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Jang, Byungki,Ishigami, Akihito,Kim, Yong-Sun,Choi, Eun-Kyoung MDPI AG 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.11
<P>The conversion of peptidylarginine into peptidylcitrulline by calcium-dependent peptidylarginine deiminases (PADs) has been implicated in the pathogenesis of a number of diseases, identifying PADs as therapeutic targets for various diseases. The PAD inhibitor Cl-amidine ameliorates the disease course, severity, and clinical manifestation in multiple disease models, and it also modulates dendritic cell (DC) functions such as cytokine production, antigen presentation, and T cell proliferation. The beneficial effects of Cl-amidine make it an attractive compound for PAD-targeting therapeutic strategies in inflammatory diseases. Here, we found that Cl-amidine inhibited nitric oxide (NO) generation in a time- and dose-dependent manner in maturing DCs activated by lipopolysaccharide (LPS). This suppression of NO generation was independent of changes in NO synthase (NOS) enzyme activity levels but was instead dependent on changes in inducible NO synthase (iNOS) transcription and expression levels. Several upstream signaling pathways for iNOS expression, including the mitogen-activated protein kinase, nuclear factor-κB p65 (NF-κB p65), and hypoxia-inducible factor 1 pathways, were not affected by Cl-amidine. By contrast, the LPS-induced signal transducer and the activator of transcription (STAT) phosphorylation and activator protein-1 (AP-1) transcriptional activities (c-Fos, JunD, and phosphorylated c-Jun) were decreased in Cl-amidine-treated DCs. Inhibition of Janus kinase/STAT signaling dramatically suppressed iNOS expression and NO production, whereas AP-1 inhibition had no effect. These results indicate that Cl-amidine-inhibited STAT activation may suppress iNOS expression. Additionally, we found mildly reduced cyclooxygenase-2 expression and prostaglandin E2 production in Cl-amidine-treated DCs. Our findings indicate that Cl-amidine acts as a novel suppressor of iNOS expression, suggesting that Cl-amidine has the potential to ameliorate the effects of excessive iNOS/NO-linked immune responses.</P>
Vitamin C deficiency increases the binucleation of hepatocytes in SMP30 knock-out mice
Park, Jin-Kyu,Hong, Il-Hwa,Ki, Mi-Ran,Chung, Hae-Young,Ishigami, Akihito,Ji, Ae-Ri,Goo, Moon-Jung,Kim, Dong-Hwan,Kwak, Ji-Hoon,Min, Chang-Woo,Lee, Seung-Sook,Jeong, Kyu-Shik Blackwell Publishing Asia 2010 Journal of Gastroenterology and Hepatology Vol.25 No.11
<P>Abstract</P><P>Background and Aims: </P><P>The binucleation of hepatocytes, which was known as an important feature of liver growth and physiology, has been reported to be increased during the chronic oxidative injury stage and has been regarded as an age-related change of hepatic structures. Therefore, we investigated the binuclearity pattern in the livers of senescence marker proteins-30 (SMP30) knock-out (KO) mice compared with wild-type (WT) mice and vitamin C-treated KO (KO + VC) mice.</P><P>Methods: </P><P>The WT, KO and KO + VC mice were fed a vitamin C free diet and VC(+) group mice were given vitamin C water containing 1.5 g/L of vitamin C, whereas VC(−) group was given normal drinking water without vitamin C, for 16 weeks.</P><P>Results: </P><P>In microscopic examination, the livers of KO mice showed a significantly increased number of binuclear hepatocytes compared with that of WT mice and KO + VC mice. KO mice also showed the most increased expression level of CYP2E1 and PCNA determined by immunohistochemistry and immunoblot analysis. Moreover, KO mice indicated the highest level of serum alanine aminotransferase and aspartate aminotransferase level in serum biochemical analysis. Accordingly, significantly decreased levels of reactive oxygen species, MDA (malondialdehyde) and HAE (4-hydroxyalkenals) were detected in KO + VC mice compared with KO mice.</P><P>Conclusion: </P><P>Therefore, it is concluded that vitamin C deficiency induces an increase of CYP2E1 expression and elevated ROS production, which causes oxidative liver injury and the elevation of hepatocyte binucleation in SMP30 KO mice.</P>
Choo, Jieun,Heo, Gwangbeom,Kim, Su Jin,Lee, Yunna,Ishigami, Akihito,Maruyama, Naoki,Chung, Hae Young,Im, Eunok Elsevier 2018 Biochimica et biophysica acta. Molecular basis of Vol.1864 No.12
<P><B>Abstract</B></P> <P>Senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases during senescence. SMP30 deficiency increases susceptibility to cytokine-induced apoptosis in the liver and to radiation-induced apoptosis in the small intestine. Furthermore, colonic epithelial cell death is associated with the severity of colitis. Therefore, in the present study, we investigated the function of SMP30 during intestinal inflammation. In SMP30 deficient mice, colitis was significantly exacerbated as demonstrated by increased mortality (<I>p</I> = 0.001), body weight loss (<I>p</I> = 0.0105 at day 8), rectal bleeding (<I>p</I> = 0.0047 at day 8) and diarrhea (<I>p</I> = 0.0030 at day 8), histological scores (ulcers, <I>p</I> = 0.0002; edema, <I>p</I> = 0.0125; leukocyte infiltration, <I>p</I> = 0.0016) and productions of pro-inflammatory cytokines (IL-1α, <I>p</I> = 0.0452; IL-6, <I>p</I> = 0.0074; G-CSF, <I>p</I> = 0.0036). In addition, greater proportions of apoptotic cells and lower levels of anti-apoptotic marker proteins (total PARP-1 and Bcl-2) were observed in the inflamed intestines of SMP30 deficient mice than in wild type controls. In vitro experiments on colonic epithelial cells showed that stable SMP30 expression inhibited but that SMP30 siRNA expression increased TNF-α-induced apoptosis. SMP30 inhibition decreased Nrf2 mRNA expression levels (<I>p</I> < 0.0001), but SMP30 overexpression increased Nrf2 mRNA expression levels (<I>p</I> = 0.0495). The underlying mechanism by which SMP30 protected cells appeared to be by inhibiting Nrf2 ubiquitination and Keap1 expression, and thus enhancing Nrf2 activity. Moreover, SMP30 deficiency increased the incidence of colitis-associated colon cancer as determined by increased mortality (<I>p</I> = 0.0572) and average polyp number (<I>p</I> = 0.0277). Collectively, these findings suggest that SMP30 protects intestinal epithelial cells from apoptosis and this can contribute to amelioration of colitis and colitis-associated colon cancer.</P> <P><B>Highlights</B></P> <P> <UL> <LI> SMP30 deficiency exacerbates colitis and colitis-associated colon cancer. </LI> <LI> SMP30 prevents epithelial cells from cytokine-induced cell death. </LI> <LI> SMP30 increases Nrf2 activity by inhibiting Nrf2 ubiquitination and Keap1 expression. </LI> <LI> Protective effect of SMP30 is mediated by increased Nrf2 activity. </LI> </UL> </P>
Protective effects of KI against on the acute hepatic Liver injury of SMP30 knock-out mice
( Moon Jung Goo ),( Hye Rim Lee ),( Mi Ran Ki ),( Hae Young Chung ),( Akihito Ishigami ),( Kyu Shik Jeong ),( Jin Kyu Park ),( Da Hee Jeong ),( Ho Yong Park ),( Kwang Hee Son ),( Dong Ha Sin ),( Sun H 한국수의병리학회 2006 학술대회 Vol.10 No.-
Son, Tae Gen,Park, Hee Ra,Kim, So Jung,Kim, Keunho,Kim, Min-Sun,Ishigami, Akihito,Handa, Setsuko,Maruyama, Naoki,Chung, Hae Young,Lee, Jaewon Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of neuroscience research Vol.87 No.13
<P>Senescence maker protein 30 (SMP30) is decreased in an androgen-independent manner in kidney and liver with age. However, regulation of SMP30 expression in the brain has not been examined in aging and neurodegenerative diseases. To investigate SMP30 expression in the brain, we utilized aging and kainate (KA)-induced neurodegenerative disease models. Interestingly, expression of SMP30 was unlikely to decrease in the aged brain, but total levels of SMP30 protein were increased at 4 weeks after KA injury. Increased glial fibrillary acidic protein (GFAP) with elevated SMP30 expression was observed at the same time post-KA, indicating that regulation of SMP30 expression in the brain may be associated with astrocytosis. We confirmed that KA induced GFAP expression with increased SMP30 in rat astrocyte cells. Moreover, we found that ERK1/2 activation was involved in the up-regulation of SMP30 in astrocytes. Our results suggest that elevated SMP30 in activated astrocytes plays an important supportive role after brain damage. © 2009 Wiley-Liss, Inc.</P>
Jeong, Da-Hee,Hwang, Meeyul,Park, Jin-Kyu,Goo, Moon-Jung,Hong, Il-Hwa,Ki, Mi-Ran,Ishigami, Akihito,Kim, Ah-Young,Lee, Eun-Mi,Lee, Eun-Joo,Jeong, Kyu-Shik Molecular Diversity Preservation International (MD 2013 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.14 No.12
<P>Smad3 is a key mediator of the transforming growth factor (TGF)-β1 signaling pathway that plays central role in inflammation and fibrosis. In present study, we evaluated the effect of Smad3 deficiency in <I>Smad3</I><SUP>−/−</SUP> mice with carbon tetrachloride (CCl<SUB>4</SUB>)-induced liver fibrosis. The animals were received CCl<SUB>4</SUB> or olive oil three times a week for 4 weeks. Histopathological analyses were performed to evaluate the fibrosis development in the mice. Alteration of protein expression controlled by Smad3 was examined using a proteomic analysis. CCl<SUB>4</SUB>-induced liver fibrosis was rarely detected in <I>Smad3</I><SUP>−/−</SUP> mice compared to <I>Smad3</I><SUP>+/+</SUP>. Proteomic analysis revealed that proteins related to antioxidant activities such as senescence marker protein-30 (<I>SMP30</I>), selenium-binding proteins (SP56) and glutathione <I>S</I>-transferases (GSTs) were up-regulated in <I>Smad3</I><SUP>−/−</SUP> mice. Western blot analysis confirmed that <I>SMP30</I> protein expression was increased in <I>Smad3</I><SUP>−/−</SUP> mice. And <I>SMP30</I> levels were decreased in CCl<SUB>4</SUB>-treated <I>Smad3</I><SUP>+/+</SUP> and <I>Smad3</I><SUP>−/−</SUP> mice. These results indicate that Smad3 deficiency influences the proteins level related to antioxidant activities during early liver fibrosis. Thus, we suggest that Smad3 deteriorate hepatic injury by inhibitor of antioxidant proteins as well as mediator of TGF-β1 signaling.</P>
Expression of Citrullinated Glial Fibrillary Acidic Protein in a Murine Model of Hepatic Fibrosis
( Sung Eun Kim ),( Ji Won Park ),( Mo Jong Kim ),( Byungki Jang ),( Yong-chul Jeon ),( Akihito Ishigami ),( Myoungkuk Jang ),( Dong Joon Kim ),( Choong Kee Park ),( Eun-kyoung Choi ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: The quiescent HSCs synthesize glial fibrillary acidic protein (GFAP) in normal liver and the expression of GFAP is noted in activated HSC. Moreover, GFAP-expressing HSCs and myofibroblasts are accumulated in and around the lesion of hepatic fibrosis. In addition, it has been reported that peptidylarginine deiminase 2 (PAD2) is responsible for the citrullination of GFAP (cit-GFAP) in the brains of Alzheimer’s disease. However, the involvement of PAD2 and cit-GFAP in hepatic fibrosis remains unclear. The aim of this study was to investigate the roles of PAD2 and cit-GFAP in hepatic fibrosis using a murine model of bile duct ligation (BDL). Methods: Eight-week-old C57B/L6 mice were subjected to BDL. We examined the profiles of PAD2, citrullinated proteins and cit-GFAP using the hepatic tissues after BDL, compared with sham operated control. Hepatic fibrosis was assessed by sirius red-positive collagen accumulation and by increased mRNA levels of fibrosis markers (α -SMA, TIMP-1 and Col1a1). Results: In BDL livers, the expression level of PAD2 protein and PAD2 enzyme activity was significantly increased compared to controls. In addition, the expression levels of citrullinated proteins by anti-modified citrulline antibody were higher in liver of BDL mouse than in the sham operated controls. Interestingly, using both western blot and immunohistochemical analyses, the expression levels of cit-GFAP as well as GFAP were higher in liver of BDL mouse than in sham operated controls. Conclusions: These results suggest that increased cit-GFAP with activated PAD2 may play an important role in hepatic fibrogenesis.
Jang, Byungki,Shin, Hae-Young,Choi, Jin-Kyu,Nguyen, Du Phuong Thao,Jeong, Byung-Hoon,Ishigami, Akihito,Maruyama, Naoki,Carp, Richard I,Kim, Yong-Sun,Choi, Eun-Kyoung Association of the Journal of Neuropathology and E 2011 Journal of neuropathology and experimental neurolo Vol.70 No.2
<P>Peptidylarginine deiminase (PAD) and citrullinated proteins have emerged as key molecules in various human diseases, but detailed subcellular localizations of PAD2 and citrullinated proteins are poorly mapped in brain under normal and pathologic conditions. We performed subcellular fractionation and electron microscopic analysis using brains of normal and scrapie-infected mice. Peptidylarginine deiminase 2 was abundantly present in cytosol and weakly in microsomal and mitochondrial fractions and expression in these fractions was higher in brains of scrapie-infected mice. Despite relatively low PAD2 expression, in microsomal and mitochondrial fractions, citrullinated proteins were present at high levels in these fractions in scrapie-infected brains. Surprisingly, increased PAD2 expression and accumulated citrullinated proteins were also found in nuclear fractions in scrapie-infected brains. By electron microscopy, PAD2 and citrullinated proteins in scrapie-infected brains were widely distributed in most cellular compartments including mitochondria, endoplasmic reticulum, glial filaments, nuclei, and Golgi apparatus in astrocytes and hippocampal neurons. Taken together, we report for the first time the nuclear localization of PAD2 and the detailed subcellular localization of PAD2 and of citrullinated proteins in scrapie-infected brains. Our findings suggest that different subcellular compartmentalization of PAD2 and citrullinated proteins may have different physiological roles in normal and neurodegenerative conditions.</P>