基本情報

所属

• 保健科学研究院

職名

• 特任講師

学位

• 理学修士（台湾台北医学大学）
• 博士（農学）（東北大学）

J-Global ID

• 201901009167423356

研究分野

• ライフサイエンス / 病態医化学
• ライフサイエンス / 応用生物化学
• ライフサイエンス / 食品科学

担当教育組織

•  修士課程　保健科学院
•  博士課程　保健科学院

研究活動情報

論文

• Kaempferol Improves Cardiolipin and ATP in Hepatic Cells: A Cellular Model Perspective in the Context of Metabolic Dysfunction-Associated Steatotic Liver Disease

  Akiko Sakurai, Toshihiro Sakurai, Hsin-Jung Ho, Hitoshi Chiba, Shu-Ping Hui

  Nutrients 2024年02月11日
• Flazin improves mitochondrial dynamics in renal tubular epithelial cells under oxidative stress

  Xun-Zhi Wu, Hsin-Jung Ho, Miki Eguchi, Zhen Chen, Hitoshi Chiba, Shu-Ping Hui

  Food Bioscience 2023年12月
• A Pacific Oyster-Derived Antioxidant, DHMBA, Protects Renal Tubular HK-2 Cells against Oxidative Stress via Reduction of Mitochondrial ROS Production and Fragmentation.

  Hsin-Jung Ho, Natsumi Aoki, Yi-Jou Wu, Ming-Chen Gao, Karin Sekine, Toshihiro Sakurai, Hitoshi Chiba, Hideaki Watanabe, Mitsugu Watanabe, Shu-Ping Hui

  International journal of molecular sciences 24 12 2023年06月13日 [査読有り]
   

  The kidney contains numerous mitochondria in proximal tubular cells that provide energy for tubular secretion and reabsorption. Mitochondrial injury and consequent excessive reactive oxygen species (ROS) production can cause tubular damage and play a major role in the pathogenesis of kidney diseases, including diabetic nephropathy. Accordingly, bioactive compounds that protect the renal tubular mitochondria from ROS are desirable. Here, we aimed to report 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), isolated from the Pacific oyster (Crassostrea gigas) as a potentially useful compound. In human renal tubular HK-2 cells, DHMBA significantly mitigated the cytotoxicity induced by the ROS inducer L-buthionine-(S, R)-sulfoximine (BSO). DHMBA reduced the mitochondrial ROS production and subsequently regulated mitochondrial homeostasis, including mitochondrial biogenesis, fusion/fission balance, and mitophagy; DHMBA also enhanced mitochondrial respiration in BSO-treated cells. These findings highlight the potential of DHMBA to protect renal tubular mitochondrial function against oxidative stress.
• Elobixibat投与マウスにおける胆汁酸および腸内細菌叢の検討

  蓑輪 圭太, 秋山 由雅子, 笠原 朋子, 何 欣蓉, 前川 正充, 菊池 晃一, 豊原 敬文, 鈴木 健弘, 鈴木 千登世, 鯨井 涼太, 松本 洋太郎, 富岡 佳久, 阿部 高明

  日本腎臓学会誌 65 3 294 - 294 (一社)日本腎臓学会 2023年05月
• メナキノン-4による腎尿細管細胞のミトコンドリア保護作用

  江口 美祈, 何 欣蓉, 青木 菜摘, 高明 晨, 鈴木 拓貴, 千葉 仁志, 惠 淑萍

  ビタミン 97 4 217 - 217 (公社)日本ビタミン学会 2023年04月
• フラジンはヒト尿細管HK-2細胞における脂肪酸を介した脂質毒性を抑制する(Flazin attenuates fatty acid mediated lipotoxicity in human tubular HK-2 cells)

  呉 訓智, 何 欣蓉, 陳 震, 陳 一凡, 沈 テン秋, 千葉 仁志, 惠 淑萍

  日本栄養・食糧学会大会講演要旨集 77回 173 - 173 2023年03月
• ビタミンKによる腎尿細管細胞のミトコンドリア保護効果

  江口 美祈, 何 欣蓉, 青木 菜摘, 高 明晨, 鈴木 拓貴, 千葉 仁志, 惠 淑萍

  日本栄養・食糧学会大会講演要旨集 77回 302 - 302 (公社)日本栄養・食糧学会 2023年03月
• Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease

  Hsin-Jung Ho, Hitoshi Shirakawa

  Cells 12 1 2022年12月 [査読有り][招待有り]
   

  The kidney contains many mitochondria that generate ATP to provide energy for cellular processes. Oxidative stress injury can be caused by impaired mitochondria with excessive levels of reactive oxygen species. Accumulating evidence has indicated a relationship between oxidative stress and kidney diseases, and revealed new insights into mitochondria-targeted therapeutics for renal injury. Improving mitochondrial homeostasis, increasing mitochondrial biogenesis, and balancing mitochondrial turnover has the potential to protect renal function against oxidative stress. Although there are some reviews that addressed this issue, the articles summarizing the relationship between mitochondria-targeted effects and the risk factors of renal failure are still few. In this review, we integrate recent studies on oxidative stress and mitochondrial function in kidney diseases, especially chronic kidney disease. We organized the causes and risk factors of oxidative stress in the kidneys based in their mitochondria-targeted effects. This review also listed the possible candidates for clinical therapeutics of kidney diseases by modulating mitochondrial function.
• Biotin Enhances Testosterone Production in Mice and Their Testis-Derived Cells

  Kota Shiozawa, Misato Maeda, Hsin-Jung Ho, Tomoko Katsurai, Md. Zakir Hossain Howlader, Kimiko Horiuchi, Yumi Sugita, Yusuke Ohsaki, Afifah Zahra Agista, Tomoko Goto, Michio Komai, Hitoshi Shirakawa

  Nutrients 14 22 4761 - 4761 2022年11月10日 [査読有り]
   

  Late-onset hypogonadism, a male age-related syndrome characterized by a decline in testosterone production in the testes, is commonly treated with testosterone replacement therapy, which has adverse side effects. Therefore, an alternative treatment is highly sought. Supplementation of a high dosage of biotin, a water-soluble vitamin that functions as a coenzyme for carboxylases involved in carbohydrate, lipid, and amino acid metabolism, has been shown to influence testis functions. However, the involvement of biotin in testis steroidogenesis has not been well clarified. In this study, we examined the effect of biotin on testosterone levels in mice and testis-derived cells. In mice, intraperitoneal treatment with biotin (1.5 mg/kg body weight) enhanced testosterone levels in the serum and testes, without elevating serum levels of pituitary luteinizing hormone. To investigate the mechanism in which biotin increased the testosterone level, mice testis-derived I-10 cells were used. The cells treated with biotin increased testosterone production in a dose- and time-dependent manner. Biotin treatment elevated intracellular cyclic adenosine monophosphate levels via adenylate cyclase activation, followed by the activation of protein kinase A and testosterone production. These results suggest that biotin may have the potential to improve age-related male syndromes associated with declining testosterone production.
• マガキ由来抗酸化物質DHMBAの腎臓尿細管細胞における抗酸化作用

  何 欣蓉, 関根 かりん, 青木 菜摘, 櫻井 俊宏, 千葉 仁志, 渡辺 秀明, 渡辺 貢, 惠 淑萍

  日本未病学会学術総会抄録集 29回 73 - 73 (一社)日本未病学会 2022年10月
• SGLT-1-specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine-induced renal failure.

  Hsin-Jung Ho, Koichi Kikuchi, Daiki Oikawa, Shun Watanabe, Yoshitomi Kanemitsu, Daisuke Saigusa, Ryota Kujirai, Wakako Ikeda-Ohtsubo, Mariko Ichijo, Yukako Akiyama, Yuichi Aoki, Eikan Mishima, Yoshiaki Ogata, Yoshitsugu Oikawa, Tetsuro Matsuhashi, Takafumi Toyohara, Chitose Suzuki, Takehiro Suzuki, Nariyasu Mano, Yoshiteru Kagawa, Yuji Owada, Takane Katayama, Toru Nakayama, Yoshihisa Tomioka, Takaaki Abe

  Physiological reports 9 24 e15092  2021年12月 [査読有り]
   

  Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.
• 酸化ストレス誘導下HK-2細胞におけるDHMBAによるカルジオリピンの組成変化に関する研究(Alteration of cardiolipin profile in HK-2 proximal tubule cells under oxidative stress and the reverse effects of 3,5-dihydroxy-4-methoxybenzyl alcohol(DHMBA))

  呉 亦柔, 何 欣蓉, 陳 震, 賈 佳萍, 青木 菜摘, 千葉 仁志, 渡辺 孝之, 渡辺 貢, 惠 淑萍

  JSBMS Letters 46 Suppl. 106 - 106 2021年08月
• Cysteine Sulfoxides Enhance Steroid Hormone Production via Activation of the Protein Kinase A Pathway in Testis-Derived I-10 Tumor Cells.

  Yuya Nakayama, Hsin-Jung Ho, Miki Yamagishi, Hiroyuki Ikemoto, Michio Komai, Hitoshi Shirakawa

  Molecules (Basel, Switzerland) 25 20 2020年10月14日 [査読有り]
   

  Testosterone plays an important role in male sexual characteristics and maturation, and decreased testosterone levels increase the risk of several diseases. Recently, onion extract rich in cysteine sulfoxides, which are amino acids unique to onions, has been reported to alleviate age-related symptoms resulting from decreased testosterone levels in males. However, the mechanism underlying the suppression of low testosterone levels by cysteine sulfoxides has not been elucidated. In this study, we found that onion extract containing cysteine sulfoxides enhanced progesterone, a precursor of testosterone, in mouse testis-derived I-10 tumor cells. Furthermore, cysteine sulfoxides activated protein kinase A (PKA) and cyclic adenosine monophosphate response element-binding protein, which are key factors in steroidogenesis. These results suggest that cysteine sulfoxides enhance steroid hormone production via activation of the PKA signaling pathway.
• Beneficial Effects of Vitamin K Status on Glycemic Regulation and Diabetes Mellitus: A Mini-Review.

  Hsin-Jung Ho, Michio Komai, Hitoshi Shirakawa

  Nutrients 12 8 2020年08月18日 [査読有り]
   

  Type 2 diabetes mellitus is a chronic disease that is characterized by hyperglycemia, insulin resistance, and dysfunctional insulin secretion. Glycemic control remains a crucial contributor to the progression of type 2 diabetes mellitus as well as the prevention or delay in the onset of diabetes-related complications. Vitamin K is a fat-soluble vitamin that plays an important role in the regulation of the glycemic status. Supplementation of vitamin K may reduce the risk of diabetes mellitus and improve insulin sensitivity. This mini-review summarizes the recent insights into the beneficial effects of vitamin K and its possible mechanism of action on insulin sensitivity and glycemic status, thereby suppressing the progression of diabetes mellitus.
• The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease.

  Fumika Nanto-Hara, Yoshitomi Kanemitsu, Shinji Fukuda, Koichi Kikuchi, Kei Asaji, Daisuke Saigusa, Tomoyuki Iwasaki, Hsin-Jung Ho, Eikan Mishima, Takehiro Suzuki, Chitose Suzuki, Tomoya Tsukimi, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Yukako Akiyama, Shigeo Kure, Yuji Owada, Yoshihisa Tomioka, Tomoyoshi Soga, Sadayoshi Ito, Takaaki Abe

  Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 35 2 250 - 264 2020年02月01日 [査読有り]
   

  BACKGROUND: Cardiorenal syndrome is a major cause of mortality in patients with chronic kidney disease (CKD). However, the involvement of detrimental humoral mediators in the pathogenesis of cardiorenal syndrome is still controversial. Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine or carnitine derived by the gut microbiota, has been linked directly with progression of cardiovascular disease and renal dysfunction. Thus, targeting TMAO may be a novel strategy for the prevention of cardiovascular disease and chronic kidney disease. METHODS: Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect. RESULTS: Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 μg/kg in the adenine-induced RF mouse model. At a high concentration of 100 μg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-β, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the 'leaky gut' in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels. CONCLUSION: Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut-cardio-renal axis.
• Geranylgeraniol Suppresses the Expression of IRAK1 and TRAF6 to Inhibit NFκB Activation in Lipopolysaccharide-Induced Inflammatory Responses in Human Macrophage-Like Cells.

  Puspo E Giriwono, Hitoshi Shirakawa, Yusuke Ohsaki, Shoko Sato, Yukihide Aoyama, Hsin-Jung Ho, Tomoko Goto, Michio Komai

  International journal of molecular sciences 20 9 2019年05月10日 [査読有り]
   

  Geranylgeraniol (GGOH), a natural isoprenoid found in plants, has anti-inflammatory effects via inhibiting the activation of nuclear factor-kappa B (NFκB). However, its detailed mechanism has not yet been elucidated. Recent studies have revealed that isoprenoids can modulate signaling molecules in innate immune responses. We found that GGOH decreased the expression of lipopolysaccharide (LPS)-induced inflammatory genes in human macrophage-like THP-1 cells. Furthermore, we observed that the suppression of NFκB signaling proteins, in particular interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), occurred in GGOH-treated cells prior to LPS stimulation, suggesting an immunomodulatory effect. These results indicate that GGOH may modulate and help prevent excessive NFκB activation that can lead to numerous diseases.
• ケモカインレセプターCCR10阻害薬による腎不全抑制効果の検討

  一條 真梨子, 何 欣蓉, 金光 祥臣, 菊地 晃一, 秋山 由雅子, 三島 英換, 鈴木 健弘, 鈴木 千登世, 富岡 佳久, 伊藤 貞嘉, 阿部 高明

  日本腎臓学会誌 61 3 325 - 325 (一社)日本腎臓学会 2019年05月
• Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease.

  Koichi Kikuchi, Daisuke Saigusa, Yoshitomi Kanemitsu, Yotaro Matsumoto, Paxton Thanai, Naoto Suzuki, Koki Mise, Hiroaki Yamaguchi, Tomohiro Nakamura, Kei Asaji, Chikahisa Mukawa, Hiroki Tsukamoto, Toshihiro Sato, Yoshitsugu Oikawa, Tomoyuki Iwasaki, Yuji Oe, Tomoya Tsukimi, Noriko N Fukuda, Hsin-Jung Ho, Fumika Nanto-Hara, Jiro Ogura, Ritsumi Saito, Shizuko Nagao, Yusuke Ohsaki, Satoshi Shimada, Takehiro Suzuki, Takafumi Toyohara, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yukako Akiyama, Mariko Ichijo, Tetsuro Matsuhashi, Akihiro Matsuo, Yoshiaki Ogata, Ching-Chin Yang, Chitose Suzuki, Matthew C Breeggemann, Jurgen Heymann, Miho Shimizu, Susumu Ogawa, Nobuyuki Takahashi, Takashi Suzuki, Yuji Owada, Shigeo Kure, Nariyasu Mano, Tomoyoshi Soga, Takashi Wada, Jeffrey B Kopp, Shinji Fukuda, Atsushi Hozawa, Masayuki Yamamoto, Sadayoshi Ito, Jun Wada, Yoshihisa Tomioka, Takaaki Abe

  Nature communications 10 1 1835 - 1835 2019年04月23日 [査読有り]
   

  Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.
• Menaquinone-4 Amplified Glucose-Stimulated Insulin Secretion in Isolated Mouse Pancreatic Islets and INS-1 Rat Insulinoma Cells.

  Hsin-Jung Ho, Hitoshi Shirakawa, Keisukei Hirahara, Hideyuki Sone, Shin Kamiyama, Michio Komai

  International journal of molecular sciences 20 8 2019年04月23日 [査読有り]
   

  Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic β-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects.
• Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model.

  Eikan Mishima, Shinji Fukuda, Yoshitomi Kanemitsu, Daisuke Saigusa, Chikahisa Mukawa, Kei Asaji, Yotaro Matsumoto, Hiroki Tsukamoto, Tatsuki Tachikawa, Tomoya Tsukimi, Noriko N Fukuda, Hsin-Jung Ho, Koichi Kikuchi, Chitose Suzuki, Fumika Nanto, Takehiro Suzuki, Sadayoshi Ito, Tomoyoshi Soga, Yoshihisa Tomioka, Takaaki Abe

  American journal of physiology. Renal physiology 315 4 F824-F833  2018年10月01日 [査読有り]
   

  Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.
• A novel function of geranylgeraniol in regulating testosterone production.

  Hsin-Jung Ho, Hitoshi Shirakawa, Puspo E Giriwono, Asagi Ito, Michio Komai

  Bioscience, biotechnology, and biochemistry 82 6 956 - 962 2018年06月 [査読有り]
   

  Isoprenoids play widely differing roles in various physiological processes in animals and plants. Geranylgeraniol (GGOH) is an isoprenoid found in plants, and is an important metabolic derivative in the isoprenoid/cholesterol synthesis pathway. Earlier studies focused on GGOH's ability to improve the side effects of bisphosphonate therapy by regulating the mevalonate pathway. More recently, the mevalonate pathway-independent effects of GGOH have been described, including anti-inflammatory, anti-tumorigenic, and neuroprotective activities. It is noteworthy that GGOH regulates the steroidogenesis pathway in testis-derived I-10 tumor cells. Testosterone is a hormone produced via steroidogenesis in testicles and plays a role in fetal development and the male reproductive system. GGOH enhanced testosterone and progesterone (its precursor) levels in I-10 cells by activating adenylate cyclase via cAMP/PKA signaling, without altering phosphodiesterase activity. These findings highlight the potential benefits of GGOH as a therapeutic agent for low testosterone levels, such as late-onset hypogonadism in men.
• Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases.

  Tetsuro Matsuhashi, Takeya Sato, Shin-Ichiro Kanno, Takehiro Suzuki, Akihiro Matsuo, Yuki Oba, Motoi Kikusato, Emi Ogasawara, Tai Kudo, Kosuke Suzuki, Osamu Ohara, Hiroko Shimbo, Fumika Nanto, Hiroaki Yamaguchi, Daisuke Saigusa, Yasuno Mukaiyama, Akiko Watabe, Koichi Kikuchi, Hisato Shima, Eikan Mishima, Yasutoshi Akiyama, Yoshitsugu Oikawa, H O Hsin-Jung, Yukako Akiyama, Chitose Suzuki, Mitsugu Uematsu, Masaki Ogata, Naonori Kumagai, Masaaki Toyomizu, Atsushi Hozawa, Nariyasu Mano, Yuji Owada, Setsuya Aiba, Teruyuki Yanagisawa, Yoshihisa Tomioka, Shigeo Kure, Sadayoshi Ito, Kazuto Nakada, Ken-Ichiro Hayashi, Hitoshi Osaka, Takaaki Abe

  EBioMedicine 20 27 - 38 2017年06月 [査読有り]
   

  Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.
• A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways.

  Hisato Shima, Kensuke Sasaki, Takehiro Suzuki, Chikahisa Mukawa, Ten Obara, Yuki Oba, Akihiro Matsuo, Takayasu Kobayashi, Eikan Mishima, Shun Watanabe, Yasutoshi Akiyama, Koichi Kikuchi, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Fumika Nanto, Yukako Akiyama, Hsin-Jung Ho, Chitose Suzuki, Daisuke Saigusa, Atsushi Masamune, Yoshihisa Tomioka, Takao Masaki, Sadayoshi Ito, Ken-Ichiro Hayashi, Takaaki Abe

  Scientific reports 7 1 1884 - 1884 2017年05月15日 [査読有り]
   

  Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis.
• Menaquinone‐4 Enhances Steroidogenesis in Testis Derived Tumor Cells Via the Elevation of cAMP Level

  Hsin-Jung Ho, Hitoshi Shirakawa, Michio Komai

  Vitamin K2 - Vital for Health and Wellbeing 2017年03月22日 [査読有り]
  
• Effect of Kaempferia paruiflora extract and its polymethoxyflavonoid components on testosterone production in mouse testis-derived tumour cells

  Satoru Horigome, Misato Maeda, Hsin-Jung Ho, Hitoshi Shirakawa, Michio Komai

  JOURNAL OF FUNCTIONAL FOODS 26 529 - 538 2016年10月 [査読有り][通常論文]
   

  Low testosterone is associated with late-onset hypogonadism, age-related disease, type 2 diabetes, and cardiovascular disease. In this study, we investigated the effects of Kaempferia parviflora extract and two of its components, 5,7-dimethoxyflavone and 5-hydroxy-3,7,3',4'-tetramethoxyflavone, on testosterone production in mouse testis-derived tumour cells I-10. K. parviflora fractions containing 5,7-dimethoxyflavone elicited testosterone production in these cells, as did nobiletin, a polymethoxyflavonoid found in citrus species, but not K. paruiflora, which was used as a comparative control. Furthermore, we found that these compounds enhanced testosterone production via cyclic AMP (cAMP)/cAMP response element binding protein signalling. In particular, the compounds inhibited activation of phosphodiesterase and thereby increased production of cAMP. These findings support the possibility that K. paruiflora extract, 5,7-dimethoxyflavone, and nobiletin may mitigate age-related disease and hypogonadism by enhancing testosterone production. (C) 2016 Elsevier Ltd. All rights reserved.
• Geranylgeraniol enhances testosterone production via the cAMP/protein kinase A pathway in testis-derived I-10 tumor cells.

  Hsin-Jung Ho, Hitoshi Shirakawa, Risa Yoshida, Asagi Ito, Misato Maeda, Tomoko Goto, Michio Komai

  Bioscience, biotechnology, and biochemistry 80 4 791 - 7 2016年 [査読有り]
   

  Testosterone levels in men decrease with age; this decline has been linked to various diseases and can shorten life expectancy. Geranylgeraniol (GGOH) is an isoprenoid found in plants that plays an important role in several biological processes; however, its role in steroidogenesis is unknown. Here, we report that GGOH enhances the production of testosterone and its precursor progesterone in testis-derived I-10 tumor cells. GGOH induced protein kinase A (PKA) activity and increased cAMP levels and was found to regulate cAMP/PKA signaling by activating adenylate cyclase without altering phosphodiesterase activity. GGOH also stimulated mRNA and protein levels of steroidogenic acute regulatory protein, a downstream effector in the cAMP/PKA pathway. These results demonstrate that GGOH enhances steroidogenesis in testis-derived cells by modulating cAMP/PKA signaling. Our findings have potential applications for the development of therapeutics that increase testosterone levels in aging men.
• The use of oral rehydration salt in managing children under 5 y old with diarrhea in the Gambia: Knowledge, attitude, and practice

  Famara Sillah, Hsin-Jung Ho, Jane C-J. Chao

  Nutrition 29 11-12 1368 - 1373 2013年11月 [査読有り]
  
• Dietary intake, glucose metabolism and sex hormones in women with polycystic ovary syndrome (PCOS) compared with women with non-PCOS-related infertility

  Ya-Hui Tsai, Ting-Wen Wang, Hsiao-Jui Wei, Chien-Yeh Hsu, Hsin-Jung Ho, Wen-Hua Chen, Robert Young, Chian-Mey Liaw, Jane C.-J. Chao

  British Journal of Nutrition 109 12 2190 - 2198 2013年06月28日 [査読有り]
   

  The present study investigated dietary intake, glucose metabolism and sex hormones in women with polycystic ovary syndrome (PCOS). A total of forty-five women (aged 25–40 years) with PCOS and 161 control women (aged 25–43 years) with non-PCOS-related infertility were recruited. Anthropometry, glucose tolerance and sex hormones were determined and dietary intake was assessed. Women with PCOS had lower serum sex hormone-binding globulin and increased BMI, waist:hip ratio, luteinising hormone, ratio of luteinising hormone:follicle-stimulating hormone, testosterone and free androgen index (FAI). Postprandial glucose, fasting insulin and insulin resistance were elevated in women with PCOS. Women with PCOS had reduced energy and carbohydrate intake but higher fat intake. Serum sex hormone-binding globulin level was negatively associated with BMI in both groups and negatively correlated with macronutrient intake in the PCOS group with hyperandrogenism. However, FAI was positively correlated with BMI, waist circumference and glucose metabolic parameters in both groups. Therefore, women with PCOS consume lower energy and carbohydrate compared with those with non-PCOS-related infertility and macronutrient intake is only negatively associated with serum sex hormone-binding globulin level in the PCOS group with hyperandrogenism.
• Lycopene inhibits growth of human colon cancer cellsvia suppression of the Akt signaling pathway

  Feng-Yao Tang, Chung-Jin Shih, Li-Hao Cheng, Hsin-Jung Ho, Hung-Jiun Chen

  Molecular Nutrition & Food Research 52 6 646 - 654 2008年06月 [査読有り]
  

書籍

• ビタミン・バイオファクター総合事典

  日本ビタミン学会, 竹谷, 豊, 生城, 浩子, 池田, 彩子, 石川, 孝博, 太田, 好次, 小暮, 健太朗, 瀧谷, 公隆, 田中, 清, 津川, 尚子, 内藤, 裕二, 野坂, 和人, 福渡, 努 (担当:共著)
  朝倉書店 2021年07月 (ISBN: 9784254102925) xv, 635p

その他活動・業績

• Elobixibat投与マウスにおける胆汁酸および腸内細菌叢の検討

  蓑輪圭太, 秋山由雅子, 笠原朋子, 何欣蓉, 前川正充, 菊池晃一, 豊原敬文, 鈴木健弘, 鈴木千登世, 鯨井涼太, 松本洋太郎, 富岡佳久, 阿部高明 日本腎臓学会誌(Web) 65 (3) 2023年
• 腎臓近位尿細管細胞におけるメナキノン-4の酸化ストレス軽減効果

  何 欣蓉, 青木 菜摘, 高 明晨, 鈴木 拓貴, 千葉 仁志, 惠 淑萍 ビタミン 96 (4) 193 -193 2022年04月
• 腸内細菌叢と胆汁酸の調節による腎不全治療

  秋山 由雅子, 前川 正充, 菊地 晃一, 何 欣蓉, 一條 真梨子, 鈴木 千登世, 渡邉 駿, 豊原 敬文, 鈴木 健弘, 富岡 佳久, 阿部 高明 日本腎臓学会誌 63 (4) 459 -459 2021年06月
• 腸内細菌叢と胆汁酸の調節による腎不全治療

  秋山 由雅子, 前川 正充, 菊地 晃一, 何 欣蓉, 一條 真梨子, 鈴木 千登世, 渡邉 駿, 豊原 敬文, 鈴木 健弘, 富岡 佳久, 阿部 高明 日本腎臓学会誌 63 (4) 459 -459 2021年06月
• サケ白子抽出物の培養ヒト肝細胞におけるミトコンドリア活性化作用

  関島 将人, 櫻井 俊宏, 佐藤 浩志, 何 欣蓉, 千葉 仁志, 惠 淑萍 臨床化学 49 (Suppl.1) 152 -152 2020年10月
• アデニン誘発腎不全マウスにおけるエロビキシバットの効果

  秋山 由雅子, 前川 正充, 金光 祥臣, 菊地 晃一, 何 欣蓉, 三島 英換, 鈴木 健弘, 一條 真梨子, 鈴木 千登世, 眞野 成康, 富岡 佳久, 阿部 高明 日本腎臓学会誌 62 (4) 337 -337 2020年07月
• アデニン誘発腎不全マウスにおけるエロビキシバットの効果

  秋山 由雅子, 前川 正充, 金光 祥臣, 菊地 晃一, 何 欣蓉, 三島 英換, 鈴木 健弘, 一條 真梨子, 鈴木 千登世, 眞野 成康, 富岡 佳久, 阿部 高明 日本腎臓学会誌 62 (4) 337 -337 2020年07月
• グアニル酸シクラーゼC受容体作動薬リナクロチドは血中TMAO値を低下させ慢性腎不全に伴う心血管疾患のリスクを緩和する

  原 文香, 金光 祥臣, 福田 真嗣, 菊地 晃一, 何 欣蓉, 鈴木 千登世, 曽我 朋義, 富岡 佳久, 阿部 高明 日本内分泌学会雑誌 95 (4) 1612 -1612 2020年02月 [査読無し][通常論文]
  
• 腸内細菌由来のフェニル硫酸は糖尿病性腎臓病でのアルブミン尿増悪の原因物質かつ予測マーカーである

  菊地晃一, 三枝大輔, 金光祥臣, 松本洋太郎, 中村智洋, 淺地圭, 三瀬広記, 何欣蓉, 三島英換, 鈴木健弘, 和田淳, 寶澤篤, 伊藤貞嘉, 阿部高明 日本腎臓学会誌 61 (3) 312 -312 2019年05月15日 [査読無し][通常論文]
  
• グアニル酸シクラーゼC受容体作動薬リナクロチドは慢性腎不全に伴う心血管疾患のリスクを緩和する

  原 文香[南都], 金光 祥臣, 福田 真嗣, 何 欣蓉, 菊地 晃一, 鈴木 千登世, 曽我 朋義, 富岡 佳久, 伊藤 貞嘉, 阿部 高明 日本腎臓学会誌 61 (3) 312 -312 2019年05月 [査読無し][通常論文]
  
• 胆汁酸トランスポーター阻害薬エロビキシバットによる腎保護作用の検討

  秋山 由雅子, 何 欣蓉, 金光 祥臣, 前川 正充, 菊地 晃一, 鈴木 健弘, 三島 英換, 一條 真梨子, 鈴木 千登世, 眞野 成康, 富岡 佳久, 伊藤 貞嘉, 阿部 高明 日本腎臓学会誌 61 (3) 403 -403 2019年05月 [査読無し][通常論文]
  
• グアニル酸シクラーゼC受容体作動薬リナクロチドは腎不全に伴う腸内環境悪性化を改善し腎線維化を抑制する

  南都文香, 福田真嗣, 金光祥臣, 三枝大輔, 菊地晃一, 何欣蓉, 三島英換, 鈴木健弘, 松橋徹郎, 及川義嗣, 鈴木千登世, 富岡佳久, 曽我朋義, 伊藤貞嘉, 阿部高明 日本腎臓学会誌 60 (3) 463 -463 2018年04月30日 [査読無し][通常論文]
  
• ビオチンによる男性ホルモン産生促進とその作用機序の解析

  塩沢浩太, 前田美里, 何欣蓉, 白川仁, 駒井三千夫 日本食品科学工学会大会講演集 65th 2018年
• グアニル酸シクラーゼC受容体作動薬リナクロチドは腎不全に伴う腸内環境悪性化を改善し腎線維化を抑制する

  南都文香, 福田真嗣, 金光祥臣, 三枝大輔, 菊地晃一, 何欣蓉, 三島英換, 鈴木健弘, 松橋徹郎, 及川義嗣, 鈴木千登世, 富岡佳久, 曽我朋義, 伊藤貞嘉, 阿部高明 日本腎臓学会誌 60 (3) 463 -463 2018年
• ビタミンKによる性ホルモン産生促進

  白川仁, 何欣蓉, 駒井三千夫 ビタミン 90 3 -8 2016年01月 [査読無し][通常論文]
   

  責任著者

共同研究・競争的資金等の研究課題

• 筋腎連関によるビタミンKのミトコンドリアを標的とした新規作用

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2022年04月 -2025年03月 

  代表者 : 何 欣蓉, 陳 震
• 脳内活性型ビタミンKの認知機能増強作用と作用機序の解析

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  研究期間 : 2020年04月 -2023年03月 

  代表者 : 白川 仁, 大崎 雄介, 何 欣蓉, SULTANA HALIMA

   

  ビタミンK（VK）は、血液凝固因子やオステオカルシンなどの骨タンパク質を活性化させるγ-グルタミルカルボキシラーゼの補因子として、必須な因子である。我々は、緑色野菜に含まれるVK1や発酵食品、動物性食品に含まれるVK2を摂取している。VKの生体内分布をみると骨や肝臓のほかに、膵臓、精巣、脳などにも存在しているが、各組織におけるVKの役割は未だ十分に明らかになっていない。本研究は、脳におけるVK、特にVK2のひとつであるメナキノン-4（MK-4）の作用を明らかにすることを目的とした。本年度は、MK-4の脳における抗炎症作用を明らかにするため、ミクログリアと神経細胞の共培養系での評価を行うとともに、炎症誘発認知症モデルにおいて、VK給餌の影響を解析した。 マウス由来株化ミクログリアをリポポリサッカライド（LPS）で刺激して、その培養上清を採取した。これを用いて、マウス海馬由来神経細胞を培養すると、細胞死が誘発され、ミクログリアからLPS刺激により神経細胞死を誘導する因子が放出されると考えられた。LPS刺激前にミクログリアをMK-4の側鎖構造体であるゲラニルゲラニオール（GGOH）で処理すると、神経細胞の細胞死が抑制された。このことから、GGOHはLPSにより誘導される炎症を抑制し、神経細胞死を引き起こす因子の発現を抑制することが示唆された。 LPSの投与によって起こる記憶障害をオープンフィールド試験、受動的回避行動試験によって評価した。VK1およびMK-4を給餌したマウスとコントロール食マウスとの間で、2つの試験結果に差は見られなかった。一方、LPSにより大脳、海馬のNFκBの発現量が上昇したが、MK-4の給餌によって有意に低下した。このことから、MK-4は脳内で起こる炎症を低下させて神経細胞死を抑制することが示唆された。
• ビタミンKによる腎脂肪毒性の改善作用と作用機構の解明

  日本学術振興会：科学研究費助成事業 若手研究

  研究期間 : 2020年04月 -2022年03月 

  代表者 : 何 欣蓉

   

  【背景】糖尿病性腎症では腎臓の近位尿細管細胞に脂肪滴の蓄積が起こる。この脂肪滴の蓄積によりミトコンドリア障害を起こし、過剰な活性酸素種（ROS）が生じることが予想され、細胞死に至ると考えられる。ビタミンK（VK）による腎臓の脂肪蓄積とミトコンドリア障害の改善作用の解明のために、近位尿細管培養細胞への脂肪酸負荷による脂肪毒性への影響を検討し、VKの保護作用の機序解明を目的とする。本研究が解明された場合、VKによる脂肪酸代謝及び酸化ストレスの抑制が新たな腎疾患の治療戦略になると考える。 【方法】腎臓近位尿細管由来HK-2細胞に脂肪酸（パルミチン酸）を処理し、ROSを上昇させ細胞毒性を引き起こすモデル、脂肪滴の蓄積するモデルを確立する。その後、細胞の生存率やATPの測定、脂肪滴の染色を行い、VKの添加によるHK-2細胞への保護効果とその作用機序を解明する。また、非刺激HK-2細胞において、VKのミトコンドリア機能促進作用を調べるためにATP産生の測定および呼吸能の評価、ミトコンドリアDNA（mtDNA）コピー数の測定を行った。 【研究成果】HK-2細胞に脂肪酸負荷を添加し、脂肪滴の蓄積やATPの低下、さらに細胞死が観察された。これは脂肪酸代謝及びミトコンドリア代謝の異常が原因と考えられる。本研究では、VK添加（0.03μM-100μM）によって脂肪毒性から細胞を保護できた。一方、ミトコンドリア呼吸能の変化を測定した結果、非刺激HK-2細胞においても、VK添加でATP産生と最大呼吸が増加した。また、VK添加でmtDNAコピー数に変化は見られなかったことから、VKはミトコンドリアの数に影響は与えずにミトコンドリア機能を活性化させることが示唆された。本研究でVKが酸化ストレスや脂肪毒性から細胞を保護し、ATP産生を増加させたことから、糖尿病性腎症の予防に働くことが期待できると考える。
• Identification and clinical implication of biomarkers for mitochondrial diseases

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists

  研究期間 : 2018年04月 -2020年03月 

  代表者 : Ho Hsinjung

   

  For seeking a novel therapeutic approach for the treatment of mitochondria disorder, several studies have been performed. First, the function of mitofilin, which play an indispensable role in the maintenance of mitochondrial function. Second, for the reason of high mitochondrial content and oxygen consumption in the kidney, the continuous mitochondrial dysfunction plays an essential role in progression of renal diseases. Here, we also investigated a new candidate drug for chronic kidney disease and focused on the correlation between lipotoxicity and mitochondrial dysfunction in the kidney. The current study found that a SGLT1 inhibitor decreased the accumulated uremic toxins in the renal failure mice, through altering the gut microbiota composition without changing renal function. Moreover, using a proximal tubule epithelial cell line, lipid droplets accumulated in fatty acids treated cells accompanied by decreased ATP production and mitochondrial dysfunction.

教育活動情報

主要な担当授業