論文 - 古橋　眞人

IgA腎症での糸球体障害における脂肪酸結合蛋白4の関与についての検討

田中 希尚, 茂庭 仁人, 禾 千絵子, 淺沼 克彦, 鈴木 祐介, 古橋 眞人

日本腎臓学会誌 ( (一社)日本腎臓学会 )  65 ( 3 ) 271 - 271  2023年05月

Chlamydia pneumoniae Lung Infection in Mice Induces Fatty Acid-Binding Protein 4-Dependent White Adipose Tissue Pathology.

Yusuke Kurihara, Nirwana Fitriani Walenna, Kazunari Ishii, Toshinori Soejima, Bin Chou, Michinobu Yoshimura, Ryo Ozuru, Akinori Shimizu, Ryota Itoh, Masato Furuhashi, Gökhan S Hotamisligil, Kenji Hiromatsu

Journal of immunology (Baltimore, Md. : 1950)   210 ( 8 ) 1086 - 1097  2023年04月  [国際誌]

　概要を見る

Fatty acid-binding protein 4 (FABP4) is a critical immune-metabolic modulator, mainly expressed in adipocytes and macrophages, secreted from adipocytes in association with lipolysis, and plays essential pathogenic roles in cardiovascular and metabolic diseases. We previously reported Chlamydia pneumoniae infecting murine 3T3-L1 adipocytes and causing lipolysis and FABP4 secretion in vitro. However, it is still unknown whether C. pneumoniae intranasal lung infection targets white adipose tissues (WATs), induces lipolysis, and causes FABP4 secretion in vivo. In this study, we demonstrate that C. pneumoniae lung infection causes robust lipolysis in WAT. Infection-induced WAT lipolysis was diminished in FABP4-/- mice or FABP4 inhibitor-pretreated wild-type mice. Infection by C. pneumoniae in wild-type but not FABP4-/- mice induces the accumulation of TNF-α- and IL-6-producing M1-like adipose tissue macrophages in WAT. Infection-induced WAT pathology is augmented by endoplasmic reticulum (ER) stress/the unfolded protein response (UPR), which is abrogated by treatment with azoramide, a modulator of the UPR. C. pneumoniae lung infection is suggested to target WAT and induce lipolysis and FABP4 secretion in vivo via ER stress/UPR. FABP4 released from infected adipocytes may be taken up by other neighboring intact adipocytes or adipose tissue macrophages. This process can further induce ER stress activation and trigger lipolysis and inflammation, followed by FABP4 secretion, leading to WAT pathology. A better understanding of the role of FABP4 in C. pneumoniae infection-induced WAT pathology will provide the basis for rational intervention measures directed at C. pneumoniae infection and metabolic syndrome, such as atherosclerosis, for which robust epidemiologic evidence exists.

DOI PubMed

代謝異常関連脂肪肝疾患(MAFLD)は収縮期血圧の経時的な上昇と関連する 線形混合効果モデルを用いた解析

遠藤 圭佑, 森 和真, 田中 希尚, 佐藤 達也, 大西 浩文, 塙 なぎさ, 古橋 眞人

糖尿病 ( (一社)日本糖尿病学会 )  66 ( Suppl.1 ) S - 264  2023年04月

Downregulation of BCKDH Activity and Uncoupling from AMP Deaminase Underlie Substrate Inflexibility in Type 2 Diabetic Hearts(タイトル和訳中)

小川 俊史, 神津 英至, 長南 新太, 清水 将輝, 戸田 悠貴, 大和田 渉, 佐藤 達也, 矢野 俊之, 久野 篤史, 丹野 雅也, 三浦 哲嗣, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   OJ03 - 2  2023年03月

心不全患者の骨粗鬆症を予測する新たなリスクスコアの開発と精度の検証

沼澤 瞭, 片野 唆敏, 長岡 凌平, 藤澤 佑輔, 山埜 光太郎, 大堀 克彦, 渡辺 絢子, 石郷 友之, 西川 諒, 大和田 渉, 永野 伸卓, 藤戸 健史, 小山 雅之, 神津 英至, 橋本 暁佳, 矢野 俊之, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   CA1 - 2  2023年03月

Impact of Iron Metabolism on Physical Function in Patients with Heart Failure(タイトル和訳中)

大堀 克彦, 矢野 俊之, 片野 唆敏, 長岡 凌平, 沼澤 瞭, 山埜 光太郎, 藤沢 祐輔, 神津 英至, 小山 雅之, 永野 伸卓, 藤戸 健史, 西川 諒, 大和田 渉, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   PJ038 - 3  2023年03月

BCKDH活性のダウンレギュレーションとAMPデアミナーゼとのアンカップリングが2型糖尿病性心臓における基質柔軟性の欠如を引き起こす(Downregulation of BCKDH Activity and Uncoupling from AMP Deaminase Underlie Substrate Inflexibility in Type 2 Diabetic Hearts)

小川 俊史, 神津 英至, 長南 新太, 清水 将輝, 戸田 悠貴, 大和田 渉, 佐藤 達也, 矢野 俊之, 久野 篤史, 丹野 雅也, 三浦 哲嗣, 古橋 眞人

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   OJ03 - 2  2023年03月

3D Spheroid Configurations Are Possible Indictors for Evaluating the Pathophysiology of Melanoma Cell Lines.

Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Fumihito Hikage, Masato Furuhashi, Masae Okura, Tokimasa Hida, Hisashi Uhara

Cells   12 ( 5 )  2023年02月  [国際誌]

　概要を見る

To study the molecular mechanisms responsible for inducing the spatial proliferation of malignant melanomas (MM), three-dimension (3D) spheroids were produced from several MM cell lines including SK-mel-24, MM418, A375, WM266-4, and SM2-1, and their 3D architectures and cellular metabolisms were evaluated by phase-contrast microscopy and Seahorse bio-analyzer, respectively. Several transformed horizontal configurations were observed within most of these 3D spheroids, and the degree of their deformity was increased in the order: WM266-4, SM2-1, A375, MM418, and SK-mel-24. An increased maximal respiration and a decreased glycolytic capacity were observed within the lesser deformed two MM cell lines, WM266-4 and SM2-1, as compared with the most deformed ones. Among these MM cell lines, two distinct cell lines, WM266-4 and SK-mel-24, whose 3D appearances were the closest and farthest, respectively, from being horizontally circular-shaped, were subjected to RNA sequence analyses. Bioinformatic analyses of the differentially expressed genes (DEGs) identified KRAS and SOX2 as potential master regulatory genes for inducing these diverse 3D configurations between WM266-4 and SK-mel-24. The knockdown of both factors altered the morphological and functional characteristics of the SK-mel-24 cells, and in fact, their horizontal deformity was significantly reduced. A qPCR analysis indicated that the levels of several oncogenic signaling related factors, including KRAS and SOX2, PCG1α, extracellular matrixes (ECMs), and ZO1 had fluctuated among the five MM cell lines. In addition, and quite interestingly, the dabrafenib and trametinib resistant A375 (A375DT) cells formed globe shaped 3D spheroids and showed different profiles in cellular metabolism while the mRNA expression of these molecules that were tested as above were different compared with A375 cells. These current findings suggest that 3D spheroid configuration has the potential for serving as an indicator of the pathophysiological activities associated with MM.

DOI PubMed

TGF-β-3 Induces Different Effects from TGF-β-1 and -2 on Cellular Metabolism and the Spatial Properties of the Human Trabecular Meshwork Cells

Megumi Watanabe, Tatsuya Sato, Yuri Tsugeno, Megumi Higashide, Masato Furuhashi, Hiroshi Ohguro

International Journal of Molecular Sciences    2023年02月  [査読有り]

DOI

Comparison of Phenotypes in Subcutaneous Fat and Perivascular Adipose Tissue Surrounding the Saphenous Vein in Coronary Artery Bypass Grafting

Takuma Mikami, Masato Furuhashi, Ryosuke Numaguchi, Itaru Hosaka, Akiko Sakai, Marenao Tanaka, Toshiro Ito, Toshiyuki Maeda, Taku Sakurada, Satoshi Muraki, Yousuke Yanase, Hiroshi Sato, Joji Fukada, Yukihiko Tamiya, Yutaka Iba, Nobuyoshi Kawaharada

Circulation Journal ( Japanese Circulation Society )   2023年02月

DOI

Thyroid-stimulating hormone高値は男性の新規CKD発症と関連する

遠藤 圭佑, 田中 希尚, 佐藤 達也, 塙 なぎさ, 大西 浩文, 古橋 眞人

日本内科学会雑誌 ( (一社)日本内科学会 )  112 ( 臨増 ) 176 - 176  2023年02月

Metabolic dysfunction-associated fatty liver disease is associated with an increase in systolic blood pressure over time: linear mixed-effects model analyses

Kazuma Mori, Marenao Tanaka, Itaru Hosaka, Takuma Mikami, Keisuke Endo, Nagisa Hanawa, Hirofumi Ohnishi, Masato Furuhashi

Hypertension Research ( Springer Science and Business Media LLC )   2023年01月

DOI

Glomerular expression and urinary excretion of fatty acid-binding protein 4 in IgA nephropathy

Marenao Tanaka, Norihito Moniwa, Chieko Nogi, Toshiki Kano, Megumi Matsumoto, Akiko Sakai, Takuto Maeda, Hideki Takizawa, Yayoi Ogawa, Katsuhiko Asanuma, Yusuke Suzuki, Masato Furuhashi

Journal of Nephrology ( Springer Science and Business Media LLC )   2023年01月

DOI

Unexpected Crosslinking Effects of a Human Thyroid Stimulating Monoclonal Autoantibody, M22, with IGF1 on Adipogenesis in 3T3L-1 Cells

Araya Umetsu, Tatsuya Sato, Megumi Watanabe, Yosuke Ida, Masato Furuhashi, Yuri Tsugeno, Hiroshi Ohguro

International Journal of Molecular Sciences    2023年01月  [査読有り]

DOI

G-Protein-Coupled Receptors Mediate Modulations of Cell Viability and Drug Sensitivity by Aberrantly Expressed Recoverin 3 within A549 Cells

Hanae Ichioka, Yoshihiko Hirohashi, Tatsuya Sato, Masato Furuhashi, Megumi Watanabe, Yosuke Ida, Fumihito Hikage, Toshihiko Torigoe, Hiroshi Ohguro

International Journal of Molecular Sciences   24 ( 1 )  2023年01月  [査読有り]  [国際誌]

　概要を見る

To elucidate the currently unknown molecular mechanisms responsible for the aberrant expression of recoverin (Rec) within cancerous cells, we examined two-dimensional (2D) and three-dimensional (3D) cultures of Rec-negative lung adenocarcinoma A549 cells which had been transfected with a plasmid containing human recoverin cDNA (A549 Rec) or an empty plasmid as a mock control (A549 MOCK). Using these cells, we measured cytotoxicity by several anti-tumor agents (2D), cellular metabolism including mitochondrial and glycolytic functions by a Seahorse bio-analyzer (2D), the physical properties, size and stiffness of the 3D spheroids, trypsin sensitivities (2D and 3D), and RNA sequencing analysis (2D). Compared with the A549 MOCK, the A549 Rec cells showed (1) more sensitivity toward anti-tumor agents (2D) and a 0.25% solution of trypsin (3D); (2) a metabolic shift from glycolysis to oxidative phosphorylation; and (3) the formation of larger and stiffer 3D spheroids. RNA sequencing analysis and bioinformatic analyses of the differentially expressed genes (DEGs) using Gene Ontology (GO) enrichment analysis suggested that aberrantly expressed Rec is most likely associated with several canonical pathways including G-protein-coupled receptor (GPCR)-mediated signaling and signaling by the cAMP response element binding protein (CREB). The findings reported here indicate that the aberrantly expressed Rec-induced modulation of the cell viability and drug sensitivity may be GPCR mediated.

DOI PubMed

Case report: Transient lactate elevation by intravenous insulin infusion therapy for diabetic ketoacidosis in a patient with mitochondrial DNA 3243 A > G mutation: A glycolysis rebooting syndrome?

Wataru Ohwada, Hidemichi Kouzu, Tatsuya Sato, Kahomi Sazawa, Azumi Matsui, Nobutaka Nagano, Masayuki Koyama, Noriko Ogasawara, Akifumi Takada, Toshiyuki Yano, Masato Furuhashi

Frontiers in cardiovascular medicine   10   1144925 - 1144925  2023年  [国際誌]

　概要を見る

Mitochondrial disease, most cases of which are caused by mitochondrial DNA (mtDNA) mutation, is present with multiple phenotypes including diabetes mellitus, sensorineural hearing loss, cardiomyopathy, muscle weakness, renal dysfunction, and encephalopathy, depending on the degree of heteroplasmy. While mitochondria play an important role in intracellular glucose and lactate metabolism in insulin-sensitive tissues such as muscles, appropriate strategies for glycemic control have not yet been established in a patient with mitochondrial disease, which is often complicated by myopathy. Here, we describe the history of a 40-year-old man with mtDNA 3243A > G who had sensorineural hearing loss, cardiomyopathy, muscle wasting, and diabetes mellitus with stage 3 chronic kidney disease. He developed mild diabetic ketoacidosis (DKA) in the process of treatment for poor glycemic control with severe latent hypoglycemia. According to the standard therapy for DKA, he was treated with continuous intravenous insulin infusion therapy, which unexpectedly resulted in an abrupt and transient elevation in blood lactate levels without exacerbation of heart failure and kidney function. Since blood lactate levels are determined by the balance between lactate production and consumption, an abrupt and transient lactate elevation following intravenous insulin injection therapy may reflect not only enhanced glycolysis in insulin-sensitive tissues with mitochondrial dysfunction but also decreased lactate consumption in the sarcopenic skeletal muscle and failing heart. Intravenous insulin infusion therapy in patients with mitochondrial disease may unmask derangements of intracellular glucose metabolism in response to insulin signaling.

DOI PubMed

Potential favorable action of sodium-glucose cotransporter-2 inhibitors on sudden cardiac death: a brief overview.

Tatsuya Sato, Hidemichi Kouzu, Toshiyuki Yano, Ichiro Sakuma, Masato Furuhashi, Noritsugu Tohse

Frontiers in cardiovascular medicine   10   1159953 - 1159953  2023年  [国際誌]

　概要を見る

The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined. The cardiorenal protective effects of SGLT2 inhibitors have been reported to include hemodynamic improvement, reverse remodeling of the failing heart, amelioration of sympathetic hyperactivity, correction of anemia and impaired iron metabolism, antioxidative effects, correction of serum electrolyte abnormalities, and antifibrotic effects, which may lead to prevent SCD and/or VAs. Recently, as possible direct cardiac effects of SGLT2 inhibitors, not only inhibition of Na+/H+ exchanger (NHE) activity, but also suppression of late Na+ current have been focused on. In addition to the indirect cardioprotective mechanisms of SGLT2 inhibitors, suppression of aberrantly increased late Na+ current may contribute to preventing SCD and/or VAs via restoration of the prolonged repolarization phase in the failing heart. This review summarizes the results of previous clinical trials of SGLT2 inhibitors for prevention of SCD, their impact on the indices of electrocardiogram, and the possible molecular mechanisms of their anti-arrhythmic effects.

DOI PubMed

Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

Satoshi Katano, Toshiyuki Yano, Hidemichi Kouzu, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Katsuhiko Ohori, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Masaki Katayose, Tatsuya Sato, Atsushi Kuno, Masato Furuhashi

Cardiovascular Diabetology ( Springer Science and Business Media LLC )  21 ( 1 )  2022年12月

　概要を見る

Abstract Aims The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). Methods We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. Results Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. Conclusion SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

DOI

血清尿酸値は女性において収縮期血圧の経時的な上昇と関連する 線形混合効果モデルでの解析

森 和真, 田中 希尚, 東浦 幸村, 小山 雅之, 塙 なぎさ, 大西 浩文, 古橋 眞人

痛風と尿酸・核酸 ( (一社)日本痛風・尿酸核酸学会 )  46 ( 2 ) 166 - 166  2022年12月

尿酸とCOVID-19の原因ウイルスSARS-CoV-2の宿主側受容体ACE2との関連についての検討

古橋 眞人, 田中 希尚, 東浦 幸村, 森 和真, 小山 雅之, 大西 浩文, 齋藤 重幸, 島本 和明

痛風と尿酸・核酸 ( (一社)日本痛風・尿酸核酸学会 )  46 ( 2 ) 160 - 160  2022年12月