Browsing by Author "Yamamoto, Masayuki"

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    CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners
    (Elsevier, 2021-11-06) Liu, Zhiyuan; Wang, Huihui; Hou, Yongyong; Yang, Yang; Jia, Jingkun; Wu, Jinzhi; Zuo, Zhuo; Gao, Tianchang; Ren, Suping; Bian, Yiying; Liu, Shengnan; Fu, Jingqi; Sun, Yongxin; Li, Jiliang; Yamamoto, Masayuki; Zhang, Qiang; Xu, Yuanyuan; Pi, Jingbo; Biology, School of Science
    Fine-tuning of osteoclast differentiation (OD) and bone remodeling is crucial for bone homeostasis. Dissecting the mechanisms regulating osteoclastogenesis is fundamental to understanding the pathogenesis of various bone disorders including osteoporosis and arthritis. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), which belongs to the CNC-bZIP family of transcription factors, orchestrates a variety of physiological processes and stress responses. While Nfe2l1 gene may be transcribed into multiple alternatively spliced isoforms, the biological function of the different isoforms of NFE2L1 in bone metabolism, osteoclastogenesis in particular, has not been reported. Here we demonstrate that knockout of all isoforms of Nfe2l1 transcripts specifically in the myeloid lineage in mice [Nfe2l1(M)-KO] results in increased activity of osteoclasts, decreased bone mass and worsening of osteoporosis induced by ovariectomy and aging. In comparison, LysM-Cre-mediated Nfe2l1 deletion has no significant effect on the osteoblast and osteocytes. Mechanistic investigations using bone marrow cells and RAW 264.7 cells revealed that deficiency of Nfe2l1 leads to accelerated and elevated OD, which is attributed, at least in part, to enhanced accumulation of ROS in the early stage of OD and expression of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1α (Nfatc1/α). In addition, NFE2L1 regulates the transcription of multiple antioxidant genes and Nfatc1/α and OD in an isoform-specific manner. While long isoforms of NFE2L1 function as accelerators of induction of Nfatc1/α and antioxidant genes and OD, the short isoform NFE2L1-453 serves as a brake that keeps the long isoforms’ accelerator effects in check. These findings provide a novel insight into the regulatory roles of NFE2L1 in osteoclastogenesis and highlight that NFE2L1 is essential in regulating bone remodeling and thus may be a valuable therapeutic target for bone disorders.
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    Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases
    (Elsevier, 2025) Cuadrado, Antonio; Cazalla, Eduardo; Bach, Anders; Bathish, Boushra; Naidu, Sharadha Dayalan; DeNicola, Gina M.; Dinkova-Kostova, Albena T.; Fernández-Ginés, Raquel; Grochot-Przeczek, Anna; Hayes, John D.; Kensler, Thomas W.; León, Rafael; Liby, Karen T.; López, Manuela G.; Manda, Gina; Shivakumar, Akshatha Kalavathi; Hakomäki, Henriikka; Moerland, Jessica A.; Motohashi, Hozumi; Rojo, Ana I.; Sykiotis, Gerasimos P.; Taguchi, Keiko; Valverde, Ángela M.; Yamamoto, Masayuki; Levonen, Anna-Liisa; Medicine, School of Medicine
    Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.
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    Whole genome sequence‐based association of cognitive decline and retinal thickness in the Japanese population
    (Wiley, 2025-01-09) Taira, Makiko; Fuse, Nobuo; Saykin, Andrew J.; Nagami, Fuji; Kinoshita, Kengo; Yamamoto, Masayuki; Radiology and Imaging Sciences, School of Medicine
    Background: Dementia is age‐related with a significant genetic contribution, yet genome‐wide association studies have not fully accounted for heritability. This discrepancy may in part be due to reliance on SNPs and small indels. Whole‐genome sequencing (WGS) data in the Japanese population may reveal population‐specific susceptibility loci for dementia. Retinal imaging with optical coherence tomography (OCT) is noninvasive, reproducible, and can detect thinning associated with progressive neurodegeneration. Association of population‐specific genetic susceptibility loci with retinal thinning and cognitive decline may reveal novel aspects of dementia risk and pathophysiology. Method: Among participants with WGS data from the Tohoku Medical Megabank Organization (ToMMo) Ophthalmology Study ("ToMMo Eye Study"), individuals with adequate quality data on retinal nerve fiber layer and ganglion cell layer thickness from spectral‐domain optical coherence tomography (SD‐OCT) scans were selected. Since retinal thinning also occurs in glaucoma, we performed a GWAS using age, sex, and 10 principal components as covariates using SAGE1.2 to obtain a set of genes responsible for glaucoma and confirm that the genotyping was successful. We then attempted to identify susceptibility loci for cognitive decline by using (1) the Mini‐Mental State Examination, Japanese version (MMSE‐J), (2) the Montreal Cognitive Assessment, Japanese version (MoCA‐J), and (3) the Mini‐COG© (a simple screening for early detection of dementia, Japanese version) scores as associated factors, respectively. Furthermore, these validation results were also compared with those obtained from GWAS using imputation data performed on custom arrays (Japonica ArrayTM, v2 or NEO) for Japanese. Result: 84 significant (p < 5.0E‐8) genome‐wide susceptibility loci (hg38) of RNFL were detected on 14K WGS‐based study (the top hit locus: Chr14, SIX6 gene, P=4.50E‐46). There were many genetic loci that have already been reported to be associated with glaucoma susceptibility, including the above locus. Among the results of GWAS for cognitive decline combining the three cognitive scores after normalization to z‐scores, several loci have shown significant susceptibility in both of RNFL and cognitive rating scale. Some loci suggested more than a high or moderate effect of altering protein efficacy. Conclusion: We present an initial WGS‐based genetic study of retinal thickness and cognitive decline in the Japanese population.