المؤلفون: Melvin Pan, Christiane Zorbas, Maki Sugaya, Kensuke Ishiguro, Miki Kato, Miyuki Nishida, Hai-Feng Zhang, Marco M. Candeias, Akimitsu Okamoto, Takamasa Ishikawa, Tomoyoshi Soga, Hiroyuki Aburatani, Juro Sakai, Yoshihiro Matsumura, Tsutomu Suzuki, Christopher G. Proud, Denis L. J. Lafontaine, Tsuyoshi Osawa

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-14 (2022)

مصطلحات موضوعية: Science

الوصف: Small molecules that target RNA Polymerase I inhibit ribosome biogenesis to activate p53 through the nucleolar surveillance response pathway. Here, the authors show that p53 induction by ribosome stress is dependent on extracellular glutamine availability.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2041-1723

URL الوصول: https://doaj.org/article/5a2c48021da748188909409721466a55

المؤلفون: Tetsuya Kadonosono, Kotaro Miyamoto, Shiori Sakai, Yoshiyuki Matsuo, Shojiro Kitajima, Qiannan Wang, Minori Endo, Mizuho Niibori, Takahiro Kuchimaru, Tomoyoshi Soga, Kiichi Hirota, Shinae Kizaka-Kondoh

المصدر: Scientific Reports, Vol 12, Iss 1, Pp 1-13 (2022)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2045-2322

URL الوصول: https://doaj.org/article/04df67d4e5dd44408996ce01414b499b

المؤلفون: Yasuhiro Saito, Shiori Matsuda, Naomi Ohnishi, Keiko Endo, Sanae Ashitani, Maki Ohishi, Ayano Ueno, Masaru Tomita, Koji Ueda, Tomoyoshi Soga, Senthil K. Muthuswamy

المصدر: Communications Biology, Vol 5, Iss 1, Pp 1-10 (2022)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: A complex involving polarity protein SCRIB and the leucine amino acid transporter SLC7A5 promotes cell proliferation and tamoxifen resistance in estrogen receptor-positive breast cancer cells.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2399-3642

URL الوصول: https://doaj.org/article/f82831f1194043f68b9e1f2c4b58a781

المؤلفون: Shuuhei Hirose, Tsuyoshi Waku, Misato Tani, Haruka Masuda, Keiko Endo, Sanae Ashitani, Iori Aketa, Hina Kitano, Sota Nakada, Ayaka Wada, Atsushi Hatanaka, Tsuyoshi Osawa, Tomoyoshi Soga, Akira Kobayashi

المصدر: iScience, Vol 26, Iss 2, Pp 106045- (2023)

مصطلحات موضوعية: Cellular physiology, Cell biology, Cancer, Science

الوصف: Summary: Cancer cells coordinate the mTORC1 signals and the related metabolic pathways to robustly and rapidly grow in response to nutrient conditions. Although a CNC-family transcription factor NRF3 promotes cancer development, the biological relevance between NRF3 function and mTORC1 signals in cancer cells remains unknown. Hence, we showed that NRF3 contributes to cancer cell viability through mTORC1 activation in response to amino acids, particularly arginine. NRF3 induced SLC38A9 and RagC expression for the arginine-dependent mTORC1 recruitment onto lysosomes, and it also enhanced RAB5-mediated bulk macropinocytosis and SLC7A1-mediated selective transport for arginine loading into lysosomes. Besides, the inhibition of the NRF3–mTORC1 axis impaired mitochondrial function, leading to cancer cell apoptosis. Consistently, the aberrant upregulation of the axis caused tumor growth and poor prognosis. In conclusion, this study sheds light on the unique function of NRF3 in arginine-dependent mTORC1 activation and the pathophysiological aspects of the NRF3–mTORC1 axis in cancer development.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2589004223001220; https://doaj.org/toc/2589-0042

URL الوصول: https://doaj.org/article/94a3d01baf604a83a67455cb7ad7597c

المؤلفون: Tetsuya Hirabayashi, Mai Kawaguchi, Sayaka Harada, Misa Mouri, Rina Takamiya, Yoshimi Miki, Hiroyasu Sato, Yoshitaka Taketomi, Kohei Yokoyama, Tetsuyuki Kobayashi, Suzumi M. Tokuoka, Yoshihiro Kita, Emiko Yoda, Shuntaro Hara, Kyohei Mikami, Yasumasa Nishito, Norihito Kikuchi, Rieko Nakata, Mari Kaneko, Hiroshi Kiyonari, Kohji Kasahara, Toshiki Aiba, Kazutaka Ikeda, Tomoyoshi Soga, Makoto Kurano, Yutaka Yatomi, Makoto Murakami

المصدر: Cell Reports, Vol 42, Iss 2, Pp 111940- (2023)

مصطلحات موضوعية: CP: Metabolism, Biology (General), QH301-705.5

الوصف: Summary: Choline supplies methyl groups for regeneration of methionine and the methyl donor S-adenosylmethionine in the liver. Here, we report that the catabolism of membrane phosphatidylcholine (PC) into water-soluble glycerophosphocholine (GPC) by the phospholipase/lysophospholipase PNPLA8-PNPLA7 axis enables endogenous choline stored in hepatic PC to be utilized in methyl metabolism. PNPLA7-deficient mice show marked decreases in hepatic GPC, choline, and several metabolites related to the methionine cycle, accompanied by various signs of methionine insufficiency, including growth retardation, hypoglycemia, hypolipidemia, increased energy consumption, reduced adiposity, increased fibroblast growth factor 21 (FGF21), and an altered histone/DNA methylation landscape. Moreover, PNPLA8-deficient mice recapitulate most of these phenotypes. In contrast to wild-type mice fed a methionine/choline-deficient diet, both knockout strains display decreased hepatic triglyceride, likely via reductions of lipogenesis and GPC-derived glycerol flux. Collectively, our findings highlight the biological importance of phospholipid catabolism driven by PNPLA8/PNPLA7 in methyl group flux and triglyceride synthesis in the liver.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2211124722018411; https://doaj.org/toc/2211-1247

URL الوصول: https://doaj.org/article/7ee32951ecd74122b19dbf4171b4e0c3

المؤلفون: Masahiro Nishi, Takehiro Ogata, Ko Kobayakawa, Reiko Kobayakawa, Tomohiko Matsuo, Carlo Vittorio Cannistraci, Shinya Tomita, Shunta Taminishi, Takaomi Suga, Tomoya Kitani, Yusuke Higuchi, Akira Sakamoto, Yumika Tsuji, Tomoyoshi Soga, Satoaki Matoba

المصدر: ESC Heart Failure, Vol 9, Iss 1, Pp 428-441 (2022)

مصطلحات موضوعية: Ischaemia/reperfusion injury, Drug therapy, Hypothermia, Metabolism, 2‐Methyl‐2‐thiazoline, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Abstract Aims Cardiac ischaemia/reperfusion (I/R) injury remains a critical issue in the therapeutic management of ischaemic heart failure. Although mild hypothermia has a protective effect on cardiac I/R injury, more rapid and safe methods that can obtain similar results to hypothermia therapy are required. 2‐Methyl‐2‐thiazoline (2MT), an innate fear inducer, causes mild hypothermia resulting in resistance to critical hypoxia in cutaneous or cerebral I/R injury. The aim of this study is to demonstrate the protective effect of systemically administered 2MT on cardiac I/R injury and to elucidate the mechanism underlying this effect. Methods and results A single subcutaneous injection of 2MT (50 mg/kg) was given prior to reperfusion of the I/R injured 10 week‐old male mouse heart and its efficacy was evaluated 24 h after the ligation of the left anterior descending coronary artery. 2MT preserved left ventricular systolic function following I/R injury (ejection fraction, %: control 37.9 ± 6.7, 2MT 54.1 ± 6.4, P

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2055-5822

URL الوصول: https://doaj.org/article/410d4334202946b9bf498e8531456aae

المؤلفون: Suguru Fujita, Yasuaki Karasawa, Masashi Fujii, Ken-ichi Hironaka, Shinsuke Uda, Hiroyuki Kubota, Hiroshi Inoue, Yohei Sumitomo, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda

المصدر: npj Systems Biology and Applications, Vol 8, Iss 1, Pp 1-16 (2022)

مصطلحات موضوعية: Biology (General), QH301-705.5

الوصف: Abstract Oral glucose ingestion induces systemic changes of many blood metabolites related not only to glucose, but also other metabolites such as amino acids and lipids through many blood hormones. However, the detailed temporal changes in the concentrations of comprehensive metabolites and hormones over a long time by oral glucose ingestion are uncharacterized. We measured 83 metabolites and 7 hormones in 20 healthy human subjects in response to glucose ingestion. We characterized temporal patterns of blood molecules by four features: (i) the decomposability into “amplitude” and “rate” components, (ii) the similarity of temporal patterns among individuals, (iii) the relation of molecules over time among individuals, and (iv) the similarity of temporal patterns among molecules. Glucose and glucose metabolism-related hormones indicated a rapid increase, and citrulline and lipids, which indicated a rapid decrease, returned to fasting levels faster than amino acids. Compared to glucose metabolism-related molecules and lipids, amino acids showed similar temporal patterns among individuals. The four features of temporal patterns of blood molecules by oral glucose ingestion characterize the differences among individuals and among molecules.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2056-7189

URL الوصول: https://doaj.org/article/ed535d8abeef4ca8a00569199c403e62

المؤلفون: Ryosuke Hayasaka, Sho Tabata, Masako Hasebe, Satsuki Ikeda, Tomoya Hikita, Chitose Oneyama, Jun Yoshitake, Daisuke Onoshima, Kumiko Takahashi, Takahiro Shibata, Koji Uchida, Yoshinobu Baba, Tomoyoshi Soga, Masaru Tomita, Akiyoshi Hirayama

المصدر: Frontiers in Molecular Biosciences, Vol 9 (2023)

مصطلحات موضوعية: small extracellular vesicles, size exclusion chromatography, ultracentrifugation, metabolome analysis, lipidome analysis, 2-hydroxyglutaric acid, Biology (General), QH301-705.5

الوصف: Cancer-derived small extracellular vesicles (sEVs) are multifunctional particles with a lipid bilayer structure that are involved in cancer progression, such as malignant proliferation, distant metastasis, and cancer immunity evasion. The separation protocol used to isolate sEVs is an important process and thus, several have been developed, including ultracentrifugation (UC), size exclusion chromatography (SEC), and affinity purification using antibodies against sEV surface antigens. However, the effects of different separation methods on sEV components have not been adequately examined. Here, we developed a semi-automated system for collecting sEVs by combining SEC and preparative high-performance liquid chromatography and applied it to metabolome analysis. The developed SEC system could recover sEVs more efficiently and non-destructively than UC, suggesting that it is an appropriate recovery method for metabolic analysis and reflects biological conditions. Furthermore, using the developed SEC system, we performed metabolome analysis of sEVs from isocitrate dehydrogenase 1 (IDH)-mutated human colon HCT116 cells, which produce the oncogenic metabolite, 2-hydroxyglutaric acid (2-HG). IDH1-mutated HCT116 cells released significantly more sEVs than wild-type (WT) cells. The metabolomic profiles of IDH1 mutant and WT cells showed distinct differences between the cells and their sEVs. Notably, in IDH mutant cells, large amounts of 2-HG were detected not only in cells, but also in sEVs. These results indicate that the SEC system we developed has wide potential applications in sEVs research.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fmolb.2022.1049402/full; https://doaj.org/toc/2296-889X

URL الوصول: https://doaj.org/article/ae8ad54e7a964820a6d9d622d040ef46

المؤلفون: Sachio Shibata, Satoshi Sogabe, Masanori Miwa, Takuya Fujimoto, Nobuyuki Takakura, Akihiko Naotsuka, Shuji Kitamura, Tomohiro Kawamoto, Tomoyoshi Soga

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2045-2322

URL الوصول: https://doaj.org/article/f9c30a90aae44dd1abe0ffa04ef29aac

المؤلفون: Masaaki Nakao, Ippei Shimizu, Goro Katsuumi, Yohko Yoshida, Masayoshi Suda, Yuka Hayashi, Ryutaro Ikegami, Yung Ting Hsiao, Shujiro Okuda, Tomoyoshi Soga, Tohru Minamino

المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Patients with type 2 diabetes treated with Sodium glucose transporter 2 (SGLT2) inhibitors show reduced mortality and hospitalization for heart failure (HF). SGLT2 inhibitors are considered to activate multiple cardioprotective pathways; however, underlying mechanisms are not fully described. This study aimed to elucidate the underlying mechanisms of the beneficial effects of SGLT2 inhibitors on the failing heart. We generated a left ventricular (LV) pressure overload model in C57BL/6NCrSlc mice by transverse aortic constriction (TAC) and examined the effects of empagliflozin (EMPA) in this model. We conducted metabolome and transcriptome analyses and histological and physiological examinations. EMPA administration ameliorated pressure overload-induced systolic dysfunction. Metabolomic studies showed that EMPA increased citrulline levels in cardiac tissue and reduced levels of arginine, indicating enhanced metabolism from arginine to citrulline and nitric oxide (NO). Transcriptome suggested possible involvement of the insulin/AKT pathway that could activate NO production through phosphorylation of endothelial NO synthase (eNOS). Histological examination of the mice showed capillary rarefaction and endothelial apoptosis after TAC, both of which were significantly improved by EMPA treatment. This improvement was associated with enhanced expression phospho-eNOS and NO production in cardiac endothelial cells. NOS inhibition attenuated these cardioprotective effects of EMPA. The in vitro studies showed that catecholamine-induced endothelial apoptosis was inhibited by NO, arginine, or AKT activator. EMPA activates the AKT/eNOS/NO pathway, which helps to suppress endothelial apoptosis, maintain capillarization and improve systolic dysfunction during LV pressure overload.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2045-2322

URL الوصول: https://doaj.org/article/d12309a66d7741a1b29740eef4e5bfd0