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Article: Editorial: Ketone bodies: friend or foe?

Sternberg, Felix / Nomura, Mitsunori / Xie, Min / Duszka, Kalina

2024 Volume 15, Page(s) 1400206

MeSH term(s)	Ketone Bodies ; Diet, Ketogenic
Chemical Substances	Ketone Bodies
Language	English
Publishing date	2024-03-22
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2024.1400206
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Article: Inhibition of HDAC6 Activity Protects Against Endothelial Dysfunction and Atherogenesis

Nomura, Yohei / Nakano, Mitsunori / Woo Sung, Hyun / Han, Mingming / Pandey, Deepesh

Frontiers in physiology

2021 Volume 12, Page(s) 675724

Abstract: We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) ... ...

Abstract	We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) function
Language	English
Publishing date	2021-06-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.675724
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Article: A ketogenic diet reduces age-induced chronic neuroinflammation in mice Running title: ketogenic diet and brain inflammaging.

Nomura, Mitsunori / Murad, Natalia Faraj / Madhavan, Sidharth S / Eap, Brenda / Garcia, Thelma Y / Aguirre, Carlos Galicia / Verdin, Eric / Ellerby, Lisa / Furman, David / Newman, John C

bioRxiv : the preprint server for biology

2023

Abstract: Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and ... ...

Abstract	Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionally
Language	English
Publishing date	2023-12-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.01.569598
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Article ; Online: Inhibition of HDAC6 Activity Protects Against Endothelial Dysfunction and Atherogenesis in vivo

Yohei Nomura / Mitsunori Nakano / Hyun Woo Sung / Mingming Han / Deepesh Pandey

Frontiers in Physiology, Vol

A Role for HDAC6 Neddylation

2021 Volume 12

Abstract: We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) function in vitro. However, whether HDAC6 plays a role in atherogenesis in vivo and the mechanism(s) that control HDAC6 activity/expression in ... ...

Abstract	We previously reported that histone deacetylase 6 (HDAC6) has an important role in endothelial cell (EC) function in vitro. However, whether HDAC6 plays a role in atherogenesis in vivo and the mechanism(s) that control HDAC6 activity/expression in response to atherogenic stimuli are unclear. The goals of this study were to determine whether HDAC6 inhibitor tubacin attenuates atherogenesis and to elucidate specific molecular mechanism(s) that regulate endothelial HDAC6 expression/activity. We evaluated whether administration of tubacin attenuated or reversed the endothelial dysfunction and atherosclerosis induced in mice by a single intraperitoneal injection of adeno-associated viruses encoding liver-target PCSK9 gain-of-function mutant followed by a high fat diet (HFD) for 18 weeks. Tubacin significantly blunted PCSK9-induced increases in pulse wave velocity (index of vascular stiffness and overall vascular health) that are also seen in atherogenic mice. Furthermore, tubacin protected vessels from defective vasorelaxation, as evaluated by acetylcholine-mediated relaxation using wire myograph. Plaque burden defined by Oil Red O staining was also found to be significantly less in mice that received tubacin than in those that received PCSK9 alone. Inhibition of the NEDDylation pathway with MLN4924, an inhibitor of NEDD8-activating enzyme 1 (NAE1), significantly increased HDAC6 activity in HAECs. Interestingly, HDAC6 expression remained unchanged. Further, HAECs exposed to the atherogenic stimulus oxidized low-density lipoprotein (OxLDL) exhibited enhanced HDAC6 activity, which was attenuated by pretreatment with MLN4924. The HDAC6 NEDDylation molecular pathway might regulate genes related to endothelial control of vasomotor tone, reactivity, and atherosclerosis. Tubacin may represent a novel pharmacologic intervention for atherogenesis and other vasculopathies.
Keywords	endothelial (dys)function ; vascular biology ; atherosclerosis ; epigentic modifier ; epigenetic regulator ; Physiology ; QP1-981
Subject code	570
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Structure of SARS-CoV-2 membrane protein essential for virus assembly

Zhikuan Zhang / Norimichi Nomura / Yukiko Muramoto / Toru Ekimoto / Tomoko Uemura / Kehong Liu / Moeko Yui / Nozomu Kono / Junken Aoki / Mitsunori Ikeguchi / Takeshi Noda / So Iwata / Umeharu Ohto / Toshiyuki Shimizu

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: M protein plays essential roles in virus assembly and morphogenesis. Here, authors reveal two cryo-EM structures of M protein from SARS-CoV-2 that suggest conformational dynamics of M protein and its role in virus assembly. ...

Abstract	M protein plays essential roles in virus assembly and morphogenesis. Here, authors reveal two cryo-EM structures of M protein from SARS-CoV-2 that suggest conformational dynamics of M protein and its role in virus assembly.
Keywords	Science ; Q
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Relationship between endothelial function and vascular stiffness on lower limit of cerebral autoregulation in patients undergoing cardiovascular surgery.

Hori, Daijiro / Nomura, Yohei / Nakano, Mitsunori / Akiyoshi, Kei / Kimura, Naoyuki / Yamaguchi, Atsushi

Artificial organs

2020 Volume 45, Issue 4, Page(s) 382–389

Abstract: Hemodynamic management based on cerebral autoregulation range is a possible strategy for preserving major organ perfusion during cardiovascular surgery. The purpose of this study was to evaluate the relation of vascular properties with lower limit of ... ...

Abstract	Hemodynamic management based on cerebral autoregulation range is a possible strategy for preserving major organ perfusion during cardiovascular surgery. The purpose of this study was to evaluate the relation of vascular properties with lower limit of cerebral autoregulation (LLA). LLA was monitored in 66 patients undergoing cardiovascular surgery using near-infrared spectroscopy. To determine the clinical importance of LLA monitoring, association of blood pressure excursions below LLA and acute kidney injury (AKI) was evaluated. Flow-mediated dilation (FMD) and pulse wave velocity (PWV) were measured for the evaluation of endothelial function and aortic stiffness. Variables associated with LLA were evaluated. Excluding patients on hemodialysis, there were 15 patients (25.9%) who developed AKI. Blood pressure excursions below LLA were higher in patients who developed AKI (4.55 mm Hg × hr vs. 1.23 mm Hg × hr, P = .017). In the univariate analysis, prevalence of ischemic heart disease (No IHD: 53 ± 13.0 mm Hg vs. IHD: 60.0 ± 13.6 mm Hg, P = .056) and FMD (r = -0.42, 95% CI -0.61 to -0.19, P < .001) were associated with LLA before cardiopulmonary bypass (CPB). During CPB, calcium channel blocker (No Ca blocker: 42 ± 10.6 mm Hg vs. Ca blocker: 49 ± 14.3 mm Hg, P = .033), diabetes (no DM: 44 ± 13.2 mm Hg vs. DM: 55 ± 10.0 mm Hg, P = .024), FMD (r = -0.32, 95% CI -0.55 to -0.05, P = .021), and PWV (r = 0.28, 95% CI 0.012 to 0.513, P = .041) were associated with LLA. Multivariate analysis showed that FMD was correlated with LLA before CPB (r = -2.19, 95% CI -3.621 to -0.755, P = .003), while PWV was correlated with LLA during CPB (r = 0.01, 95% CI 0.001-0.019, P = .023). Endothelial function and aortic stiffness may be important factors in determining LLA at different phases in cardiovascular surgery.
MeSH term(s)	Acute Kidney Injury/physiopathology ; Aged ; Cardiopulmonary Bypass ; Cerebrovascular Circulation/physiology ; Endothelium, Vascular/physiopathology ; Female ; Homeostasis/physiology ; Humans ; Male ; Monitoring, Intraoperative ; Spectroscopy, Near-Infrared ; Vascular Stiffness
Language	English
Publishing date	2020-12-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	441812-8
ISSN	1525-1594 ; 0160-564X
ISSN (online)	1525-1594
ISSN	0160-564X
DOI	10.1111/aor.13868
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Article ; Online: Structure of SARS-CoV-2 membrane protein essential for virus assembly.

Zhang, Zhikuan / Nomura, Norimichi / Muramoto, Yukiko / Ekimoto, Toru / Uemura, Tomoko / Liu, Kehong / Yui, Moeko / Kono, Nozomu / Aoki, Junken / Ikeguchi, Mitsunori / Noda, Takeshi / Iwata, So / Ohto, Umeharu / Shimizu, Toshiyuki

Nature communications

2022 Volume 13, Issue 1, Page(s) 4399

Abstract: The coronavirus membrane protein (M) is the most abundant viral structural protein and plays a central role in virus assembly and morphogenesis. However, the process of M protein-driven virus assembly are largely unknown. Here, we report the cryo- ... ...

Abstract	The coronavirus membrane protein (M) is the most abundant viral structural protein and plays a central role in virus assembly and morphogenesis. However, the process of M protein-driven virus assembly are largely unknown. Here, we report the cryo-electron microscopy structure of the SARS-CoV-2 M protein in two different conformations. M protein forms a mushroom-shaped dimer, composed of two transmembrane domain-swapped three-helix bundles and two intravirion domains. M protein further assembles into higher-order oligomers. A highly conserved hinge region is key for conformational changes. The M protein dimer is unexpectedly similar to SARS-CoV-2 ORF3a, a viral ion channel. Moreover, the interaction analyses of M protein with nucleocapsid protein (N) and RNA suggest that the M protein mediates the concerted recruitment of these components through the positively charged intravirion domain. Our data shed light on the M protein-driven virus assembly mechanism and provide a structural basis for therapeutic intervention targeting M protein.
MeSH term(s)	COVID-19 ; Cryoelectron Microscopy ; Humans ; Membrane Proteins ; SARS-CoV-2 ; Virus Assembly
Chemical Substances	Membrane Proteins
Language	English
Publishing date	2022-08-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-32019-3
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Article ; Online: Real-Time Intraoperative Determination and Reporting of Cerebral Autoregulation State Using Near-Infrared Spectroscopy.

Montgomery, Dean / Brown, Charles / Hogue, Charles W / Brady, Ken / Nakano, Mitsunori / Nomura, Yohei / Antunes, Andre / Addison, Paul S

Anesthesia and analgesia

2020 Volume 131, Issue 5, Page(s) 1520–1528

Abstract: Background: Cerebral blood flow (CBF) is maintained over a range of blood pressures through cerebral autoregulation (CA). Blood pressure outside the range of CA, or impaired autoregulation, is associated with adverse patient outcomes. Regional oxygen ... ...

Abstract	Background: Cerebral blood flow (CBF) is maintained over a range of blood pressures through cerebral autoregulation (CA). Blood pressure outside the range of CA, or impaired autoregulation, is associated with adverse patient outcomes. Regional oxygen saturation (rSO2) derived from near-infrared spectroscopy (NIRS) can be used as a surrogate CBF for determining CA, but existing methods require a long period of time to calculate CA metrics. We have developed a novel method to determine CA using cotrending of mean arterial pressure (MAP) with rSO2that aims to provide an indication of CA state within 1 minute. We sought to determine the performance of the cotrending method by comparing its CA metrics to data derived from transcranial Doppler (TCD) methods. Methods: Retrospective data collected from 69 patients undergoing cardiac surgery with cardiopulmonary bypass were used to develop a reference lower limit of CA. TCD-MAP data were plotted to determine the reference lower limit of CA. The investigated method to evaluate CA state is based on the assessment of the instantaneous cotrending relationship between MAP and rSO2 signals. The lower limit of autoregulation (LLA) from the cotrending method was compared to the manual reference derived from TCD. Reliability of the cotrending method was assessed as uptime (defined as the percentage of time that the state of autoregulation could be measured) and time to first post. Results: The proposed method demonstrated minimal mean bias (0.22 mmHg) when compared to the TCD reference. The corresponding limits of agreement were found to be 10.79 mmHg (95% confidence interval [CI], 10.09-11.49) and -10.35 mmHg (95% CI, -9.65 to -11.05). Mean uptime was 99.40% (95% CI, 99.34-99.46) and the mean time to first post was 63 seconds (95% CI, 58-71). Conclusions: The reported cotrending method rapidly provides metrics associated with CA state for patients undergoing cardiac surgery. A major strength of the proposed method is its near real-time feedback on patient CA state, thus allowing for prompt corrective action to be taken by the clinician.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Algorithms ; Arterial Pressure ; Blood Pressure ; Cardiopulmonary Bypass ; Cerebrovascular Circulation ; Female ; Homeostasis ; Humans ; Intraoperative Neurophysiological Monitoring/methods ; Male ; Middle Aged ; Oxygen/blood ; Retrospective Studies ; Spectroscopy, Near-Infrared/methods ; Ultrasonography, Doppler, Transcranial
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2020-09-29
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, N.I.H., Extramural
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000004614
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Uk I Zs.78: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 149: Show issues

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Article ; Online: Endothelial-Specific Overexpression of Histone Deacetylase 2 Protects Mice against Endothelial Dysfunction and Atherosclerosis.

Hori, Daijiro / Nomura, Yohei / Nakano, Mitsunori / Han, Mingming / Bhatta, Anil / Chen, Ke / Akiyoshi, Kei / Pandey, Deepesh

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2020 Volume 54, Issue 5, Page(s) 947–958

Abstract: Background/aims: We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in protecting endothelial cells from oxidized low-density lipoprotein (OxLDL)-induced injury. In this study, we examined the effects of endothelial-specific ...

Abstract	Background/aims: We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in protecting endothelial cells from oxidized low-density lipoprotein (OxLDL)-induced injury. In this study, we examined the effects of endothelial-specific HDAC2 overexpression on endothelial-dependent vasorelaxation and atherogenesis in vivo. Methods: Endothelial-specific HDAC2-overexpressing transgenic mice (HDAC2-Tg) were generated under control of the Tie2 promoter. An atherosclerosis model was produced by injecting HDAC2-Tg and wild-type (WT) mice with adeno-associated virus encoding a PCSK9 gain-of-function mutant under control of a liver-specific promoter and feeding them a high-fat diet for 12 weeks. Aortic stiffness in vivo was determined by measuring pulse wave velocity. Wire myography was used to measure endothelium dependent (acetylcholine) and independent (sodium nitroprusside) relaxation in isolated mice aortas. Atherosclerotic plaque burden in aortas was determined by Oil Red O staining and protein expression was determined by western blotting. Results: At baseline, HDAC2-Tg mice had normal mean arterial blood pressure (MAP) and body weight, but pulse wave velocity (PWV), an inverse measure of vascular health and stiffness, was decreased, suggesting that their vessels were more compliant. Moreover, basal nitric oxide production was enhanced in the vessels of HDAC2-Tg mice as compared to that in WT controls, although no significant differences in acetylcholine (endothelial component)- or sodium nitroprusside (non-endothelial component)-mediated relaxation were observed. However, after exposure to OxLDL, aortas from HDAC2-Tg mice exhibited greater acetylcholine-induced relaxation than did those from WT mice. Thus, endothelial-specific vasodilator production was enhanced despite oxidative injury. Atherosclerosis induction in WT mice led to a significant increase in PWV, but in HDAC2-Tg mice, PWV and MAP remained unchanged. Further, aortic rings from HDAC2-Tg exhibited better endothelial-dependent vascular relaxation than did those from WT mice, but not when treated with nitric oxide synthase inhibitor L-NAME. Finally, plaque burden, determined by Oil red O staining, was significantly increased in WT, but not HDAC2-Tg mice, subjected to the atherogenic model. Deletion of endothelial HDAC2 led to impaired endothelial cell-dependent vascular relaxation and increased PWV, compared with those in littermate controls. Conclusion: HDAC2 protects against endothelial dysfunction and atherogenesis induced by oxidized lipids. Hence, overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis. HDAC2-Tg mice provide an opportunity to determine the role of endothelial HDAC2 in vascular endothelial homeostasis.
MeSH term(s)	Animals ; Aorta/metabolism ; Apolipoproteins E/genetics ; Apolipoproteins E/metabolism ; Atherosclerosis/enzymology ; Atherosclerosis/metabolism ; Atherosclerosis/pathology ; Endothelial Cells/enzymology ; Endothelial Cells/metabolism ; Endothelium/enzymology ; Endothelium/metabolism ; Endothelium, Vascular/metabolism ; HEK293 Cells ; Histone Deacetylase 2/biosynthesis ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism ; Humans ; Lipoproteins, LDL ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nitric Oxide/metabolism ; Plaque, Atherosclerotic/metabolism ; Proprotein Convertase 9/metabolism ; Pulse Wave Analysis ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology
Chemical Substances	Apolipoproteins E ; Lipoproteins, LDL ; Vasodilator Agents ; oxidized low density lipoprotein ; Nitric Oxide (31C4KY9ESH) ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; HDAC2 protein, human (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98)
Keywords	covid19
Language	English
Publishing date	2020-09-25
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.33594/000000280
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Zs.A 3160: Show issues

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Article: Rate-dependent and unidirectional conduction block between the left pulmonary vein and left atrium after catheter ablation for atrial fibrillation.

Oi, Maki / Nomura, Shinnosuke / Miho, Mitsunori / Kobayashi, Takayasu / Okabayashi, Marie / Higami, Hirooki / Onishi, Naoaki / Higashitani, Nobuya / Saijo, Sayaka / Nakazeki, Fumiko / Oyamada, Naofumi / Jinnai, Toshikazu / Terada, Shohei / Osaki, Shota / Horii, Katsutoshi / Kaitani, Kazuaki

Journal of arrhythmia

2020 Volume 36, Issue 6, Page(s) 1096–1099

Abstract: A 77-year-old woman with symptomatic paroxysmal atrial fibrillation (PAF) underwent pulmonary vein isolation (PVI), but subsequently experienced recurrence. In the second session, unidirectional left atrium (LA)-left superior pulmonary vein (LSPV) ... ...

Abstract	A 77-year-old woman with symptomatic paroxysmal atrial fibrillation (PAF) underwent pulmonary vein isolation (PVI), but subsequently experienced recurrence. In the second session, unidirectional left atrium (LA)-left superior pulmonary vein (LSPV) conduction was revealed to exist at the carina of the LSPV. Left pulmonary vein (LPV) pacing performed in a cycle between 300 and 260 ms revealed rate-dependent pulmonary vein (PV)-LA conduction, and the location was estimated to be in the roof of the LSPV. PV isolation was achieved after ablation of two gaps. Consideration of the presence of rate-dependent gaps may be useful to confirm bidirectional block lines after ablation.
Language	English
Publishing date	2020-09-10
Publishing country	Japan
Document type	Case Reports
ZDB-ID	2696593-8
ISSN	1883-2148 ; 1880-4276
ISSN (online)	1883-2148
ISSN	1880-4276
DOI	10.1002/joa3.12425
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