Publications by authors named "Hiromasa Tanaka"

111 Publications

Non-thermal plasma-induced DMPO-OH yields hydrogen peroxide.

Arch Biochem Biophys 2021 Jul 6;705:108901. Epub 2021 May 6.

Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Showa-Ku, Nagoya, 466-8550, Japan; Center for Low-temperature Plasma Sciences, Nagoya University, Chikusa-ku, Nagoya, 464-8603, Japan. Electronic address:

Recent developments in electronics have enabled the medical applications of non-thermal plasma (NTP), which elicits reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as hydroxyl radical (OH), hydrogen peroxide (HO), singlet oxygen (O), superoxide (O), ozone, and nitric oxide at near-physiological temperatures. In preclinical studies or human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral and biofilm-related infections, wound healing, and cancer cell death. To elucidate the solution-phase biological effects of NTP in the presence of biocompatible reducing agents, we employed electron paramagnetic resonance (EPR) spectroscopy to quantify OH using a spin-trapping probe, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO); O using a fluorescent probe; and O and HO using luminescent probes in the presence of thiols or tempol. NTP-induced OH was significantly scavenged by dithiothreitol (DTT), reduced glutathione (GSH), and oxidized glutathione (GSSG) in 2 or 5 mM DMPO. NTP-induced O was significantly scavenged by 10 μM DTT and GSH, while O was not efficiently scavenged by these compounds. GSSG degraded HO more effectively than GSH and DTT, suggesting that the disulfide bonds reacted with HO. In the presence of 1-50 mM DMPO, NTP-induced HO quantities were unchanged. The inhibitory effect of tempol concentration (50 and 100 μM) on HO production was observed in 1 and 10 mM DMPO, whereas it became ineffective in 50 mM DMPO. Furthermore, DMPO-OH did not interact with tempol. These results suggest that DMPO and tempol react competitively with O. Further studies are warranted to elucidate the interaction between NTP-induced ROS and biomolecules.
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http://dx.doi.org/10.1016/j.abb.2021.108901DOI Listing
July 2021

Lysosomal nitric oxide determines transition from autophagy to ferroptosis after exposure to plasma-activated Ringer's lactate.

Redox Biol 2021 Jul 23;43:101989. Epub 2021 Apr 23.

Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan; Center for Low Temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan; Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia. Electronic address:

Non-thermal plasma (NTP), an engineered technology to generate reactive species, induces ferroptosis and/or apoptosis specifically in various-type cancer cells. NTP-activated Ringer's lactate (PAL) is another modality for cancer therapy at preclinical stage. Here we found that PAL induces selective ferroptosis of malignant mesothelioma (MM) cells, where non-targeted metabolome screening identified upregulated citrulline-nitric oxide (NO) cycle as a PAL target. NO probe detected biphasic peaks transiently at PAL exposure with time-dependent increase, which was responsible for inducible NO synthase (iNOS) overexpression through NF-κB activation. NO and lipid peroxidation occupied lysosomes as a major compartment with increased TFEB expression. Not only ferrostatin-1 but inhibitors for NO and/or iNOS could suppress this ferroptosis. PAL-induced ferroptosis accompanied autophagic process in the early phase, as demonstrated by an increase in essential amino acids, LC3B-II, p62 and LAMP1, transforming into the later phase with boosted lipid peroxidation. Therefore, NO-mediated lysosomal impairment is central in PAL-induced ferroptosis.
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http://dx.doi.org/10.1016/j.redox.2021.101989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105670PMC
July 2021

Plasma-Treated Solutions (PTS) in Cancer Therapy.

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Plasma Engineering and Medicine Institute, Old Dominion University, Norfolk, VA 23508, USA.

Cold physical plasma is a partially ionized gas generating various reactive oxygen and nitrogen species (ROS/RNS) simultaneously. ROS/RNS have therapeutic effects when applied to cells and tissues either directly from the plasma or via exposure to solutions that have been treated beforehand using plasma processes. This review addresses the challenges and opportunities of plasma-treated solutions (PTSs) for cancer treatment. These PTSs include plasma-treated cell culture media in experimental research as well as clinically approved solutions such as saline and Ringer's lactate, which, in principle, already qualify for testing in therapeutic settings. Several types of cancers were found to succumb to the toxic action of PTSs, suggesting a broad mechanism of action based on the tumor-toxic activity of ROS/RNS stored in these solutions. Moreover, it is indicated that the PTS has immuno-stimulatory properties. Two different routes of application are currently envisaged in the clinical setting. One is direct injection into the bulk tumor, and the other is lavage in patients suffering from peritoneal carcinomatosis adjuvant to standard chemotherapy. While many promising results have been achieved so far, several obstacles, such as the standardized generation of large volumes of sterile PTS, remain to be addressed.
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http://dx.doi.org/10.3390/cancers13071737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038720PMC
April 2021

Differential data on the responsiveness of multiple cell types to cell death induced by non-thermal atmospheric pressure plasma-activated solutions.

Data Brief 2021 Jun 26;36:106995. Epub 2021 Mar 26.

Institute of Innovation for Future Society, Nagoya University, Japan.

A discovery that cells die of a novel and distinctive process, along with some characteristic events, such as cellular shrinkage and Programmed cell death 4 disappearance, has been done by using non-thermal atmospheric pressure plasma-activated solutions [1]. Data on the responsiveness of multiple cell types to the induction of cellular shrinkage and cell death and the loss of Programmed cell death 4 by exposure to the non-thermal atmospheric pressure plasma-activated solutions were collected. Human neuroblastoma SH-SY5Y cells, murine myoblast C2C12 cells, and murine embryonic fibroblasts were cultured for various periods in each of the non-thermal atmospheric pressure plasma-activated solutions and then examined by light field microscopic observation for their effects on cell morphology, by Trypan blue dye exclusion assay for those on cell death, and by Western blotting for those on Programmed cell death 4 disappearance. The data clarified some differences in the responsiveness to the induction of cellular shrinkage, cell death, and Pdcd4 disappearance by all the non-thermal atmospheric pressure plasma-activated solutions among the cells.
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http://dx.doi.org/10.1016/j.dib.2021.106995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056420PMC
June 2021

Ammonia Formation Catalyzed by a Dinitrogen-Bridged Dirhenium Complex Bearing PNP-Pincer Ligands under Mild Reaction Conditions*.

Angew Chem Int Ed Engl 2021 Jun 10;60(25):13906-13912. Epub 2021 May 10.

Department of Applied Chemistry, School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.

A series of rhenium complexes bearing a pyridine-based PNP-type pincer ligand are synthesized from rhenium phosphine complexes as precursors. A dinitrogen-bridged dirhenium complex bearing the PNP-type pincer ligands catalytically converts dinitrogen into ammonia during the reaction with KC as a reductant and [HPCy ]BAr (Cy=cyclohexyl, Ar =3,5-(CF ) C H ) as a proton source at -78 °C to afford 8.4 equiv of ammonia based on the rhenium atom of the catalyst. The rhenium-dinitrogen complex also catalyzes silylation of dinitrogen in the reaction with KC as a reductant and Me SiCl as a silylating reagent under ambient reaction conditions to afford 11.7 equiv of tris(trimethylsilyl)amine based on the rhenium atom of the catalyst. These results demonstrate the first successful example of catalytic nitrogen fixation under mild reaction conditions using rhenium-dinitrogen complexes as catalysts.
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http://dx.doi.org/10.1002/anie.202102175DOI Listing
June 2021

Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy.

Cancers (Basel) 2021 Mar 7;13(5). Epub 2021 Mar 7.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8550, Japan.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC's lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in vitro and in vivo. Here we investigated how PAM inhibits intraperitoneal metastasis. We studied PAM's inhibition of micro-dissemination onto the omentum by performing in vivo imaging in combination with a sequential histological analysis. The results revealed that PAM induced macrophage infiltration into the disseminated lesion. The iNOS-positive signal was co-localized at the macrophages in the existing lesion, indicating that PAM might induce M1-type macrophages. This may be another mechanism of the antitumor effect through a PAM-evoked immune response. Intraperitoneal lavage with plasma-activated lactate Ringer's solution (PAL) significantly improved the overall survival rate in an ovarian cancer mouse model. Our results demonstrated the efficiency and practicality of aqueous plasma for clinical applications.
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http://dx.doi.org/10.3390/cancers13051141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962102PMC
March 2021

A novel and distinctive mode of cell death revealed by using non-thermal atmospheric pressure plasma: The involvements of reactive oxygen species and the translation inhibitor Pdcd4.

Chem Biol Interact 2021 Apr 11;338:109403. Epub 2021 Feb 11.

Institute of Innovation for Future Society, Nagoya University, Japan.

Cells death is indispensable for embryonic development, tissue homeostasis, and the elimination of cancer, virally infected, or degenerated cells in multicellular organisms. It occurs not only via existing modes but also via unidentified modes, whose elucidation requires. Exposure to non-thermal atmospheric pressure plasma (NTAPP) has been demonstrated to induce cell death, probably because of its ability to generate reactive oxygen species (ROS). However, the mode of this cell death and its underlying mechanism remained elusive. Here we show cell death occurring in a novel and distinctive mode different from apoptosis and necrosis/necroptosis through a mechanism that ROS mediate the loss of the translation inhibitor Programmed cell death 4 (Pdcd4) when cells are cultured in solutions activated by NTAPP irradiation. Thus, our study performed with NTAPP-activated solutions may provide insight into the existence of the atypical cell death in cells and some features of its distinguishing mode and underlying mechanism.
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http://dx.doi.org/10.1016/j.cbi.2021.109403DOI Listing
April 2021

L-Dehydroascorbate efficiently degrades non-thermal plasma-induced hydrogen peroxide.

Arch Biochem Biophys 2021 03 20;700:108762. Epub 2021 Jan 20.

Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Showa-Ku, Nagoya, 466-8550, Japan; Center for Low-temperature Plasma Sciences, Nagoya University, Chikusa-ku, Nagoya, 464-8603, Japan. Electronic address:

Non-thermal plasma (NTP) devices generate reactive oxygen species (ROS) and reactive nitrogen species, such as singlet oxygen (O), superoxide (O), hydroxyl radical (OH), hydrogen peroxide (HO), ozone, and nitric oxide at near-physiological temperature. In preclinical studies, NTP promotes blood coagulation, wound healing with disinfection, and selective killing of cancer cells. Although these biological effects of NTP have been widely explored, the stoichiometric quantitation of ROS in the liquid phase has not been performed in the presence of biocompatible reducing agents, which may modify the final biological effects of NTP. Here, we utilized electron paramagnetic resonance spectroscopy to quantitate OH, using a spin-trapping probe 5,5-dimethyl-1-pyrroline-N-oxide; O, using a fluorescent probe; and O and HO, using luminescent probes, after NTP exposure in the presence of antioxidants. l-ascorbate (Asc) at 50 μM concentration (physiological concentration in serum) significantly scavenged OH, whereas (-)-epigallocatechin gallate (EGCG) and α-tocopherol were also effective at performing scavenging activities at 250 μM concentrations. Asc significantly scavenged O and HO at 100 μM. l-Dehydroascorbate (DHA), an oxidized form of Asc, degraded HO, whereas it did not quench OH or O, which are sources of HO. Furthermore, EGCG efficiently scavenged NTP-induced O, O, and HO in Chelex-treated water. These results indicate that the redox cycling of Asc/DHA and metabolites of DHA are important to be considered when applying NTP to cells and tissues. Additionally, ROS-reducing compounds, such as EGCG, affect the outcome. Further studies are warranted to elucidate the interaction between ROS and biomolecules to promote the medical applications of NTP.
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http://dx.doi.org/10.1016/j.abb.2021.108762DOI Listing
March 2021

Cycling between Molybdenum-Dinitrogen and -Nitride Complexes to Support the Reaction Pathway for Catalytic Formation of Ammonia from Dinitrogen.

Chemistry 2020 Oct 7;26(59):13321. Epub 2020 Sep 7.

Department of Systems Innovation, School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo 1, 13-8656, Japan.

Invited for the featured front cover of Kazuya Arashiba, Hiromasa Tanaka, Kazunari Yoshizawa, and Yoshiaki Nishibayashi at The University of Tokyo, Daido University, and Kyushu University. The image depicts a roulette wheel to represent the cycling reaction used in this work. Read the full text of the article at 10.1002/chem.202002200.
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http://dx.doi.org/10.1002/chem.202003159DOI Listing
October 2020

Cycling between Molybdenum-Dinitrogen and -Nitride Complexes to Support the Reaction Pathway for Catalytic Formation of Ammonia from Dinitrogen.

Chemistry 2020 Oct 7;26(59):13383-13389. Epub 2020 Sep 7.

Department of Systems Innovation, School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo 1, 13-8656, Japan.

Cycling between molybdenum(I)-dinitrogen and molybdenum(IV)-nitride complexes was investigated under ambient reaction conditions. A kinetic study of the second-order reaction rate for the conversion of the molybdenum-dinitrogen complex into the molybdenum-nitride complex indicates that the formation of the dinitrogen-bridged dimolybdenum complex is involved in the rate-determining step. DFT calculations indicate that the molybdenum-dinitrogen complex transforms into the molybdenum-nitride complex via direct cleavage of the nitrogen-nitrogen triple bond of the bridging dinitrogen ligand of the dinitrogen-bridged dimolybdenum complex. The corresponding reaction of the molybdenum-nitride complex transforming into the molybdenum-dinitrogen complex proceeds via the ligand exchange of ammonia for dinitrogen at the dinitrogen-bridged dimolybdenum complexes. A new modified reaction pathway has been proposed based on the findings of our experimental and theoretical results.
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http://dx.doi.org/10.1002/chem.202002200DOI Listing
October 2020

Preparation and reactivity of molybdenum complexes bearing pyrrole-based PNP-type pincer ligand.

Chem Commun (Camb) 2020 Jun;56(51):6933-6936

Department of Systems Innovation, School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Molybdenum complexes bearing an anionic pyrrole-based PNP-type pincer ligand have been prepared and have been found to work as catalysts for the conversion of N2 into NH3 under ambient conditions.
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http://dx.doi.org/10.1039/d0cc02852eDOI Listing
June 2020

Non-thermal plasma-activated lactate solution kills U251SP glioblastoma cells in an innate reductive manner with altered metabolism.

Arch Biochem Biophys 2020 07 25;688:108414. Epub 2020 May 25.

Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, 484-8601, Japan.

Ringer's lactate solution irradiated by non-thermal plasma, comprised of radicals, electrons, and ions, is defined as plasma-activated lactate (PAL). PAL exhibited antitumor effects in glioblastoma U251SP cells, which we termed PAL-specific regulated cell death. In contrast to the oxidative stress condition typical of cells incubated in plasma-activated medium (PAM), U251SP cells treated with Ringer's lactate solution or PAL exhibited changes in intracellular metabolites that were reductive in the redox state, as measured by the ratio of oxidative/reductive glutathione concentrations. In the metabolomic profiles of PAL-treated cells, the generation of acetyl-CoA increased for lipid metabolism from alanine and asparagine. PAL thus induces regulated death of U251SP glioblastoma cells in more innate microenvironments than PAM.
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http://dx.doi.org/10.1016/j.abb.2020.108414DOI Listing
July 2020

Structural characterization of molybdenum-dinitrogen complex as key species toward ammonia formation by dispersive XAFS spectroscopy.

Phys Chem Chem Phys 2020 Jun 6;22(22):12368-12372. Epub 2020 May 6.

Department of Interdisciplinary Environment, Graduate School of Human and Environmental Studies, Kyoto University, Yoshida Nihonmatsu-cho, Sakyo-ku, Kyoto 606-8501, Japan.

The structural characterization of a hardly-isolatable molybdenum-dinitrogen complex bearing a PNP-type pincer ligand, which is assumed to be a key reactive complex in the stoichiometric transformation of a molybdenum triiodide complex [MoI(PNP)] into the corresponding molybdenum nitride complex under an atmospheric pressure of dinitrogen, was carried out by using dispersive XAFS.
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http://dx.doi.org/10.1039/c9cp06761bDOI Listing
June 2020

Plasma-activated medium promotes autophagic cell death along with alteration of the mTOR pathway.

Sci Rep 2020 01 31;10(1):1614. Epub 2020 Jan 31.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The biological function of non-thermal atmospheric pressure plasma has been widely accepted in several types of cancer. We previously developed plasma-activated medium (PAM) for clinical use, and demonstrated that PAM exhibits a metastasis-inhibitory effect on ovarian cancer through reduced MMP-9 secretion. However, the anti-tumor effects of PAM on endometrial cancer remain unknown. In this study, we investigated the inhibitory effect of PAM on endometrial cancer cell viability in vitro. Our results demonstrated that AMEC and HEC50 cell viabilities were reduced by PAM at a certain PAM ratio, and PAM treatment effectively increased autophagic cell death in a concentration dependent manner. In addition, we evaluated the molecular mechanism of PAM activity and found that the mTOR pathway was inactivated by PAM. Moreover, our results demonstrated that the autophagy inhibitor MHY1485 partially inhibited the autophagic cell death induced by PAM treatment. These findings indicate that PAM decreases the viability of endometrial cancer cells along with alteration of the mTOR pathway, which is critical for cancer cell viability. Collectively, our data suggest that PAM inhibits cell viability while inducing autophagic cell death in endometrial cancer cells, representing a potential novel treatment for endometrial cancer.
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http://dx.doi.org/10.1038/s41598-020-58667-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994502PMC
January 2020

A Mass Balance Study of C-Labeled JTZ-951 (Enarodustat), a Novel Orally Available Erythropoiesis-Stimulating Agent, in Patients With End-Stage Renal Disease on Hemodialysis.

Clin Pharmacol Drug Dev 2020 08 25;9(6):728-741. Epub 2019 Dec 25.

Drug Metabolism and Pharmacokinetics, Central Pharmaceutical Research Institute, Japan Tobacco Inc, Osaka, Japan.

The mass balance, pharmacokinetics, and biotransformation of JTZ-951 (enarodustat), a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, were characterized in patients (N = 6) with end-stage renal disease on hemodialysis. Following a 10-mg (100 µCi) oral dose of C-JTZ-951, whole blood, feces, dialysate, and, if feasible, urine were obtained for pharmacokinetic assessments and for metabolite profiling and identification in appropriate matrices. Fecal excretion was the major route of elimination of radioactivity, and urinary excretion a minor route, with mean (coefficient of variation [%CV]) recovery of 77.1 (16.2)% and 10.9 (92.0)% of the dose, respectively. Radioactivity was not detected in the dialysate, and mean (%CV) total recovery in excreta was 88.0 (14.9)%. For parent JTZ-951 in plasma, the mean (%CV) effective half-life was 8.96 (7.7)% hours, and area under the curve over 24 hours comprised the majority (>80%) of total exposure, with relatively low variability in these pharmacokinetic variables. Based on profiling of plasma radioactivity, parent JTZ-951 was the predominant circulating component, accounting for 93.7% or more of radioactivity, and metabolite M2 (hydroxylated product) was the only detectable metabolite, but its exposure was minor (<5%) versus unchanged JTZ-951. In urine and feces, the predominant analyte was JTZ-951, and metabolite M2 was the predominant albeit minor metabolite, with small amounts of other metabolites. Thus, plasma exposure to drug-derived radioactivity was primarily due to parent JTZ-951, and the drug was cleared mainly by excretion of unchanged JTZ-951. The study appropriately characterized the disposition of JTZ-951 in patients with end-stage renal disease.
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http://dx.doi.org/10.1002/cpdd.752DOI Listing
August 2020

Propofol inhibits stromatoxin-1-sensitive voltage-dependent K channels in pancreatic β-cells and enhances insulin secretion.

PeerJ 2019 2;7:e8157. Epub 2019 Dec 2.

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

Background: Proper glycemic control is an important goal of critical care medicine, including perioperative patient care that can influence patients' prognosis. Insulin secretion from pancreatic β-cells is generally assumed to play a critical role in glycemic control in response to an elevated blood glucose concentration. Many animal and human studies have demonstrated that perioperative drugs, including volatile anesthetics, have an impact on glucose-stimulated insulin secretion (GSIS). However, the effects of the intravenous anesthetic propofol on glucose metabolism and insulin sensitivity are largely unknown at present.

Methods: The effect of propofol on insulin secretion under low glucose or high glucose was examined in mouse MIN6 cells, rat INS-1 cells, and mouse pancreatic β-cells/islets. Cellular oxygen or energy metabolism was measured by Extracellular Flux Analyzer. Expression of glucose transporter 2 (GLUT2), potassium channels, and insulin mRNA was assessed by RT-PCR. Protein expression of voltage-dependent potassium channels (Kv2) was also assessed by immunoblot. Propofol's effects on potassium channels including stromatoxin-1-sensitive Kv channels and cellular oxygen and energy metabolisms were also examined.

Results: We showed that propofol, at clinically relevant doses, facilitates insulin secretion under low glucose conditions and GSIS in MIN6, INS-1 cells, and pancreatic β-cells/islets. Propofol did not affect intracellular ATP or ADP concentrations and cellular oxygen or energy metabolism. The mRNA expression of GLUT2 and channels including the voltage-dependent calcium channels Cav1.2, Kir6.2, and SUR1 subunit of K, and Kv2 were not affected by glucose or propofol. Finally, we demonstrated that propofol specifically blocks Kv currents in β-cells, resulting in insulin secretion in the presence of glucose.

Conclusions: Our data support the hypothesis that glucose induces membrane depolarization at the distal site, leading to K channel closure, and that the closure of Kv channels by propofol depolarization in β-cells enhances Ca entry, leading to insulin secretion. Because its activity is dependent on GSIS, propofol and its derivatives are potential compounds that enhance and initiate β-cell electrical activity.
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http://dx.doi.org/10.7717/peerj.8157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894434PMC
December 2019

Catalytic reduction of dinitrogen to tris(trimethylsilyl)amine using rhodium complexes with a pyrrole-based PNP-type pincer ligand.

Chem Commun (Camb) 2019 Dec;55(99):14886-14889

Department of Systems Innovation, and School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Rhodium complexes bearing an anionic pyrrole-based PNP-type pincer ligand are synthesised and found to work as effective catalysts for the transformation of molecular dinitrogen into tris(trimethylsilyl)amine under mild reaction conditions. This is the first successful example of rhodium-catalysed dinitrogen reduction under mild reaction conditions.
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http://dx.doi.org/10.1039/c9cc06896aDOI Listing
December 2019

Oxidative stress-dependent and -independent death of glioblastoma cells induced by non-thermal plasma-exposed solutions.

Sci Rep 2019 09 20;9(1):13657. Epub 2019 Sep 20.

Center for Low-temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8603, Japan.

Non-thermal atmospheric pressure plasma has been widely used for preclinical studies in areas such as wound healing, blood coagulation, and cancer therapy. We previously developed plasma-activated medium (PAM) and plasma-activated Ringer's lactate solutions (PAL) for cancer treatments. Many in vitro and in vivo experiments demonstrated that both PAM and PAL exhibit anti-tumor effects in several types of cancer cells such as ovarian, gastric, and pancreatic cancer cells as well as glioblastoma cells. However, interestingly, PAM induces more intracellular reactive oxygen species in glioblastoma cells than PAL. To investigate the differences in intracellular molecular mechanisms of the effects of PAM and PAL in glioblastoma cells, we measured gene expression levels of antioxidant genes such as CAT, SOD2, and GPX1. Microarray and quantitative real-time PCR analyses revealed that PAM elevated stress-inducible genes that induce apoptosis such as GADD45α signaling molecules. PAL suppressed genes downstream of the survival and proliferation signaling network such as YAP/TEAD signaling molecules. These data reveal that PAM and PAL induce apoptosis in glioblastoma cells by different intracellular molecular mechanisms.
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http://dx.doi.org/10.1038/s41598-019-50136-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754505PMC
September 2019

Non-thermal plasma specifically kills oral squamous cell carcinoma cells in a catalytic Fe(II)-dependent manner.

J Clin Biochem Nutr 2019 Jul 1;65(1):8-15. Epub 2019 Jun 1.

Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya 466-8550, Japan.

Oral cancer accounts for ~2% of all cancers worldwide, and therapeutic intervention is closely associated with quality of life. Here, we evaluated the effects of non-thermal plasma on oral squamous cell carcinoma cells with special reference to catalytic Fe(II). Non-thermal plasma exerted a specific killing effect on oral squamous cell carcinoma cells in comparison to fibroblasts. Furthermore, the effect was dependent on the amounts of catalytic Fe(II), present especially in lysosomes. After non-thermal plasma application, lipid peroxidation occurred and peroxides and mitochondrial superoxide were generated. Cancer cell death by non-thermal plasma was promoted dose-dependently by prior application of ferric ammonium citrate and prevented by desferrioxamine, suggesting the association of ferroptosis. Potential involvement of apoptosis was also observed with positive terminal deoxynucleaotidyl transferase-mediated dUTP nick end labeling and annexin V results. Non-thermal plasma exposure significantly suppressed the migratory, invasive and colony-forming abilities of squamous cell carcinoma cells. The oral cavity is easily observable; therefore, non-thermal plasma can be directly applied to the oral cavity to kill oral squamous cell carcinoma without damaging fibroblasts. In conclusion, non-thermal plasma treatment is a potential therapeutic option for oral cancer.
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http://dx.doi.org/10.3164/jcbn.18-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667380PMC
July 2019

Molybdenum-Catalyzed Ammonia Formation Using Simple Monodentate and Bidentate Phosphines as Auxiliary Ligands.

Inorg Chem 2019 Jul 25;58(14):8927-8932. Epub 2019 Jun 25.

Institute for Materials Chemistry and Engineering , Kyushu University , Nishi-ku, Fukuoka 819-0395 , Japan.

We have found molybdenum-catalyzed ammonia formation using simple and commercially available monodentate and bidentate phosphines as auxiliary ligands with a simple and convenient procedure. Molybdenum complexes generated in situ from [MoI(THF)] and the corresponding phosphines such as PMePh and 1,5-bis(diphenylphosphino)pentane worked effectively toward ammonia formation.
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http://dx.doi.org/10.1021/acs.inorgchem.9b01340DOI Listing
July 2019

l-Dehydroascorbic acid recycled by thiols efficiently scavenges non-thermal plasma-induced hydroxyl radicals.

Arch Biochem Biophys 2019 07 31;669:87-95. Epub 2019 May 31.

Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Showa-Ku, Nagoya, 466-8550, Japan. Electronic address:

Recent development in electronics has enabled the use of non-thermal plasma (NTP) to strictly direct oxidative stress in a defined location at near-physiological temperature. In preclinical studies or human clinical trials, NTP promotes blood coagulation, wound healing with disinfection, and selective killing of cancer cells. Although these biological effects of NTP have been widely explored, the stoichiometric quantitation of free radicals in liquid phase has not been performed in the presence of biocompatible reducing agents, which may modify the final biological effects of NTP. Here we quantitated hydroxyl radicals, a major reactive oxygen species generated after NTP exposure, by electron paramagnetic resonance (EPR) spectroscopy using two distinct spin-trapping probes, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO), in the presence of thiols or antioxidants. l-Ascorbic acid (AsA) at 25-50 μM concentrations (physiological concentration in the serum) significantly scavenged these hydroxyl radicals, whereas dithiothreitol (DTT), reduced glutathione (GSH), and N-acetyl-cysteine (NAC) as thiols were required in millimolar concentrations to perform scavenging activities. l-Dehydroascorbic acid (DHA), an oxidized form of AsA, necessitated the presence of 25-50 μM DTT or sub-millimolar concentrations of GSH and NAC for the scavenging of hydroxyl radicals and failed to scavenge hydroxyl radicals by itself. These results suggest that the redox cycling of AsA/DHA via thiols and cellular AsA metabolism are important processes to be considered while applying NTP to cells and tissues. Further studies are warranted to elucidate the interaction between other reactive species generated by NTP and biomolecules to promote biological and medical applications of NTP.
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http://dx.doi.org/10.1016/j.abb.2019.05.019DOI Listing
July 2019

Catalytic Reactivity of Molybdenum-Trihalide Complexes Bearing PCP-Type Pincer Ligands.

Chem Asian J 2019 Jun 20;14(12):2091-2096. Epub 2019 May 20.

Department of Systems Innovation, School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.

Molybdenum-iodide complexes bearing a PCP[1] ligand have been found to work as excellent catalysts toward ammonia formation under ambient reaction conditions among dinitrogen-bridged dimolybdenum complexes and other molybdenum complexes bearing PNP and PCP[2] ligands.
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http://dx.doi.org/10.1002/asia.201900496DOI Listing
June 2019

The threat of longitudinal cracking after distal radius fracture treatment with volar locking plate.

Acta Orthop Belg 2018 Dec;84(4):554-560

The purpose of this study was to examine the occurrence rate of longitudinal cracks and associated characteristics following volar locking plate fixation of the distal radius. Using case records from Shizuoka Saiseikai General Hospital dated between March 2008 and March 2015, a total of 419 eligible adult patients were identified. Standard anteroposterior postoperative radiographs were evaluated to classify longitudinal crack occurrence. Documented variables were compared between patients with longitudinal cracking and those without. Univariate analyses were conducted among each plate group. There were 38 confirmed cases of cracking (Acu-Loc: n = 25, Acu- Loc 2: n = 11, VA-TCP: n = 2). All cracks healed within 4 to 6 weeks after the operation. Plate type, along with patient age and sex were significantly associated with the occurrence of a longitudinal crack (p < 0.05). Although no severe complications related to longitudinal cracking were observed, associated risks for specific patient groups should be considered.
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December 2018

Rapid bacterial identification by direct PCR amplification of 16S rRNA genes using the MinION™ nanopore sequencer.

FEBS Open Bio 2019 03 29;9(3):548-557. Epub 2019 Jan 29.

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

Rapid identification of bacterial pathogens is crucial for appropriate and adequate antibiotic treatment, which significantly improves patient outcomes. 16S ribosomal RNA (rRNA) gene amplicon sequencing has proven to be a powerful strategy for diagnosing bacterial infections. We have recently established a sequencing method and bioinformatics pipeline for 16S rRNA gene analysis utilizing the Oxford Nanopore Technologies MinION™ sequencer. In combination with our taxonomy annotation analysis pipeline, the system enabled the molecular detection of bacterial DNA in a reasonable time frame for diagnostic purposes. However, purification of bacterial DNA from specimens remains a rate-limiting step in the workflow. To further accelerate the process of sample preparation, we adopted a direct PCR strategy that amplifies 16S rRNA genes from bacterial cell suspensions without DNA purification. Our results indicate that differences in cell wall morphology significantly affect direct PCR efficiency and sequencing data. Notably, mechanical cell disruption preceding direct PCR was indispensable for obtaining an accurate representation of the specimen bacterial composition. Furthermore, 16S rRNA gene analysis of mock polymicrobial samples indicated that primer sequence optimization is required to avoid preferential detection of particular taxa and to cover a broad range of bacterial species. This study establishes a relatively simple workflow for rapid bacterial identification via MinION™ sequencing, which reduces the turnaround time from sample to result, and provides a reliable method that may be applicable to clinical settings.
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http://dx.doi.org/10.1002/2211-5463.12590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396348PMC
March 2019

Non-thermal plasma-activated medium modified metabolomic profiles in the glycolysis of U251SP glioblastoma.

Arch Biochem Biophys 2019 02 5;662:83-92. Epub 2018 Dec 5.

Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya, 484-8603, Japan; Plasma Medical Science Global Innovation Center, Nagoya University, Furo-cho, Chikusa, Nagoya, 484-8601, Japan; Institute of Innovation for Future Society, Nagoya University, Furo-cho, Chikusa, Nagoya, 484-8601, Japan.

Non-equilibrium atmospheric pressure plasma (NEAPP) is a mixture of radicals, electrons, anions, cations and light at near body temperature. Plasma-activated medium (PAM) is realized using NEAPP provided by engineered devices and irradiated to a cell culture medium for a period of 600 s. Glioblastoma cells U251SP cultivated in PAM previously indicated that antitumor effects induced PAM-specific apoptotic cell-death. Metabolomic profiles of a hundred intracellular metabolites were analyzed using capillary electrophoresis mass spectrometry. The metabolomic profiles of the PAM-treated U251SP cells were changed significantly with inhibition of the glycolysis pathway and with enhancement of the pentose phosphate pathway.
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http://dx.doi.org/10.1016/j.abb.2018.12.001DOI Listing
February 2019

A 65-nm CMOS Fully Integrated Analysis Platform Using an On-Chip Vector Network Analyzer and a Transmission-Line-Based Detection Window for Analyzing Circulating Tumor Cell and Exosome.

IEEE Trans Biomed Circuits Syst 2019 04 20;13(2):470-479. Epub 2018 Nov 20.

A fully integrated CMOS circuit based on a vector network analyzer and a transmission-line-based detection window for circulating tumor cell (CTC) and exosome analysis is presented for the first time. We have introduced a fully integrated architecture, which eliminates the undesired parasitic components and enables high-sensitivity, to analyze extremely low-concentration CTC in blood. The detection window was designed on the high-sensitive coplanar waveguide line. To validate the operation of the proposed system, a test chip was fabricated using 65-nm CMOS technology. Measurements were performed after adding a tiny lump of silicone or a droplet of water on its detection window. The measured results show |S_21| degradation of -1.96 dB and -6.04 dB for the silicone and the droplet, respectively, at 1.4 GHz. In addition, in another measurement using magnetic beads, it is confirmed that the proposed circuit can analyze even low concentrations of 20 beads/μL. As well as microbeads, measurement with CTCs was successfully demonstrated.
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http://dx.doi.org/10.1109/TBCAS.2018.2882472DOI Listing
April 2019

Density-Functional Tight-Binding Study on the Effects of Interfacial Water in the Adhesion Force between Epoxy Resin and Alumina Surface.

Langmuir 2018 11 12;34(47):14428-14438. Epub 2018 Nov 12.

School of Liberal Arts and Sciences , Daido University , Minami-Ku, Nagoya 457-8530 , Japan.

Adhesion is one of the most interesting subjects in interface phenomena from the viewpoint of wide-range applications as well as basic science. Interfacial water has significant effects on coatings, adhesives, and fiber-reinforced polymer composites, often causing adhesion loss. The way of thinking based on quantum mechanics is essential for a better understanding of physical and chemical properties of adhesive interfaces. In this work, the molecular mechanism of the adhesion interaction between epoxy resin and hydroxylated alumina surface in the presence of interfacial water molecules is investigated by using density-functional tight-binding calculations. Periodic slab model calculations demonstrate that hydrogen bond is an important factor at the adhesion interface. Effects of interfacial water molecules located between epoxy resin and hydroxylated alumina surface are assessed by using a dry model without interfacial water and wet models with water layers of 3, 6, and 9 Å thicknesses. Interesting first- and second-layer structures are observed in the distribution of interfacial water molecules in the tight space between the adhesive and adherend. Energy plots with respect to the displacement of epoxy resin from the alumina surface are nicely approximated by the Morse potential. The adhesion force and stress are theoretically obtained by differentiating the potential curve with respect to the displacement of epoxy resin. Computational results show that the adhesion force and stress are significantly weakened with an increase in the thickness of interfacial water layer. Thus, interfacial water molecules have a clue as to the role of water in the loss of adhesion.
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http://dx.doi.org/10.1021/acs.langmuir.8b02490DOI Listing
November 2018

Molecular understanding of the adhesive interactions between silica surface and epoxy resin: Effects of interfacial water.

J Comput Chem 2019 Jan 10;40(1):164-171. Epub 2018 Oct 10.

Institute for Materials Chemistry and Engineering and IRCCS, Kyushu University, Fukuoka, 819-0395, Japan.

The molecular mechanism of the adhesion between silica surface and epoxy resin under atmospheric conditions is investigated by periodic density-functional-theory (DFT) calculations. Slab models of the adhesion interface were built by integrating a fragment of epoxy resin and hydroxylated (0 0 1) surface of α-cristobalite in the presence of adsorbed water molecules. Effects of adsorbed water on the adhesion interaction are evaluated on the basis of geometry-optimized structures, adhesion energies, and forces. Calculated results demonstrate that adsorbed water molecules significantly reduce both the adhesion energies and forces of the silica surface-epoxy resin interface. The reduction of adhesion properties can be associated with structural deformation of water molecules confined in the tight space between the adhesive and adherend as well as structural flexibility of the hydrogen-bonding network in the interfacial region during detachment of the epoxy resin from the hydrophilic silica surface. © 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcc.25559DOI Listing
January 2019

Molecular mechanisms of non-thermal plasma-induced effects in cancer cells.

Biol Chem 2018 12;400(1):87-91

Institute of Innovation for Future Society, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.

Plasma is the fourth state of matter with higher energy than gas; non-thermal plasma (NTP) is currently available. As NTP is useful in sterilization, promoting wound healing and cancer treatments, the molecular mechanisms of plasma-induced effects in living cells and microorganisms are of significant interest in plasma medicine with medical-engineering collaboration. Molecular mechanisms of plasma-induced effects in cancer cells will be described in this minireview. Both direct and indirect methods to treat cancer cells with NTP have been developed. NTP interacts directly with not only cancer cells but also the liquids surrounding cancer cells and the immune cells that target them. Reactive oxygen and nitrogen species play key roles in NTP-induced effects; however, other mechanisms have been suggested. The complex interactions between NTP, cells and liquids have been extensively studied. In the future, details regarding NTP-induced effects on gene regulatory networks, signaling networks, and metabolic networks will be elucidated.
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http://dx.doi.org/10.1515/hsz-2018-0199DOI Listing
December 2018