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Chin Hee Mun,Won Taek Lee,Kyung Ah Park,Jong Eun Lee 대한해부학회 2010 Anatomy & Cell Biology Vol.43 No.3
Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) plays a protective role in cerebral ischemia by maintaining vascular permeability, whereas NO derived from neuronal and inducible NOS is neurotoxic and can participate in neuronal damage occurring in ischemia. Matrix metalloproteinases (MMPs) are up-regulated by ischemic injury and degrade the basement membrane if brain vessels to promote cell death and tissue injury. We previously reported that agmatine, synthesized from L-arginine by arginine decarboxylase (ADC) which is expressed in endothelial cells, has shown a direct increased eNOS expression and decreased MMPs expression in bEnd3 cells. But, there are few reports about the regulation of eNOS by agmatine in ischemic animal model. In the present study, we examined the expression of eNOS and MMPs by agmatine treatment after transient global ischemia in vivo. Global ischemia was induced with four vessel occlusion (4-VO) and agmatine (100 mg/kg) was administered intraperitoneally at the onset of reperfusion. The animals were euthanized at 6 and 24 hours after global ischemia and prepared for other analysis. Global ischemia led severe neuronal damage in the rat hippocampus and cerebral cortex, but agmatine treatment protected neurons from ischemic injury. Moreover, the level and expression of eNOS was increased by agmatine treatment, whereas inducible NOS (iNOS) and MMP-9 protein expressions were decreased in the brain. These results suggest that agmatine protects microvessels in the brain by activation eNOS as well as reduces extracellular matrix degradation during the early phase of ischemic insult.
Mun, Chin Hee,Kim, Jin-Ock,Ahn, Sung Soo,Yoon, Taejun,Kim, Su Jeong,Ko, Eunhee,Noh, Hee-Dong,Park, Yong-Beom,Jung, Hak-Jun,Kim, Tae Sung,Lee, Sang-Won,Park, Sang Gyu Elsevier 2019 Biomaterials Vol.220 No.-
<P><B>Abstract</B></P> <P>Aminoacyl-tRNA synthetase (ARS)-interacting multifunctional protein 1 (AIMP1) enhances the expression of proinflammatory cytokines. In our previous study, we have shown that serum AIMP1 in patients with SLE was significantly higher than that of healthy controls. To address whether neutralization of AIMP1 could ameliorate nephritis in lupus-prone mice, we generated atializumab, a humanized antibody against AIMP1 and investigated its therapeutic efficacy. ELISA showed that serum AIMP1 at 23 weeks old was significantly higher than that at 13 weeks old in lupus-prone mice. Therefore, lupus-prone mice were randomly assigned to 5 groups (vehicle, methylprednisolone and 0.5, 2, and 5 mg/kg atializumab). After treatment, disease severity was assessed using a variety of phenotypes, including proteinuria, histological damages, renal deposition of immune-complex. In addition, serum cytokines, anti-dsDNA and IgG subclasses were determined. T cell subsets were analyzed using a fluorescence-activated cell sorter. Atializumab significantly diminished proteinuria, improved glomerular and tubular damages and reduced the renal deposition of immune-complexes. Moreover, atializumab significantly decreased serum interferon (IFN)-γ, interleukin (IL)-17A, and IL-6, whereas it increased serum IL-10. Similarly, atializumab reduced the numbers of T<SUB>H</SUB>1, T<SUB>H</SUB>2 and T<SUB>H</SUB>17 cells in a dose-dependent manner, while atializumab enhanced the number of regulatory T (Treg) cells. Furthermore, atializumab decreased not only splenic plasma cells and serum anti-dsDNA but also pathogenic IgG subclasses for nephritis. It suppressed NF-κB activation by inhibiting IκBα degradation in a dose-dependent manner <I>in vitro</I>. Atializumab alleviated nephritis by inhibiting autoreactive T, B, and plasma cells and decreasing NF-κB-related proinflammatory cytokines in lupus-prone mice. These results suggest that treatment targeting AIMP1 could be a novel and highly immune-modulating therapeutic strategy in lupus nephritis.</P>
Moon, Jae-Seung,Mun, Chin Hee,Kim, Jung-Ho,Cho, Jen-Young,Park, Sung-Dong,Park, Tae-Yoon,Shin, Jin-Su,Ho, Chun-Chang,Park, Yong-Beom,Ghosh, Sankar,Bothwell, Alfred L.M.,Lee, Sang-Won,Lee, Sang-Kyou Springer-Verlag 2018 Kidney international Vol.93 No.5
<P>Excessive expression of Tbet and IFN gamma is evidence of systemic lupus erythematosus (SLE) in lupus patients. In this study, the nucleus-transducible form of Transcription Modulation Domain (TMD) of Tbet (ntTbet-TMD), which is a fusion protein between Protein Transduction Domain Hph-1 (Hph-1-PTD) and the TMD of Tbet comprising DNA binding domain and isotype-specific domain, was generated to inhibit Tbet-mediated transcription in the interactomic manner. ntTbet-TMD was effectively delivered into the nucleus of the cells and specifically inhibited Tbet-mediated transcription without influencing the differentiation of other T cell subsets and signaling events for T cell activation. The severity of nephritis was significantly reduced by ntTbet-TMD as effectively as methylprednisolone in lupus-prone mice. The number of Th1, Th2 or Th17 cells and the secretion of their cytokines substantially decreased in the spleen and kidney of lupus-prone mice by ntTbet-TMD treatment. In contrast to methylprednisolone, the marked increase of Treg cells and the secretion of their immunosuppressive cytokine were detected in the spleen of (NZB/NZW) F1 mice treated with ntTbet-TMD. Thus, ntTbet-TMD can improve nephritis in lupus-prone mice by modulating the overall proinflammatory microenvironment and rebalancing T cell subsets, leading to new immune therapeutics for Th1-mediated autoimmune diseases.</P>