone marrow (BM) cells from patients with chronic myeloid leukemia (CML). However, it has not been established whether SOCS2 is involved in CML, caused by the BCR/ABL1 fusion gene, or important for normal hematopoietic stem cell (HSC) function. In this study, we demonstrate that although Socs2 was found to be preferentially expressed in long-term HSCs, Socs2-deficient HSCs were indistinguishable from wild-type HSCs when challenged in competitive BM transplantation experiments. Furthermore, by using a retroviral BCR/ABL1-induced mouse model of CML, we demonstrate that SOCS2 is dispensable for the induction and propagation of the disease, suggesting that the SOCS2-mediated feedback regulation of the JAK/STAT pathway is deficient in BCR/ABL1-induced CML.N Hansen, H Ă
gerstam, M Wahlestedt, N Landberg, M Askmyr, M Ehinger, M Rissler, H Lilljebjörn, P Johnels, J Ishiko, J V Melo, W S Alexander, D Bryder, M JÀrÄs, and T Fioreto
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