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ABSTRACT: Pathological angiogenesis usually involves disrupted vascular integrity, vascular leakage, and infiltration of inflammatory
cells, which are governed mainly by VEGF-A and TNF-α. Although many inhibitors targeting either VEGF-A or TNF-α have been
developed, there is no single inhibitor molecule that simultaneously targets both molecules. Here, we designed and generated
a novel chimeric decoy receptor (Valpha) that can simultaneously bind to VEGF-A and TNF-α and block their actions. In this
experimental design, we have shown that Valpha, which is an effective synchronous blocker of VEGF-A and TNF-α, can drastically
increase treatment effectiveness through its dual-blocking characteristics. Valpha contains the VEGF-A-binding domain of VEGFR1,
the TNF-α-binding domain of TNFR2, and the Fc domain of IgG1. Valpha exhibited strong binding characteristics for its original
counterparts, VEGF-A and TNF-α, but not for the extracellular matrix, resulting in a highly favorable pharmacokinetic profile
in vivo. Compared with VEGF-Trap or Enbrel, both of which block either VEGF-A or TNF-α, singularly, Valpha is a highly effective
molecule for reducing abnormal vascular tufts and the number of F4/80+ macrophages in a retinopathy model. In addition, Valpha showed superior relief effects in a psoriasis model with regard to
epidermal thickness and the area of blood and lymphatic vessels. Thus, the simultaneous blocking of VEGF-A and TNF-α using
Valpha is an effective therapeutic strategy and cost-efficient for treatment of retinopathy and psoriasis.
Journal of Biological Chemistry 04/2011; 286(16):14410-14418. · 4.77 Impact Factor
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ABSTRACT: Pathological angiogenesis usually involves disrupted vascular integrity, vascular leakage, and infiltration of inflammatory cells, which are governed mainly by VEGF-A and TNF-α. Although many inhibitors targeting either VEGF-A or TNF-α have been developed, there is no single inhibitor molecule that simultaneously targets both molecules. Here, we designed and generated a novel chimeric decoy receptor (Valpha) that can simultaneously bind to VEGF-A and TNF-α and block their actions. In this experimental design, we have shown that Valpha, which is an effective synchronous blocker of VEGF-A and TNF-α, can drastically increase treatment effectiveness through its dual-blocking characteristics. Valpha contains the VEGF-A-binding domain of VEGFR1, the TNF-α-binding domain of TNFR2, and the Fc domain of IgG1. Valpha exhibited strong binding characteristics for its original counterparts, VEGF-A and TNF-α, but not for the extracellular matrix, resulting in a highly favorable pharmacokinetic profile in vivo. Compared with VEGF-Trap or Enbrel, both of which block either VEGF-A or TNF-α, singularly, Valpha is a highly effective molecule for reducing abnormal vascular tufts and the number of F4/80(+) macrophages in a retinopathy model. In addition, Valpha showed superior relief effects in a psoriasis model with regard to epidermal thickness and the area of blood and lymphatic vessels. Thus, the simultaneous blocking of VEGF-A and TNF-α using Valpha is an effective therapeutic strategy and cost-efficient for treatment of retinopathy and psoriasis.
Journal of Biological Chemistry 02/2011; 286(16):14410-8. · 4.77 Impact Factor
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Young-Sool Hah,
Young-Rae Lee,
Jin-Su Jun, Hye-Song Lim,
Hyun-Ok Kim,
Yong-Geun Jeong,
Gang Min Hur,
Sang Yong Lee,
Myoung Ja Chung,
Jin-Woo Park,
Sang-Il Lee,
Byung-Hyun Park
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ABSTRACT: Nuclear factor-kappaB (NF-kappaB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-kappaB, might have antiarthritic effects.
An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally.
In vitro experiments demonstrated that AdA20 suppressed NF-kappaB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus-injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-kappaB signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-kappaB. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study.
These results suggest that using A20 to block the NF-kappaB pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA.
Arthritis & Rheumatism 08/2010; 62(8):2313-21. · 7.87 Impact Factor
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Young-Sool Hah,
Mi Jeong Sung, Hye Song Lim,
Jin-Su Jun,
Yong-Genu Jeong,
Hyun-Ok Kim,
Junghwan Kim,
Haeng Jeon Hur,
Munkhtugs Davaatseren,
Dae Young Kwon,
Sang-Il Lee
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by chronic inflammation and joint destruction. In this study, we investigated whether dietary supplementation with alpha lipoic acid (ALA) suppresses collagen-induced arthritis (CIA) in mice. Mice were randomly divided into three groups: (1) a control CIA group was fed a normal diet, (2) a CIA group was fed a 0.1% ALA diet (average ALA intake of 160 mg/kg/day), and (3) a CIA group was fed a 0.5% ALA diet (average ALA intake of 800 mg/kg/day). The ALA-fed mice showed a decreased incidence and severity of arthritis compared to the normal diet group. Radiographic findings revealed a dramatic decrease in bone destruction, and histological findings showed extensively suppressed pathological changes in the ALA-fed mice. The ALA-fed mice exhibited inhibited generation of tartrate resistant acid phosphatase (TRAP)-positive osteoclasts in vivo. Additionally, ALA-fed mice reduced production of various proinflammatory cytokines and the soluble receptor activator of NF-κB ligand (sRANKL) in the joint tissues and the sera. In conclusion, dietary supplementation with ALA attenuated inflammatory responses and bone destruction in CIA mice.
Rheumatology International 05/2010; 31(12):1583-90. · 1.88 Impact Factor
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Jeong Chan Moon,
Ho Hee Jang,
Ho Byoung Chae,
Jung Ro Lee,
Sun Yong Lee,
Young Jun Jung,
Mi Rim Shin, Hye Song Lim,
Woo Sik Chung,
Dae-Jin Yun,
Kyun Oh Lee,
Sang Yeol Lee
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ABSTRACT: 2-Cys peroxiredoxins (Prxs) play important roles in the antioxidative defense systems of plant chloroplasts. In order to determine the interaction partner for these proteins in Arabidopsis, we used a yeast two-hybrid screening procedure with a C175S-mutant of Arabidopsis 2-Cys Prx-A as bait. A cDNA encoding an NADPH-dependent thioredoxin reductase (NTR) isotype C was identified and designated ANTR-C. We demonstrated that this protein effected efficient transfer of electrons from NADPH to the 2-Cys Prxs of chloroplasts. Interaction between 2-Cys Prx-A and ANTR-C was confirmed by a pull-down experiment. ANTR-C contained N-terminal TR and C-terminal Trx domains. It exhibited both TR and Trx activities and co-localized with 2-Cys Prx-A in chloroplasts. These results suggest that ANTR-C functions as an electron donor for plastidial 2-Cys Prxs and represents the NADPH-dependent TR/Trx system in chloroplasts.
Biochemical and Biophysical Research Communications 10/2006; 348(2):478-84. · 2.48 Impact Factor
