Language：English   Publishing type：Research paper (scientific journal)  

Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor-neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague-Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

DOI： 10.1038/s41598-022-09094-z

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Language：English   Publishing type：Research paper (scientific journal)  

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture. Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE - / - mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS). Results: The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate. Conclusion: Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.

DOI： 10.3389/fcvm.2022.904215

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Publishing type：Research paper (scientific journal)   Publisher：Association for Research in Vision and Ophthalmology (ARVO)  

DOI： 10.1167/iovs.62.9.8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G&gt;A, p.Gly591Ser) in <italic>COL4A6</italic>, encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the <italic>COL4A6</italic> mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated <italic>Col4a6</italic> knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner’s membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of <italic>Col4a6</italic> KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of <italic>Col4a6</italic> KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of <italic>Col4a6</italic> gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the <italic>COL4A6</italic> missense mutation c.1771G&gt;A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in <italic>COL4A6</italic> are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.

DOI： 10.1371/journal.pone.0249909

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Language：English   Publishing type：Research paper (scientific journal)  

Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44-/-) mice. The incidence of TAD in CD44-/- mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44-/- mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44-/- mice (all p < 0.01). In vitro transmigration of neutrophils from CD44-/- mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia.

DOI： 10.1038/s41598-020-63824-9

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Language：Japanese   Publisher：日本結合組織学会  

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Language：Japanese   Publisher：日本結合組織学会  

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Event date： 2023.10.27 - 2023.10.28

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Event date： 2022.6.25 - 2022.6.26

Language：Japanese  

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Event date： 2022.6.25 - 2022.6.26

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2020.9

Language：Japanese  

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Event date： 2019.5.31 - 2019.6.1

Presentation type：Poster presentation  

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