Publications by authors named "Hideo Kimura"

147 Publications

Hydrogen Sulfide (HS) and Polysulfide (HS) Signaling: The First 25 Years.

Authors:
Hideo Kimura

Biomolecules 2021 06 16;11(6). Epub 2021 Jun 16.

Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan.

Since the first description of hydrogen sulfide (HS) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on HS have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous HS in the brain, suggesting that HS may have physiological roles. In 1996, we demonstrated that hydrogen sulfide (HS) is a potential signaling molecule, which can be produced by cystathionine β-synthase (CBS) to modify neurotransmission in the brain. Subsequently, we showed that HS relaxes vascular smooth muscle in synergy with nitric oxide (NO) and that cystathionine γ-lyase (CSE) is another producing enzyme. This study also opened up a new research area of a crosstalk between HS and NO. The cytoprotective effect, anti-inflammatory activity, energy formation, and oxygen sensing by HS have been subsequently demonstrated. Two additional pathways for the production of HS with 3-mercaptopyruvate sulfurtransferase (3MST) from l- and d-cysteine have been identified. We also discovered that hydrogen polysulfides (HS, n ≥ 2) are potential signaling molecules produced by 3MST. HS regulate the activity of ion channels and enzymes, as well as even the growth of tumors. -Sulfuration (-sulfhydration) proposed by Snyder is the main mechanism for HS/HS underlying regulation of the activity of target proteins. This mini review focuses on the key findings on HS/HS signaling during the first 25 years.
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http://dx.doi.org/10.3390/biom11060896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235506PMC
June 2021

Multiple reflection and scattering effects of the lotus seedpod-based activated carbon decorated with CoO microwave absorbent.

J Colloid Interface Sci 2021 Nov 9;602:344-354. Epub 2021 Jun 9.

School of Environmental and Material Engineering, Yantai University, No. 30 Qingquan Road, Yantai 264005, PR China. Electronic address:

The lotus seedpod-based activated carbon (LSAC) is derived from pyrolysis of lotus seedpod as biomass carbon precursor, and CoO is then deposited to LSAC by oxidation-precipitation and crystallization process of Co ions from Co(NO) solution. The CoO particles uniformly decorate on the surface and/or the inner channels of LSAC. The optimal reflection loss (RL) value of LSAC/CoO-paraffin wax (PW) composite reaches -39.8 dB, and the bandwidth for RL below -10 dB and -20 dB are 10.3 and 3.0 GHz, respectively, much better than that of LSAC-PW composite for the higher magnetic loss. The addition of CoO particles in LSAC-PW composite significantly enhance the RL values in various thicknesses. The channels of the LSAC and decorated CoO can improve the abilities of multiple scattering, dipole polarization, interface polarization and magnetic loss. This composite provides a promising method to construct high performance absorbers by using biomass carbon to tune the dielectric properties of the ferromagnetic materials.
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http://dx.doi.org/10.1016/j.jcis.2021.06.048DOI Listing
November 2021

Polysulfide inhibits hypoxia-elicited hypoxia-inducible factor activation in a mitochondria-dependent manner.

Mitochondrion 2021 07 13;59:255-266. Epub 2021 Jun 13.

Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Japan. Electronic address:

In cellular signaling, the diverse physiological actions of biological gases, including O, CO, NO, and HS, have attracted much interest. Hypoxia-inducible factors (HIFs), including HIF-1 and HIF-2, are transcription factors that respond to reduced intracellular O availability. Polysulfides are substances containing varying numbers of sulfur atoms (HS) that are generated endogenously from HS by 3-mercaptopyruvate sulfurtransferase in the presence of O, and regulate ion channels, specific tumor suppressors, and protein kinases. However, the effect of polysulfides on HIF activation in hypoxic mammalian cells is largely unknown. Here, we have investigated the effect of polysulfide on cells in vitro. In established cell lines, polysulfide donors reversibly reduced cellular O consumption and inhibited hypoxia-induced HIF-1α protein accumulation and the expression of genes downstream of HIFs; however, these effects were not observed in anoxia. In Von Hippel-Lindau tumor suppressor (VHL)- and mitochondria-deficient cells, polysulfides did not affect HIF-1α protein synthesis but destabilized it in a VHL- and mitochondria-dependent manner. For the first time, we show that polysulfides modulate intracellular O homeostasis and regulate HIF activation and subsequent hypoxia-induced gene expression in a VHL- and mitochondria-dependent manner.
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http://dx.doi.org/10.1016/j.mito.2021.06.007DOI Listing
July 2021

Weight Loss Intervention before Cord Blood Transplantation in an Obese Patient with Acute Myeloid Leukemia: A Case Study.

Prog Rehabil Med 2021 19;6:20210018. Epub 2021 Mar 19.

Department of Hematology, Fukushima Medical University, Fukushima, Japan.

Background: A severely obese woman (39.8 kg/m) with relapsed acute myeloid leukemia was admitted to our hospital to undergo salvage chemotherapy followed by cord blood transplantation (CBT).

Case: During the salvage chemotherapy period, a 70-day weight loss program addressing diet and exercise was administered. After the 70-day intervention, the patient's body weight and body fat mass had decreased (8.6% and 15.0%, respectively) without any adverse events. The number of available cord blood units with total nucleated cells per body weight greater than 2 × 10/kg was zero at admission and two after weight loss; therefore, CBT could be performed.

Discussion: Considering this case, we suggest that a weight loss program combining exercise and nutrition therapy may help patients scheduled for hematopoietic stem cell transplantation by focusing on risk management.
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http://dx.doi.org/10.2490/prm.20210018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972948PMC
March 2021

From neurotransmission to neuronal disorders.

Authors:
Hideo Kimura

Br J Pharmacol 2021 02;178(4):747-749

Department of Pharmacology, Sanyo-Onoda City University (Tokyo University of Science, Yamaguchi), Sanyo-Onoda, Yamaguchi, Japan.

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http://dx.doi.org/10.1111/bph.15354DOI Listing
February 2021

Hydrogen sulfide signalling in the CNS - Comparison with NO.

Authors:
Hideo Kimura

Br J Pharmacol 2020 11 20;177(22):5031-5045. Epub 2020 Sep 20.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda, Japan.

Hydrogen sulfide (H S) together with polysulfides (H S , n > 2) are signalling molecules like NO with various physiological roles including regulation of neuronal transmission, vascular tone, inflammation and oxygen sensing. H S and H S diffuse to the target proteins for S-sulfurating their cysteine residues that induces the conformational changes to alter the activity. On the other hand, 3-mercaptopyruvate sulfurtransferase transfers sulfur from a substrate 3-mercaptopyruvate to the cysteine residues of acceptor proteins. A similar mechanism has also been identified in S-nitrosylation. S-sulfuration and S-nitrosylation by enzymes proceed only inside the cell, while reactions induced by H S, H S and NO even extend to the surrounding cells. Disturbance of signalling by these molecules as well as S-sulfuration and S-nitrosylation causes many nervous system diseases. This review focuses on the signalling by H S and H S with S-sulfuration comparing to that of NO with S-nitrosylation and discusses on their roles in physiology and pathophysiology.
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http://dx.doi.org/10.1111/bph.15246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589025PMC
November 2020

Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma.

Ann Hematol 2020 May 4;99(5):1063-1072. Epub 2020 Apr 4.

Higashi Nagoya National Hospital, Nagoya, Japan.

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.
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http://dx.doi.org/10.1007/s00277-020-03988-6DOI Listing
May 2020

van der Waals force layered multiferroic hybrid perovskite (CHNH)CuCl single crystals.

Phys Chem Chem Phys 2020 Feb 11;22(7):4235-4239. Epub 2020 Feb 11.

Hubei Key Laboratory of Plasma Chemistry and Advanced Materials, Wuhan Institute of Technology, No. 206 Guanggu 1st Road, Wuhan 430205, China.

In inorganic-organic perovskites, the three-dimensional arrangement of the organic group results in more subtle balance of charge, spin and space, thereby providing an attractive route toward new multiferroics. Here we report the existing of multiple ferroic orderings in inorganic-organic layered perovskites with relative strong hydrogen bond ordering of the organic chains intra plane. In addition, the inter plane in perovskite is stacking via van der Waals force. However, such magnetoelectric coupling properties for this compound have not been reported since it is difficult to characterize the properties in single crystals since most of the hybrid perovskites are usually deliquescent and unstable when exposed to air. To deal with these problems, we synthesized a (CHNH)CuCl single crystal by using a simple evaporation technique, and demonstrated ferroelectric, magnetic and magneto-electric properties of (CHNH)CuCl. The internal hydrogen bonding of easily tunable organic unit combined with 3d transition-metal layers in such hybrid perovskites make (CHNH)CuCl a multiferroic crystal with magnetoelectrical coupling and offer an new way to engineer multifunctional multiferroic.
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http://dx.doi.org/10.1039/c9cp05976hDOI Listing
February 2020

Pharmacological polysulfide suppresses glucose-stimulated insulin secretion in an ATP-sensitive potassium channel-dependent manner.

Sci Rep 2019 12 18;9(1):19377. Epub 2019 Dec 18.

Department of Human Stress Response Science, Institute of Biomedical Science, Kansai Medical University, Hirakata, Japan.

Hydrogen sulfide (HS) is an endogenous gaseous transmitter synthesized in various cell types. It is well established that HS functions in many physiological processes, including the relaxation of vascular smooth muscle, mediation of neurotransmission, regulation of inflammation, and modulation of insulin signaling. In recent years, it has been revealed that polysulfides, substances with a varying number of sulfur atoms (HSn), are generated endogenously from HS in the presence of oxygen. A series of studies describes that sulfane sulfur has the unique ability to bind reversibly to other sulfur atoms to form hydropersulfides and polysulfides, and that polysulfides activate ion channels and promote calcium influx. Furthermore, polysulfides regulate tumor suppressor activity, promote the activation of transcription factors targeting antioxidant genes and regulate blood pressure by vascular smooth muscle relaxation. Insulin secretion from pancreatic β cells plays a critical role in response to increased blood glucose concentration. HS has emerged as an important regulator of glycemic control and exhibits characteristic regulation of glucose homeostasis. However, the effects of polysulfides on glucose-stimulated insulin secretion (GSIS) are largely unknown. In this study, we demonstrated that pharmacological polysulfide salts including NaS, NaS, and NaS considerably inhibit GSIS in mouse and rat pancreatic β-cell-derived MIN6 and INS-1 cell lines, and that the effect is dependent on the activation of ATP-sensitive potassium channels. In addition, we demonstrated that a mixture of NaS and diethylamine NONOate inhibits GSIS in a similar way to the pharmacological administration of polysulfide salts.
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http://dx.doi.org/10.1038/s41598-019-55848-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920347PMC
December 2019

DOSE ESTIMATION FOR CONTAMINATED SOIL STORAGE IN LIVING ENVIRONMENT.

Radiat Prot Dosimetry 2020 Jun;188(1):1-7

Japan Atomic Energy Agency, 2-4 Shirakata, Tokai-mura, Ibaraki 319-1195, Japan.

After the Fukushima Nuclear Power Plant accident, most of radiocesium-contaminated soil generated from decontamination activities outside Fukushima prefecture has been stored at decontamination sites such as schools, parks and residential lands (storage at sites) according to the Decontamination Guidelines. However, additional exposure due to the present storage has not been evaluated. Moreover, entering storage sites, which is not restricted for storage at sites, was not considered in safety assessment conducted in the guidelines. To continue the storage and confirm the effectiveness, understanding of present possible exposures is important. In this study, we evaluated exposure doses for residents and users of storage sites based on the present situation. As a result, annual doses due to residence were 10-2 to 10-3 mSv y-1 and doses due to annual entries were of the order of 10-3 mSv y-1. Hence, we confirmed that the exposure due to present storage outside Fukushima is significantly <1 mSv y-1.
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http://dx.doi.org/10.1093/rpd/ncz250DOI Listing
June 2020

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.

EMBO Mol Med 2019 12 28;11(12):e10695. Epub 2019 Oct 28.

Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that "sulfide stress" may be linked to PPI impairment. Analysis of human samples demonstrated that the H S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H S/polysulfides production.
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http://dx.doi.org/10.15252/emmm.201910695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895609PMC
December 2019

Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network.

Blood Cancer J 2019 10 8;9(10):83. Epub 2019 Oct 8.

National University Cancer Institute, Singapore, Singapore.

Pomalidomide is a third generation immunomodulatory drug which in combination with dexamethasone, has been shown to be active in relapsed/refractory multiple myeloma. However, the data in Asian patients remain limited. We conducted a prospective phase two clinical trial in major cancer centers in Singapore, South Korea, Taiwan, Japan and Hong Kong to assess the efficacy and safety of pomalidomide and dexamethasone combination (PomDex) +/- cyclophosphamide in Asian patients with relapsed/refractory multiple myeloma who failed lenalidomide and bortezomib. Patients were treated with pomalidomide (4 mg daily for 21 days every 4 weeks) and dexamethasone (40 mg weekly). If there is less than a minimal response after three cycles of PomDex, cyclophosphamide 300 mg/m can be added (PomCyDex). A total of 136 patients were enrolled. The median PFS was 9 and 10.8 months for the PomDex and PomCyDex group, respectively. The median OS was 16.3 months. This regimen appears to be active across age groups and prior lines of treatment. This combination was overall well tolerated with grade 3 and 4 adverse events of mainly cytopenias. PomDex is highly active and well-tolerated in Asian patients. The addition of cyclophosphamide can improve the response and outcomes further in patients with suboptimal response to PomDex.
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http://dx.doi.org/10.1038/s41408-019-0245-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783445PMC
October 2019

[Signaling molecules hydrogen sulfide (HS), polysulfides (HS), and sulfite (HSO)].

Authors:
Hideo Kimura

Nihon Yakurigaku Zasshi 2019 ;154(3):115-120

Department of Pharmacology, Faculty of Pharmaceutical Science, Sanyo Onoda City University.

More than twenty years have passed since the demonstration of hydrogen sulfide (HS) as a signaling molecule. Various roles of this molecule have been reported including neuromodulation, vascular relaxation, cytoprotection, anti-inflammation, and oxygen sensing. During the study of its effect on neuromodulation, we found TRP channels as a target of HS, and later identified polysulfides (HS) as chemical entity of the ligand. We found that HS relaxes vasculatures in synergy with NO, and recently identified HS as products produced by the chemical interaction between HS and NO to exert the effect, suggesting that it may be a mechanism for the synergy between the two molecules. It has attracted attention that sulfite, a further metabolite of HS and HS, protects neurons from oxidative stress by a mechanism different from that by HS and HS.
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http://dx.doi.org/10.1254/fpj.154.115DOI Listing
September 2019

Signaling by hydrogen sulfide (HS) and polysulfides (HS) in the central nervous system.

Authors:
Hideo Kimura

Neurochem Int 2019 06 6;126:118-125. Epub 2019 Mar 6.

National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan. Electronic address:

Hydrogen sulfide (HS) is a signaling molecule used to modify neuronal transmission, regulate vascular tone, protect tissues from oxidative stress, sense oxygen, and generate ATP. Hydrogen polysulfides (HS) have recently been identified as signaling molecules that mediate the activation of ion channels, regulation of tumor growth, and the transcriptional regulation of oxidative stress; some of which were previously ascribed to HS. Cystathionine β-synthetase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) are known as HS-producing enzymes. 3MST also produces HS and other persulfurated molecules such as cysteine persulfide, glutathione persulfide, and persulfurated proteins. The chemical interaction of HS and nitric oxide (NO) also produces HS, which may be the mechanism underlying the synergistic effect of HS and NO that was initially reported on vascular relaxation. HS and other persulfurated molecules elicit their effect via S-sulfuration (S-sulfhydration) of specific cysteine residues of the target proteins. This review article focuses on the production and roles of HS as well as HS in the central nervous system.
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http://dx.doi.org/10.1016/j.neuint.2019.01.027DOI Listing
June 2019

Signalling by hydrogen sulfide and polysulfides via protein S-sulfuration.

Authors:
Hideo Kimura

Br J Pharmacol 2020 02 4;177(4):720-733. Epub 2019 Mar 4.

National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Hydrogen sulfide (H S) is a signalling molecule that regulates neuronal transmission, vascular tone, cytoprotection, inflammatory responses, angiogenesis, and oxygen sensing. Some of these functions have recently been ascribed to its oxidized form polysulfides (H S ), which can be produced by 3-mercaptopyruvate sulfurtransferase (MPST), also known as a H S-producing enzyme. H S activate ion channels, tumour suppressors, transcription factors, and protein kinases. H S S-sulfurate (S-sulfhydrate) cysteine residues of these target proteins to modify their activity by inducing conformational changes through the formation of a disulfide bridge between the two cysteine residues involved. The chemical interaction between H S and NO also generates H S , which may be a chemical entity that exerts the synergistic effect of H S and NO. MPST also produces redox regulators cysteine persulfide (CysSSH), GSH persulfide (GSSH), and persulfurated proteins. In addition to MPST, haemoproteins such as haemoglobin, myoglobin, neuroglobin, and catalase as well as SOD can produce H S , and sulfide quinone oxidoreductase and cysteinyl tRNA synthetase can make GSSH and CysSSH. This review focuses on the recent progress in the study of the production and physiological roles of these persulfurated and polysulfurated molecules. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
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http://dx.doi.org/10.1111/bph.14579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024735PMC
February 2020

A placement of totally implantable venous access devices for patients receiving home medical treatment in their home.

J Vasc Access 2019 07 11;20(4):451-452. Epub 2019 Jan 11.

1 Soka Green Clinics, Soka, Japan.

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http://dx.doi.org/10.1177/1129729818820224DOI Listing
July 2019

Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan.

Haematologica 2018 11 5;103(11):1835-1842. Epub 2018 Jul 5.

Department of Hematology and Oncology, Japanese Red Cross Narita Hospital.

The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid leukemia patients with a deep molecular response ( ≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4-78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 48.6%, respectively; =0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).
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http://dx.doi.org/10.3324/haematol.2018.194894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278957PMC
November 2018

Multifield Control of Domains in a Room-Temperature Multiferroic 0.85BiTiFeMgO-0.15CaTiO Thin Film.

ACS Appl Mater Interfaces 2018 Jun 12;10(24):20712-20719. Epub 2018 Jun 12.

Shenzhen Key Laboratory of Nanobiomechanics , Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen , Guangdong 518055 , China.

Single-phase materials that combine electric polarization and magnetization are promising for applications in multifunctional sensors, information storage, spintronic devices, etc. Following the idea of a percolating network of magnetic ions (e.g., Fe) with strong superexchange interactions within a structural scaffold with a polar lattice, a solid solution thin film with perovskite structure at a morphotropic phase boundary with a high level of Fe atoms on the B site of perovskite structure is deposited to combine both ferroelectric and ferromagnetic ordering at room temperature with magnetoelectric coupling. In this work, a 0.85BiTiFeMgO-0.15CaTiO thin film has been deposited by pulsed laser deposition (PLD). Both the ferroelectricity and the magnetism were characterized at room temperature. Large polarization and a large piezoelectric effective coefficient d were obtained. Multifield coupling of the thin film has been characterized by scanning force microscopy. Ferroelectric domains and magnetic domains could be switched by magnetic field ( H), electric field ( E), mechanical force ( F), and, indicating that complex cross-coupling exists among the electric polarization, magnetic ordering and elastic deformation in 0.85BiTiFMgO-0.15CaTiO thin film at room temperature. This work also shows the possibility of writing information with electric field, magnetic field, and mechanical force and then reading data by magnetic field. We expect that this work will benefit information applications.
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http://dx.doi.org/10.1021/acsami.8b05289DOI Listing
June 2018

Sulfite protects neurons from oxidative stress.

Br J Pharmacol 2019 02 1;176(4):571-582. Epub 2018 Jul 1.

National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.

Background And Purpose: Hydrogen sulfide (H S) and polysulfides (H S ) are signalling molecules that mediate various physiological responses including cytoprotection. Their oxidized metabolite sulfite (SO ) is found in blood and tissues. However, its physiological role remains unclear. In this study, we investigated the cytoprotective effect of sulfite on neurons exposed to oxidative stress caused by high concentrations of the neurotransmitter glutamate, known as oxytosis.

Experimental Approach: Concentrations of sulfite as well as those of cysteine and GSH in rats were measured by HPLC. Cytoprotective effects of sulfite on primary cultures of rat neurons against oxytosis was examined by WST-8 cytoprotective and LDH cytotoxicity assays and compared with that of H S, H S and thiosulfate.

Key Results: Free sulfite, present at approximately 2 μM in the rat brain, converts cystine to cysteine more efficiently than H S and H S and facilitates transport of cysteine into cells. Physiological concentrations of sulfite protected neurons from oxytosis and were accompanied by increased intracellular concentrations of cysteine and GSH probably due to converting extracellular cystine to cysteine, more efficiently than H S and H S . In contrast, thiosulfate only slightly protected neurons from oxytosis.

Conclusions And Implications: Our present data have shown sulfite to be a novel cytoprotective molecule against oxytosis, through maintaining cysteine levels in the extracellular milieu, leading to increased intracellular cysteine and GSH. Although there may be adverse clinical effects in sensitive individuals, our results provide a new insight into the therapeutic application of sulfite to neuronal diseases caused by oxidative stress.

Linked Articles: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.
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http://dx.doi.org/10.1111/bph.14373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346068PMC
February 2019

Switching to nilotinib is associated with deeper molecular responses in chronic myeloid leukemia chronic phase with major molecular responses to imatinib: STAT1 trial in Japan.

Int J Hematol 2018 Aug 30;108(2):176-183. Epub 2018 Apr 30.

Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR, BCR-ABL1 ≤ 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1 ≤ 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study. The median age was 55.0 years. The median duration of IM treatment was 69.0 months. All patients showed MMR at the time of entry into the study; the median time to MMR on IM therapy was 20.4 months. The proportion of patients who achieved MR increased over time. The rates of MR in the 74 evaluable patients were 27.0% [90% confidence interval (CI) (18.7-36.8%)] and 44.6% [90% CI (34.7-54.8%)] at 12 and 24 months, respectively. The frequency of ABCG2 421C/A + A/A was an independent predictive biomarker for achieving a 24-month MR. Switching to NIL led to safer, deeper molecular responses in patients with MMR on long-term IM therapy for future treatment-free remission.
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http://dx.doi.org/10.1007/s12185-018-2459-6DOI Listing
August 2018

Alternative pathway of HS and polysulfides production from sulfurated catalytic-cysteine of reaction intermediates of 3-mercaptopyruvate sulfurtransferase.

Biochem Biophys Res Commun 2018 02 10;496(2):648-653. Epub 2018 Jan 10.

Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose-shi, Tokyo, 204-8588, Japan. Electronic address:

It has been known that hydrogen sulfide and/or polysulfides are produced from a (poly)sulfurated sulfur-acceptor substrate of 3-mercaptopyruvate sulfurtransferase (MST) via thioredoxin (Trx) reduction in vitro. In this study, we used thiosulfate as the donor substrate and the catalytic reaction was terminated on the formation of a persulfide or polysulfides. We can present alternative pathway of production of hydrogen sulfide and/or polysulfides from (poly)sulfurated catalytic-site cysteine of reaction intermediates of MST via Trx reduction. Matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometric analysis revealed that after prolonged incubation of MST with thiosulfate, a trisulfide adduct becomes predominant at the sulfurated catalytic-site cysteine. When these adducts were reduced by Trx with reducing system (MST:Escherichia coli Trx:E. coli Trx reductase:NADPH = 1:5:0.02:12.5 molar ratio), liquid chromatography with tandem mass spectrometric analysis for monobromobimane-derivatized HS revealed that HS first appeared, and then HS and HS did later. The results were confirmed by high-performance liquid chromatography-fluorescence analysis.
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http://dx.doi.org/10.1016/j.bbrc.2018.01.056DOI Listing
February 2018

Integrating radiation protection criteria for radioactive waste management into remediation procedures in existing exposure situations after a nuclear accident.

J Radiol Prot 2018 03 13;38(1):456-462. Epub 2017 Dec 13.

Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo 201-8511, Japan.

Experience after the accident at the Fukushima Daiichi nuclear power station has shown that there is a need to establish radiation protection criteria for radioactive waste management consistent with the criteria adopted for the remediation of existing exposure situations. A stepwise approach to setting such criteria is proposed. Initially, a reference level for the annual effective dose from waste management activities in the range 1-10 mSv should be set, with the reference level being less than the reference level for the ambient dose. Subsequently, the reference level for the annual effective dose from waste management activities should be reduced in one or more steps to achieve a final target value of 1 mSv. The dose criteria at each stage should be determined with relevant stakeholder involvement. Illustrative case studies show how this stepwise approach might be applied in practice.
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http://dx.doi.org/10.1088/1361-6498/aaa155DOI Listing
March 2018

Analysis of endogenous HS and HS in mouse brain by high-performance liquid chromatography with fluorescence and tandem mass spectrometric detection.

Free Radic Biol Med 2017 12 18;113:355-362. Epub 2017 Oct 18.

Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. Electronic address:

Previous studies indicated that bound sulfur species (BSS), including hydrogen polysulfide (HS), have various physiological functions in mammalian cells. Although HS molecules have been considered as secondary metabolites derived from hydrogen sulfide (HS) based on in vitro studies or predetermined reaction formula, the physiological form of BSS and their endogenous concentration remain unclear. In the present study, we aimed to improve the usual method using monobromobimane (mBB) followed by high performance liquid chromatographic (HPLC) analysis for HS for simultaneous determination of HS, HS, HS and cysteine persulfide in biological samples. We demonstrated that mBB derivatization of HS and HS standards under alkaline conditions (pH 9.5) induced significant decreases in HS and HS levels and a significant increase in the HS level in an incubation time-dependent manner. Conversely, the derivatization of mBB adducts of HS and HS were stable under neutral conditions (pH 7.0), which is physiologically relevant. Therefore, we re-examined the method using mBB and applied an improved method for the evaluation of HS, HS, and HS in mouse brain under physiological pH conditions. The concentrations of HS and HS were 0.030 ± 0.004μmol/g protein and 0.026 ± 0.002μmol/g protein, respectively. Although the level of HS was below the quantification limit of this method, HS was detected in mouse brain. Using the method established here, we reveal for the first time the existence of endogenous HS and HS in mammalian brain tissues. HS and HS exert anti-oxidant activity and anti-carbonyl stress effects through the regulation of redox balance in neuronal cells. Thus, our observations provide novel insights into the physiological functions of BSS in the brain and into neuronal diseases involved in redox imbalance.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.10.346DOI Listing
December 2017

3-Mercaptopyruvate sulfurtransferase produces potential redox regulators cysteine- and glutathione-persulfide (Cys-SSH and GSSH) together with signaling molecules HS, HS and HS.

Sci Rep 2017 09 5;7(1):10459. Epub 2017 Sep 5.

National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.

Cysteine-persulfide (Cys-SSH) is a cysteine whose sulfhydryl group is covalently bound to sulfur (sulfane sulfur). Cys-SSH and its glutathione (GSH) counterpart (GSSH) have been recognized as redox regulators, some of which were previously ascribed to cysteine and GSH. However, the production of Cys-SSH and GSSH is not well understood. Here, we show that 3-mercaptopyruvate sulfurtransferase (3MST) produces Cys-SSH and GSSH together with the potential signaling molecules hydrogen per- and tri-sulfide (HS and HS). Cys-SSH and GSSH are produced in the brain of wild-type mice but not in those of 3MST-KO mice. The levels of total persulfurated species in the brain of 3MST-KO mice are less than 50% of that in the brain of wild-type mice. Purified recombinant 3MST and lysates of COS cells expressing 3MST showed that Cys-SSH and GSSH were produced in the presence of physiological concentrations of cysteine and glutathione, while those with longer sulfur chains, Cys-SSH and GSSH, were produced in the presence of lower than physiological concentrations of cysteine and glutathione. The present study provides new insights into the production and physiological roles of these persulfurated species as well as the therapeutic targets for diseases in which these molecules are involved.
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http://dx.doi.org/10.1038/s41598-017-11004-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585270PMC
September 2017

Hydrogen Sulfide and Polysulfide Signaling.

Authors:
Hideo Kimura

Antioxid Redox Signal 2017 Oct 27;27(10):619-621. Epub 2017 Jun 27.

National Institute of Neuroscience, National Center of Neurology and Psychiatry , Kodaira, Japan .

Hydrogen sulfide (HS) has been demonstrated to have physiological roles such as neuromodulation, vascular tone regulation, cytoprotection, oxygen sensing, inflammatory regulation, and cell growth. Recently, hydrogen polysulfides (HS) have been found to be produced by 3-mercaptopyruvate sulfurtransferase and to regulate the activity of ion channels, tumor suppressers, and protein kinases. Furthermore, some of the effects previously reported to be mediated by HS are now ascribed to HS. Cysteine persulfide and cysteine polysulfide may also be involved in cellular redox regulation. The chemical interaction between HS and nitric oxide (NO) can also produce HS, nitroxyl, and nitrosopersulfide, suggesting their involvement in the reactions previously thought to be mediated by NO alone. This Forum focuses on and critically discusses the recent progress in the study of HS, HS, and NO as well as other per- or polysulfide species. Antioxid. Redox Signal. 00, 000-000.
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http://dx.doi.org/10.1089/ars.2017.7076DOI Listing
October 2017

Polysulfides (HS) produced from the interaction of hydrogen sulfide (HS) and nitric oxide (NO) activate TRPA1 channels.

Sci Rep 2017 04 5;7:45995. Epub 2017 Apr 5.

Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.

Hydrogen sulfide (HS) exerts synergistic effects with another gaseous signaling molecule nitric oxide (NO) on ion channels and vasculature. However, the mechanism of the synergy is not well understood. Here, we show that the interaction between HS and NO generates polysulfides (HS), which activate transient receptor potential ankyrin 1 (TRPA1) channels. High performance liquid chromatography with tandem mass spectrometry analysis, along with the imaging of intracellular Ca and HS, showed that HS and their effects were abolished by cyanolysis and by reducing substances such as dithiothreitol (DTT), cysteine, and glutathione (GSH). However, the effects of nitroxyl or nitrosopersulfide, other potential products of HS and NO interaction, are not affected by cyanolysis or reducing substances. This study demonstrates that HS are products of synergy between HS and NO and provides a new insight into the signaling mechanisms.
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http://dx.doi.org/10.1038/srep45995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380989PMC
April 2017

Mechanisms of Impaired Neutrophil Migration by MicroRNAs in Myelodysplastic Syndromes.

J Immunol 2017 03 27;198(5):1887-1899. Epub 2017 Jan 27.

Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan.

In myelodysplastic syndromes (MDS), functional defects of neutrophils result in high mortality because of infections; however, the molecular basis remains unclear. We recently found that miR-34a and miR-155 were significantly increased in MDS neutrophils. To clarify the effects of the aberrant microRNA expression on neutrophil functions, we introduced miR-34a, miR-155, or control microRNA into neutrophil-like differentiated HL60 cells. Ectopically introduced miR-34a and miR-155 significantly attenuated migration toward chemoattractants fMLF and IL-8, but enhanced degranulation. To clarify the mechanisms for inhibition of migration, we studied the effects of miR-34a and miR-155 on the migration-regulating Rho family members, Cdc42 and Rac1. The introduced miR-34a and miR-155 decreased the fMLF-induced active form of Cdc42 to 29.0 ± 15.9 and 39.7 ± 4.8% of that in the control cells, respectively, although Cdc42 protein levels were not altered. miR-34a decreased a Cdc42-specific guanine nucleotide exchange factor (GEF), dedicator of cytokinesis (DOCK) 8, whereas miR-155 reduced another Cdc42-specific GEF, FYVE, RhoGEF, and PH domain-containing (FGD) 4. The knockdown of DOCK8 and FGD4 by small interfering RNA suppressed Cdc42 activation and fMLF/IL-8-induced migration. miR-155, but not miR-34a, decreased Rac1 protein, and introduction of Rac1 small interfering RNA attenuated Rac1 activation and migration. Neutrophils from patients showed significant attenuation in migration compared with healthy cells, and protein levels of DOCK8, FGD4, and Rac1 were well correlated with migration toward fMLF ( = 0.642, 0.686, and 0.436, respectively) and IL-8 ( = 0.778, 0.659, and 0.606, respectively). Our results indicated that reduction of DOCK8, FGD4, and Rac1 contributes to impaired neutrophil migration in MDS.
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http://dx.doi.org/10.4049/jimmunol.1600622DOI Listing
March 2017

Discovery and Mechanistic Characterization of Selective Inhibitors of HS-producing Enzyme: 3-Mercaptopyruvate Sulfurtransferase (3MST) Targeting Active-site Cysteine Persulfide.

Sci Rep 2017 01 12;7:40227. Epub 2017 Jan 12.

Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Very recent studies indicate that sulfur atoms with oxidation state 0 or -1, called sulfane sulfurs, are the actual mediators of some physiological processes previously considered to be regulated by hydrogen sulfide (HS). 3-Mercaptopyruvate sulfurtransferase (3MST), one of three HS-producing enzymes, was also recently shown to produce sulfane sulfur (HS). Here, we report the discovery of several potent 3MST inhibitors by means of high-throughput screening (HTS) of a large chemical library (174,118 compounds) with our HS-selective fluorescent probe, HSip-1. Most of the identified inhibitors had similar aromatic ring-carbonyl-S-pyrimidone structures. Among them, compound 3 showed very high selectivity for 3MST over other HS/sulfane sulfur-producing enzymes and rhodanese. The X-ray crystal structures of 3MST complexes with two of the inhibitors revealed that their target is a persulfurated cysteine residue located in the active site of 3MST. Precise theoretical calculations indicated the presence of a strong long-range electrostatic interaction between the persulfur anion of the persulfurated cysteine residue and the positively charged carbonyl carbon of the pyrimidone moiety of the inhibitor. Our results also provide the experimental support for the idea that the 3MST-catalyzed reaction with 3-mercaptopyruvate proceeds via a ping-pong mechanism.
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http://dx.doi.org/10.1038/srep40227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228037PMC
January 2017

Development of a reversible fluorescent probe for reactive sulfur species, sulfane sulfur, and its biological application.

Chem Commun (Camb) 2017 Jan;53(6):1064-1067

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. and Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan and AMED CREST (Japan) Agency for Medical Research and Development 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.

We report a reversible off/on fluorescent probe for monitoring concentration changes of sulfane sulfur by utilizing the unique ability of sulfane sulfur to bind reversibly to other sulfur atoms and the intramolecular spirocyclization reaction of xanthene dyes. It reversibly visualized sulfane sulfur in living A549 cells and primary-cultured hippocampal astrocytes.
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http://dx.doi.org/10.1039/c6cc08372bDOI Listing
January 2017

Tiny adiabatic-demagnetization refrigerator for a commercial superconducting quantum interference device magnetometer.

Rev Sci Instrum 2016 Dec;87(12):123905

National Institute for Materials Science, 1-2-1 Sengen, Tsukuba 305-0047, Japan.

A tiny adiabatic-demagnetization refrigerator (T-ADR) has been developed for a commercial superconducting quantum interference device magnetometer [Magnetic Property Measurement System (MPMS) from Quantum Design]. The whole T-ADR system is fit in a cylindrical space of diameter 8.5 mm and length 250 mm, and can be inserted into the narrow sample tube of MPMS. A sorption pump is self-contained in T-ADR, and hence no complex gas handling system is necessary. With the single crystalline GdGaO garnet (∼2 g) used as a magnetic refrigerant, the routinely achievable lowest temperature is ∼0.56 K. The lower detection limit for a magnetization anomaly is ∼1 × 10 emu, estimated from fluctuation of the measured magnetization. The background level is ∼5 × 10 emu below 2 K at H = 100 Oe, which is largely attributable to a contaminating paramagnetic signal from the magnetic refrigerant.
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http://dx.doi.org/10.1063/1.4972249DOI Listing
December 2016
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