Publications (2)17.13 Total impact
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Article: Overexpression of SIRT6 suppresses inflammatory responses and bone destruction in collagen-induced arthritic mice.
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ABSTRACT: OBJECTIVE.: SIRT6, an NAD(+) -dependent deacetylase and mono-ADP-ribosyl transferase, is predominantly expressed in the nucleus. It is known to interfere with the NF-κB signaling pathway and thereby has an anti-inflammatory function. Due to the central role of NF-κB in rheumatoid arthritis (RA) development, we postulated that SIRT6 could have anti-arthritic effects. METHODS.: An adenovirus containing SIRT6 cDNA (Ad-SIRT6) was used to deliver SIRT6 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to collagen-induced arthritis (CIA) mice in vivo via a bilateral intraarticular injection into the ankle joints. RESULTS.: In vitro experiments demonstrated that SIRT6 overexpression suppressed the NF-κB target gene expression induced by tumor necrosis factor-α. SIRT6 overexpression inhibited osteoclast differentiation induced by macrophage colony-stimulating factor and receptor activator of NF-κB ligand in bone marrow-derived macrophages. Mice with CIA had an increased incidence of disease and developed arthritis in the hind paws. In contrast, mice injected with Ad-SIRT6 showed attenuated severity of arthritis based on clinical scores, hind paw thickness, and radiological and pathological findings. Moreover, the injection of Ad-SIRT6 down-regulated local and systemic levels of proinflammatory cytokines. After the onset of arthritis, CIA mice injected with Ad-SIRT6 showed significantly decreased arthritis severity from the onset of clinical signs to the end of the study. CONCLUSION.: These results suggest that blocking the NF-κB pathway by SIRT6 in rheumatoid joints reduces both inflammatory response and tissue destruction. Therefore, the development of an immunoregulatory strategy based on SIRT6 may have therapeutic potential for the treatment of RA. © 2013 American College of Rheumatology.Arthritis & Rheumatism 04/2013; · 7.87 Impact Factor -
Article: Aggravation of post-ischemic liver injury by overexpression of A20, an NF-κB suppressor.
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ABSTRACT: BACKGROUD & AIMS: A20 is an intracellular ubiquitin-editing enzyme that plays an important role in the negative feedback regulation of NF-κB activation in response to a diverse range of stimuli. Liver ischemia/reperfusion injury is associated with rapid activation of NF-κB signaling, but the role of NF-κB in hepatic ischemia/reperfusion injury remains controversial. The NF-κB signaling pathway mediates both protective and deleterious effects in the liver. Here, we examined whether A20 inhibited or aggravated hepatic ischemia/reperfusion injury. We used IκBα super-repressor as a positive control and overexpressed A20 and IκBα super-repressor in the liver of C57BL/6 mice. Mice underwent 45min of partial hepatic ischemia and were then reperfused. Protein level of A20 was increased after reperfusion. Mice subjected to ischemia/reperfusion injury showed increased NF-κB activation, as evidenced by phosphorylation of IκBα and nuclear translocation of NF-κB. Prior transfection with Ad-A20 or Ad-IκBα super-repressor attenuated NF-κB activation and aggravated liver injury. Serum aminotransferases and proinflammatory cytokines, hepatocellular necrosis, and hepatic neutrophil infiltration were markedly increased compared to those of uninfected or control virus infected mice. In addition, A20 abolished the beneficial effect of ischemic preconditioning. Our results suggest that inhibition of NF-κB activation by A20 aggravated partial hepatic ischemia/reperfusion injury. Understanding how the NF-κB pathway plays a role in directing a clinical outcome may lead to better prospects of more rational approaches to reduce post-ischemic liver injury.Journal of Hepatology 12/2010; 55(2):328-36. · 9.26 Impact Factor
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2013
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Chonbuk National University Hospital
Seoul, Seoul, South Korea
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