研究者基本情報

• https://researchmap.jp/igarashiagingbiol

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=202301007218702409

• 202301007218702409

研究活動情報

• Effects of lifetime supplementation with ubiquinol 10 on the lifespan and progression of aging in female C57BL/6 mice.
  Yuichi Igarashi; Sakiko Hamada; Jin Dai; Masayuki Mori; Hiroki Miyahara; Jinko Sawashita; Keiichi Higuchi
  Experimental gerontology, 211, 112924, 112924, 2025年11月, ［国際誌］
  英語, 研究論文（学術雑誌）, Supplementation with ubiquinol 10 has been shown to improve the health of experimental animals and elderly individuals. The present study investigated the effects of lifetime supplementation with ubiquinol 10 on the progression of aging and lifespan in C57BL/6 mice, a standard strain for biomedical and aging research. A diet containing ubiquinol 10 (0.3 % w/w) and a control diet were fed to female C57BL/6J mice from 8 weeks of age until death, and the progression of senescence, lifespan, and physiological and pathological findings were examined. Body weights increased until 72 weeks of age and then decreased gradually in both groups. Food intake was significantly higher in the ubiquinol 10 group until 56 weeks of age. The median, 10th decile (10 % survivors), and maximum lifespans and survival curves did not significantly differ between the ubiquinol 10 and control groups. The grading score of senescence improved only at the age of 48 weeks in ubiquinol 10 group. No significant differences were observed in major physiological markers, such as the glucose tolerance test, serum triglycerides, and cholesterol concentrations. The expression levels of genes regulating aging in the liver markedly decreased with age in both groups. Organ weights did not significantly differ, except for significantly lighter brown adipose tissue in the ubiquinol 10 group. Senile AApoAII amyloidosis was noted in old mice; however, the degree of amyloid deposition was similar in the two groups. The degree of senescence only improved in middle-aged mice (48 weeks of age), and no apparent anti-aging or lifespan-extending effects were observed with lifetime supplementation with ubiquinol 10 in female C57BL/6J mice, which are standard laboratory mice considered to exhibit normal aging processes.
• Role of IL-34 in Tumors and Its Application to Regulate Inflammation.
  Yuichi Igarashi; Ken-Ichiro Seino
  Cancer science, 116, 5, 1164, 1170, 2025年05月, ［国際誌］
  英語, 研究論文（学術雑誌）, Interleukin (IL)-34 is a relatively recently discovered cytokine which binds to colony-stimulating factor-1 receptor (CSF-1R). So far, there has been no clear explanation as to why CSF-1R requires two ligands. While CSF-1 is ubiquitously expressed, the expression of IL-34 is relatively restricted. However, it has been revealed that IL-34 expression increases in various diseases and is associated with their pathology. Naturally, both IL-34 and CSF-1 stimulate CSF-1R, thereby contributing to the differentiation of monocytes into macrophages. In many cases, the induced macrophages significantly influence the disease pathology. In particular, we have demonstrated that IL-34 expression in cancer is deeply involved in tumor progression and therapeutic resistance. We have shown that the blockade of IL-34 significantly improved therapeutic efficacy such as chemotherapy, radiotherapy, and immune checkpoint blockade against IL-34-expressing cancers. Recently, since macrophages induced by IL-34 exhibit immunosuppressive properties, whereas IL-34 can enhance inflammation, there is growing interest in actively regulating inflammation utilizing IL-34. In this review article, we provide an overview of the characteristics and roles of IL-34 and discuss how it could be applied to future diagnostics and therapeutics.
• Amelioration of liver fibrosis with autologous macrophages induced by IL-34-based condition.
  Yuichi Igarashi; Haruka Wada; Masato Muto; Ryohei Sone; Yoshinori Hasegawa; Ken-Ichiro Seino
  Inflammation and regeneration, 45, 1, 2, 2, 2025年01月24日, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: For the treatment of liver fibrosis, several novel cell therapies have been proposed. Autologous macrophage therapy has been reported as one of the promising treatments. So far, most studies have used colony-stimulating factor 1 (CSF-1) to induce the differentiation of macrophage progenitor cells. The receptor for CSF-1, CSF-1R possesses another ligand, interleukin 34. However, the therapeutic capacity for liver fibrosis by interleukin 34-induced macrophages has not been evaluated. METHODS: We have employed acute (bile duct ligation) and chronic (administration of carbon tetrachloride or thioacetamide) liver fibrosis models. Using these models, we evaluated the therapeutic capacity of macrophages induced by interleukin 34-based conditions. In most experiments, interleukin 4 was also added to the differentiation process to induce alternative-activated macrophages. As a mechanism analysis, we have examined liver inflammation and damage, the status of stellate cells, and the immunosuppressive capacity of the macrophages. Human macrophages were differentiated from CD14+ monocytes and analyzed. RESULTS: In both acute and chronic liver damage experiments, interleukin 34-induced macrophages significantly ameliorated liver fibrosis. The addition of interleukin 4 to the differentiation process resulted in an increase of obtained macrophages and a bias to alternative activated macrophages (so-called M2). The alternative activated macrophages (M2-type) showed a reproducible therapeutic effect of liver fibrosis with a suppression of parameters of liver inflammation and damage, stellate cells, and T cell activation. Similar macrophages could be differentiated from human CD14+ monocytes in the presence of interleukin 34 plus interleukin 4, and a therapeutic effect was observed using a humanized mouse model. CONCLUSIONS: Interleukin 34-induced macrophages, particularly when additionally stimulated with interleukin 4, significantly ameliorated the liver fibrosis.
• Polygenic control of the wavy coat of the NCT mouse: involvement of an intracisternal A particle insertional mutation of the protease, serine 53 (Prss53) gene, and a modifier gene.
  Masayuki Mori; Chang Liu; Takahiro Yoshizawa; Hiroki Miyahara; Jian Dai; Yuichi Igarashi; Xiaoran Cui; Ying Li; Xiaojing Kang; Keiichi Higuchi
  Mammalian genome : official journal of the International Mammalian Genome Society, 33, 3, 451, 464, 2022年09月, ［国際誌］
  英語, 研究論文（学術雑誌）, The Nakano cataract mouse (NCT) manifests a wavy coat for their first hair as a genetic trait. In this study, we explored the molecular genetic basis of the wavy coat. We revealed by crossing experiments that the wavy coat is controlled by a major gene on chromosome 7 of NCT, homozygosity of which is a prerequisite for developing the wavy coat, and by a gene on chromosome 9 with a minor effect to reinforce the manifestation of the trait. In humans, a polymorphism of the protease, serine 53 (PRSS53) gene on the homologous chromosome is known to be associated with curly scalp hair. We then investigated the Prss53 gene and discovered that NCT has an insertion of an intracisternal A particle element in the first intron of the gene. Nevertheless, the expression of the Prss53 is not altered in the NCT skin both in transcript and protein levels. Subsequently, we created C57BL/6J-Prss53em1 knockout mice and found that these mice manifest vague wavy coats. A portion of backcross and intercross mice between the C57BL/6J-Prss53em1 and NCT manifested intense or vague wavy coats. These findings demonstrate the polygenic nature of the wavy coat of NCT and Prss53 knockout mice and highlight the similarity of the trait to the curly hair of humans associated with the PRSS53 alteration.
• Exercise suppresses mouse systemic AApoAII amyloidosis through enhancement of the p38 MAPK signaling pathway.
  Xiaoran Cui; Jinko Sawashita; Jian Dai; Chang Liu; Yuichi Igarashi; Masayuki Mori; Hiroki Miyahara; Keiichi Higuchi
  Disease models & mechanisms, 15, 3, 2022年03月01日, ［国際誌］
  英語, 研究論文（学術雑誌）, Exercise interventions are beneficial for reducing the risk of age-related diseases, including amyloidosis, but the underlying molecular links remain unclear. Here, we investigated the protective role of interval exercise training in a mouse model of age-related systemic apolipoprotein A-II amyloidosis (AApoAII) and identified potential mechanisms. Mice subjected to 16 weeks of exercise showed improved whole-body physiologic functions and exhibited substantial inhibition of amyloidosis, particularly in the liver and spleen. Exercise activated the hepatic p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and the downstream transcription factor tumor suppressor p53. This activation resulted in elevated expression and phosphorylation of heat shock protein beta-1 (HSPB1), a chaperone that defends against protein aggregation. In amyloidosis-induced mice, the hepatic p38 MAPK-related adaptive responses were additively enhanced by exercise. We observed that with exercise, greater amounts of phosphorylated HSPB1 accumulated at amyloid deposition areas, which we suspect inhibits amyloid fibril formation. Collectively, our findings demonstrate the exercise-activated specific chaperone prevention of amyloidosis, and suggest that exercise may amplify intracellular stress-related protective adaptation pathways against age-associated disorders, such as amyloidosis.
• Glavonoid-rich oil supplementation reduces stearoyl-coenzyme A desaturase 1 expression and improves systemic metabolism in diabetic, obese KK-Ay mice.
  Yuichi Igarashi; Shiho Iida; Jian Dai; Jia Huo; Xiaoran Cui; Jinko Sawashita; Masayuki Mori; Hiroki Miyahara; Keiichi Higuchi
  Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 140, 111714, 111714, 2021年08月, ［国際誌］
  英語, 研究論文（学術雑誌）, AIMS: Glavonoid-rich oil (GRO) derived from ethanol extraction of licorice (Glycyrrhiza glabra Linne) root has been reported to have beneficial effects on health. In this study, we aimed to determine the effect of long-term administration of GRO on metabolic disorders and to elucidate the molecular mechanism. MAIN METHODS: Female obese, type 2 diabetic KK-Ay mice were fed diets supplemented with 0.3% or 0.8% GRO (w/w) for 4-12 weeks. Mice were euthanized and autopsied at 20 weeks old. The effects of GRO on lipid and glucose metabolism were evaluated by measuring physiological and biochemical markers using mRNA sequencing, quantitative reverse-transcription PCR, and western blot analyses. KEY FINDINGS: Compared to mice fed the control diet, GRO-supplemented mice had reduced body and white adipose tissue weights, serum levels of triglycerides and cholesterol, and improved glucose tolerance, while food intake was not affected. We found remarkable reductions in the gene expression levels of stearoyl-coenzyme A desaturase 1 (Scd1) and pyruvate dehydrogenase kinase isoenzyme 4 (Pdk4) in the liver, in addition to decreased expression of fatty acid synthase (Fasn) in inguinal white adipose tissue (iWAT). These results suggest that GRO supplementation improves lipid profiles via reduced de novo lipogenesis in the liver and white adipose tissue. Glucose metabolism may also be improved by increased glycolysis in the liver. SIGNIFICANCE: Our analysis of long-term supplementation of GRO in obese and diabetic mice should provide novel insight into preventing insulin resistance and metabolic syndromes.
• Curcumin promotes AApoAII amyloidosis and peroxisome proliferation in mice by activating the PPARα signaling pathway.
  Jian Dai; Ying Li; Fuyuki Kametani; Xiaoran Cui; Yuichi Igarashi; Jia Huo; Hiroki Miyahara; Masayuki Mori; Keiichi Higuchi
  eLife, 10, 2021年01月26日, ［国際誌］
  英語, 研究論文（学術雑誌）, Curcumin is a polyphenol compound that exhibits multiple physiological activities. To elucidate the mechanisms by which curcumin affects systemic amyloidosis, we investigated amyloid deposition and molecular changes in a mouse model of amyloid apolipoprotein A-II (AApoAII) amyloidosis, in which mice were fed a curcumin-supplemented diet. Curcumin supplementation for 12 weeks significantly increased AApoAII amyloid deposition relative to controls, especially in the liver and spleen. Liver weights and plasma ApoA-II and high-density lipoprotein concentrations were significantly elevated in curcumin-supplemented groups. RNA-sequence analysis revealed that curcumin intake affected hepatic lipid metabolism via the peroxisome proliferator-activated receptor (PPAR) pathway, especially PPARα activation, resulting in increased Apoa2 mRNA expression. The increase in liver weights was due to activation of PPARα and peroxisome proliferation. Taken together, these results demonstrate that curcumin is a PPARα activator and may affect expression levels of proteins involved in amyloid deposition to influence amyloidosis and metabolism in a complex manner.
• Suppression of Mouse AApoAII Amyloidosis Progression by Daily Supplementation with Oxidative Stress Inhibitors.
  Jian Dai; Xin Ding; Hiroki Miyahara; Zhe Xu; Xiaoran Cui; Yuichi Igarashi; Jinko Sawashita; Masayuki Mori; Keiichi Higuchi
  Oxidative medicine and cellular longevity, 2019, 1263274, 1263274, 2019年, ［国際誌］
  英語, 研究論文（学術雑誌）, Amyloidosis is a group of diseases characterized by protein misfolding and aggregation to form amyloid fibrils and subsequent deposition within various tissues. Previous studies have indicated that amyloidosis is often associated with oxidative stress. However, it is not clear whether oxidative stress is involved in the progression of amyloidosis. We administered the oxidative stress inhibitors tempol and apocynin via drinking water to the R1.P1-Apoa2c mouse strain induced to develop mouse apolipoprotein A-II (AApoAII) amyloidosis and found that treatment with oxidative stress inhibitors led to reduction in AApoAII amyloidosis progression compared to an untreated group after 12 weeks, especially in the skin, stomach, and liver. There was no effect on ApoA-II plasma levels or expression of Apoa2 mRNA. Detection of the lipid peroxidation markers 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) revealed that the antioxidative effects of the treatments were most obvious in the skin, stomach, and liver, which contained higher levels of basal oxidative stress. Moreover, the unfolded protein response was reduced in the liver and was associated with a decrease in oxidative stress and amyloid deposition. These results suggest that antioxidants can suppress the progression of AApoAII amyloid deposition in the improved microenvironment of tissues and that the effect may be related to the levels of oxidative stress in local tissues. This finding provides insights for antioxidative stress treatment strategies for amyloidosis.