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edited by Abha Chauhan, Ved Chauhan and Ted Brown
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Higuchi, Akihiro ; 樋口, 明弘
概要:
金沢大学先端科学・社会共創推進機構<br />Dry eye syndrome is a multifactorial condition on the tear and ocular surface. Autologous serum e
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ye drop is an effective method for treating dry eye. Autologous serum eye drops are now widely used by specialists since a first report in 1975. The results of a systematic study showed that the efficacy of autologous serum eye drops remains ambiguous because its preparation methods and clinical application have not been standardized. To elucidate the efficacy of autologous serum eye drops, well-designed, large-scale, high-quality randomized controlled trials need to be conducted with standardized treatment and use. Since serum components are partially similar to tear components, autologous serum eye drops improve dry eye by supplying tear components such as growth factors, proteins, and vitamins. Adding to the evidence based on the treatment of dry eye, we have found a new treatment candidate from serum: selenoprotein P (SeP). The efficacy of SeP as a treatment for dry eye was revealed by applying SeP eye drops to a dry eye rat model. Compared with phosphate-buffered saline treatment, SeP eye drops significantly reduced the fluorescein score of the cornea and suppressed the oxidative stress in the cornea, which is related to onset of dry eye, leading to improved corneal disorder. We have developed a new dry eye model caused by oxidative stress that will be used to screen candidate molecules for antioxidative activity. © 2018 The Authors.
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Xu, Liang ; Nagata, Naoto ; Nagashimada, Mayumi ; Zhuge, Fen ; Ni, Yinhua ; Chen, Guanliang ; Kamei, Junzo ; Ishikawa, Hiroki ; Komatsu, Yasuhiko ; Kaneko, Shuichi ; Ota, Tsuguhito ; 長田, 直人 ; 金子, 周一 ; 太田, 嗣人
概要:
金沢大学医薬保健研究域医学系<br />Nonalcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver. NAFLD i
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s associated with hepatic inflammation and oxidative stress, resulting in nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Placental extracts have been used to treat various chronic diseases due to their antioxidative effect. However, the effects of the extracts on the development of NASH have yet to be elucidated. Here, we demonstrated that supplementation with an oral porcine placental extract (PPE) attenuated lipid accumulation and peroxidation, insulin resistance, inflammatory and stress signaling, and fibrogenesis in the liver of NASH model mice fed a high-cholesterol and high-fat diet. The PPE reduced the number of M1-like liver macrophages, but increased the number of anti-inflammatory M2-like macrophages, resulting in a predominance of M2 over M1 macrophage populations in the liver of NASH mice. Accordingly, the PPE suppressed lipopolysaccharide-induced M1 polarization in isolated murine peritoneal macrophages, whereas it facilitated interleukin 4-induced M2 polarization. Furthermore, the PPE reduced the hepatic stellate cell (HSC) activation associated with the attenuated transforming growth factor-β/Smad3 signaling, both in the liver of NASH mice and in RI-T cells, a HSC line. The PPE may be a potential approach to prevent NASH by limiting lipid peroxidation, promoting M2 macrophage polarization, and attenuating HSC activation. © Xu et al.
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Kambayashi, Yasuhiro ; Ogino, Keiki ; Takemoto, Kei ; Imagama, Takashi ; Takigawa, Tomoko ; Kimura, Shingo ; Hibino, Yuri ; Hitomi, Yoshiaki ; Nakamura, Hiroyuki
概要:
金沢大学医薬保健研究域医学系<br />(Di)bromotyrosine is formed by the specific reaction of eosinophil peroxidase and can be used as an
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eosinophil activation marker. In the present study, an antibody for (di)bromotyrosine in proteins was prepared to investigate the pathogenesis of eosinophil-related diseases such as allergic responses. A rabbit polyclonal antibody was raised against brominated keyhole limpet hemocyanin. The specificity of the antiserum was investigated with an enzyme-linked immunosorbent assay (ELISA). The antiserum recognized brominated bovine serum albumin (BSA) and dibromotyrosine-conjugated BSA. The antiserum also reacted with chlorinated BSA and di-iodotyrosine-conjugated BSA. Moreover, the specificity of the antiserum was investigated using competitive ELISA. Dibromotyrosine and di-iodotyrosine inhibited the recognition of brominated BSA by the antiserum. However, the recognition of brominated BSA by the antiserum was not inhibited by bromotyrosine, chlorotyrosine, iodotyrosine, nitrotyrosine, aminotyrosine, phosphotyrosine, or tyrosine. These results suggested that the epitope of the antiserum is dihalogenated tyrosine. Immunohistochemically, the antiserum stained brominated rat eosinophils but not chlorinated or nitrated eosinophils. In conclusion, an antiserum for dihalogenated protein was prepared. It is expected that the antiserum will be useful for the analysis of the pathogenesis of allergic diseases such as asthma and atopic dermatitis.
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Ando, Hitoshi ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Shima, Kosuke R. ; Nakamura, Seiji ; Kumazaki, Masafumi ; Kurita, Seiichiro ; Misu, Hirofumi ; Togawa, Naoyuki ; Fukushima, Tatsunobu ; Fujimura, Akio ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Recent studies have correlated metabolic diseases, such as metabolic syndrome and non-alcoholic fatt
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y liver disease, with the circadian clock. However, whether such metabolic changes per se affect the circadian clock remains controversial. To address this, we investigated the daily mRNA expression profiles of clock genes in the liver of a dietary mouse model of non-alcoholic steatohepatitis (NASH) using a custom-made, high-precision DNA chip. C57BL/6J mice fed an atherogenic diet for 5 weeks developed hypercholesterolemia, oxidative stress, and NASH. DNA chip analyses revealed that the atherogenic diet had a great influence on the mRNA expression of a wide range of genes linked to mitochondrial energy production, redox regulation, and carbohydrate and lipid metabolism. However, the rhythmic mRNA expression of the clock genes in the liver remained intact. Most of the circadianly expressed genes also showed 24-h rhythmicity. These findings suggest that the biological clock is protected against such a metabolic derangement as NASH. © 2009 Elsevier Inc. All rights reserved.
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論文
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Hosozumi, Chiemi ; Toriba, Akira ; Chuesaard, Thanyarat ; Kameda, Takayuki ; Tang, Ning ; Hayakawa, Kazuichi
概要:
Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a widely used noninvasive biomarker of oxidative stress. A selective, se
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nsitive and rapid method for determining 8-OHdG in human urine was developed using hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) with electrospray ionization. 8-OHdG and isotopically labeled 8-OHdG (internal standard) were separated on a HILIC column with a mobile phase of 10. mM ammonium acetate: acetonitrile (1:9, v/v) within 10. min and detected by using a positive electrospray ionization interface under the selected reaction monitoring mode. The detection limits of 8-OHdG (corresponding to a signal-to-noise ratio of 3) for the HILIC-MS/MS system and the conventional method using a reversed-phase column with MS/MS were 1.0 and 26.0. fmol/injection, respectively. The proposed method makes it possible to monitor the basal level of urinary 8-OHdG from non-exposed healthy subjects and can be used for large-scale human studies. © 2012 Elsevier B.V.
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論文
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Motoyama, Yumi ; Bekki, Kanae ; Chung, Sang Woon ; Tang, Ning ; Kameda, Takayuki ; Toriba, Akira ; Taguchi, Keiko ; Hayakawa, Kazuichi
概要:
The effect of four ortho-quinoid polycyclic aromatic hydrocarbons (PAHs) and seven para-quinoid PAHs on the viability of
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A549 cells were examined. The ortho-quinoid PAHs [1,2-naphthoquinone (1,2-NQ), 9,10-phenanthrenquinone (9,10-PQ), 5,6-chrysenequinone (5,6-CQ), and benzo[c]phenanthrene-5,6-quinone (B[c]P-5,6-Q)] overproduced hydrogen peroxide (H2O2) without being consumed themselves. These ortho-quinoid had strong cytotoxic effects except for 1,2-NQ, since of its tendency to covalently bind to thiol groups. The cytotoxicity appears to be due to the overproduction of H 2O2 by ortho-quinoid PAHs in a redox cycle coupled with the consumption of thiol group. In contrast, the para-quinoid PAHs were not as strong cytotoxic and did not produce H2O2. ©2009 The Pharmaceutical Society of Japan.
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Kurita, Seiichiro ; Takamura, Toshinari ; Ota, Tsuguhito ; Matsuzawa-Nagata, Naoto ; Kita, Yuki ; Uno, Masafumi ; Nabemoto, Satoko ; Ishikura, Kazuhide ; Misu, Hirofumi ; Ando, Hitoshi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
金沢大学大学院医学系研究科<br />金沢大学医薬保健研究域医学系<br />Insulin resistance is a major pathological condition associated with obesity and
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metabolic syndrome. Insulin resistance and the renin-angiotensin system are intimately linked. We evaluated the role of the renin-angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats. Components of the renin-angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis. © 2008 Elsevier B.V. All rights reserved.
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論文
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谷内江, 昭宏
概要:
金沢大学医薬保健研究域医学系<br />ヘムオキシゲナーゼ（heme oxygenase ; HO）はヘム代謝に関わる酵素であると同時に，細胞を酸化ストレスによる傷害から守る細胞保護蛋白である．HOの内，誘導酵素であるHO-1を欠損する症例
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の病態解析により，このようなHOの働きが特定の細胞の保護にとどまらず，多様な組織や臓器における細胞保護に関与していることが示された．また，腎組織や腎由来細胞株を用いた検討では，HO-1蛋白が特定の細胞に局在していること，それらの細胞ではHO-1産生が特に重要な意味を持つことが示唆された．さらに末梢血単球を用いた解析では，特定の単球亜群で恒常的にHO-1蛋白が発現していること，これらの単球が急性炎症疾患で増加することが示され，単球/マクロファージによるHO-1産生が炎症制御に重要な役割を果たすことが明らかとされた．一方で，HO-1遺伝子導入により過剰にHO-1蛋白を発現させた場合には，むしろ細胞傷害を促進する可能性があることも示され，生体内ではHO-1産生の局在や量が巧妙に制御されていることが示唆された．最近の報告では，HO-1蛋白が制御性T細胞による免疫制御に深く関わっている可能性も示されており，HO-1産生の誘導を標的とした介入が多様な炎症性疾患に対する新たな治療戦略の一つとして期待される． Heme oxygenase (HO) plays a central role in heme metabolism. At the same time, it protects cells from injury evoked by various oxidative stresses. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs. It is particularly important that in vivo HO-1 production is localized to selected cell types, e.g. renal tubular epithelium, reflecting the fact that HO-1 plays particularly important protective roles in these cells. In addition to renal epithelial cells and tissue macrophages, a minor subpopulation of circulating monocytes produced low, but significant levels of HO-1 and the number of these monocytes increased during episodes of acute inflammatory illnesses, indicating that monocytes play significant roles in controlling inflammation. On the other hand, excessive level of HO-1 induced by HO-1 gene transfection led to paradoxical susceptibility of the cells to oxidative injury. These results indicated that HO-1 expression is carefully controlled in vivo with regard to its location and the magnitude. Furthermore, it has been recently shown that HO-1 is involved in the immune regulation mediated by regulatory T cells. From these findings, it seems feasible to meticulously induce HO-1 protein in vivo as a novel therapeutic intervention to control various forms of inflammatory disorders.
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論文
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谷内江, 昭宏
概要:
ヘムオキシゲナーゼ（heme oxygenase ; HO）はヘム代謝に関わる酵素であると同時に，細胞を酸化ストレスによる傷害から守る細胞保護蛋白である．HOの内，誘導酵素であるHO-1を欠損する症例の病態解析により，このようなHOの働きが
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特定の細胞の保護にとどまらず，多様な組織や臓器における細胞保護に関与していることが示された．また，腎組織や腎由来細胞株を用いた検討では，HO-1蛋白が特定の細胞に局在していること，それらの細胞ではHO-1産生が特に重要な意味を持つことが示唆された．さらに末梢血単球を用いた解析では，特定の単球亜群で恒常的にHO-1蛋白が発現していること，これらの単球が急性炎症疾患で増加することが示され，単球/マクロファージによるHO-1産生が炎症制御に重要な役割を果たすことが明らかとされた．一方で，HO-1遺伝子導入により過剰にHO-1蛋白を発現させた場合には，むしろ細胞傷害を促進する可能性があることも示され，生体内ではHO-1産生の局在や量が巧妙に制御されていることが示唆された．最近の報告では，HO-1蛋白が制御性T細胞による免疫制御に深く関わっている可能性も示されており，HO-1産生の誘導を標的とした介入が多様な炎症性疾患に対する新たな治療戦略の一つとして期待される． Heme oxygenase (HO) plays a central role in heme metabolism. At the same time, it protects cells from injury evoked by various oxidative stresses. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs. It is particularly important that in vivo HO-1 production is localized to selected cell types, e.g. renal tubular epithelium, reflecting the fact that HO-1 plays particularly important protective roles in these cells. In addition to renal epithelial cells and tissue macrophages, a minor subpopulation of circulating monocytes produced low, but significant levels of HO-1 and the number of these monocytes increased during episodes of acute inflammatory illnesses, indicating that monocytes play significant roles in controlling inflammation. On the other hand, excessive level of HO-1 induced by HO-1 gene transfection led to paradoxical susceptibility of the cells to oxidative injury. These results indicated that HO-1 expression is carefully controlled in vivo with regard to its location and the magnitude. Furthermore, it has been recently shown that HO-1 is involved in the immune regulation mediated by regulatory T cells. From these findings, it seems feasible to meticulously induce HO-1 protein in vivo as a novel therapeutic intervention to control various forms of inflammatory disorders.
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