Article
Multidisciplinary Sciences
Athena Jessica S. Ong, Cerys E. Bladen, Tara A. Tigani, Anthony P. Karamalakis, Kimberley J. Evason, Kristin K. Brown, Andrew G. Cox
Summary: The maintenance of redox and metabolic homeostasis is crucial for embryonic development. The transcription factor NRF2 plays a central role in regulating redox balance and cellular metabolism and is repressed by KEAP1 under normal conditions. In this study, we show that loss of Keap1 leads to activation of Nrf2 and postdevelopmental lethality due to severe liver abnormalities characterized by an accumulation of lysosomes. We also demonstrate that loss of Keap1 promotes aberrant activation of transcription factors TFEB and TFE3, resulting in lysosomal biogenesis. The findings highlight the importance of the KEAP1-NRF2 pathway in regulating lysosomal homeostasis during embryonic development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Developmental Biology
Rebecca K. Schiavo, Owen J. Tamplin
Summary: This study reveals the role of Vegfc in the emergence of HSPCs in the zebrafish dorsal aorta and suggests that it regulates HSPC fate by suppressing a myeloid cell fate.
Article
Endocrinology & Metabolism
Sharon Baumel-Alterzon, Liora S. Katz, Gabriel Brill, Clairete Jean-Pierre, Yansui Li, Isabelle Tse, Shyam Biswal, Adolfo Garcia-Ocana, Donald K. Scott
Summary: By manipulating Nrf2 levels, researchers have discovered the importance of managing reactive oxygen species in regulating beta-cell mass, highlighting Nrf2 as an exciting therapeutic target for expanding and protecting beta-cell mass in diabetes.
Article
Multidisciplinary Sciences
Jiexiang Zhao, Ping Lu, Cong Wan, Yaping Huang, Manman Cui, Xinyan Yang, Yuqiong Hu, Yi Zheng, Ji Dong, Mei Wang, Shu Zhang, Zhaoting Liu, Shuhui Bian, Xiaoman Wang, Rui Wang, Shaofang Ren, Dazhuang Wang, Zhaokai Yao, Gang Chang, Fuchou Tang, Xiao-Yang Zhao
Summary: Through single-cell sequencing, the study investigates the transcriptome landscapes of mouse male germ cells throughout development and identifies critical regulators for prenatal cell-fate determination.
NATURE COMMUNICATIONS
(2021)
Article
Cell & Tissue Engineering
Dachuan Zhang, Xin Gao, Huihui Li, Daniel K. Borger, Qiaozhi Wei, Eva Yang, Chunliang Xu, Sandra Pinho, Paul S. Frenette
Summary: This study reveals that the microbiota regulates hematopoietic stem cells (HSCs) self-renewal and differentiation by modulating local iron availability in the bone marrow. Microbiota depletion enhances HSC self-renewal but compromises differentiation under stress conditions. The interplay between the microbiota, macrophages, and iron is essential for regulating critical HSC fate decisions.
Review
Endocrinology & Metabolism
Sharon Baumel-Alterzon, Liora S. Katz, Gabriel Brill, Adolfo Garcia-Ocana, Donald K. Scott
Summary: Prolonged hyperglycemia is harmful to pancreatic beta cells, and Nrf2 plays a crucial role in protecting these cells from oxidative stress. Modulating Nrf2 activity is a promising therapeutic approach for the treatment of diabetes.
TRENDS IN ENDOCRINOLOGY AND METABOLISM
(2021)
Review
Cell Biology
Sydney Treichel, Marie-Dominique Filippi
Summary: Hematopoietic stem cells have the ability to self-renew or differentiate into various blood cell lineages. The cell fate decisions of self-renewal or differentiation must be tightly controlled to prevent diseases like bone marrow failure or leukemia. Studies have shown that the cell cycle length plays a crucial role in hematopoietic stem cell fate. Cell cycle kinetics, divisional history, asymmetric cell divisions, metabolic and organelle activity all have an impact on hematopoietic stem cell fate decisions.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Cell Biology
Dinisha Kamble, Megharani Mahajan, Rohini Dhat, Sandhya Sitasawad
Summary: This study reveals the role of Nrf2-Keap1-Bach1 signaling in radioresistance of breast cancer stem cells (BCSCs) and suggests that targeting the ALDH(+) BCSC population with miR200a may reduce tumor recurrence after radiotherapy. Additionally, the findings demonstrate that Nrf2-Keap1 signaling controls mesenchymal-epithelial plasticity and regulates tumor-initiating ability of BCSCs, promoting their radioresistance.
Review
Chemistry, Medicinal
Bo-Hyun Choi, Jin Myung Kim, Mi-Kyoung Kwak
Summary: NEF2L2 (NRF2) plays a crucial role in the defense system, but its multifaceted role in tumors, including in tumor growth and progression, therapy resistance, and cancer stem cells, is rapidly expanding. Understanding NRF2's role in CSCs could lead to novel therapeutic approaches for controlling tumor relapse after therapy.
ARCHIVES OF PHARMACAL RESEARCH
(2021)
Review
Cell Biology
Emiliano Panieri, Sonia A. Pinho, Goncalo J. M. Afonso, Paulo J. Oliveira, Teresa Cunha-Oliveira, Luciano Saso
Summary: The NRF2-KEAP1 system regulates a wide range of transcriptional targets involved in redox homeostasis and cellular protection. NRF2 is a key driver of tumor progression and treatment resistance in cancer cells, making it a promising therapeutic target. Additionally, NRF2 has functional crosstalk with mitochondria, influencing mitochondrial homeostasis and cancer cell biology.
Article
Immunology
Lifei Hou, Koichi Yuki
Summary: CD11a plays a critical role in leukocyte arrest and immunological synapse formation, but its role in the bone marrow is not well studied. This research showed that CD11a is expressed on all subsets of hematopoietic stem and progenitor cells (HPSCs). CD11a deficiency enhances HSPCs activity under LPS stimulation, possibly by upregulating the production of IL-27 to promote cell proliferation.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Jessica Iegre, Sona Krajcovicova, Anders Gunnarsson, Lisa Wissler, Helena Kaeck, Anna Luchniak, Stefan Tangefjord, Frank Narjes, David R. Spring
Summary: The study presents a two-component peptide stapling strategy to inhibit the protein-protein interaction between Nrf2 and Keap1. The most promising peptide, P8-H, binds to Keap1 with nanomolar affinity and effectively induces gene transcription in specific cells at sub-micromolar concentration. This strategy provides a new approach to develop cell-permeable peptide-based inhibitors.
Article
Engineering, Biomedical
Yanqun Li, Jianhui Yue, Yuan Liu, Jun Wu, Min Guan, Di Chen, Haobo Pan, Xiaoli Zhao, William W. Lu
Summary: The study revealed that strontium promotes osteogenic differentiation of mesenchymal stem cells and balances stemness maintenance and osteogenic differentiation through asymmetric cell division. Strontium activates noncanonical Wnt signaling to regulate cell division and enhance osteogenic differentiation.
ACTA BIOMATERIALIA
(2021)
Article
Cell & Tissue Engineering
Kenji Kitajima, Minako Shingai, Hikaru Ando, Mako Hamasaki, Takahiko Hara
Summary: Researchers developed a novel method for hematopoietic differentiation of human-induced pluripotent stem cells to address the issue of low production of CD38(+) hematopoietic progenitor cells. They found that the lack of FLT3 expression was responsible for this problem and solved it by adding interferon-gamma.
Article
Genetics & Heredity
Ying Zhang, Ling Ling, Arya Ajay D. O. Ajayakumar, Yating Michelle Eio, Andre J. van Wijnen, Victor Nurcombe, Simon M. Cool
Summary: This study reveals a positive correlation between FGFR2 expression and osteogenic potential in human adult bone marrow-derived MSCs. Knockdown of FGFR2 leads to downregulation of pro-osteogenic genes and upregulation of pro-adipogenic genes, suppressing osteogenesis. Furthermore, FGFR2 knockdown results in upregulation of EZH2, an enzyme that regulates MSC lineage commitment and suppresses osteogenesis under osteogenic induction.
Article
Ophthalmology
Akiko Hanyuda, Atsushi Goto, Masahiro Nakatochi, Yoichi Sutoh, Akira Narita, Shiori Nakano, Ryoko Katagiri, Kenji Wakai, Naoyuki Takashima, Teruhide Koyama, Kokichi Arisawa, Issei Imoto, Yukihide Momozawa, Kozo Tanno, Atsushi Shimizu, Atsushi Hozawa, Kengo Kinoshita, Taiki Yamaji, Norie Sawada, Masao Iwagami, Kenya Yuki, Kazuo Tsubota, Kazuno Negishi, Keitaro Matsuo, Masayuki Yamamoto, Makoto Sasaki, Shoichiro Tsugane, Motoki Iwasaki
Summary: This study conducted a Mendelian randomization analysis to assess the causal association between genetically predicted glycemic traits and the risk of primary open-angle glaucoma (POAG). The results did not provide strong evidence to support the association between genetically predicted glycemic traits and POAG in the Japanese population.
AMERICAN JOURNAL OF OPHTHALMOLOGY
(2023)
Article
Dermatology
Julien Coutier, Frederic Auvre, Gilles Lemaitre, Jean-Jacques Lataillade, Jean-Francois Deleuze, Paul-Henri Romeo, Michele T. Martin, Nicolas O. Fortunel
Summary: Characterizing the pathways that regulate human epidermal precursor cell fate is crucial for advancements in skin repair and graft bioengineering. This study reveals that the transcription factor MXD4/MAD4 plays a role in maintaining the stemness of keratinocyte (KC) precursor cells in the human epidermis. Decreased expression of MXD4/MAD4 increases MYC expression, leading to enhanced proliferation and clonogenic potential of KC precursors, and preserving their functionality in generating three-dimensional epidermis organoids.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2023)
Article
Oncology
Kinuko Ohneda, Yohei Hamanaka, Hiroshi Kawame, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Yumi Yamaguchi-Kabata, Muneaki Shimada, Atsushi Masamune, Yoko Aoki, Takanori Ishida, Masayuki Yamamoto
Summary: Returning individual genomic results to participants in a population-based genome cohort study is beneficial for preventing or providing early intervention for associated diseases. In this study, the majority of participants were willing to know their genomic information and did not experience remarkable negative psychological impact.
Article
Endocrinology & Metabolism
Akiko Saito-Hakoda, Atsuo Kikuchi, Tadahisa Takahashi, Yu Yokoyama, Noriko Himori, Mika Adachi, Ryoukichi Ikeda, Yuri Nomura, Jun Takayama, Junko Kawashima, Fumiki Katsuoka, Fumiyoshi Fujishima, Takehiko Yamaguchi, Akiyo Ito, Takushi Hanita, Junko Kanno, Toshimi Aizawa, Toru Nakazawa, Tetsuaki Kawase, Gen Tamiya, Masayuki Yamamoto, Ikuma Fujiwara, Shigeo Kure
Summary: This study identified a novel duplication variant of TNFRSF11A (72dup27) and suggested a broad spectrum of phenotypes in bone disorders associated with this variant.
JOURNAL OF BONE AND MINERAL METABOLISM
(2023)
Article
Genetics & Heredity
Yuka Sugawara, Yosuke Hirakawa, Hajime Nagasu, Akira Narita, Akihiro Katayama, Jun Wada, Miho Shimizu, Takashi Wada, Hiromasa Kitamura, Toshiaki Nakano, Hideki Yokoi, Motoko Yanagita, Shin Goto, Ichiei Narita, Seizo Koshiba, Gen Tamiya, Masaomi Nangaku, Masayuki Yamamoto, Naoki Kashihara
Summary: This study conducted a genome-wide association study (GWAS) in Japanese individuals to identify genetic loci related to kidney-related traits. The results identified 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among these loci, 22 have not been previously reported. The study also found that the group characterized by increased UACR had genetically distinct features from the group characterized by decreased eGFR.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Md Morshedul Alam, Akihiro Kishino, Eunkyu Sung, Hiroki Sekine, Takaaki Abe, Shohei Murakami, Takaaki Akaike, Hozumi Motohashi
Summary: NRF2 increases intracellular persulfides levels by upregulating the expression of cystine transporter xCT, thereby enhancing mitochondrial function.
Article
Biochemistry & Molecular Biology
Ryo Ikeda, Daisuke Noshiro, Hideaki Morishita, Shuhei Takada, Shun Kageyama, Yuko Fujioka, Tomoko Funakoshi, Satoko Komatsu-Hirota, Ritsuko Arai, Elena Ryzhii, Manabu Abe, Tomoaki Koga, Hozumi Motohashi, Mitsuyoshi Nakao, Kenji Sakimura, Arata Horii, Satoshi Waguri, Yoshinobu Ichimura, Nobuo N. Noda, Masaaki Komatsu
Summary: ULK1 is a kinase responsible for the phosphorylation of p62, which activates NRF2. p62(S351E/+) mice, with phosphorylation-mimicking mutation, exhibit NRF2 hyperactivation and growth retardation.
Article
Biochemistry & Molecular Biology
Qamarul Hafiz Zainol Abidin, Tomoaki Ida, Masanobu Morita, Tetsuro Matsunaga, Akira Nishimura, Minkyung Jung, Naim Hassan, Tsuyoshi Takata, Isao Ishii, Warren Kruger, Rui Wang, Hozumi Motohashi, Masato Tsutsui, Takaaki Akaike
Summary: Reactive sulfur species, such as cysteine hydropersulfide and glutathione persulfide, are produced abundantly in both prokaryotes and eukaryotes, including mammals. Cysteinyl-tRNA synthetase (CARS) has been identified as a new cysteine persulfide synthase (CPERS) responsible for the production of most reactive persulfides. However, the contribution of other enzymes, such as 3-mercaptopyruvate sulfurtransferase (3-MST), cystathionine beta-synthase (CBS), and cystathionine gamma-lyase (CSE), to reactive persulfide production is still debated. In this study, the authors used sulfur metabolome analysis to demonstrate that 3-MST, CBS, and CSE are not major sources of reactive persulfides in mammals, and CARS/CPERS is the principal enzyme involved.
Article
Biochemistry & Molecular Biology
Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N. Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita
Summary: Personalized medicine focuses on multi-omics data, and cohort studies from different ethnic populations contribute to understanding disease mechanisms and developing personalized medicine. The Tohoku Medical Megabank project collects biological specimens for multi-omics analysis, providing a multidimensional approach to the diversity of the Japanese population.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Tetsuro Matsunaga, Hirohito Sano, Katsuya Takita, Masanobu Morita, Shun Yamanaka, Tomohiro Ichikawa, Tadahisa Numakura, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Sunghyeon Yoon, Naoya Fujino, Yorihiko Kyogoku, Yusaku Sasaki, Akira Koarai, Tsutomu Tamada, Atsuhiko Toyama, Takakazu Nakabayashi, Lisa Kageyama, Shigeru Kyuwa, Kenji Inaba, Satoshi Watanabe, Peter Nagy, Tomohiro Sawa, Hiroyuki Oshiumi, Masakazu Ichinose, Mitsuhiro Yamada, Hisatoshi Sugiura, Fan-Yan Wei, Hozumi Motohashi, Takaaki Akaike
Summary: Supersulphides have diverse physiological functions and their synthesis is mediated by CARS2. They play a protective role in viral airway infections, aged lungs, and chronic lung diseases. Supersulphides can mitigate lung pathology and lethal effects in animal models, highlighting their potential as a therapeutic target.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Liam Baird, Masayuki Yamamoto
Summary: In human cancer, abnormal activation of the NRF2 pathway can allow cancer cells to evade immune surveillance and develop into malignant tumors by reducing antigen presentation and activating signals for NK cells, which inhibits the involvement of immune effector cells.
Article
Biochemistry & Molecular Biology
Haruna Takeda, Shohei Murakami, Zun Liu, Tomohiro Sawa, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyo Sato, Takaaki Akaike, Hiroki Sekine, Hozumi Motohashi
Summary: The excessive inflammatory response of macrophages is regulated by the metabolic alteration involving cysteine and its related metabolites. Activation of the cystine transporter xCT increases cysteine uptake by macrophages and contributes to the production of supersulfides, creating a negative feedback loop to limit excessive inflammation. Understanding the finely tuned regulation of macrophage inflammatory response by sulfur metabolism is important for disease pathogenesis and potential therapeutic strategies.
Article
Multidisciplinary Sciences
Shingo Kasamatsu, Akira Nishimura, Md. Morshedul Alam, Masanobu Morita, Kakeru Shimoda, Tetsuro Matsunaga, Minkyung Jung, Seiryo Ogata, Uladzimir Barayeu, Tomoaki Ida, Motohiro Nishida, Akiyuki Nishimura, Hozumi Motohashi, Takaaki Akaike
Summary: Research has found that abundant formation of endogenous supersulfides catalyzes S-nitrosoglutathione (GSNO) metabolism by utilizing alcohol dehydrogenase 5 (ADH5), which serves as GSNO reductase (GSNOR) and formaldehyde dehydrogenase (FDH). The C174S mutation in ADH5 significantly reduces supersulfidation and GSNOR activity but spares FDH activity. ADH5 supersulfides play a substantial role in GSNO metabolism by mediating electron transfer from aldehydes.
Article
Geriatrics & Gerontology
Kota Sato, Daisuke Saigusa, Taiki Kokubun, Amane Fujioka, Qiwei Feng, Ritsumi Saito, Akira Uruno, Naomi Matsukawa, Michiko Ohno-Oishi, Hiroshi Kunikata, Yu Yokoyama, Masayuki Yasuda, Noriko Himori, Kazuko Omodaka, Satoru Tsuda, Shigeto Maekawa, Masayuki Yamamoto, Toru Nakazawa
Summary: Glaucoma is a leading cause of blindness in older people, and studying the metabolites in the aqueous humor can provide insights into its physiological and pathological conditions. This study used mass spectrometry to characterize the metabolomic profile of the aqueous humor in glaucoma patients. The findings showed that glutathione levels were significantly reduced in glaucoma patients and correlated with visual field defects. The study demonstrates the potential of aqueous humor profiling in diagnosing glaucoma and suggests that oxidative stress may be involved in its pathogenesis.
Article
Urology & Nephrology
Kazuaki Ikejiri, Takafumi Suzuki, Satsuki Muto, Hirotaka Takama, Kengo Yamawaki, Tatsuya Miyazawa, Itaru Urakawa, Yuichi Aoki, Akihito Otsuki, Fumiki Katsuoka, Kengo Kinoshita, Masaomi Nangaku, Tadao Akizawa, Masayuki Yamamoto
Summary: This study investigated the impact of the regulatory single nucleotide polymorphism, rs6721961, on the effects of bardoxolone methyl in patients with chronic kidney disease. The results showed that the efficacy and safety of bardoxolone methyl were unaffected by the rs6721961 polymorphism, indicating its positive impact on renal function in patients with various forms of CKD.
CLINICAL AND EXPERIMENTAL NEPHROLOGY
(2023)
