Publications by authors named "Takumi Watanabe"

94 Publications

Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment.

iScience 2021 Dec 25;24(12):103497. Epub 2021 Nov 25.

Laboratory of Oncology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo 141-0021, Japan.

The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.
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http://dx.doi.org/10.1016/j.isci.2021.103497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8661540PMC
December 2021

Hybridization of Two Species of Japanese Toads, and , in the Central Part of Japan.

Zoolog Sci 2021 Dec;38(6):506-512

University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan.

Interspecific hybridization between two species of Japanese toads, (Bt) and (Bjf), was not thought to have occurred due to the differences in their spawning habitats, although their hybridization was reported by previous research in a limited area. Such hybridization could have pivotal effects, such as genetic admixture, on Bt, which has a limited distribution and habitat. In this study, to clarify the details of hybridization, a total of 192 individuals were collected from multiple parapatric regions and an only Bjf allopatric region and analyzed based on morphology, mtDNA sequences, and nuclear DNA microsatellite loci. Each individual was identified based on morphological type and mtDNA lineage, and two mismatched combinations, Bt or an intermediate morphological type and the Bjf mtDNA lineage, were detected. In particular, the combination of Bt type and Bjf lineage was dominant in parapatric regions, and it was considered that asymmetric hybridization in which Bjf became a matriline had occurred. In addition, a Bayesian clustering method based on the microsatellite loci was conducted to detect a genetic admixture of the two toad species. Individuals representing a combination of the Bt type and Bjf lineage in the parapatric regions were largely assigned to the Bt cluster or equally to both clusters. These results indicate that backcross with Bt has been repeated, and therefore the traits of Bt might be maintained in this study.
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http://dx.doi.org/10.2108/zs210023DOI Listing
December 2021

Virucidal effect of monogalactosyl diacylglyceride from a green microalga, Coccomyxa sp. KJ, against clinical isolates of SARS-CoV-2 as assessed by a plaque assay.

J Clin Lab Anal 2022 Jan 27;36(1):e24146. Epub 2021 Nov 27.

College of Life and Health Sciences, Chubu University, Kasugai, Japan.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and is capable of human-to-human transmission and rapid global spread. Thus, the establishment of high-quality viral detection and quantification methods, and the development of anti-SARS-CoV-2 agents are critical.

Methods: Here, we present the rapid detection of infectious SARS-CoV-2 particles using a plaque assay with 0.5% agarose-ME (Medium Electroosmosis) as an overlay medium.

Results: The plaques were capable of detecting the virus within 36-40 h post-infection. In addition, we showed that a monogalactosyl diacylglyceride isolated from a microalga (Coccomyxa sp. KJ) could inactivate the clinical isolates of SARS-CoV-2 in a time- and concentration-dependent manner.

Conclusions: These results would allow rapid quantification of the infectious virus titers and help develop more potent virucidal agents against SARS-CoV-2.
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http://dx.doi.org/10.1002/jcla.24146DOI Listing
January 2022

Topical Administration of Heat-Killed Strain KH2 Promotes Re-Epithelialization and Granulation Tissue Formation during Skin Wound-Healing.

Biomedicines 2021 Oct 22;9(11). Epub 2021 Oct 22.

Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

Lactic acid bacteria (LAB) are known to have beneficial effects on immune responses when they are orally administered as bacterial products. Although the beneficial effects of LAB have been reported for the genera and , little has been uncovered on the effects of the genus on skin wound-healing. In this study, we aimed to clarify the effect of heat-killed KH2 (heat-killed KH2) strain on the wound-healing process and to evaluate the therapeutic potential in chronic skin wounds. We analyzed percent wound closure, re-epithelialization, and granulation area, and cytokine and growth factor production. We found that heat-killed KH2 contributed to the acceleration of re-epithelialization and the formation of granulation tissue by inducing tumor necrosis factor-α, interleukin-6, basic fibroblast growth factor, transforming growth factor (TGF)-β1, and vascular endothelial growth factor production. In addition, heat-killed KH2 also improved wound closure, which was accompanied by the increased production of TGF-β1 in diabetic mice. Topical administration of heat-killed KH2 might have therapeutic potential for the treatment of chronic skin wounds in diabetes mellitus. In the present study, we concluded that heat-killed KH2 promoted skin wound-healing through the formation of granulation tissues and the production of inflammatory cytokines and growth factors.
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http://dx.doi.org/10.3390/biomedicines9111520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614852PMC
October 2021

Author Correction: Androprostamine A: a unique antiprostate cancer agent.

J Antibiot (Tokyo) 2021 Oct;74(10):767

Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.

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http://dx.doi.org/10.1038/s41429-021-00467-6DOI Listing
October 2021

Androprostamine A: a unique antiprostate cancer agent.

J Antibiot (Tokyo) 2021 10 28;74(10):717-725. Epub 2021 Jul 28.

Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, 141-0021, Japan.

The androgen receptor (AR) is an important therapeutic target for all clinical states of prostate cancer. We screened cultured broths of microorganisms for their ability to suppress androgen-dependent growth of human prostate cancer LNCaP and VCaP cells without cytotoxicity. We have already identified androprostamine A (APA) from a Streptomyces culture broth as a functional inhibitor of AR. APA repressed R1881 (the synthetic androgen methyltrienolone)-induced androgen-regulated gene expression and dramatically inhibited R1881-induced prostate-specific antigen levels. However, APA did not act as an AR antagonist and did not inhibit AR transcriptional activity. Moreover, AS2405, an APA derivative, significantly inhibited the growth of VCaP cells in SCID mice upon oral administration.
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http://dx.doi.org/10.1038/s41429-021-00449-8DOI Listing
October 2021

Spatiogenetic characterization of S receptor kinase (SRK) alleles in naturalized populations of Raphanus sativus L. var. raphanistroides on Yakushima island.

Genes Genet Syst 2021 Oct 18;96(3):129-139. Epub 2021 Jun 18.

Graduate School of Life Sciences, Tohoku University.

In various coastal areas of Japan, naturalized radish populations are observed. Radish is a cruciferous plant and exhibits self-incompatibility, involving a system controlled by a single locus with multiple S alleles. Although the S allele diversity of radish cultivars and wild radishes has been characterized, the S allele distribution in naturalized populations has not yet been analyzed in relation to the positions of the plants in situ. Here, we show the S allele distribution in naturalized radish populations of Yakushima, a small island in the East China Sea, with positions of the plants. Radish plants were sampled in coastal areas in Yakushima, and their S alleles were detected and characterized. Most of the S alleles had been previously identified in radish cultivars. However, four novel S alleles, which may be unique to Yakushima, were also found. Moreover, seeds in siliques from plants growing in the study areas were sampled, and S allele determination in DNA extracted from these seeds suggested that the plants had exchanged their pollen among their close neighbors. There was also a problem in that the PCR amplification of some SRK alleles was difficult because of their sequence diversity in the naturalized populations, as occurs in cultivars. Our results suggest that the exchange of S alleles between cultivars and naturalized populations occurs and that S alleles in naturalized populations are highly diverse. The methodology established in our study should be applicable to other self-incompatible species to dissect the diversity of S allele distribution in naturalized populations.
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http://dx.doi.org/10.1266/ggs.20-00066DOI Listing
October 2021

Direct catalytic asymmetric and -selective vinylogous addition of butenolides to chromones.

Chem Sci 2020 Jun 22;11(27):7170-7176. Epub 2020 Jun 22.

Institute of Microbial Chemistry (BIKAKEN) Tokyo 141-0021 Japan

An -selective catalytic asymmetric Michael-type vinylogous addition of β,γ-butenolides to chromones was developed. The catalyst system developed herein is characterized by tuning of the steric and electronic effects using a proper Biphep-type chiral ligand to invert the diastereoselection, and improvement of the catalyst turnover by a coordinative phenolic additive. The catalytic protocol renders potentially biologically active natural product analogs accessible in good yield with moderate diastereoselectivity and high enantiomeric purity, mostly greater than 99% ee.
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http://dx.doi.org/10.1039/d0sc01914cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159409PMC
June 2020

Physical properties of lactic acid bacteria influence the level of protection against influenza infection in mice.

PLoS One 2021 18;16(5):e0251784. Epub 2021 May 18.

College of Life and Health Sciences, Chubu University, Kasugai, Japan.

We evaluated whether the water dispersibility of lactic acid bacteria (Enterococcus faecalis KH2) affects their efficacy. When cultured lactic acid bacteria are washed, heat-killed, and powdered, adhesion occurs between results in aggregation (non-treated lactic acid bacteria, n-LAB). However, dispersed lactic acid bacteria (d-LAB) with a lower number of aggregates can be prepared by treating them with a high-pressure homogenizer and adding an excipient during powdering. Mice were administered n-LAB or d-LAB Peyer's patches in the small intestine were observed. Following n-LAB administration, a high amount of aggregated bacteria drifting in the intestinal mucosa was observed; meanwhile, d-LAB reached the Peyer's patches and was absorbed into them. Evaluation in a mouse influenza virus infection model showed that d-LAB was more effective than n-LAB in the influenza yield of bronchoalveolar lavage fluids on day 3 post-infection and neutralizing antibody titers of sera and influenza virus-specific immunoglobulin A in the feces on day 14 post-infection. Therefore, the physical properties of lactic acid bacteria affect their efficacy; controlling their water dispersibility can improve their effectiveness.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251784PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130949PMC
October 2021

Excited-State Intramolecular Proton Transfer Reaction and Ground-State Hole Dynamics of 4'-,-Dialkylamino-3-hydroxyflavone in Ionic Liquids Studied by Transient Absorption Spectroscopy.

J Phys Chem B 2021 05 18;125(20):5373-5386. Epub 2021 May 18.

Department of Applied Chemistry, Graduate School of Science and Engineering, Doshisha University, Kyotanabe 610-0321, Kyoto, Japan.

The excited-state intramolecular proton transfer (ESIPT) of 4'-,-dialkylamino-3-hydroxyflavone (CHF) having different alkyl chain lengths (ethyl, butyl, and octyl chains) was investigated in ionic liquids (ILs) by steady-state fluorescence and transient absorption spectroscopy. Upon photoexcitation, CHF underwent ESIPT from the normal form to the tautomer form, and dual emissions from both states were detected. For CHF and CHF, the tautomerization yields determined from the fluorescence intensity ratios increased with the increasing number of alkyl chain carbon atoms in the cation and on reducing the excitation wavelength as reported for CHF [K. Suda et al., , 12567 ()]. The transient absorption spectra of CHF were measured at excitation wavelengths of 360, 400, and 450 nm. The ESIPT rate determined from the induced emission of the tautomer was correlated with the tautomerization yield for CHF and CHF. In addition, the recovery of the ground-state bleach was found to be strongly dependent on the excitation wavelength. This result indicates that the solvated state of the molecule before photoexcitation is dependent on the excitation wavelengths. The time constant for the ground-state relaxation was slower than that for the excited state.
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http://dx.doi.org/10.1021/acs.jpcb.1c02360DOI Listing
May 2021

Anti-Influenza virus effects of KH2 and SNK12 RNA.

Biosci Microbiota Food Health 2021 12;40(1):43-49. Epub 2020 Sep 12.

College of Life and Health Sciences, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan.

Bacterial RNA has recently emerged as an immune-stimulating factor during viral infection. The immune response in an organism is directly related to the progression of virus infections. Lactic acid bacteria in particular have anticancer, bioprotective, and antiallergic effects by modulating immunity. Here, we aimed to demonstrate the effect of bacterial RNA on production of IL-12, a proinflammatory cytokine, and on activity against influenza A virus (IFV) infection. Oral administration of heat-killed KH2 (KH2) or SNK12 (SNK) in IFV-infected mice suppressed viral replication and stimulated production of virus-specific antibodies. However, ribonuclease-treated KH2 or SNK abrogated the effect, reducing IL-12 production and anti-IFV effects . Taken together, KH2 or SNK showed antiviral effects when administered orally, and the RNAs of KH2 and SNK play a part in these effects, despite the phylogenetic differences between the bacteria.
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http://dx.doi.org/10.12938/bmfh.2020-019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817512PMC
September 2020

Catalytic Asymmetric Total Synthesis of Leucinostatin A.

Chem Rec 2021 Jan 27;21(1):175-187. Epub 2020 Oct 27.

Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan.

This review describes our efforts toward achieving catalytic asymmetric total synthesis of leucinostatin A, a compound that interferes with the tumor-stroma interaction. The synthesis utilizes four catalytic asymmetric reactions, including direct-type reactions exemplified by high atom-economy, and three C-C bond forming reactions. Thorough analysis of the NMR data, HPLC profiles, and biologic activity led us to unambiguously revise the absolute configuration regarding the 6-position of the AHMOD residue side chain from S (reported) to R. Other examples of previously reported important studies on the stereoselective synthesis of HyLeu and AHMOD are also described.
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http://dx.doi.org/10.1002/tcr.202000108DOI Listing
January 2021

Two-step yielding behavior of densely packed microgel mixtures with chemically dissimilar surfaces and largely different sizes.

Soft Matter 2020 Aug;16(31):7400-7413

Department of Macromolecular Science and Engineering, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585, Japan.

Steady-state flow and elastic behavior is investigated for the moderately concentrated binary suspensions of soft microgels (pastes) with chemically dissimilar surfaces, and various degrees of size- and stiffness disparities. The pastes of poly(N-isopropyl acrylamide) (N) and poly(N-isopropyl methacrylamide) (NM) microgels with different values of yield strain γc (γNc > γNMc) are employed as the components. For the single microgel pastes (φ ≈ 1 where φ is apparent volume fraction), the values of γc are governed by the chemical species of constituent polymer in microgel surface whereas γc is insensitive to cross-link density and particle size. We demonstrate that the binary N/NM pastes with large size disparity (RN/NM = DN/DNM < 0.26 where D is the microgel diameter) at low φN (φN: weight fraction of small N microgels) exhibit the peculiarities in several rheological aspects, i.e., the two-step yielding in steady-state flow, and their values of γc and equilibrium shear modulus (G0) being equivalent to those of the single large NM microgel paste. These peculiarities are attributed to the characteristic packing resulting from large size disparity in which all or almost of the small N microgels tend to be accommodated in the gap between the large NM microgels even in moderately concentrated state. This characteristic packing substantially masks the contribution of the small N microgels at low φN, explaining the φN-independent G0 and γc as well as the first yielding governed solely by the large NM microgels. The second yielding results from the emerged contribution of the small N microgels expelled out from the gap by the positional rearrangements after the first yielding. The binary homo-N/N pastes with the similarly large size disparity at low φsmall also exhibit the φsmall-independent values of G0, but they show one-step yielding, indicating that the two-step yielding requires not only sufficiently large size disparity but also chemical dissimilarity (different values of γc) between the two components.
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http://dx.doi.org/10.1039/d0sm00366bDOI Listing
August 2020

Enzyme-assisted Extraction of Bioactive Phytochemicals from Japanese Peppermint (Mentha arvensis L. cv. 'Hokuto').

J Oleo Sci 2020 Jun 14;69(6):635-642. Epub 2020 May 14.

School of Earth, Energy and Environmental Engineering, Kitami Institute of Technology.

In this study, we provide a method for obtaining essential oil from Mentha arvensis L. in large quantities. Three types of polysaccharide-degrading enzymes were investigated, namely cellulase A "Amano" 3, cellulase T "Amano" 4, and hemicellulase "Amano" 90. The optimum extraction conditions were the combined use of 2 wt% cellulase T and 2 wt% hemicellulase 90, and 3 h of incubation. Enzymeassisted extraction increased the amount of the essential oil from 2.2 mL to 3.0 mL, compared with the amount extracted without an enzyme.
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http://dx.doi.org/10.5650/jos.ess19181DOI Listing
June 2020

The Belousov-Zhabotinsky Reaction in Thermoresponsive Core-Shell Hydrogel Microspheres with a Tris(2,2'-bipyridyl)ruthenium Catalyst in the Core.

J Phys Chem B 2020 05 24;124(18):3828-3835. Epub 2020 Apr 24.

Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

The Belousov-Zhabotinsky (BZ) reaction shows temporal or spatiotemporal structures such as redox oscillation of the catalyst, [ruthenium(II)tris(2,2'-bipyridine)][PF] ([Ru(bpy)][PF]). In this study, autonomously oscillating hydrogel microspheres (microgels) were investigated, which show swelling/deswelling oscillation induced by the redox oscillation of the BZ reaction inside the gel. Despite the periodically and autonomously induced oscillation that does not require an external stimulus, it has not been possible to perform any manipulation of the oscillatory behavior over time. The results of the present study show that it is possible to reversibly switch the microgel oscillations from an "on" active state of the BZ reaction to an "off" inactive state by changing the temperature in combination with thermoresponsive microgels. To realize on-demand switching, the construction of double-shell structures is crucial; the thermoresponsive first shell allows the microgels to modulate the diffusion of the substrates or intermediates in the BZ reaction, while the second shell maintains colloidal stability under high temperatures and high ion concentrations. The functionalized double-shell microgels were prepared via multistep seeded precipitation polymerization. The oscillatory switching behavior of the BZ reaction was observed directly and evaluated by ultraviolet-visible (UV-vis) spectroscopy. The central concept of this study, i.e., "on-off switching" can be expected to benefit the development of advanced bioinspired materials.
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http://dx.doi.org/10.1021/acs.jpcb.0c02238DOI Listing
May 2020

Hydrophobic Monomers Recognize Microenvironments in Hydrogel Microspheres during Free-Radical-Seeded Emulsion Polymerization.

Angew Chem Int Ed Engl 2020 06 28;59(23):8849-8853. Epub 2020 Apr 28.

Graduate School of Textile Science & Technology, Shinshu University, 3-15-1 Tokida Ueda, Nagano, 386-8567, Japan.

The three-dimensional structure of nanocomposite microgels was precisely determined by cryo-electron micrography. Several nanocomposite microgels that differ with respect to their nanocomposite structure, which were obtained from seeded emulsion polymerization in the presence of microgels, were used as model nanocomposite materials for cryo-electron micrography. The obtained three-dimensional segmentation images of these nanocomposite microgels provide important insights into the interactions between the hydrophobic monomers and the microgels, that is, hydrophobic styrene monomers recognize molecular-scale differences in polarity within the microgels during the emulsion polymerization. This result led to the formation of unprecedented multi-layered nanocomposite microgels, which promise substantial potential in colloidal applications.
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http://dx.doi.org/10.1002/anie.202003493DOI Listing
June 2020

Inhibition of mitochondria ATP synthase suppresses prostate cancer growth through reduced insulin-like growth factor-1 secretion by prostate stromal cells.

Int J Cancer 2020 06 19;146(12):3474-3484. Epub 2020 Mar 19.

Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Japan.

Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.
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http://dx.doi.org/10.1002/ijc.32959DOI Listing
June 2020

Criteria for colloidal gelation of thermo-sensitive poly(N-isopropylacrylamide) based microgels.

J Colloid Interface Sci 2020 May 14;568:165-175. Epub 2020 Feb 14.

Department of Macromolecular Science and Engineering, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585, Japan. Electronic address:

Hypothesis: Suspensions of the poly(N-isopropylacrylamide) (PNIPAM) based temperature(T)-sensitive microgels can undergo colloidal gelation forming a three-dimensional sparse network-like structure in the hydrophobic and shrunken state of T > T* (T*: volume transition temperature), despite their considerably low particle volume fractions (<0.2). The effective surface charge density is expected to be a key factor governing the colloidal gelation and gel modulus.

Experiments: The combined analysis of the viscoelasticity and electrophoretic mobility (EPM) was performed varying systematically pH and ionic strength (I). The microgels containing the extremely small content of electrolyte (0.1 mol%) with the T* and swelling degree being insensitive to pH and I were employed to facilitate the exclusive analysis of their effects on colloidal gelation.

Findings: The results unambiguously reveal (1) that the gelation requires the adequate suppressions of the interparticle charge repulsion, and (2) that a reduction in the interparticle charge repulsion results in an increase in gel modulus by several orders of magnitude. The long-term linear creep behavior show that the colloidal gels are identified as a viscoelastic fluid with a long relaxation time and a high viscosity whereas they behave elastically at relatively short timescale in conventional oscillatory tests.
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http://dx.doi.org/10.1016/j.jcis.2020.02.047DOI Listing
May 2020

Irreversible adsorption of acidic, basic, and water gas molecules on calcium-deficient hydroxyapatite.

Dalton Trans 2019 Dec;48(47):17507-17515

Tobacco Science Research Center, Japan Tobacco Inc., 6-2 Umegaoka, Aoba-ku, Yokohama, Kanagawa 227-8512, Japan.

Hydroxyapatite [Ca10(PO4)6(OH)2, HAP] has P-OH Brønsted acidic sites, Ca2+ Lewis acidic sites, and OH- and O2- basic sites on which acidic and basic gas molecules can be selectively adsorbed, and has no micropore onto which various molecules adsorb regardless of the chemical properties of gas molecules. The interaction between the surface sites and acidic and basic gas and water molecules has been investigated by evaluating the adsorption properties of various molecules on the surfaces of calcium-deficient HAP. The specific adsorption sites were assessed by examining the reversible and irreversible adsorption of NH3, CO2, aldehydes, and water vapor on HAP at the temperature of 298 K, using two HAP samples with different Ca/P ratios, but similar structures and surface areas: Ca-deficient HAP with an extreme lower Ca/P ratio (named P-HAP) and one with a higher Ca/P ratio (named C-HAP). Irreversible adsorption of NH3 on C-HAP is attributed to the adsorption on both Ca2+ Lewis acidic and P-OH Brønsted acidic sites. Irreversible adsorption on P-HAP is attributed to the adsorption on P-OH Brønsted acidic sites only. Irreversible adsorption of CO2 occurred on C-HAP only, and preferentially on OH- basic sites. Acetaldehyde undergoes a catalytic reaction over both OH- basic sites and surface P-OH Brønsted acidic sites at 298 K. Water irreversible adsorption was extensively observed for P-HAP, and water was barely desorbed at low pressures. In situ powder X-ray diffraction showed an asymmetric expansion of the lattice in the [100] direction, indicating that water was incorporated into P-HAP crystals, especially on structural OH- sites. Irreversible adsorption of acidic and basic molecules was therefore less observed on P-HAP than on C-HAP, but P-HAP had considerable irreversible adsorption of water vapor with associated asymmetric lattice expansion. The incorporation of water vapor was first observed and could be useful to improve adsorption or catalytic performance with the mediation of water vapor and/or hydration.
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http://dx.doi.org/10.1039/c9dt03704gDOI Listing
December 2019

Enzymatic syntheses of novel carbocyclic scaffolds with a 6,5 + 5,5 ring system by squalene-hopene cyclase.

Org Biomol Chem 2019 10;17(42):9375-9389

Department of Applied Biological Chemistry, Faculty of Agriculture, and Graduate School of Science and Technology, Niigata University, Ikarashi 2-8050, Nishi-ku, Niigata, Japan950-2181.

Squalene-hopene cyclase (SHC) converts acyclic squalene 1 into the 6,6,6,6,5-fused pentacyclic triterpenes hopene and hopanol. Previously, we reported the polycyclization products 14-17 of 27-norsqualene (13a) and 28-norsqualene (13b) by SHC, and suggested the importance of Me-27 of 1 for the normal polycyclization pathway. To further ensure the theory, (3R,S)-27-noroxidosqualenes (18 and 19) were incubated, and the structures of products 20-25 thus obtained prompted us to reinvestigate the SHC reaction of 13a (13b). One new product 29, composed of a 6,5 + 5,5 ring system with 13α-H and 17α-H, was obtained from 13a in addition to both the previously isolated products 14-17 and the 6,6,6,5-fused tetracyclic dammarenyl compounds, which were overlooked before. We propose the name "nor-allodammarane" for this novel tetracyclic 6,5 + 5,5 ring system and the name "nor-allogammacerane" for the pentacyclic 6,5 + 5,5 + 6 ring system. The stereochemistry of 29 indicated that 13a folded in the following chair-boat-boat-boat conformation: 10α-H, 11β-H; 14α-H, 15β-Me; 18α-H and 19β-Me, which further allowed us to predict the configuration of 20R for 14 and that of 20S for 15. Substrates 18 and 19 were also cyclized only into allodammarane scaffolds 20-25, and all the structures of 20-25 further indicated that 18 and 19 also folded in the same conformation as 13a, providing further evidence that Me-27 groups of 1 and oxidosqualene are essential for the normal polycyclization pathway by SHC.
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http://dx.doi.org/10.1039/c9ob01941cDOI Listing
October 2019

Chemical Studies on Bioactive Natural Products Directed toward Development of Novel Antiinfective and Anticancer Medicines.

Authors:
Takumi Watanabe

Chem Pharm Bull (Tokyo) 2019 ;67(7):620-631

Institute of Microbial Chemistry (BIKAKEN).

Natural products are still rich sources of clinically used medicines and lead compounds for them. This review summarizes chemical studies carried out by the author on natural products of microorganism origin, many of which were discovered at the Institute of Microbial Chemistry (BIKAKEN). Caprazamycin B is a liponucleoside antibiotic from which CPZEN-45, an antituberculosis agent with a unique mode of action, was developed. Intervenolin and leucinostatin A exert antiproliferative activity toward tumor cells in the presence of the corresponding stromal cells, which implies that the primary molecular targets of these molecules should be related to growth signals from normal (stromal) cells. Details of the endeavors to establish efficient synthetic routes to these compounds which accelerated structure-activity relationship studies and further evaluation of biological activity are described.
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http://dx.doi.org/10.1248/cpb.c19-00215DOI Listing
July 2019

Hydrophobized nanocomposite hydrogel microspheres as particulate stabilizers for water-in-oil emulsions.

Chem Commun (Camb) 2019 May;55(43):5990-5993

Graduate School of Textile Science & Technology, Shinshu University, 3-15-1 Tokida Ueda, Nagano 386-8567, Japan.

Hydrophobized nanocomposite microgels can serve as particulate emulsifiers for water-in-oil (W/O) emulsions with different types of oils, including non-polar oils, which usually do not form W/O emulsions with conventional microgels. The emulsion type can be controlled via the amount or type of hydrophobic polymer formed within the microgels.
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http://dx.doi.org/10.1039/c9cc01497gDOI Listing
May 2019

Hydrogel Microellipsoids that Form Robust String-Like Assemblies at the Air/Water Interface.

Angew Chem Int Ed Engl 2019 05 25;58(22):7294-7298. Epub 2019 Apr 25.

Graduate School of Textile Science & Technology, Shinshu University, 3-15-1 Tokida Ueda, Nagano, 386-8567, Japan.

Soft colloidal particles such as hydrogel microspheres assemble at air/water or oil/water interfaces, where the soft colloids are highly deformed and their surface polymer chains are highly entangled with each other. Herein, we report the formation of robust one-dimensional, string-like colloidal assemblies through self-organization of hydrogel microspheres with shape anisotropy at the air/water interface of sessile droplets. Shape-anisotropic hydrogel microspheres were synthesized via two-step polymerization, whereby a hydrogel shell was formed onto preformed rigid microellipsoids. The shape anisotropy of the hydrogel microspheres was confirmed by transmission electron microscopy and high-speed atomic force microscopy as well as by light-scattering measurements. The present findings are crucial for the understanding of natural self-organization phenomena, where "softness" influences microscopic assembled structures such as those of Nostoc bacteria.
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http://dx.doi.org/10.1002/anie.201901611DOI Listing
May 2019

Hydrogen Isotope Absorption in Unary Oxides and Nitrides with Anion Vacancies and Substitution.

Chemphyschem 2019 05 14;20(10):1369-1375. Epub 2019 Feb 14.

Center for Advanced Research of Energy and Materials, Hokkaido University, Kita 13 Nishi 8, Kitaku, Sapporo, 060-8628, Japan.

The absorption states of hydrogen isotopes in various ceramic materials were investigated by density functional theory. For pristine ceramic materials, main-group oxides do not form any bond with a hydrogen atom. However, transition metal oxides form hydroxyl groups and absorb hydrogen atoms. Main-group and transition metal nitrides form ionic bonds between a hydrogen atom and the surrounded cation. For anion-deficient ceramic materials, hydrogen atoms are negatively charged because of excess electrons induced by anion vacancies, and ionic bonds form with the surrounded cation, which stabilizes the hydrogen absorption state. N substitutional doping into oxides introduces an electron hole, while O substitutional doping into the nitrides introduces an excess of electrons. Therefore, hydrogen isotopes form covalent bonds in N-substituted oxides, and form hydride ions in O-substituted nitrides. Thus, Al O , SiO , CrN, and TiN are promising materials as hydrogen permeation barriers.
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http://dx.doi.org/10.1002/cphc.201801091DOI Listing
May 2019

Triple Function Lubricant Additives Based on Organic-Inorganic Hybrid Star Polymers: Friction Reduction, Wear Protection, and Viscosity Modification.

ACS Appl Mater Interfaces 2019 Jan 26;11(1):1363-1375. Epub 2018 Dec 26.

Polymer-based lubricant additives for friction reduction, wear protection, or viscosity improvement have been widely studied. However, single additives achieving all three functions are rare. To address this need, we have explored the combination of polymer topology with organic-inorganic hybrid chemistry to simultaneously vary the temperature- and shear-dependent properties of polymer additives in solution and at solid surfaces. A topological library of lubricant additives, based on statistical copolymers of stearyl methacrylate and methyl methacrylate, ranging from linear to branched star architectures, was prepared using ruthenium-catalyzed controlled radical polymerization. Control over the polymerization yielded additives with low dispersity and comparable molecular weights, allowing evaluation of the influence of polymer architecture on friction reduction, wear protection, and bulk viscosity improvement in a commercial base oil (Yubase 4). Structure-performance relationships for these functions were assessed by a combination of a high-speed surface force apparatus (HS-SFA) experiments, wear track profilometry, quartz crystal microbalance analysis, and solution viscometry. The custom-built HS-SFA provides a unique experimental environment to measure the boundary lubrication performance under extreme shear rates (≈10 s) for prolonged times (24 h), mimicking the extreme conditions of automotive applications. These experiments revealed that the performance of the additives as boundary lubricants and wear protectants scales with the degree of branching. The branched architectures prohibit ordering of the additives in thin films under high-load conditions, leading to a thicker absorbed polymer brush boundary layer and therefore enhanced film fluidity and lubricity. Additionally, star polymers with increasing arm number lead to bulk viscosity modification, reflected by a significant increase in the viscosity index compared to the commercial base oil. Although outperformed by linear polymers for bulk viscosity improvement, the (hybrid) star polymers successfully combine the three distinct lubricant additive functions: friction reduction, wear protection, and bulk viscosity improvement-in a single polymeric structure. It should also be noted that, judging from HS-SFA experiments, hybrid stars carrying a silicate-based core outperform their fully organic analogues as boundary lubricants. The enhanced performance is most likely driven by attractive forces between the silicate cores and the employed metallic surfaces. Combining three function in one minimizes formulation complexity and thus opens a route to fundamentally understand and formulate key design parameters for the development of novel multifunction lubricant additives.
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http://dx.doi.org/10.1021/acsami.8b16849DOI Listing
January 2019

Intervenolin suppresses gastric cancer cell growth through the induction of TSP-1 secretion from fibroblast-like stromal cells.

Oncol Lett 2018 Nov 21;16(5):6777-6785. Epub 2018 Sep 21.

Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Research Foundation, Tokyo 141-0021, Japan.

Fibroblast-like stromal cells modulate the growth of cancer cells, both positively and negatively. Growth modulation is achieved through the secretion of regulatory factors as well as by proteins within the extracellular matrix. Those cellular interactions present attractive targets for cancer chemotherapy. It was demonsrated a novel natural compound, intervenolin (ITV), inhibited the growth of human gastric cancer cells when co-cultured with stromal cells. Importantly, the inhibition was enhanced by the presence of stromal cells. The present study reported a mechanism of ITV action. Human gastric fibroblast-like stromal cells (Hs738) were treated with ITV. The resultant conditioned medium (ITV CM) inhibited the growth of human gastric cancer cells and suppressed the level of c-Myc protein. This result suggested that ITV negatively modulated cancer cell growth by upregulating the secretion of factors originating from stromal cells in the co-culture system. To better understand the mechanism, ITV CM was subjected to proteomic analysis. The data revealed that one of the candidate regulators was thrombospondin-1 (TSP-1). Recombinant human TSP-1 protein inhibited the growth of gastric cancer cells. Moreover, the growth-inhibitory activities of ITV CM as well as that of recombinant TSP-1 were blocked by neutralizing antibody targeting TSP-1. These results suggested that ITV inhibited the growth of gastric cancer cells through its modulation of stromal cell function.
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http://dx.doi.org/10.3892/ol.2018.9485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202497PMC
November 2018

Thermally Stimulated Light Reflection and Photoluminescence of BaTiO.

Langmuir 2018 09 23;34(35):10250-10253. Epub 2018 Aug 23.

Graduate School of Science , Chiba University , 1-33 Yayoi , Inage, Chiba 263-8522 , Japan.

Perovskites have been attracting attention because of their considerable luminescence properties. A conventional perovskite such as BaTiO has no intrinsic photoluminescence. Doping with rare metals, nanocrystallization, and addition of organometallic halides induce significant photoluminescence and photovoltages. Here, we report anomalous light reflection and photoluminescence of BaTiO on heating. Light absorption shifted from the near-ultraviolet region to the visible region on heating. The small emission peaks at around 400-500 nm disappeared and new peaks appeared above 800 nm; the quantum yields of these peaks were less than 1% and more than 7%, respectively.
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http://dx.doi.org/10.1021/acs.langmuir.8b01615DOI Listing
September 2018

Seeded Emulsion Polymerization of Styrene in the Presence of Water-Swollen Hydrogel Microspheres.

Langmuir 2018 07 11;34(29):8571-8580. Epub 2018 Jul 11.

National Institute for Physiological Sciences , 38 Nishigonaka , Okazaki , Aichi 444-8585 , Japan.

In a previous study, we have ascertained that the charge distribution in hydrogel microspheres (microgels) plays a crucial role in controlling the nanocomposite structure of the polystyrene obtained from the seeded emulsion polymerization (SEP) of styrene in the presence of microgels. However, all these polymerizations were conducted at high temperature, where most of these microgels were dehydrated and deswollen. In the present study, we initially verified that the nanocomposite microgels can be synthesized even when the seed microgels are swollen and hydrated during the SEP of styrene. These highly swollen microgels were used as the nucleation sites for the polystyrene, and subsequently the propagation of the hydrophobic polystyrenes proceeded within water-swollen microgels.
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http://dx.doi.org/10.1021/acs.langmuir.8b01047DOI Listing
July 2018

Label-free and spectral-analysis-free detection of neuropsychiatric disease biomarkers using an ion-sensitive GaInAsP nanolaser biosensor.

Biosens Bioelectron 2018 Oct 2;117:161-167. Epub 2018 Jun 2.

Department of Electrical and Computer Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan.

The emission intensity of GaInAsP semiconductors that show an ion sensitivity is altered by the surface charge. In this study, we propose a biosensing technique using GaInAsP photonic crystal nanolasers based on this principle. Here, simple and rapid detection of collapsin response mediator protein 2 (CRMP2) is demonstrated, which is a promising biomarker candidate for neuropsychiatric diseases existing in peripheral white blood cells. We prepared CRMP2 as a standard protein and introduced sodium dodecyl sulfate (SDS) as an anionic surfactant to enhance the net negative charge of the protein. The nanolaser was modified in advance with an anti-CRMP2 antibody and then photopumped at a constant power. The laser emission intensity was monitored during the antibody-antigen reaction. Consequently, CRMP2 was detected as a decrease in the emission intensity. We achieved a lower limit for detection of 3.8 μg/mL that satisfies the requirement for clinical biomarker testing. Without the requirements of any kind of labels and spectral analyses, this technique allows for simple, rapid, and low-cost biomarker detection.
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http://dx.doi.org/10.1016/j.bios.2018.05.059DOI Listing
October 2018

Anti-influenza virus activity of a salcomine derivative mediated by inhibition of viral RNA synthesis.

Arch Virol 2018 Jun 1;163(6):1607-1614. Epub 2018 Mar 1.

Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.

Influenza virus infection is a major threat to global health. Although vaccines and anti-influenza virus drugs are available, annual influenza virus epidemics result in severe illness, and an influenza pandemic occurs every 20-30 years. To identify candidate anti-influenza virus compounds, we screened approximately 5,000 compounds in an in-house library. We identified MZ7465, a salcomine derivative, as a potent inhibitor of influenza virus propagation. We analyzed the antiviral propagation mechanism of the hit compound by determining the amounts of viral proteins and RNA in infected cells treated with or without the hit compound. Treatment of infected cells with MZ7465 decreased both viral protein and RNA synthesis. In addition, an in vitro assay showed that viral RNA synthesis was directly inhibited by MZ7465. These results suggest that salcomine and its derivatives are potential candidates for the treatment of influenza virus infections.
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http://dx.doi.org/10.1007/s00705-018-3779-9DOI Listing
June 2018
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