Yasutaka Iizuka's research while affiliated with Daiichi Sankyo and other places

Tranexamic acid exerts various effects on living bodies; however, its effects on asthenopia remain unknown. In this study, an asthenopia-like model was developed and used to investigate the effects of tranexamic acid on asthenopia. Mice were placed in special cages constructed for the test, and continuous irradiation with blue light was applied for 20 days. The tranexamic acid-treated group was orally administered tranexamic acid daily during the test period. Motor activity was measured for 10 days after irradiation, and reactive oxygen species (ROS), plasmin, and transforming growth factor (TGF)-β levels in the ciliary muscle of the mice were measured on the last day. Blue light irradiation induced asthenopia and increased ROS, plasmin, and TGF-β levels. In contrast, tranexamic acid administration improved asthenopia and significantly decreased plasmin and TGF-β levels compared to blue light irradiation alone; however, ROS levels remained unchanged. The study results indicate that blue light irradiation induces asthenopia by activating the ROS/plasmin/TGF-β pathways and that tranexamic acid improves asthenopia by suppressing plasmin production.

Background: Lactic acid bacteria consumption serves several health benefits to humans. However, their effect on natural skin aging is still unclear. Methods: This study examined the effects of skin naturalization (particularly skin drying) by administering a spore-bearing lactic acid bacteria (Bacillus coagulans) in mice for 2 years. Results: B. coagulans administration improved the natural skin of mice and significantly increased proportions of the genera Bacteroides and Muribaculum, among other intestinal bacteria. As metabolites, increases in nicotinic acid, putrescin, and pantothenic acid levels and a decrease in choline levels were observed. Increased hyaluronic acid, interleukin-10, and M2 macrophage levels indicate aging-related molecules in the skin. Intestinal permeability was also suppressed. Thus, these changes together improved natural skin aging. Conclusions: This study revealed that B. coagulans administration improved the natural skin aging in mice. This enhancement might be induced by the interaction of alterations in intestinal flora, metabolites, or inflammatory substances.

Lactic acid bacteria exhibit antitumor effects in mouse models of cancer. However, the effects of lactic acid bacteria on cancer remain unknown. This study investigated its effect in a mouse model of chronic inflammation-associated colon cancer induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). Administration of Bacillus coagulans ameliorated AOM+DSS-induced colon cancer in mice. B. coagulans increased the expression of transforming growth factor (TGF)-β, mothers against decapentaplegic homolog (Smad) 2/3, and p21, a cyclin-dependent kinase inhibitor (CDKI); and decreased that of the c-myelocytomatosis oncogene product (c-Myc). Furthermore, reductions in phosphatidylinositol-3 kinase (PI3K), phospho-protein kinase B (pAKT), and mechanistic target of rapamycin (mTOR) levels were observed after B. coagulans administration. Additionally, increased I kappa B (IκB) and decreased interleukin (IL)-6 and interferon (IFN)-γ levels were detected. The ameliorating effect of B. coagulans on colon cancer may be induced by the combined actions of TGF-β/Smad2/3/p21・C-Myc, PI3K/AKT/mTOR, and IκB/IL-6・IFN-γ.

Purpose: Although the onset mechanism of Alzheimer's disease, which co-occurs with aging, has been extensively studied, no effective methods that improve the decline in memory and learning abilities following aging have been developed. Tranexamic acid provided promising results for ameliorating photo-aging and extending the natural lifespan. However, it is unknown whether it affects the decline in memory and learning abilities due to aging. In this study, we examined the effect of tranexamic acid on memory and learning abilities of naturally aging mice. Methods: ICR mice were orally administered with tranexamic acid (12 mg/kg/day) three times weekly for 2 years, and their memory and learning abilities were compared between the tranexamic acid-treated and non-treated groups. Results: The decline in memory and learning abilities due to aging was ameliorated by tranexamic acid administration. The expression of plasmin and amyloid-β decreased following the treatment with tranexamic acid. Furthermore, the number of M1-type brain macrophages diminished and that of M2 macrophages increased. In addition, administration of tranexamic acid decreased the concentrations of interleukin (IL)-1β and tumor necrosis factor-α, while it increased the levels of IL-10 and transforming growth factor-α in the brain. Conclusion: These results indicated that tranexamic acid suppressed the secretion of the inflammatory cytokines aging M1-type macrophages, thereby improving age-related memory and learning abilities.

An effective method to protect the skin from natural aging is unknown. Therefore, in this study, we examined the ameliorative effects of tranexamic acid on natural skin aging. In addition, we examined the sex difference in the effect exhibited by tranexamic acid. We bred hairless mice without ultraviolet ray irradiation and physical stress for 2 years. During the study period, mice were orally administered tranexamic acid (12 mg/kg/day) three times per week. Development of signs of skin aging was found to be ameliorated by tranexamic acid. Furthermore, synthetic inhibition of plasmin was observed following tranexamic acid treatment. The synthetic reinforcement of hyaluronic acid by an increase in the number of epidermal cells and the degradative inhibition of extracellular matrix (ECM) by matrix metalloproteinase (MMP) suppression were observed. These results indicate that natural skin aging was ameliorated by tranexamic acid via the regulation of the plasmin/TGF-β/epidermal cells/hyaluronic acid and plasmin/MMPs/ECM signal transmission pathways. Taken together, sex difference was observed for the ameliorative effect of tranexamic acid on skin aging, with a stronger effect observed in females than in males. More importantly, we found that the synthesis of hyaluronic acid was stronger in female mice than in male mice.

An effective method to improve lifespan is not known. Therefore, in this study, we examined the lifespan-extending effect of tranexamic acid in normal mice. We bred hairless mice without exposure to ultraviolet radiation and psychical stress until they died naturally. During the study period, the mice were orally administered tranexamic acid (12 mg/kg/day) three times weekly. An increase in the lifespan of mice was observed by tranexamic acid administration. Furthermore, age-related diseases of the skin were ameliorated by tranexamic acid administration. Moreover, the blood level of tumor necrosis factor-α, interleukin-6, reactive oxygen species (ROS), and matrix metalloproteinase (MMP)-9 was decreased by tranexamic acid administration. These results indicate that tranexamic acid suppresses the secretion of inflammatory cytokines, MMP-9, and ROS induced by natural aging, ameliorating age-related diseases, and, consequently, extending the lifespan.

To date, there have been no treatments developed to ameliorate non‐melanoma skin cancer induced by long‐term exposure to ultraviolet A (UVA) irradiation. In this study, we examined the effects of tranexamic acid (trans‐4‐aminomethyl cyclohexanecarboxylic acid) on long‐term UVA‐induced skin cancer. We exposed the dorsal skin of male hairless mice to UVA at a dose of 110 kJ/m² using an FL20SBLB‐A lamp three times weekly for 15 weeks after application of 7,12‐dimethylbenz [a] anthracene (DMBA). During the experimental period, the mice were administered tranexamic acid (750 mg/kg/day) three times weekly. We found that cancer development was ameliorated by administration of tranexamic acid. Furthermore, tranexamic acid treatment was observed to suppress increases in the plasma levels of matrix metalloproteinase‐9 and interleukin (IL)‐6, and skin expression of plasmin, C‐C chemokine2, macrophages, signal transducer and activator of transcription (STAT)3, cyclin D, and vascular endothelial growth factor (VEGF)‐A that occurred in mice subjected to long‐term UVA irradiation. These results indicated that the non‐melanoma skin cancer induced by DMBA+UVA long‐term irradiation is ameliorated by tranexamic acid through regulation of the plasmin/macrophage/IL‐6/STAT3/cyclin D signal transmission pathway. In addition, this ameliorative effect against skin cancer may be mediated via inhibition of the IL‐6‐induced expression of VEGF‐A. This article is protected by copyright. All rights reserved.

Photoaging can be induced by long-term ultraviolet (UV)A eye irradiation, but an ameliorating method for such photoaging is not known. In this study, we examined the effects of tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) on photoaging of the skin induced by UVA eye irradiation. We used the C57BL/6 j female mice and locally exposed their eyes to UVA at a dose of 110 kJ/m2 using an FL20SBLB-A lamp multiple times a week for one year. The plasma urocortin 2, β-endorphin, methionine enkephalin (OGF), and histamine content, as well as the expression of the corticotropin-releasing hormone receptor (CRHR) type 2, μ-opioid receptor, opioid growth factor receptor (OGFR), T-bet, and GATA3 increased in the mice subjected to UVA eye irradiation. However, the increased levels of urocortin 2, methionine enkephalin, histamine, OGFR, T-bet, and GATA3 were suppressed by tranexamic acid treatment. Conversely, the levels of β-endorphin and μ-opioid receptor increased with tranexamic acid treatment. In addition, the expression of the estrogen receptor-β on the surface of mast cells was increased by tranexamic acid. These results indicate that photoaging induced by UVA eye irradiation can be ameliorated by tranexamic acid through the regulation of hypothalamo-pituitary hormones. Furthermore, this ameliorative effect on photoaging may be due to an increase in estrogen receptor-β after tranexamic acid treatment.

Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) exerts an amelioration effect on wrinkle formation due to skin dryness. We examined the sex differences in this effect. We administered tranexamic acid (750mg/kg/day) orally for 20 consecutive days to male and female Naruto Research Institute Otsuka Atrichia (NOA) mice, which naturally develop skin dryness. In the treated female mice, the amelioration effect on the wrinkle score, deterioration of transepidermal water loss (TEWL), capacitance, and decrease in the expression of collagen type I was stronger than in the male treated mice. Furthermore, the level of β-endorphin in the plasma and the expression of β-endorphin, μ-opioid receptor, and macrophages in the dorsal skin increased after the administration of tranexamic acid, and this increase was higher in female mice than in males. In addition, the macrophage production was increased by the administration of tranexamic acid in the ovary but did not change after administration in the testes. A histological examination revealed that these macrophages produce the β-endorphin, clarifying the source of the elevated levels. The amelioration effect in the female treated mice was decreased by the administration of clophosome (a macrophage inhibitor) to a degree that did not markedly differ from the effect observed in the male treated mice. These results suggest that the amelioration effect on wrinkles is stronger in female NOA mice than in males and that β-endorphin produced by macrophages plays an important role in this sex difference.