191 results on '"Sassa, T."'
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2. Photorefractivity and photocurrent dynamics of triphenylamine-based polymer composites.
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Tsutsumi N, Sassa T, Van Nguyen T, Tsujimura S, Ha GN, Mizuno Y, Jackin BJ, Kinashi K, and Sakai W
- Abstract
The photorefractive properties of triphenylamine polymer-based composites with various composition ratios were investigated via optical diffraction, response time, asymmetric energy transfer, and transient photocurrent. The composite consisted of a photoconductive polymer of poly((4-diphenylamino)benzyl acrylate), a photoconductive plasticizer of (4-diphenylamino)phenyl)methanol, a sensitizer of [6,6]-phenyl-C61-butyric acid methyl ester, and a nonlinear optical dye of (4-(azepan-1-yl)-benzylidene)malononitrile. The photorefractive properties and related quantities were dependent on the composition, which was related to the glass transition temperature of the photorefractive polymers. The quantum efficiency (QE) of photocarrier generation was evaluated from the initial slope of the transient photocurrent. Transient photocurrents were measured and showed two unique peaks: one in the range of 10
-4 to 10-3 s and the other in the range of 10-1 to 1 s. The transient photocurrents was well simulated (or reproduced) by the expanded two-trapping site model with two kinds of photocarrier generation and recombination processes and two different trapping sites. The obtained photorefractive quantity of trap density was significantly related to the photoconductive parameters of QE., (© 2024. The Author(s).)- Published
- 2024
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3. Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.
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Hagihara H, Shoji H, Hattori S, Sala G, Takamiya Y, Tanaka M, Ihara M, Shibutani M, Hatada I, Hori K, Hoshino M, Nakao A, Mori Y, Okabe S, Matsushita M, Urbach A, Katayama Y, Matsumoto A, Nakayama KI, Katori S, Sato T, Iwasato T, Nakamura H, Goshima Y, Raveau M, Tatsukawa T, Yamakawa K, Takahashi N, Kasai H, Inazawa J, Nobuhisa I, Kagawa T, Taga T, Darwish M, Nishizono H, Takao K, Sapkota K, Nakazawa K, Takagi T, Fujisawa H, Sugimura Y, Yamanishi K, Rajagopal L, Hannah ND, Meltzer HY, Yamamoto T, Wakatsuki S, Araki T, Tabuchi K, Numakawa T, Kunugi H, Huang FL, Hayata-Takano A, Hashimoto H, Tamada K, Takumi T, Kasahara T, Kato T, Graef IA, Crabtree GR, Asaoka N, Hatakama H, Kaneko S, Kohno T, Hattori M, Hoshiba Y, Miyake R, Obi-Nagata K, Hayashi-Takagi A, Becker LJ, Yalcin I, Hagino Y, Kotajima-Murakami H, Moriya Y, Ikeda K, Kim H, Kaang BK, Otabi H, Yoshida Y, Toyoda A, Komiyama NH, Grant SGN, Ida-Eto M, Narita M, Matsumoto KI, Okuda-Ashitaka E, Ohmori I, Shimada T, Yamagata K, Ageta H, Tsuchida K, Inokuchi K, Sassa T, Kihara A, Fukasawa M, Usuda N, Katano T, Tanaka T, Yoshihara Y, Igarashi M, Hayashi T, Ishikawa K, Yamamoto S, Nishimura N, Nakada K, Hirotsune S, Egawa K, Higashisaka K, Tsutsumi Y, Nishihara S, Sugo N, Yagi T, Ueno N, Yamamoto T, Kubo Y, Ohashi R, Shiina N, Shimizu K, Higo-Yamamoto S, Oishi K, Mori H, Furuse T, Tamura M, Shirakawa H, Sato DX, Inoue YU, Inoue T, Komine Y, Yamamori T, Sakimura K, and Miyakawa T
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- Animals, Mice, Humans, Brain metabolism, Disease Models, Animal, Lactates metabolism, Hydrogen-Ion Concentration, Endophenotypes, Cognitive Dysfunction metabolism
- Abstract
Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature., Competing Interests: HH, HS, SH, GS, YT, MT, MI, MS, IH, KH, MH, AN, YM, SO, MM, AU, YK, AM, KN, SK, TS, TI, HN, YG, MR, TT, KY, NT, HK, JI, IN, TK, TT, MD, HN, KT, KS, KN, TT, HF, YS, KY, LR, NH, HM, TY, SW, TA, KT, TN, HK, FH, AH, HH, KT, TT, TK, TK, IG, GC, NA, HH, SK, TK, MH, YH, RM, KO, AH, LB, IY, YH, HK, YM, KI, HK, BK, HO, YY, AT, NK, SG, MI, MN, KM, EO, IO, TS, KY, HA, KT, KI, TS, AK, MF, NU, TK, TT, YY, MI, TH, KI, KN, SH, KE, KH, YT, SN, NS, TY, NU, TY, YK, RO, NS, KS, SH, KO, HM, TF, MT, HS, DS, YI, TI, YK, TY, KS, TM No competing interests declared, SY, NN Employee of Takeda Pharmaceutical Company, Ltd
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- 2024
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4. Endogenous chondroitin extends the lifespan and healthspan in C. elegans.
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Shibata Y, Tanaka Y, Sasakura H, Morioka Y, Sassa T, Fujii S, Mitsuzumi K, Ikeno M, Kubota Y, Kimura K, Toyoda H, Takeuchi K, and Nishiwaki K
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- Animals, Chondroitin metabolism, Longevity genetics, Glycosaminoglycans metabolism, Metalloendopeptidases metabolism, Disintegrins metabolism, Caenorhabditis elegans genetics, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Caenorhabditis elegans Proteins metabolism
- Abstract
Chondroitin, a class of glycosaminoglycan polysaccharides, is found as proteoglycans in the extracellular matrix, plays a crucial role in tissue morphogenesis during development and axonal regeneration. Ingestion of chondroitin prolongs the lifespan of C. elegans. However, the roles of endogenous chondroitin in regulating lifespan and healthspan mostly remain to be investigated. Here, we demonstrate that a gain-of-function mutation in MIG-22, the chondroitin polymerizing factor (ChPF), results in elevated chondroitin levels and a significant extension of both the lifespan and healthspan in C. elegans. Importantly, the remarkable longevity observed in mig-22(gf) mutants is dependent on SQV-5/chondroitin synthase (ChSy), highlighting the pivotal role of chondroitin in controlling both lifespan and healthspan. Additionally, the mig-22(gf) mutation effectively suppresses the reduced healthspan associated with the loss of MIG-17/ADAMTS metalloprotease, a crucial for factor in basement membrane (BM) remodeling. Our findings suggest that chondroitin functions in the control of healthspan downstream of MIG-17, while regulating lifespan through a pathway independent of MIG-17., (© 2024. The Author(s).)
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- 2024
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5. Impact of left atrium plication on chronic heart failure with atrial functional mitral regurgitation.
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Nakamae K, Oshitomi T, Uesugi H, Ideta I, Takaji K, Sassa T, Murata H, and Hirota M
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Purpose: We hypothesized that a giant left atrium may oppress the posterior left ventricle and aggravate diastolic dysfunction and heart failure. We evaluated the effect of left atrial plication (LAP) on atrial functional mitral regurgitation., Methods: We retrospectively reviewed patients who underwent LAP for atrial functional mitral regurgitation at our institution between January 2017 and December 2021. Early outcomes, follow-up echocardiography data, and heart failure indicators were compared., Results: Eighteen patients were divided into two groups: LAP + (n = 9) or LAP- (n = 9). There were no significant differences in patient characteristics and preoperative echocardiographic parameters, except for the preoperative New York Heart Association classification. Operative (505.7 [standard deviation: 100.0] minutes vs. 382.9 [standard deviation: 58.1] minutes, P = .0055) and cardiopulmonary bypass times (335.6 [standard deviation: 50.4] minutes vs. 246.9 [standard deviation: 62.7] minutes, P = .0044) were significantly longer in the LAP + group. No in-hospital mortalities were observed in both groups. The postoperative left atrial volume was significantly reduced in the LAP + group, and mitral regurgitation was controlled at less than mild levels in both groups. At follow-up, the left ventricular end-diastolic volume was reduced significantly in the LAP + group. Brain natriuretic peptide, cardiothoracic ratio, and the New York Heart Association classification were improved in the LAP + group., Conclusions: Additional left atrial plication contributes to the control of atrial functional mitral regurgitation and heart failure at a later stage. A careful long-term follow-up is needed as re-expansion of the left atrium is possible., Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-023-01569-6., Competing Interests: Competing interestsThe authors have no competing interests to declare that are relevant to the content of this article., (© Indian Association of Cardiovascular-Thoracic Surgeons 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
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- 2024
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6. Comparison of skin barrier abnormalities and epidermal ceramide profiles among three ω-O-acylceramide synthesis-deficient mouse strains.
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Yamamoto Y, Sassa T, and Kihara A
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- Animals, Humans, Mice, Epidermis, Mice, Knockout, Tolonium Chloride, Water, Ceramides, Skin
- Abstract
Background: The epidermis contains many structurally diverse ceramides, which form the skin permeability barrier (skin barrier). Mutations in genes involved in the synthesis of ω-O-acylceramides (acylceramides) and protein-bound ceramides cause ichthyosis., Objective: We aimed to elucidate the relationship between the degree of skin barrier impairment and changes in epidermal ceramide profiles caused by mutations in acylceramide synthesis genes., Methods: Knockout (KO) mice of three genes-fatty acid (FA) ω-hydroxylase Cyp4f39 (human CYP4F22 ortholog), FA elongase Elovl1, and acyl-CoA synthetase Fatp4-were subjected to transepidermal water loss measurement, toluidine blue staining, and epidermal ceramide profiling via liquid chromatography coupled with tandem mass spectrometry., Results: Transepidermal water loss was highest in Cyp4f39 KO mice, followed by Elovl1 KO and Fatp4 KO mice, and Cyp4f39 KO mice also showed the strongest degree of toluidine blue staining. In Cyp4f39 KO, Elovl1 KO, and Fatp4 KO mice, acylceramide levels were 0.6%, 1.6%, and 12%, respectively, of those in wild-type mice. Protein-bound ceramide levels were 0.2%, 30%, and 33%, respectively, of those in wild-type mice. We also observed a near-complete absence of ω-hydroxy ceramides in Cyp4f39 KO mice, reduced total ceramide levels and shortened FA moieties in Elovl1 KO mice, and increased hydroxylated ceramide levels and slightly shortened FA moieties in Fatp4 KO mice., Conclusions: The degree of reduction in protein-bound ceramide levels is probably related to the severity of skin barrier defects in these three strains. However, reduced acylceramide levels and other changes in ceramide composition unique to each KO strain are also involved., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
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- 2024
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7. Long-term outcomes of left ventricular posterior wall plication for ischemic mitral regurgitation.
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Nakamae K, Oshitomi T, Uesugi H, Ideta I, Takaji K, Sassa T, Murata H, and Hirota M
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Purpose: To evaluate the early and long-term outcomes of left ventricular posterior wall plication for ischemic mitral regurgitation., Methods: Patients with ischemic mitral regurgitation who underwent left ventricular posterior wall plication via right-sided left atriotomy at our institution between 2010 and 2020 were retrospectively reviewed. Cases with normal cardiac function, left ventricular end-systolic diameter < 50 mm, and left ventriculotomy approach were excluded., Results: The mean follow-up period was 5.3 years [standard deviation (SD) = 3.5], with a maximum of 10 years. Among the 21 patients enrolled, 9 had New York Heart Association (NYHA) class ≥ III. Three patients required preoperative inotrope support, while two preoperative ventilator support. The mean left ventricular ejection fraction was 31.4% (SD: 8.6), and 16 patients had mitral regurgitation grade ≥ III. All patients underwent coronary artery bypass grafting and mitral annuloplasty. Concomitant surgeries included 11 chordae cutting and 3 tricuspid annuloplasties. One in-hospital death occurred due to sepsis. At the follow-up, echocardiographic data showed significant improvement in cardiac dilation and function and good control of mitral regurgitation. The serum brain natriuretic peptide level was significantly reduced, and 85% of patients improved to NYHA class I. Four deaths occurred later due to sudden, unknown causes. The 5- and 8-year survival rates were 60.2% and 46.8%, respectively, and the 5- and 8-year hospitalization rates due to heart failure were 14.9% and 21.3%, respectively., Conclusion: The long-term outcomes of left ventricular posterior wall plication were satisfactory for controlling heart failure and improving survival rate and patient prognosis., Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-023-01527-2., Competing Interests: Competing interestsThe authors have no competing interests to declare that are relevant to the content of this article., (© Indian Association of Cardiovascular-Thoracic Surgeons 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
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- 2023
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8. LMNA Mutations and Right Heart Failure in Patients With Cardiomyopathy and With Left Ventricular Assist Devices.
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Yamada T, Nomura S, Amiya E, Katoh M, Inoue S, Hatsuse S, Fujita K, Ito M, Fujita T, Bujo C, Tsuji M, Ishida J, Ko T, Yamada S, Katagiri M, Sassa T, Kinoshita O, Nawata K, Tobita T, Satoh M, Ishiwata J, Daimon M, Tatsuno K, Fukuda S, Kashimura T, Minamino T, Hatano M, Ono M, Aburatani H, and Komuro I
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- Humans, Mutation, Lamin Type A genetics, Heart Failure diagnosis, Heart Failure genetics, Heart Failure therapy, Heart-Assist Devices, Cardiomyopathies
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Competing Interests: Disclosure All authors have nothing to disclose.
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- 2023
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9. Involvement of ω-O-acylceramides and protein-bound ceramides in oral permeability barrier formation.
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Sassa T and Kihara A
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- Humans, Mice, Animals, Epidermal Cells, Permeability, Gingiva, Ceramides, Epidermis
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The permeability barrier present in the oral cavity is critical for protection from infection. Although lipids have properties suitable for permeability barrier formation, little is known about their role in oral barrier formation. Here, we show the presence of ω-O-acylceramides (acylceramides) and protein-bound ceramides, which are essential for the formation of permeability barriers in the epidermis, in the oral mucosae (buccal and tongue mucosae), esophagus, and stomach in mice. Conditional knockout of the fatty acid elongase Elovl1, which is involved in the synthesis of ≥C24 ceramides including acylceramides and protein-bound ceramides, in the oral mucosae and esophagus causes increased pigment penetration into the mucosal epithelium of the tongue and enhanced aversive responses to capsaicin-containing water. We find acylceramides in the buccal and gingival mucosae and protein-bound ceramides in the gingival mucosa in humans. These results indicate that acylceramides and protein-bound ceramides are important for oral permeability barrier formation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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10. TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.
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Yamada S, Ko T, Ito M, Sassa T, Nomura S, Okuma H, Sato M, Imasaki T, Kikkawa S, Zhang B, Yamada T, Seki Y, Fujita K, Katoh M, Kubota M, Hatsuse S, Katagiri M, Hayashi H, Hamano M, Takeda N, Morita H, Takada S, Toyoda M, Uchiyama M, Ikeuchi M, Toyooka K, Umezawa A, Yamanishi Y, Nitta R, Aburatani H, and Komuro I
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- Humans, Lamin Type A genetics, Myocytes, Cardiac metabolism, Mutation, TEA Domain Transcription Factors, Cardiomyopathy, Dilated metabolism
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Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R -LMNA- related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA -related DCM.
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- 2023
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11. Incomplete Elongation of Ultra-long-chain Polyunsaturated Acyl-CoAs by the Fatty Acid Elongase ELOVL4 in Spinocerebellar Ataxia Type 34.
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Tamura Y, Sassa T, Nishizawa T, and Kihara A
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Spinocerebellar ataxias (SCAs) are autosomal dominant diseases characterized by cerebellar atrophy and ataxia. The SCA subtype SCA34 is caused by specific mutations in the gene ELOVL4 , which encodes a fatty acid (FA) elongase that synthesizes ultra-long-chain (ULC; ≥C26) FAs. However, the pathogenesis and molecular mechanism that confers dominant inheritance remains unknown. Here, a cell-based assay demonstrated that each of the five known SCA34 mutants produced shorter ULC polyunsaturated FA-containing phosphatidylcholines (ULC-PCs) than wild-type protein, in the following order of severity: Q180P and T233M > W246G > I171T and L168F. Next, we generated knock-in mouse embryonic stem cells that contained heterozygous Q180P, heterozygous W246G, or homozygous W246G mutations. Neuronal differentiation-dependent production of ULC-PCs was reduced in heterozygous Q180P and homozygous W246G cells relative to control cells, and we observed shortening of the FA moiety in all mutant cells. This FA shortening was consistent with our prediction that amino acid residues substituted by SCA34 mutations are located in the transmembrane helices that interact with the ω-end region of the FA moiety of the substrate acyl-CoA. Hence, reduced levels and shortening of ULC-PCs in neurons may cause SCA34, and incomplete elongation of ULC polyunsaturated acyl-CoAs by mutated ELOVL4 may induce dominant inheritance.
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- 2023
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12. Noncommunicating acute type A aortic dissection in elderly patients: Surgery versus medical management.
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Nakamae K, Oshitomi T, Uesugi H, Ideta I, Takaji K, Sassa T, Murata H, and Hirota M
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- Humans, Aged, Retrospective Studies, Aorta, Acute Disease, Treatment Outcome, Aortic Aneurysm, Thoracic surgery, Aortic Dissection surgery, Thrombosis
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Objectives: Our goal was to evaluate the surgical and conservative outcomes of acute type A aortic dissection with a thrombosed false lumen of the ascending aorta in elderly patients., Methods: Patients older than 75 years with acute type A aortic dissection admitted to our hospital from October 2011 to December 2020 were reviewed retrospectively, including those with the noncommunicating type without malperfusion and low physical capacity prehospitalization., Results: Sixty-six patients were enrolled consecutively in the medical (M, n = 30) and surgical (S, n = 36) groups. The ascending aorta was the most replaced section in the S group (78%). Groups did not differ significantly in hospital deaths and in intensive care unit and hospital stays. Two patients (7%) underwent surgery and 3 (10%) underwent redissection in the M group. No significant difference existed between the groups in the decline of physical performance during hospitalization. Seven patients in the M group (24%) had aorta-related events in the late period as opposed to none in the S group (P=0.003). Survival rates after 4 years were 78.3% and 71.4% in the S and M groups, respectively (P=0.154). The cumulative incidence of overall reintervention due to an aortic event was significantly higher in the M group; however, the 2 groups did not differ significantly in overall aorta-related deaths., Conclusions: Surgical outcomes of noncommunicating acute type A aortic dissection in elderly patients were favorable. There was no significant difference in maintaining physical function at discharge, and the medical group had a significantly higher overall aortic event rate than the surgical group., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)
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- 2022
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13. Spatiotemporal transcriptome analysis reveals critical roles for mechano-sensing genes at the border zone in remodeling after myocardial infarction.
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Yamada S, Ko T, Hatsuse S, Nomura S, Zhang B, Dai Z, Inoue S, Kubota M, Sawami K, Yamada T, Sassa T, Katagiri M, Fujita K, Katoh M, Ito M, Harada M, Toko H, Takeda N, Morita H, Aburatani H, and Komuro I
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The underlying mechanisms of ventricular remodeling after myocardial infarction (MI) remain largely unknown. In this study, we performed an integrative analysis of spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a murine MI model and found that mechanical stress-response genes are expressed at the border zone and play a critical role in left ventricular remodeling after MI. An integrative analysis of snRNA-seq and spatial transcriptome of the heart tissue after MI identified the unique cluster that appeared at the border zone in an early stage, highly expressing mechano-sensing genes, such as Csrp3. AAV9-mediated gene silencing and overexpression of Csrp3 demonstrated that upregulation of Csrp3 plays critical roles in preventing cardiac remodeling after MI by regulation of genes associated with mechano-sensing. Overall, our study not only provides an insight into spatiotemporal molecular changes after MI but also highlights that the mechano-sensing genes at the border zone act as adaptive regulators of left ventricular remodeling., (© 2022. The Author(s).)
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- 2022
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14. Ceramide profiling of stratum corneum in Sjögren-Larsson syndrome.
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Arai A, Takeichi T, Wakamoto H, Sassa T, Ito Y, Murase Y, Ogi T, Akiyama M, and Kihara A
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- Ceramides analysis, Epidermis pathology, Fatty Acids, Female, Humans, Ichthyosis genetics, Ichthyosis pathology, Ichthyosis, Lamellar pathology, Sjogren-Larsson Syndrome genetics, Sjogren-Larsson Syndrome pathology
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Background: Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation., Objectives: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS., Methods: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry., Results: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes., Conclusion: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
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- 2022
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15. Transfemoral Transcatheter Aortic Valve Implantation by Three-Dimensional Computed Tomography/Fluoroscopy Fusion Imaging Guidance in a Patient With Right-Sided Aortic Arch and Chronic Aortic Dissection.
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Konami Y, Sakamoto T, Horio E, Suzuyama H, Taguchi E, Sassa T, Ideta I, Yamada M, Horibata Y, and Nakao K
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- Aorta, Thoracic surgery, Aortic Valve diagnostic imaging, Aortic Valve surgery, Fluoroscopy, Humans, Tomography, X-Ray Computed, Treatment Outcome, Aortic Dissection diagnostic imaging, Aortic Dissection etiology, Aortic Dissection surgery, Aortic Valve Stenosis diagnostic imaging, Aortic Valve Stenosis etiology, Aortic Valve Stenosis surgery, Heart Valve Prosthesis, Transcatheter Aortic Valve Replacement adverse effects, Transcatheter Aortic Valve Replacement methods
- Abstract
Transcatheter aortic valve implantation (TAVI) represents the standard of care for relieving aortic stenosis in high-risk patients for surgery. The transfemoral approach is preferable with respect to invasiveness, but is often difficult in patients with complex vascular structures. Recently, the clinical application of advanced visualization and guidance technology with three-dimensional computed tomography (3D-CT) during TAVI has received considerable attention. Herein we report successful transfemoral TAVI in a patient with a right-sided aortic arch and chronic aortic dissection without vascular complications by 3D-CT/fluoroscopy fusion imaging guidance., Competing Interests: Declaration of competing interest Dr. Sakamoto is a clinical proctor for Edwards Lifesciences. The other authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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16. Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis.
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Ko T, Nomura S, Yamada S, Fujita K, Fujita T, Satoh M, Oka C, Katoh M, Ito M, Katagiri M, Sassa T, Zhang B, Hatsuse S, Yamada T, Harada M, Toko H, Amiya E, Hatano M, Kinoshita O, Nawata K, Abe H, Ushiku T, Ono M, Ikeuchi M, Morita H, Aburatani H, and Komuro I
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- Fibroblasts metabolism, Fibrosis, Humans, Insulin-Like Growth Factor Binding Proteins metabolism, Myocardium metabolism, Myocytes, Cardiac metabolism, Serine Endopeptidases genetics, Serine Endopeptidases metabolism, Heart Failure metabolism, Transforming Growth Factor beta metabolism
- Abstract
Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure., (© 2022. The Author(s).)
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- 2022
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17. Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1.
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Takahashi T, Mercan S, Sassa T, Akçapınar GB, Yararbaş K, Süsgün S, İşeri SAU, Kihara A, and Akçakaya NH
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- Humans, Ceramides metabolism, Chromatography, Liquid, Exons, Fatty Acid Elongases, Fatty Acids, Muscle Spasticity genetics, Mutation genetics, Pedigree, Tandem Mass Spectrometry, Cerebral Palsy genetics, Dyskinesias genetics, Ichthyosis genetics
- Abstract
Introduction: Next generation sequencing technologies allow detection of very rare pathogenic gene variants and uncover cerebral palsy. Herein, we describe two siblings with cerebral palsy due to ELOVL1 splice site mutation in autosomal recessive manner. ELOVL1 catalyzes fatty acid elongation to produce very long-chain fatty acids (VLCFAs; ≥C21), most of which are components of sphingolipids such as ceramides and sphingomyelins. Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (MIM: 618527) stem from ELOVL1 gene deficiency in human., Methods: We have studied a consanguineous family with whole exome sequencing (WES) and performed in depth analysis of cryptic splicing on the molecular level using RNA. Comprehensive analysis of ceramides in the skin stratum corneum of patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS). ELOVL1 protein structure was computationally modelled., Results: The novel c.376-2A > G (ENST00000372458.8) homozygous variant in the affected siblings causes exon skipping. Comprehensive analysis of ceramides in the skin stratum corneum of patients using LC-MS/MS demonstrated significant shortening of fatty acid moieties and severe reduction in the levels of acylceramides., Discussion: It has recently been shown that disease associated variants of ELOVL1 segregate in an autosomal dominant manner. However, our study for the first time demonstrates an alternative autosomal recessive inheritance model for ELOVL1. In conclusion, we suggest that in ultra-rare diseases, being able to identify the inheritance patterns of the disease-associated gene or genes can be an important guide to identifying the molecular mechanism of genetic cerebral palsy., Competing Interests: Conflict of Interest The authors declare no competing interests., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
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- 2022
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18. Surgical repair for systolic anterior motion of anterior mitral leaflet due to mitral annular calcification.
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Nakamae K, Oshitomi T, Sassa T, and Uesugi H
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- Aged, Female, Humans, Mitral Valve diagnostic imaging, Mitral Valve surgery, Systole, Calcinosis complications, Calcinosis diagnostic imaging, Calcinosis surgery, Heart Valve Diseases complications, Mitral Valve Insufficiency diagnostic imaging, Mitral Valve Insufficiency etiology, Mitral Valve Insufficiency surgery
- Abstract
Systolic anterior motion of the anterior mitral leaflet with anterior displacement of the coaptation site of the bi-leaflets due to mitral annular calcification on the posterior side, causing left ventricular outflow tract obstruction, is rare. We report the case of a 72-year-old woman with exertional dyspnea due to systolic anterior motion who underwent surgical repair to decalcify the mitral annular calcification and mitral valve repair. Hence, the systolic anterior motion, mitral valve regurgitation, and symptoms improved significantly. This report illustrates the novelty of surgical technique, the indication, and the limitation of mitral valve repair for such rare cases. A proper understanding of the mechanism in each patient and enhanced techniques for decalcification of posterior mitral annular calcification are needed to treat such complex cases., (© 2021. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)
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- 2022
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19. Comparison of left ventricular pacing performance among pre-shaped guidewires designed for transfemoral-approach transcatheter aortic valve implantation.
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Tamura Y, Tamura Y, Konami Y, Suzuyama H, Horio E, Yamada M, Sassa T, Taguchi E, Horibata Y, Ideta I, Kawamura A, and Sakamoto T
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- Aged, 80 and over, Aortic Valve diagnostic imaging, Aortic Valve surgery, Heart Ventricles diagnostic imaging, Humans, Male, Retrospective Studies, Treatment Outcome, Aortic Valve Stenosis diagnosis, Aortic Valve Stenosis surgery, Transcatheter Aortic Valve Replacement adverse effects
- Abstract
TAVI is an established therapy for patients with severe aortic stenosis. Rapid or control pacing is necessary for TAVI, and most centers are familiar with right ventricular (RV) pacing. Although there are several reports on the efficacy and safety of LV pacing, they are still few. In addition, LV pacing has not been studied for different LV guidewires. Our aim is to study the effectiveness of left ventricular (LV) pacing and the thresholds of LV guidewires in patients who underwent transcatheter aortic valve implantation (TAVI). We retrospectively analyzed 252 consecutive patients who underwent trans-femoral TAVI (TF-TAVI) with LV pacing in our institute between December 2017 and November 2020. We excluded 48 patients from the total cohort due to TAVI with RV pacing, and the remaining 204 patients were analyzed (52 males, mean age 85 ± 5 years). Among them, 202 patients (99.0%) had successful LV pacing. In the two patients with failed LV pacing, SAFARI2™ Small was used. The CONFIDA™ group (n = 34) showed a significantly lower threshold than the SAFARI2™ group (n = 163) (median 3.0 vs. 5.0 V; P = 1.1 × 10
-7 ). LV pacing with Lunderquist® was successful in all patients (n = 7). LV pacing in TAVI was an effective and safe strategy. CONFIDA™ wire may be particularly well suited for LV pacing in TAVI., (© 2021. Springer Japan KK, part of Springer Nature.)- Published
- 2022
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20. Protein-bound ceramide levels in the epidermis of transglutaminase 1-deficient mice.
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Sassa T, Imai Y, Kihara A, and Yamanishi K
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- Animals, Epidermal Cells, Mice, Transglutaminases, Ceramides, Epidermis
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- 2021
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21. Erratum: Diverse meibum lipids produced by Awat1 and Awat2 are important for stabilizing tear film and protecting the ocular surface.
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Sawai M, Watanabe K, Tanaka K, Kinoshita W, Otsuka K, Miyamoto M, Sassa T, and Kihara A
- Abstract
[This corrects the article DOI: 10.1016/j.isci.2021.102478.]., (© 2021 The Author(s).)
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- 2021
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22. Impaired Skin Barrier Function Due to Reduced ω- O -Acylceramide Levels in a Mouse Model of Sjögren-Larsson Syndrome.
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Nojiri K, Fudetani S, Arai A, Kitamura T, Sassa T, and Kihara A
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- Aldehyde Dehydrogenase genetics, Aldehyde Oxidoreductases genetics, Aldehyde Oxidoreductases metabolism, Aldehydes metabolism, Animals, Cell Differentiation, Ceramides metabolism, Ceramides physiology, Disease Models, Animal, Epidermis metabolism, Epidermis physiopathology, Fatty Acids genetics, Fatty Acids metabolism, Female, Keratinocytes metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Sjogren-Larsson Syndrome physiopathology, Aldehyde Dehydrogenase metabolism, Sjogren-Larsson Syndrome metabolism, Skin metabolism
- Abstract
Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of ω- O -acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (ω-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2 . Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism.
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- 2021
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23. Current Awareness and Status of Venous Ultrasonography in Kumamoto Prefecture - A Report of the Kumamoto Cardiovascular Echocardiography Standardization Project.
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Usuku H, Yamamoto E, Oike F, Yoshinouchi T, Imamura K, Yoshida K, Kanesaki D, Toma Y, Tomita A, Ogata Y, Matsumoto S, Iwayama Y, Sassa T, Tanaka S, Fukuyoshi Y, Matsumoto T, Tanaka E, Misumi I, Shono H, Nishigami K, Tsujita K, and Matsui H
- Abstract
Background: There are few reports on the current awareness and status of venous ultrasonography, including the number of specialists who perform this procedure, in a specific regional area in Japan. Methods and Results: This cross-sectional survey study was conducted in Kumamoto Prefecture from October 2018 to March 2019. Of the 366 medical institutions providing cardiology services in Kumamoto Prefecture, 259 (101 general hospitals, 158 small clinics) responded to our questionnaire. In 2017, 21,773 venous ultrasound tests were performed, 21,101 (97%) of which were performed in hospitals and only 672 (3%) were performed in clinics. Both the number of institutions performing venous ultrasounds and the number of tests performed increased over time. Although 317 medical staff in Kumamoto Prefecture were performing transthoracic echocardiography (TTE) when the questionnaires were collected, only 210 performed venous ultrasounds. Although 91% (61/67) of medical institutions could perform TTE within 30 min, only 77% (53/69) performed venous ultrasounds within 30 min. The number of venous ultrasounds per population×100 was largest in the Kumamoto and Kamimashiki areas (1.67) and smallest in the Kamoto area (0.05). Conclusions: This is the first report to reveal the current awareness and status of venous ultrasonography in a specific region in Japan. There are several problems to be overcome, such as a lack of venous ultrasound specialists and the regional disparity in venous ultrasounds in Kumamoto Prefecture., Competing Interests: K.T. is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to declare., (Copyright © 2021, THE JAPANESE CIRCULATION SOCIETY.)
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- 2021
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24. Diverse meibum lipids produced by Awat1 and Awat2 are important for stabilizing tear film and protecting the ocular surface.
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Sawai M, Watanabe K, Tanaka K, Kinoshita W, Otsuka K, Miyamoto M, Sassa T, and Kihara A
- Abstract
A lipid layer consisting of meibum lipids exists in the tear film and functions in preventing dry eye disease. Although the meibum lipids include diverse lipid classes, the synthesis pathway and role of each class remain largely unknown. Here, we created single and double knockout (KO and DKO, respectively) mice for the two acyl-CoA wax alcohol acyltransferases ( Awat1 and Awat2 ) and investigated their dry eye phenotypes and meibum lipid composition. Awat2 KO and DKO mice exhibited severe dry eye with meibomian gland dysfunction, whereas Awat1 KO mice had mild dry eye. In these mice, specific meibum lipid classes were reduced: ( O -acyl)-ω-hydroxy fatty acids and type 1ω wax diesters in Awat1 KO mice, wax monoesters and types 1ω and 2ω wax diesters in Awat2 KO mice, and most of these in DKO mice. Our findings reveal that Awat1 and Awat2 show characteristic substrate specificity and together produce diverse meibum lipids., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
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- 2021
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25. Comprehensive stratum corneum ceramide profiling reveals reduced acylceramides in ichthyosis patient with CERS3 mutations.
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Yamamoto M, Sassa T, Kyono Y, Uemura H, Kugo M, Hayashi H, Imai Y, Yamanishi K, and Kihara A
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- Ceramides, Epidermis, Humans, Mutation, Ichthyosis, Ichthyosis, Lamellar genetics
- Abstract
The stratum corneum (SC) of the epidermis acts as a skin permeability barrier, and abnormalities in SC formation lead to several skin disorders. Lipids, especially the epidermis-specific ceramide classes ω-O-acylceramides (acylceramides) and protein-bound ceramides, are essential for skin barrier formation. Ceramide synthase 3 (CERS3) is involved in the synthesis of acylceramides and protein-bound ceramides, and CERS3 mutations cause autosomal recessive congenital ichthyosis. In the present study, we measured ceramide synthase activity and performed comprehensive SC ceramide profiling in an ichthyosis patient with compound heterozygous CERS3 mutations: nonsense mutation p.Arg75* and missense mutation p.Arg229His. The activity of p.Arg75* and p.Arg229His mutant CERS3 proteins was reduced to 4% and 56%, respectively, of the wild-type protein. In the patient's SC, acylceramide levels were greatly reduced, but the levels of protein-bound ceramides remained almost unchanged. Non-acylated ceramide levels were also affected in the patient; in particular, the levels of ceramides composed of sphingosine and non-hydroxy or α-hydroxy fatty acid were substantially higher than in healthy controls. These results suggest that a reduction in acylceramide levels alone leads to ichthyosis. Although protein-bound ceramides are synthesized from acylceramides, levels of acylceramides and protein-bound ceramides are not necessarily correlated., (© 2020 Japanese Dermatological Association.)
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- 2021
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26. Improvement of Evaporative Dry Eye With Meibomian Gland Dysfunction in Model Mice by Treatment With Ophthalmic Solution Containing Mineral Oil.
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Watanabe K, Yoshida M, Okumura T, Sassa T, Kihara A, and Uchiyama A
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- Animals, Meibomian Glands, Mice, Mineral Oil, Ophthalmic Solutions, Dry Eye Syndromes drug therapy, Meibomian Gland Dysfunction
- Abstract
Purpose: Meibomian gland dysfunction (MGD) is a major cause of evaporative dry eye. The purpose of this study is to assess the efficacy of a mineral oil-containing ophthalmic solution (MO) in mitigating the evaporative dry eye phenotypes in a mouse model in which fatty acid elongase Elovl1 is disrupted., Methods: Elovl1-deficient mice were assessed in terms of number of plugged meibomian gland orifices, tear film breakup time (BUT), corneal fluorescein staining (CFS) score, tear quantity, and histology. The effects of the MO on the dry eye phenotypes were compared with those in groups not treated or treated with blank ophthalmic solution (BL)., Results: Untreated Elovl1-deficient mice exhibited dry eye phenotypes with MGD symptoms such as plugging of meibomian gland orifices (P = 0.002 compared with control mice), high CFS scores (P = 0.002), and shortened BUT (P < 0.001). Among three groups of Elovl1-deficient mice (MO treated, BL treated, and untreated), the MO-treated group exhibited fewer plugged orifices (MO treated, 7.6; BL treated, 10.5 [P = 0.033]; untreated, 13.0 [P < 0.001]), lower CFS scores (MO treated, 1.1; BL treated, 2.7 [P = 0.013]; untreated, 2.5 [P = 0.050]), and improved BUT (MO treated, 19.4 seconds; BL treated, 8.3 seconds [P = 0.098]; untreated, 1.5 seconds [P = 0.008])., Conclusions: Elovl1-deficient mice exhibited multiple MGD symptoms, which were improved by MO., Translational Relevance: Our findings reveal the usefulness of Elovl1-deficient mice as a model for dry eye with MGD and suggest the potential of mineral oil eye drops as a treatment for this condition.
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- 2021
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27. Production of branched-chain very-long-chain fatty acids by fatty acid elongases and their tissue distribution in mammals.
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Tanno H, Sassa T, Sawai M, and Kihara A
- Subjects
- Acyltransferases genetics, Acyltransferases metabolism, Aldehyde Oxidoreductases genetics, Aldehyde Oxidoreductases metabolism, Amino Acids, Branched-Chain classification, Animals, Ceramides classification, Ceramides metabolism, Cholesterol Esters classification, Cholesterol Esters metabolism, Fatty Acid Elongases genetics, Gene Expression Regulation, HEK293 Cells, Humans, Lipidomics methods, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Skin metabolism, Sterol O-Acyltransferase genetics, Sterol O-Acyltransferase metabolism, Substrate Specificity, Acyl Coenzyme A metabolism, Amino Acids, Branched-Chain metabolism, Fatty Acid Elongases metabolism, Meibomian Glands metabolism
- Abstract
Although most mammalian fatty acids (FAs) are straight-chain, there also exist branched-chain FAs such as iso- and anteiso-FAs, especially in the meibomian glands. Meibum lipids, which are secreted from the meibomian glands and are important for dry eye prevention, contain abundant branched-chain lipids, such as cholesteryl esters and wax esters with chain-lengths of ≥C21 (very-long-chain; VLC). However, the exact tissue distribution of branched-chain lipids or the enzymes involved in the production of branched-chain VLCFAs has remained poorly understood. Here, we revealed that FA elongases ELOVL1, ELOVL3, and ELOVL7, of the seven mammalian ELOVL isozymes, elongated saturated branched-chain acyl-CoAs. ELOVL3 was highly active toward iso-C17:0 and anteiso-C17:0 acyl-CoAs and elongated them up to iso-C23:0 and anteiso-C25:0 acyl-CoAs, respectively. ELOVL1 elongated both iso- and anteiso-C23:0 acyl-CoAs to C25:0 acyl-CoAs. By establishing a liquid chromatography-tandem mass spectrometry method capable of separating branched- and straight-chain lipids, we showed that essentially all of the cholesteryl esters and 88% of the wax esters in the mouse meibomian glands are branched. In Elovl1 mutant mice, the levels of ≥C24:0 branched-chain cholesteryl esters and ≥C25:0 branched-chain wax esters were decreased, indicating that ELOVL1 indeed elongates branched-chain VLC acyl-CoAs in vivo. In addition, substantial amounts of ceramides containing branched-chain FAs were present in the skin, meibomian glands, and liver. Our findings provide new insights into the molecular mechanisms that create FA and lipid diversity., (Copyright © 2020 Elsevier B.V. All rights reserved.)
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- 2021
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28. Current Awareness and Status of Transthoracic Echocardiography in Kumamoto Prefecture - A Report of the Kumamoto Cardiovascular Echocardiography Standardization Project.
- Author
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Usuku H, Yamamoto E, Oike F, Yoshinouchi T, Imamura K, Yoshida K, Kanesaki D, Toma Y, Tomita A, Ogata Y, Matsumoto S, Iwayama Y, Sassa T, Tanaka S, Fukuyoshi Y, Matsumoto T, Tanaka E, Shono H, Nishigami K, Tsujita K, and Matsui H
- Abstract
Background: There are few reports on current awareness and status of transthoracic echocardiography (TTE), including the actual performance rate according to echocardiographic guidelines, in a specific area or region. Methods and Results: This cross-sectional survey study was conducted in Kumamoto Prefecture from October 2018 to March 2019. There are 366 medical institutions advocating cardiology in Kumamoto Prefecture. Of these, 259 (101 hospitals and 158 clinics) returned questionnaires regarding TTE. In all, 150,570 TTEs were performed in 2017. Of these, 132,771 (88%) were performed in hospitals and 17,799 (12%) were performed in clinics. Physicians performed only 5% of TTEs, whereas sonographers performed 86%. Although the modified Simpson method was performed in 90% of hospitals, 3-dimensional echocardiography was performed in only 2% of hospitals. In addition, the left atrial volume index was not examined in approximately 60% of hospitals, and the mean E/E' ratio was not examined in 80% of hospitals. Multivariable logistic regression analysis revealed that having a Fellow of the Japan Society of Ultrasonic in Medicine was significantly and independently associated with guideline-oriented TTE (odds ratio 9.43; 95% confidence interval 1.22-72.71, P<0.05). Conclusions: The rate of echocardiographic measurements performed according to echocardiographic guidelines is exceptionally low in Kumamoto Prefecture. Sufficient dissemination of echocardiographic guidelines may be important in improving this rate., Competing Interests: K.T. is a member of Circulation Reports’ Editorial Team. The remaining authors have no potential conflicts of interest to disclose., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)
- Published
- 2020
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29. Lipid polarity gradient formed by ω-hydroxy lipids in tear film prevents dry eye disease.
- Author
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Miyamoto M, Sassa T, Sawai M, and Kihara A
- Subjects
- Animals, Cytochrome P450 Family 4 genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Cytochrome P450 Family 4 physiology, Dry Eye Syndromes prevention & control, Fatty Acids chemistry, Tears chemistry
- Abstract
Meibum lipids form a lipid layer on the outermost side of the tear film and function to prevent water evaporation and reduce surface tension. ( O -Acyl)-ω-hydroxy fatty acids (OAHFAs), a subclass of these lipids, are thought to be involved in connecting the lipid and aqueous layers in tears, although their actual function and synthesis pathway have to date remained unclear. Here, we reveal that the fatty acid ω-hydroxylase Cyp4f39 is involved in OAHFA production. Cyp4f39 -deficient mice exhibited damaged corneal epithelium and shortening of tear film break-up time, both indicative of dry eye disease. In addition, tears accumulated on the lower eyelid side, indicating increased tear surface tension. In Cyp4f39 -deficient mice, the production of wax diesters (type 1ω and 2ω) and cholesteryl OAHFAs was also impaired. These OAHFA derivatives show intermediate polarity among meibum lipids, suggesting that OAHFAs and their derivatives contribute to lipid polarity gradient formation for tear film stabilization., Competing Interests: MM, TS, MS, AK No competing interests declared, (© 2020, Miyamoto et al.)
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- 2020
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30. Novel biallelic FA2H mutations in a Japanese boy with fatty acid hydroxylase-associated neurodegeneration.
- Author
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Kawaguchi M, Sassa T, Kidokoro H, Nakata T, Kato K, Muramatsu H, Okuno Y, Yamamoto H, Kaname T, Kihara A, and Natsume J
- Subjects
- Brain metabolism, Child, Demyelinating Diseases diagnostic imaging, Demyelinating Diseases genetics, Demyelinating Diseases metabolism, Gait genetics, Heredodegenerative Disorders, Nervous System diagnostic imaging, Heredodegenerative Disorders, Nervous System metabolism, Heterozygote, Humans, Japan, Magnetic Resonance Imaging, Male, Mixed Function Oxygenases metabolism, Mutation, Myelin Sheath genetics, Myelin Sheath metabolism, Spastic Paraplegia, Hereditary diagnostic imaging, Spastic Paraplegia, Hereditary genetics, Spastic Paraplegia, Hereditary metabolism, Heredodegenerative Disorders, Nervous System genetics, Mixed Function Oxygenases genetics
- Abstract
FA2H encodes fatty acid 2-hydroxylase, which plays a significant role in maintaining the neuronal myelin sheath. Previous reports have revealed that a FA2H mutation leads to spastic paraplegia, leukodystrophy, and neurodegeneration with brain iron accumulation, collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN). The disease severity of FAHN varies among individual patients and may be explained by the enzyme activity of FA2H mutant proteins. Here we report a 10-year-old Japanese boy with FAHN having novel heterozygous mutations in FA2H. The patient presented with a spastic gait since the age of 5 years and was unable to walk without a cane by the time he was 8 years old. Brain MRI demonstrated a partial thinning of the corpus callosum, slight reduction of cerebellar volume, and posterior dominant periventricular leukodystrophy. Whole exome sequencing revealed two novel missense mutations in FA2H with compound heterozygous inheritance (NM_024306, p.Val149Leu, and p.His260Gln mutations). The enzyme activities of the p.Val149Leu and p.His260Gln variants were 60%-80% and almost 0%, respectively. Our cell-based enzyme assay demonstrated partial functionality for one of the variants, indicating a milder phenotype. However, considered along with previous reports, there was no definite relationship between the disease severity and residual enzyme activity measured using a similar method. Further research is needed to precisely predict the phenotypic severity of this disorder., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
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31. Severe Skin Permeability Barrier Dysfunction in Knockout Mice Deficient in a Fatty Acid ω-Hydroxylase Crucial to Acylceramide Production.
- Author
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Miyamoto M, Itoh N, Sawai M, Sassa T, and Kihara A
- Subjects
- Animals, Cytochrome P450 Family 4 genetics, Desmosomes pathology, Disease Models, Animal, Epidermal Cells cytology, Female, Humans, Ichthyosis diagnosis, Ichthyosis genetics, Male, Mice, Mice, Knockout, Permeability, Severity of Illness Index, Ceramides biosynthesis, Cytochrome P450 Family 4 metabolism, Epidermal Cells pathology, Epidermis pathology, Ichthyosis pathology
- Abstract
The skin permeability barrier is indispensable for maintaining water inside the body and preventing the invasion of pathogens and allergens; abnormalities lead to skin disorders such as atopic dermatitis and ichthyosis. Acylceramide is an essential lipid for skin barrier formation, and CYP4F22 is a fatty acid ω-hydroxylase involved in its synthesis. Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis, although the symptoms vary among mutation sites and types. Here, we generated knockout mice deficient in Cyp4f39, the mouse ortholog of human CYP4F22, to investigate the effects of completely abrogating the function of the fatty acid ω-hydroxylase involved in acylceramide production on skin barrier formation. Cyp4f39 knockout mice died within 8 hours of birth. Large increases in transepidermal water loss and penetration of a dye from outside the body were observed, indicating severe skin barrier dysfunction. Histologic analyses of the epidermis revealed impairment of lipid lamella formation, accumulation of corneodesmosomes in the stratum corneum, and persistence of periderm. In addition, lipid analyses by mass spectrometry showed almost complete loss of acylceramide and its precursor ω-hydroxy ceramide. In conclusion, our findings provide clues to the molecular mechanisms of skin barrier abnormalities and the pathogenesis of ichthyosis caused by Cyp4f39 and CYP4F22 by association., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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32. Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1 .
- Author
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Isokawa M, Sassa T, Hattori S, Miyakawa T, and Kihara A
- Abstract
Very-long-chain fatty acids, with a chain length of >C20, are abundant in myelin sphingolipids. Recently, a de novo mutation in the ELOVL1 gene, which encodes fatty acid elongase, was identified in patients with neurocutaneous disorders involving skin ichthyosis and multiple neurological abnormalities, including hypomyelination, spastic paraplegia, and high-frequency deafness. However, the consequences of ELOVL1 deficiency for lipid composition and detailed pathological changes in the brain remain unclear. Here, we analyzed Elovl1 mutant mice as a model of human ELOVL1 deficiency. The mice exhibited a decreased postnatal survival rate, and some died of startle epilepsy. The acyl chain length of sphingolipids such as galactosylceramides, sulfatides, sphingomyelins, and ceramides in the brains of these mice was markedly shortened. Moreover, the mice exhibited reduced levels of galactosylceramides, which are important for myelin formation and stability. Electron microscope analysis of the corpus callosum in Elovl1 mutant mice revealed modest hypomyelination, especially in large-diameter axons. Furthermore, behavioral testing of the mice revealed deficits such as poorer motor coordination and reduced acoustic startle response to high-intensity stimulus. These findings provide clues to the molecular mechanism of the neurological symptoms of patients with the ELOVL1 mutation., Competing Interests: The authors declare no conflicts of interest., (© 2019 The Authors.)
- Published
- 2019
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33. Combination Therapy of Fenestrated-Fontan Procedure with Medication Improved Double-outlet Right Ventricle in Adulthood.
- Author
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Sassa T, Nakayama A, Saito A, Soma K, Inuzuka R, Hirata Y, and Komuro I
- Abstract
Competing Interests: The authors have no financial conflicts of interest.
- Published
- 2019
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34. De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans , hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy.
- Author
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Mueller N, Sassa T, Morales-Gonzalez S, Schneider J, Salchow DJ, Seelow D, Knierim E, Stenzel W, Kihara A, and Schuelke M
- Subjects
- Acanthosis Nigricans diagnosis, Adolescent, Amino Acid Sequence, Biomarkers, Biopsy, Child, Preschool, Deafness diagnosis, Demyelinating Diseases diagnosis, Female, Fibroblasts metabolism, Gene Expression, Genetic Predisposition to Disease, Genotype, Humans, Ichthyosis diagnosis, Magnetic Resonance Imaging, Male, Optic Atrophy diagnosis, Paraplegia diagnosis, Pedigree, Peroxisome Proliferator-Activated Receptors metabolism, Phenotype, Exome Sequencing, Acanthosis Nigricans genetics, Deafness genetics, Demyelinating Diseases genetics, Fatty Acid Elongases genetics, Ichthyosis genetics, Mutation, Optic Atrophy genetics, Paraplegia genetics
- Abstract
Background: Very long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant ELOVL1 mutation. Independently, Kutkowska-Kaźmierczak et al. had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects., Methods: We did mutation screening by whole exome sequencing. RNA-sequencing was performed in patient and control fibroblasts. Ceramide and sphingomyelin levels were measured by LC-MS/MS. ELOVL1 activity was determined by a stable isotope-labelled [
13 C]malonyl-CoA elongation assay. ELOVL1 expression patterns were investigated by immunofluorescence, in situ hybridisation and RT-qPCR. As treatment option, we investigated VLCFA loading of fibroblasts., Results: Both patients carried an identical heterozygous de novo ELOVL1 mutation (c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele. Patients suffered from epidermal hyperproliferation and increased keratinisation (ichthyosis). Hypomyelination of the central white matter explained spastic paraplegia and central nystagmus, while optic atrophy was causative for reduction of peripheral vision and visual acuity. The mutation abrogated ELOVL1 enzymatic activity and reduced ≥C24 ceramides and sphingomyelins in patient cells. Fibroblast loading with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins. We found competitive inhibition for ceramide and sphingomyelin synthesis between saturated and monounsaturated VLCFAs. Transcriptome analysis revealed upregulation of modules involved in epidermal development and keratinisation, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis. Many regulated genes carried consensus proliferator-activated receptor (PPAR)α and PPARγ binding motifs in their 5'-regions., Conclusion: A dominant ELOVL1 mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2019
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35. Neural symptoms in a gene knockout mouse model of Sjögren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide.
- Author
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Kanetake T, Sassa T, Nojiri K, Sawai M, Hattori S, Miyakawa T, Kitamura T, and Kihara A
- Subjects
- Aldehyde Oxidoreductases genetics, Aldehyde Oxidoreductases metabolism, Animals, Anxiety metabolism, Depression metabolism, Galactosylceramides genetics, Humans, Light, Lipid Metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Sjogren-Larsson Syndrome genetics, Sjogren-Larsson Syndrome metabolism, Behavior, Animal, Galactosylceramides deficiency, Sjogren-Larsson Syndrome physiopathology
- Abstract
Insulation by myelin lipids is essential to fast action potential conductivity: changes in their quality or amount can cause several neurologic disorders. Sjögren-Larsson syndrome (SLS) is one such disorder, which is caused by mutations in the fatty aldehyde dehydrogenase ALDH3A2. To date, the molecular mechanism underlying SLS pathology has remained unknown. In this study, we found that Aldh3a2 is expressed in oligodendrocytes and neurons in the mouse brain, and neurons of Aldh3a2 knockout (KO) mice exhibited impaired metabolism of the long-chain base, a component of sphingolipids. Aldh3a2 KO mice showed several abnormalities corresponding to SLS symptoms in behavioral tests, including increased paw slips on a balance beam and light-induced anxiety. In their brain tissue, 2-hydroxygalactosylceramide, an important lipid for myelin function and maintenance, was reduced by the inactivation of fatty acid 2-hydroxylase. Our findings provide important new insights into the molecular mechanisms responsible for neural pathogenesis caused by lipid metabolism abnormalities.-Kanetake, T., Sassa, T., Nojiri, K., Sawai, M., Hattori, S., Miyakawa, T., Kitamura, T., Kihara, A. Neural symptoms in a gene knockout mouse model of Sjögren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide.
- Published
- 2019
- Full Text
- View/download PDF
36. Very long-chain tear film lipids produced by fatty acid elongase ELOVL1 prevent dry eye disease in mice.
- Author
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Sassa T, Tadaki M, Kiyonari H, and Kihara A
- Subjects
- Acetyltransferases genetics, Animals, Corneal Opacity genetics, Corneal Opacity metabolism, Corneal Opacity pathology, Dry Eye Syndromes genetics, Dry Eye Syndromes pathology, Dry Eye Syndromes prevention & control, Fatty Acid Elongases, Mice, Mice, Transgenic, Acetyltransferases metabolism, Dry Eye Syndromes metabolism, Fatty Acids, Monounsaturated metabolism, Tears metabolism
- Abstract
Lipids secreted from the meibomian gland (meibum) form the superficial layer of the tear film and prevent water evaporation from the ocular surface and infection. Here, we identified the fatty acid (FA) elongases responsible for the synthesis of very long-chain FAs (VLCFAs) that constitute the meibum lipids. Elongation of VLCFAs (ELOVL)1 is primarily responsible for the production of saturated VLCFAs, whereas ELOVL1, ELOVL3, and ELOVL4 redundantly participate in the synthesis of monounsaturated VLCFAs. Gene disruption of Elovl1 in mice shortened acyl moieties in the 2 major meibum lipids: cholesteryl esters and wax esters. These changes were associated with dry eye phenotypes, including increases in eye-blink frequency and water evaporation from the ocular surface at younger ages. Aged Elovl1 mutant mice developed corneal opacity with vascular invasion, accompanied by epidermalization of the cornea. Thus, in addition to the well-known VLC ceramides (acylceramides) in the epidermis, VLC meibum lipids are barrier-forming lipids.-Sassa, T., Tadaki, M., Kiyonari, H., Kihara, A. Very long-chain tear film lipids produced by fatty acid elongase ELOVL1 prevent dry eye disease in mice.
- Published
- 2018
- Full Text
- View/download PDF
37. Decreased Skin Barrier Lipid Acylceramide and Differentiation-Dependent Gene Expression in Ichthyosis Gene Nipal4-Knockout Mice.
- Author
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Honda Y, Kitamura T, Naganuma T, Abe T, Ohno Y, Sassa T, and Kihara A
- Subjects
- Animals, Animals, Newborn, Disease Models, Animal, Epidermis pathology, Filaggrin Proteins, Ichthyosis metabolism, Ichthyosis pathology, Mice, Mice, Knockout, Permeability, Receptors, Cell Surface metabolism, DNA genetics, Epidermis metabolism, Gene Expression Regulation, Developmental, Ichthyosis genetics, Lipid Metabolism, Receptors, Cell Surface genetics
- Abstract
NIPAL4 is one of the causative genes for autosomal recessive congenital ichthyosis. However, the role of NIPAL4 in skin barrier formation and the molecular mechanism of ichthyosis pathology caused by NIPAL4 mutations, have not yet been determined. Here, we found that Nipal4-knockout (KO) mice exhibited neonatal lethality due to skin barrier defects. Histological analyses showed several morphological abnormalities in the Nipal4-KO epidermis, including impairment of lipid multilayer structure formation, hyperkeratosis, immature keratohyalin granules, and developed heterochromatin structures. The levels of the skin barrier lipid acylceramide were decreased in Nipal4-KO mice. Expression of genes involved in skin barrier formation normally increases during keratinocyte differentiation, in which chromatin remodeling is involved. However, the induction of Krt1, Lor, Flg, Elovl1, and Dgat2 was impaired in Nipal4-KO mice. NIPAL4 is a putative Mg
2+ transporter, and Mg2+ concentration in differentiated keratinocytes of Nipal4-KO mice was indeed lower than that of wild-type mice. Our results suggest that low Mg2+ concentration causes aberration in the proper chromatin remodeling process, which in turn leads to failure of differentiation-dependent gene induction in keratinocytes. Our findings provide insights into Mg2+ -dependent regulation of gene expression and skin barrier formation during keratinocyte differentiation., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
38. Comparison between cylindrical axis-reference and articular surface-reference femoral bone cut for total knee arthroplasty.
- Author
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Niki Y, Nagai K, Sassa T, Harato K, and Suda Y
- Subjects
- Aged, Biomechanical Phenomena, Cadaver, Collateral Ligaments surgery, Humans, Male, Middle Aged, Range of Motion, Articular physiology, Arthroplasty, Replacement, Knee methods, Femur physiology, Osteoarthritis, Knee surgery, Weight-Bearing physiology
- Abstract
Purpose: Reproducing a functional flexion-extension axis (FEA) of the femur is key to achieving successful collateral ligament balance and joint line in total knee arthroplasty (TKA). This study compared the feasibility of cylindrical axis (CA)-reference bone cut and articular surface-reference bone cuts in reproducing the FEA for Japanese osteoarthritis patients., Methods: The study enrolled 122 knees from 86 patients who underwent primary TKA due to grade III or IV osteoarthritis. Data from pre-operative CT were reconstructed into three-dimensional (3D) models using 3D-planning software. Cylindrical radii of the condyles were measured, and femoral bone cut angles relative to anatomical landmarks were determined in the coronal and axial reference planes based on CA-reference and articular surface-reference methods., Results: Mean cylindrical radii for medial and lateral femoral condyles were 17.4 ± 1.6 and 17.3 ± 1.4 mm, respectively. Of the 122 knees, 46 exhibited >1 mm of difference between condyles. Fifty-three and 22 knees exhibited >2° of angular difference between CA-reference and articular surface-reference bone cuts in the coronal and axial planes. Mean angle of the CA and surgical epicondylar axis in 3D space was 4.6 ± 2.1°. As practical parameters for TKA, the angle between CA and IM rod was significantly larger than that between the distal articular surface line and IM rod in the coronal plane (p < 0.0001), indicating that CA-reference involves a smaller valgus bone cut of the distal femur than articular surface reference., Conclusions: CA-reference bone cut of the femur is preferable to articular surface-reference bone cut for reproducing FEA in Japanese OA patients, in whom more than one-third of knees exhibited asymmetry of radii between medial and lateral condyles. In clinical practice, the CA-reference bone cut represents a good technical option for kinematically aligned TKA in the Japanese population.
- Published
- 2017
- Full Text
- View/download PDF
39. Mechanically aligned total knee arthroplasty carries a risk of bony gap changes and flexion-extension axis displacement.
- Author
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Niki Y, Sassa T, Nagai K, Harato K, Kobayashi S, and Yamashita T
- Subjects
- Aged, Aged, 80 and over, Bone Malalignment diagnostic imaging, Bone Malalignment etiology, Computer Simulation, Female, Femur physiopathology, Humans, Imaging, Three-Dimensional, Knee Prosthesis, Male, Middle Aged, Osteoarthritis, Knee diagnostic imaging, Osteoarthritis, Knee physiopathology, Range of Motion, Articular, Risk, Tibia surgery, Tomography, X-Ray Computed, Arthroplasty, Replacement, Knee adverse effects, Arthroplasty, Replacement, Knee methods, Bone Malalignment physiopathology, Femur surgery, Knee Joint surgery, Osteoarthritis, Knee surgery
- Abstract
Purpose: The flexion-extension axis (FEA) of the femur is substantially changed after mechanically aligned total knee arthroplasty (TKA) due to a discrepancy in bone cut thickness between the posterior and distal femoral regions. This study assessed the bony gap changes and FEA displacement caused by this problem in osteoarthritis patients., Methods: The study enrolled 60 knees from 60 patients for whom primary TKA was planned due to medial knee osteoarthritis. All patients underwent computed tomography, and 3-dimensional (3D) bone models were reconstructed on 3D-planning software. Bone cuts of the distal femur and proximal tibia were simulated to be perpendicular to each mechanical axis. Bony gap change was computed as the difference in bone cut thickness between medial and lateral compartments. Each femoral condyle was assessed for potential FEA displacement, as the difference in bone cut thickness between posterior and distal femoral regions., Results: The mean magnitude of bony gap discrepancy necessary for mediolateral balancing was 1.6 ± 3.3 mm (range -7 to 8.2 mm) at 0° extension and -0.2 ± 2.6 mm (range -6.4 to 4.3 mm) at 90° flexion. At least 2 mm of bony gap discrepancy at 0° extension and 90° flexion was found in 40 patients (67%) and 26 patients (43%), respectively. In terms of femoral bone cut, posterior bone cut thickness was significantly larger than distal bone cut thickness in the medial compartment (p < 0.001). Bony gap discrepancy between distal and posterior regions of the femoral condyle was ≥2 mm in 28 patients (47%)., Conclusions: This study focused on two flaws of mechanically aligned TKA in OA patients. Substantial numbers of patients inevitably required >2 mm of medial collateral ligament release at 0° extension and showed a bone cut discrepancy between distal and posterior regions, carrying a risk of FEA displacement and subsequent unnatural knee motions during knee extension and flexion. Level of evidence IV.
- Published
- 2017
- Full Text
- View/download PDF
40. The 3-hydroxyacyl-CoA dehydratases HACD1 and HACD2 exhibit functional redundancy and are active in a wide range of fatty acid elongation pathways.
- Author
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Sawai M, Uchida Y, Ohno Y, Miyamoto M, Nishioka C, Itohara S, Sassa T, and Kihara A
- Subjects
- Animals, CRISPR-Cas Systems, Catalytic Domain, Cell Line, Tumor, Cells, Cultured, Fatty Acids chemistry, Gene Expression Regulation, Enzymologic, Humans, Hydro-Lyases genetics, Isoenzymes genetics, Isoenzymes metabolism, Male, Membrane Proteins genetics, Mice, Knockout, Molecular Structure, Molecular Weight, Muscle, Skeletal cytology, Muscle, Skeletal pathology, Muscular Diseases enzymology, Muscular Diseases genetics, Muscular Diseases pathology, Myoblasts, Skeletal cytology, Myoblasts, Skeletal pathology, Protein Tyrosine Phosphatases genetics, Recombinant Fusion Proteins metabolism, Substrate Specificity, Fatty Acids metabolism, Hydro-Lyases metabolism, Membrane Proteins metabolism, Muscle, Skeletal enzymology, Myoblasts, Skeletal enzymology, Protein Tyrosine Phosphatases metabolism
- Abstract
Differences among fatty acids (FAs) in chain length and number of double bonds create lipid diversity. FA elongation proceeds via a four-step reaction cycle, in which the 3-hydroxyacyl-CoA dehydratases (HACDs) HACD1-4 catalyze the third step. However, the contribution of each HACD to 3-hydroxyacyl-CoA dehydratase activity in certain tissues or in different FA elongation pathways remains unclear. HACD1 is specifically expressed in muscles and is a myopathy-causative gene. Here, we generated Hacd1 KO mice and observed that these mice had reduced body and skeletal muscle weights. In skeletal muscle, HACD1 mRNA expression was by far the highest among the HACDs However, we observed only an ∼40% reduction in HACD activity and no changes in membrane lipid composition in Hacd1 -KO skeletal muscle, suggesting that some HACD activities are redundant. Moreover, when expressed in yeast, both HACD1 and HACD2 participated in saturated and monounsaturated FA elongation pathways. Disruption of HACD2 in the haploid human cell line HAP1 significantly reduced FA elongation activities toward both saturated and unsaturated FAs, and HACD1 HACD2 double disruption resulted in a further reduction. Overexpressed HACD3 exhibited weak activity in saturated and monounsaturated FA elongation pathways, and no activity was detected for HACD4. We therefore conclude that HACD1 and HACD2 exhibit redundant activities in a wide range of FA elongation pathways, including those for saturated to polyunsaturated FAs, with HACD2 being the major 3-hydroxyacyl-CoA dehydratase. Our findings are important for furthering the understanding of the molecular mechanisms in FA elongation and diversity., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
41. Cyclization mechanism of phomopsene synthase: mass spectrometry based analysis of various site-specifically labeled terpenes.
- Author
-
Shinde SS, Minami A, Chen Z, Tokiwano T, Toyomasu T, Kato N, Sassa T, and Oikawa H
- Subjects
- Cyclization, Deuterium chemistry, Hemiterpenes chemistry, Organophosphorus Compounds chemistry, Alkyl and Aryl Transferases metabolism, Mass Spectrometry methods, Polyisoprenyl Phosphates chemical synthesis, Terpenes chemistry
- Abstract
Elucidation of the cyclization mechanism catalyzed by terpene synthases is important for the rational engineering of terpene cyclases. We developed a chemoenzymatic method for the synthesis of systematically deuterium-labeled geranylgeranyl diphosphate (GGPP), starting from site-specifically deuterium-labeled isopentenyl diphosphates (IPPs) using IPP isomerase and three prenyltransferases. We examined the cyclization mechanism of tetracyclic diterpene phomopsene with phomopsene synthase. A detailed EI-MS analysis of phomopsene labeled at various positions allowed us to propose the structures corresponding to the most intense peaks, and thus elucidate a cyclization mechanism involving double 1,2-alkyl shifts and a 1,2-hydride shift via a dolabelladien-15-yl cation. Our study demonstrated that this newly developed method is highly sensitive and provides sufficient information for a reliable assignment of the structures of fragmented ions.
- Published
- 2017
- Full Text
- View/download PDF
42. Tricuspid Valve Repair With Artificial Chorda After Previous Ventricular Septal Defect Repair.
- Author
-
Sassa T, Okamoto K, Tazume H, Noguchi R, Koga A, and Fukui T
- Subjects
- Coronary Artery Bypass, Coronary Artery Disease complications, Coronary Artery Disease surgery, Heart Septal Defects, Ventricular complications, Humans, Male, Middle Aged, Polytetrafluoroethylene, Tricuspid Valve Insufficiency diagnostic imaging, Tricuspid Valve Insufficiency etiology, Cardiac Valve Annuloplasty methods, Chordae Tendineae surgery, Heart Septal Defects, Ventricular surgery, Suture Techniques, Tricuspid Valve Insufficiency surgery
- Abstract
We evaluated a 49-year-old man with severe tricuspid valve regurgitation and coronary artery disease who had undergone congenital ventricular septal defect repair four decades previously. We found an enlarged, prolapsed commissure between the anterior and septal leaflets and a ruptured septal leaflet chorda. Two mattress sutures closed the commissure, with the leaflets' height matched by inverting the prolapsed site ventricularly. After implanting the annuloplasty band, we undertook chordal replacement using expanded polytetrafluoroethylene sutures. Artificial chorda length was determined using a small tourniquet and the saline test. Two coronary artery bypass grafts were also implanted. Postoperative echocardiography demonstrated no tricuspid regurgitation., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
43. Reconstruction of the Popliteomeniscal Fascicles for Treatment of Recurrent Subluxation of the Lateral Meniscus.
- Author
-
Suganuma J, Inoue Y, Tani H, Sugiki T, Sassa T, and Shibata R
- Abstract
Recurrent subluxation of the lateral meniscus is characterized by episodes of mechanical locking of the knee joint. To completely preclude the posterior segment of the lateral meniscus from undergoing anterior dislocation during deep knee flexion, the structures to which it is attached need to be relatively taut. The posterosuperior popliteomeniscal fascicle retains its tension during deep knee flexion; therefore, reconstruction of the posterosuperior and anteroinferior popliteomeniscal fascicles was performed with an autograft harvested from the iliotibial band. This technique provides stabilization of the posterior segment of the lateral meniscus during deep knee flexion without interfering with the normal movement of the lateral meniscus throughout the range of motion of the knee joint.
- Published
- 2017
- Full Text
- View/download PDF
44. Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery.
- Author
-
Naganuma T, Takagi S, Kanetake T, Kitamura T, Hattori S, Miyakawa T, Sassa T, and Kihara A
- Subjects
- Aldehyde Oxidoreductases genetics, Animals, Apoptosis, Blotting, Western, Cell Proliferation, Cells, Cultured, Female, Keratinocytes metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Sjogren-Larsson Syndrome etiology, Skin metabolism, Aldehyde Oxidoreductases metabolism, Aldehyde Oxidoreductases physiology, Cell Membrane Permeability, Keratinocytes cytology, Sjogren-Larsson Syndrome pathology, Skin pathology
- Abstract
The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS). To date, the molecular mechanism underlying the symptoms characterizing SLS has been poorly understood. Using Aldh3a2(-/-) mice, we found here that Aldh3a2 was the major FALDH active in undifferentiated keratinocytes. Long-chain base metabolism was greatly impaired in Aldh3a2(-/-) keratinocytes. Phenotypically, the intercellular spaces were widened in the basal layer of the Aldh3a2(-/-) epidermis due to hyperproliferation of keratinocytes. Furthermore, oxidative stress-induced genes were up-regulated in Aldh3a2(-/-) keratinocytes. Upon keratinocyte differentiation, the activity of another FALDH, Aldh3b2, surpassed that of Aldh3a2 As a result, Aldh3a2(-/-) mice were indistinguishable from wild-type mice in terms of their whole epidermis FALDH activity, and their skin barrier function was uncompromised under normal conditions. However, perturbation of the stratum corneum caused increased transepidermal water loss and delayed barrier recovery in Aldh3a2(-/-) mice. In conclusion, Aldh3a2(-/-) mice replicated some aspects of SLS symptoms, especially at the basal layer of the epidermis. Our results suggest that hyperproliferation of keratinocytes via oxidative stress responses may partly contribute to the ichthyosis symptoms of SLS., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
45. Enzyme Activities of the Ceramide Synthases CERS2-6 Are Regulated by Phosphorylation in the C-terminal Region.
- Author
-
Sassa T, Hirayama T, and Kihara A
- Subjects
- Animals, Casein Kinase II antagonists & inhibitors, Casein Kinase II genetics, Enzyme Activation drug effects, Enzyme Activation physiology, HEK293 Cells, Humans, Mice, Naphthyridines pharmacology, Phenazines, Phosphorylation drug effects, Phosphorylation physiology, Protein Structure, Tertiary, Sphingolipids genetics, Sphingosine N-Acyltransferase genetics, Substrate Specificity drug effects, Substrate Specificity physiology, Brain metabolism, Casein Kinase II metabolism, Sphingolipids biosynthesis, Sphingosine N-Acyltransferase metabolism
- Abstract
Ceramide and complex sphingolipids regulate important cellular functions including cell growth, apoptosis, and signaling. Dysregulation of sphingolipid metabolism leads to pathological consequences such as sphingolipidoses and insulin resistance. Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. In the present study, we demonstrated that CERS2-6 were phosphorylated at the cytoplasmic C-terminal regions. Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. Phosphorylation modestly increased the catalytic activities of CERS4 and -5 and mildly increased those of CERS3 and -6. Dephosphorylation of endogenous ceramide synthases in the mouse brain led to severely reduced activity toward the Cers2 substrates C22:0/C24:0-CoAs and modestly reduced activity toward the Cers5/6 substrate C16:0-CoA. These results suggest that the phosphorylation of ceramide synthases may be a key regulatory point in the control of the distribution and levels of sphingolipids of various acyl-chain lengths., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
46. Resting angina due to papillary fibroelastoma of the right coronary cusp.
- Author
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Taguchi E, Nakao K, Sassa T, Kamio T, Sakanashi M, Miyamoto S, Sakamoto T, Nishigami K, Uesugi H, and Hirayama T
- Subjects
- Chest Pain etiology, Echocardiography, Transesophageal, Heart Neoplasms surgery, Heart Valve Diseases surgery, Heart Valve Prosthesis, Humans, Male, Middle Aged, Angina, Unstable pathology, Aortic Valve surgery, Cardiomyopathies pathology, Heart Neoplasms pathology, Heart Valve Diseases pathology
- Abstract
A 63-year-old man with chest pain at rest was referred to our hospital. Transthoracic echocardiography showed a mobile ball-like mass at the top of the right coronary cusp. Subsequently, transesophageal echocardiography also showed a mobile mass at the right coronary cusp. Aortic valve replacement with a mechanical valve was performed under general anesthesia. We diagnosed this condition as papillary fibroelastoma based upon the pathological findings with hematoxylin and eosin staining, and Elastica van Gieson staining. Coronary angiography revealed no organic lesions. The operation was successful, and the patient remains asymptomatic. We speculate that the resting chest pain was induced by transient occlusion of the right coronary orifice by the tumor. We describe this rare case in detail including a review of the literature.
- Published
- 2016
- Full Text
- View/download PDF
47. Anterior mediastinal abscess diagnosed in a young sumo wrestler after closed blunt chest trauma.
- Author
-
Sassa T, Kobayashi K, Ota M, Washino T, Hikone M, Sakamoto N, Iwabuchi S, Otsuji M, and Ohnishi K
- Subjects
- Abscess diagnosis, Adolescent, Anti-Bacterial Agents therapeutic use, Combined Modality Therapy, Debridement, Diagnosis, Differential, Drainage, Humans, Magnetic Resonance Imaging, Male, Mediastinal Diseases diagnosis, Staphylococcal Infections diagnosis, Thoracic Injuries diagnosis, Tomography, X-Ray Computed, Wounds, Nonpenetrating diagnosis, Abscess microbiology, Abscess therapy, Mediastinal Diseases microbiology, Mediastinal Diseases therapy, Staphylococcal Infections microbiology, Staphylococcal Infections therapy, Thoracic Injuries microbiology, Thoracic Injuries therapy, Wounds, Nonpenetrating microbiology, Wounds, Nonpenetrating therapy, Wrestling injuries
- Abstract
Most mediastinal abscesses result from infections after thoracotomy, esophageal perforation or pene- trating chest trauma. This disease is rarely caused by closed blunt chest trauma. All previously reported such cases after closed blunt chest trauma presented with hematoma and sternal osteomyelitis resulting from sternal fracture. Here we report a 15-year-old sumo wrestler who presented with an anterior mediastinal abscess without any mediastinal fracture. The mediastinal abscess resulted from the hematogenous spread of Staphylococcus aureus to a hematoma that might have been caused by a closed blunt chest trauma incurred during sumo wrestling exercises.
- Published
- 2015
- Full Text
- View/download PDF
48. Seed dormancy breaking diterpenoids from the liverwort Plagiochila sciophila and their differentiation inducing activity in human promyelocytic leukemia HL-60 cells.
- Author
-
Kenmoku H, Tada H, Oogushi M, Esumi T, Takahashi H, Noji M, Sassa T, Toyota M, and Asakawa Y
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Diterpenes chemistry, HL-60 Cells, Humans, KB Cells, Lactuca drug effects, Models, Molecular, Molecular Structure, Polycyclic Compounds chemistry, Polycyclic Compounds pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Diterpenes pharmacology, Germination drug effects, Hepatophyta physiology, Lymphocytes drug effects, Seeds physiology
- Abstract
To obtain the structural diversity of bioactive compounds similar to cotylenins and fusicoccins that modulate 14-3-3 protein-protein interactions in eukaryotes, screening tests were carried out using the lettuce seed dormancy breaking-assay. An acetone extract of the liverwort Plagiochila sciophila exhibited significant activity against the seeds in the presence of the plant hormone abscisic acid. Activity-guided fractionation of the extract afforded the isolation of seven novel fusicoccane-type diterpenoids, named fusicosciophins A-E (1-5), 8-deacetyl (6) and 9-deacetyl fusicosciophin E (7). Their structures were determined by spectroscopic methods and X-ray crystallographic analyses. All the pure isolated compounds (1-7) exhibited moderate lettuce seed dormancy breaking activity. In addition, the differentiation-inducing activity and cytotoxicity of these isolates, together with fusicoccin A (FC-A) and all-trans retinoic acid (ATRA), were evaluated in human promyelocytic leukemia HL-60 cells and human mouth epidermal carcinoma KB cells, respectively. Fusicosciophins (2 and 4) and FC-A exhibited moderate differentiation-inducing activity (EC50 31.2-59.1 microM) compared with ATRA (EC50 0.3 microM), while 2, 4 and ATRA exhibited higher selectivity indices (IC50/EC50 >3.38-667) than FC-A (IC50/EC50 1.05). This is the first report on the isolation of fusicoccane-type diterpenoids from liverworts having seed dormancy breaking activity and differentiation-inducing activity in mammal cells.
- Published
- 2014
49. Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid.
- Author
-
Sassa T, Wakashima T, Ohno Y, and Kihara A
- Subjects
- Acetyltransferases genetics, Acetyltransferases metabolism, Dose-Response Relationship, Drug, Drug Combinations, Fatty Acid Elongases, Gene Expression Regulation, Enzymologic drug effects, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Kinetics, Oleic Acid pharmacology, Palmitic Acid pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Stearic Acids pharmacology, Acetyltransferases antagonists & inhibitors, Erucic Acids pharmacology, Fatty Acids metabolism, Sphingomyelins metabolism, Triolein pharmacology
- Abstract
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by impaired degradation of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene responsible for VLCFA transport into peroxisomes. Lorenzo's oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, has been used to reduce the saturated VLCFA level in the plasma of X-ALD patients; however, the mechanism by which this occurs remains elusive. We report the biochemical characterization of Lorenzo's oil activity toward elongation of very long-chain fatty acid (ELOVL) 1, the primary enzyme responsible for the synthesis of saturated and monounsaturated VLCFAs. Oleic and erucic acids inhibited ELOVL1, and, moreover, their 4:1 mixture (the FA composition of Lorenzo's oil) exhibited the most potent inhibitory activity. The kinetics analysis revealed that this was a mixed (not a competitive) inhibition. At the cellular level, treatment with the 4:1 mixture reduced the level of SM with a saturated VLCFA accompanied by an increased level of SM with a monounsaturated VLCFA, probably due to the incorporation of erucic acid into the FA elongation cycle. These results suggest that inhibition of ELOVL1 may be an underlying mechanism by which Lorenzo's oil exerts its action.
- Published
- 2014
- Full Text
- View/download PDF
50. Seed dormancy breaking diterpenoids, including novel brassicicenes J and K, from fungus Alternaria brassicicola, and their necrotic/apoptotic activities in HL-60 cells.
- Author
-
Kenmoku H, Takeue S, Oogushi M, Yagi Y, Sassa T, Toyota M, and Asakawa Y
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Diterpenes chemistry, Diterpenes pharmacology, Drug Screening Assays, Antitumor, HL-60 Cells, Humans, Lactuca, Alternaria chemistry, Antineoplastic Agents isolation & purification, Diterpenes isolation & purification, Plant Dormancy drug effects
- Abstract
To find new metabolites similar to cotylenins and fusicoccins from the fungus Alternaria brassicicola, screening tests were carried out using the lettuce seed dormancy breaking assay. Activity-guided fractionation of the EtOAc extract from the culture using the assay afforded the isolation of two novel fusicoccane diterpenoids named brassicicenes J (1) and K (2), along with three known brassicicenes A (3), B (4), and F (5). Their structures were elucidated from extensive NMR spectral data and by comparison of these with those reported in the literature. Brassicicenes (1-5) exhibited weak to moderate seed dormancy breaking activities against lettuce seeds in the presence of abscisic acid. In addition, the necrotic/apoptotic activities of the brassicicenes (1-5), fusicoccin A (6) and cotylenin A (7) were evaluated by determining their cytotoxicity, cell viability and caspase-3/7 activation on the HL-60 cell line. Brassicicene K (2) exhibited similar cytostatic profiles to that of cotylenin A (7), and brassicicenes J (1), A (3), B (4), and F (5) exhibited necrotic activity. This is the first report of the seed dormancy breaking activity of brassicicenes in plants, and of necrotic/apoptotic activity in mammalian cells.
- Published
- 2014
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