Publications by authors named "Chihiro Kato"

20 Publications

  • Page 1 of 1

Oleic acid and oleoylethanolamide decrease interferon-γ-induced expression of PD-L1 and induce apoptosis in human lung carcinoma cells.

Eur J Pharmacol 2021 May 3:174116. Epub 2021 May 3.

Department of Internal Medicine, Sanraku Hospital, Chiyoda-Ku, Tokyo, Japan.

Inhibition of programmed death-ligand 1 (PD-L1) in cancer cells provides a reasonable avenue to prevent cancer progression. Although oleate is known to exert anti-cancer effects, its PD-L1 inhibitory effects have not been proven. This study investigated the effects of oleic acid and an oleic acid metabolite, oleoylethanolamide (OEA), on PD-L1 expression and biomarkers of tumorigenesis in several cancer cell lines, namely A549, HuH-7, MCF-7, DLD-1, and LoVo cells. Specifically, we analyzed the expression of PD-L1 and several apoptosis-related genes using RT-PCR. Interferon-gamma (IFN-γ)-induced modulation of PD-L1 protein expression was investigated using western blotting. Results indicate that IFN-γ stimulation increased the expression of PD-L1 in the chosen cancer cell lines. The IFN-γ-induced expression of PD-L1 was greater in A549 cells, than in other cancerous cell lines. In A549 cells, oleic acid and OEA decreased IFN-γ-induced expression of PD-L1, Bax, Bcl-2, and caspase 3. Oleic acid and OEA decreased IFN-γ-induced phosphorylation of STAT. These results indicate that oleic acid and OEA inhibit PD-1 expression, and induce apoptosis via STAT phosphorylation. Therefore, oleic acid and OEA may prevent cancer formation through STAT phosphorylation with IFN-γ. These findings provide novel insights into the anti-cancer effects of oleic acid-rich oil, such as olive oil.
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http://dx.doi.org/10.1016/j.ejphar.2021.174116DOI Listing
May 2021

Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment.

Sci Rep 2021 Apr 28;11(1):9168. Epub 2021 Apr 28.

Mouse Epigenetics Project, ISS/Kibo Experiment, Japan Aerospace Exploration Agency (JAXA), Ibaraki, 305-8505, Japan.

Spaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (μg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.
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http://dx.doi.org/10.1038/s41598-021-88392-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080648PMC
April 2021

The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors.

Med Oncol 2021 Apr 21;38(6):60. Epub 2021 Apr 21.

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

The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study, we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.
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http://dx.doi.org/10.1007/s12032-021-01503-zDOI Listing
April 2021

Development of X-ray contrast agents using single nanometer-sized gold nanoparticles and lactoferrin complex and their application in vascular imaging.

Colloids Surf B Biointerfaces 2021 Apr 1;203:111732. Epub 2021 Apr 1.

Department of Medical Physics, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan; International Center for Synchrotron Radiation InnovationSmart (SRIS), Tohoku University, 2-1-1, Katahira, Aoba-ku, Sendai 980-8577, Japan. Electronic address:

The technology to accurately image the morphology of tumor vessels with X-ray contrast agents is important to clarify mechanisms underlying tumor progression and evaluate the efficacy of chemotherapy. However, in clinical practice, iodine-based contrast agents present problems such as short blood retention owing to a high clearance ability and insufficient X-ray absorption capacity when compared with other high atomic number elements. To resolve these issues, gold nanoparticles (AuNPs), with a high atomic number, have attracted a great deal of attention as contrast agents for angiography, and have been employed in small animal models. Herein, we developed novel contrast agents using AuNPs and captured changes in tumor vessel morphology with time using X-ray computed tomography (CT). First, glutathione-supported single nanometer-sized AuNPs (sAu/GSH) (diameter, 2.2 nm) were fabricated using tetrakis(hydroxymethyl)phosphonium chloride as a reducing agent. The sAu/GSH particles were intravenously injected into mice, remained in vessels for a few minutes, and were then excreted by the kidneys after 24 h, similar to the commercial contrast agent iopamidol. Next, the Au/GSH and lactoferrin (sAu/GSH-LF) (long axis size, 17.3 nm) complex was produced by adding lactoferrin to the sAu/GSH solution under the influence of a condensing agent. On intravenously administering sAu/GSH-LF to mice, the blood retention time was 1-3 h, which was considerably longer than that observed with iopamidol and sAu/GSH. Moreover, we succeeded in imaging morphological changes in identical tumor vessels for several days using X-ray CT with sAu/GSH-LF.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111732DOI Listing
April 2021

Binding affinities of paclitaxel and docetaxel for generic and nanoparticle albumin-bound paclitaxel-derived albumin from human serum.

Biomed Rep 2021 Apr 11;14(4):35. Epub 2021 Feb 11.

Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo 115-0042, Japan.

Nanoparticle albumin-bound (nab)-paclitaxel is a 130-nm formulation containing human serum albumin (HSA). The clinical efficacy of this formulation is considered to depend on its affinity for HSA. The high pressure employed during the manufacture of nab-paclitaxel HSA (nab HSA) may influence its conformation and/or oligomerization, and ultimately its affinity for HSA. Therefore, studies are required to evaluate whether the affinity of paclitaxel for nab HSA is similar to that of generic HSA (control HSA). In the present study, nab HSA was isolated from nab-paclitaxel by gel filtration, and the binding affinities (Ks) were determined by surface plasmon resonance. Furthermore, the affinity of docetaxel for nab HSA and control HSA was measured, as their binding sites are similar. Paclitaxel showed Ks of 8.93±8.60 and 7.39±5.81 µM for nab HSA and control HSA, respectively, whereas the corresponding Ks for docetaxel were 44.3±9.50 and 55.9±2.28 µM, respectively. This suggests that the paclitaxel binding site was not modified during the nab-paclitaxel manufacturing process. Additionally, nab HSA likely does not affect paclitaxel and blood HSA binding, as evidenced by the similar affinities of paclitaxel and docetaxel for nab HSA and control HSA. In conclusion, the binding affinities of paclitaxel and docetaxel for nab HSA and control HSA were found to be comparable. Additionally, the manufacturing process did not influence the paclitaxel binding affinity for nab HSA. These results also suggest that nab HSA may not affect the clinical effectiveness of nab-paclitaxel.
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http://dx.doi.org/10.3892/br.2021.1411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907966PMC
April 2021

Changes in 3-month mineral and bone disorder patterns were associated with all-cause mortality in prevalent hemodialysis patients with secondary hyperparathyroidism.

BMC Nephrol 2020 10 12;21(1):432. Epub 2020 Oct 12.

Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Background: There is limited evidence on the association between short-term changes in mineral and bone disorder parameters and survival in maintenance hemodialysis patients.

Methods: We investigated the association between changing patterns of phosphorus, calcium and intact parathyroid hormone levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism. Each parameter was divided into three categories (low [L], middle [M] and high [H]), and the changing patterns between two consecutive visits at 3-month intervals were categorized into nine groups (e.g., L-L and M-H). The middle category was defined as 4.0-7.0 mg/dL for phosphorous, 8.5-9.5 mg/dL for calcium and 200-500 pg/mL for intact parathyroid hormone. Adjusted incidence rates and rate ratios were analyzed by weighted Poisson regression models accounting for time-dependent exposures.

Results: For phosphorus, shifts from low/high to middle category (L-M/H-M) were associated with a lower mortality compared with the L-L and H-H groups, whereas shifts from middle to low/high category (M-L/M-H) were associated with a higher mortality compared with the M-M group. For calcium, shifts from low/middle to high category (L-H/M-H) were associated with a higher mortality compared with the L-L and M-M groups, whereas shifts from high to middle category (H-M) were associated with a lower mortality compared with the H-H group. For intact parathyroid hormone, shifts from low to middle category (L-M) were associated with a lower mortality compared with the L-L group.

Conclusions: Changes in the 3-month patterns of phosphorus and calcium toward the middle category were associated with lower mortality. Our study also suggests the importance of avoiding hypercalcemia.
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http://dx.doi.org/10.1186/s12882-020-02088-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552558PMC
October 2020

Isolation and genetic properties of Bartonella in eastern bent-wing bats (Miniopterus fuliginosus) in Japan.

Infect Genet Evol 2020 09 5;83:104354. Epub 2020 May 5.

Laboratory of Veterinary Public Health, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan. Electronic address:

The prevalence and genetic characteristics of Bartonella species in eastern bent-wing bats (Miniopterus fuliginosus) from Japan were investigated. Bartonella bacteria were isolated from 12/50 (24%) of bats examined. Analyses of sequence similarities of the citrate synthase gene (gltA) and RNA polymerase beta-subunit-encoding (rpoB) gene indicated that the isolates from M. fuliginosus were distinct from those present in known Bartonella species as the levels of similarity for both of the genes were lower than the cut-off values for species identification in Bartonella. A phylogenetic analysis of the gltA sequences revealed that the Miniopterus bat-associated strains fell into five genotypes (I to V). Though genotypes I to IV formed a clade with Bartonella from Miniopterus bats from Taiwan, genotype V made a monophyletic clade separate from other bat isolates. In a phylogenetic analysis with the concatenated sequences of the 16S rRNA, gltA, rpoB, cell division protein (ftsZ) gene, and riboflavin synthase gene (ribC), isolates belonging to genotypes I to IV clustered with Bartonella strains from Taiwanese Miniopterus bats, similar to the outcome of the phylogenetic analysis with gltA, whereas genotype V also made a monophyletic clade separate from other bat-associated Bartonella strains. The present study showed that M. fuliginosus in Japan harbor both genus Miniopterus-specific Bartonella suggesting to be specific to the bats in Japan.
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http://dx.doi.org/10.1016/j.meegid.2020.104354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198413PMC
September 2020

Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori-Infected CAPZA1-Overexpressing Cells.

Cell Mol Gastroenterol Hepatol 2019 27;8(3):319-334. Epub 2019 May 27.

Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan. Electronic address:

Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain.

Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells.

Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori-infected gastric mucosa.

Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.
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http://dx.doi.org/10.1016/j.jcmgh.2019.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713896PMC
July 2020

Prevalence of Rapid Eye Movement-related Obstructive Sleep Apnea in Adult Narcolepsy.

Intern Med 2019 Aug 17;58(15):2151-2157. Epub 2019 Apr 17.

Department of Sleep Medicine and Sleep Disorders Center, Aichi Medical University Hospital, Japan.

Objective The association between narcolepsy and rapid eye movement (REM)-related obstructive sleep apnea (OSA) has not been reported. This study aimed to examine the prevalence of REM-related OSA in narcolepsy patients. Methods From January 2013 to April 2018, 141 adult patients were diagnosed with narcolepsy using nocturnal polysomnography and the multiple sleep latency test. The prevalence of REM-related OSA in narcolepsy patients was retrospectively reviewed. Three criteria were used to determine REM-related OSA: Definition #1, an overall apnea-hypopnea index (AHI) ≥5 and AHI during REM (AHIREM)/AHI during non-rapid eye movement (NREM) (AHINREM) ≥2; Definition #2, an overall AHI ≥5 and AHI/AHI≥2 and AHI <15; and Definition #3, an overall AHI ≥5 and AHI/AHI≥2 and AHI <8 plus an REM sleep duration >10.5 minutes. Results Of the 141 narcolepsy patients, 26 were diagnosed with narcolepsy with cataplexy (NA-CA) and 115 with narcolepsy without cataplexy (NA w/o CA). Seventeen patients with NA-CA and 39 with NA w/o CA had OSA. According to Definition #1, the prevalence of REM-related OSA was 47.1% and 41.0%, respectively, in OSA patients with NA-CA and NA w/o CA; according to Definition #2, the respective prevalence was 47.1% and 38.5%, while that according to Definition #3 was 41.2% and 25.6%. No significant differences were found in the prevalence of REM-related OSA for each definition. Conclusion A high prevalence of REM-related OSA was confirmed in adult narcolepsy patients with OSA. Compared to previous reports, we noted a high frequency of REM-related OSA satisfying the relatively strict Definition #3. These results might reflect the pathophysiological characteristics of narcolepsy.
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http://dx.doi.org/10.2169/internalmedicine.2601-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709340PMC
August 2019

Inhibition of mast cell degranulation by melanin.

Biochem Pharmacol 2019 05 20;163:178-193. Epub 2019 Feb 20.

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

Melanin is a dark naturally occurring pigment produced in nature and in many organisms. Although several reports have demonstrated applications for melanins in various therapeutic treatments, to date, no research has examined the anti-allergic effect of melanin. In this study, we for the first time found that solubilized or synthesized soluble melanin acts as a potent inhibitor of the degranulation of mast cells. We found that squid-ink-derived melanin significantly inhibited antigen-IgE-FcεRI-mediated degranulation of the mucosal mast cell line RBL-2H3. A homogenized melanin nanoparticle prepared by laser ablation also clearly suppressed antigen-induced mast cell degranulation. We also successfully solubilized synthetic melanin in a neutral biochemical buffer and found that it also significantly inhibited IgE-sensitized mast cells. The anti-degranulation activity of synthesized melanin was abolished in the melanin fraction below 50-kD molecular weight. All melanins used in this study did not exert significant cell death. Signal transduction analysis revealed that melanin suppressed antigen-triggered phosphorylation of signaling molecules as well as calcium influx. Transmission electron microscopy revealed that homogenized melanin nanoparticles partially attached to the cell surface and some nanoparticles were internalized to the cell. Flow cytometry revealed that the number of FcεRI-bound IgE molecules was decreased by melanin. Fluorescence recovery after photobleaching analysis indicated that melanin attenuated both plasma membrane and cytoplasmic fluidity, implying that melanin increased their viscosities. In vivo experiments using passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA) mouse models demonstrated that oral administration of melanin accelerated the recovery of decreased body temperature after antigen infection in PSA, and combination sensitization of IgE with melanin attenuated antigen-induced extravasation in PCA. These findings indicated that melanin exhibits preventative effects against IgE-mast cell-mediated anaphylaxis. This study provides the first evidence that homogenized melanin may be a potential therapeutic agent for diseases involving mast cells.
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http://dx.doi.org/10.1016/j.bcp.2019.02.015DOI Listing
May 2019

Efficacy and safety of reinfusion of concentrated ascitic fluid for malignant ascites: a concept-proof study.

Support Care Cancer 2018 May 22;26(5):1489-1497. Epub 2017 Nov 22.

Department of Palliative Care, Hoshigaoka Medical Center, Osaka, Japan.

Purpose: Malignant ascites is one of the symptoms causing discomfort in advanced cancer patients. Cell-free and concentrated ascites reinfusion therapy (CART) is one treatment modality, but controlled trials are limited. The primary aim of this study was to explore the efficacy and safety of CART, as well as their predictors, to obtain data for planning a further controlled trial.

Methods: This was a single center retrospective cohort study in patients with refractory malignant ascites. Consecutive adult patients who underwent CART were enrolled. The primary endpoints were the time to next paracentesis and seven patient-reported symptoms (e.g., abdominal pain and distension). The secondary endpoints were adverse events, laboratory findings, and physical findings.

Results: A total of 104 CART procedures for 51 patients were analyzed. The median time to next paracentesis was 27 days (95% CI, 21-35). Intensities of all seven symptoms were significantly improved after CART (p < 0.0001 for all symptoms). Grade 3 hypotension occurred during one procedure, and mild fever occurred in 5%. Total protein, albumin, and estimated glomerular filtration rate were significantly increased. Hemorrhagic ascites, ascites white blood cell count, serum total protein, and lymphocyte percentages were the independent predictors of the time to next paracentesis.

Conclusion: The effects of reinfusion of concentrated ascitic fluid may be maintained for 1 month, being potentially longer than that of total paracentesis alone. This study had no comparison groups and examined the short-term effect. A randomized controlled study to compare the long-term effects of total paracentesis alone vs. CART is necessary.
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http://dx.doi.org/10.1007/s00520-017-3980-5DOI Listing
May 2018

Layer-by-Layer Growth of Graphene on Insulator in CO-Oxidizing Environment.

ACS Omega 2017 Apr 18;2(4):1523-1528. Epub 2017 Apr 18.

Tokyo Institute of Technology, Yokohaama 226-8503, Kanagawa, Japan.

Since the discovery of graphene by sticking and peeling scotch tape off graphite, it has also been prepared by other methods, such as thermal decomposition of SiC and chemical vapor deposition (CVD) with catalytic layer. Both the exfoliation and CVD methods impose to transfer the graphene layers on other insulating substrates for device applications. We reported that diamond grows in oxygen atmosphere (Yoshimoto M.; Nature1999, 399, 340-342) in which oxidative etching and depositing carbon compete under equivalent conditions. However, oxygen atmosphere is too intense for graphite growth. Although carbon dioxide (CO) is produced after hydrocarbon combustion, it can be a oxidant in certain situations. Here, we show the direct growth of graphene on insulating substrates in 100% CO environment and observe its layer-by-layer growth on the stepped edge of an insulating substrate. The direct growth can have a significant advantage of excluding the necessary process of transferring the graphene on the insulating substrate over other common methods.
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http://dx.doi.org/10.1021/acsomega.7b00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641100PMC
April 2017

Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model.

Int J Oncol 2016 Apr 1;48(4):1399-407. Epub 2016 Feb 1.

Department of Pharmacokinetics and Biopharmaceutics, Institute of Health Biosciences, Tokushima University, Tokushima, Japan.

Malignant pleural mesothelioma (MPM) is an incurable cancer with an increasing incidence. Currently, pemetrexed (PMX)-based chemotherapy is the mainstay of chemotherapy for MPM, however, the outcome of PMX-based chemotherapy in patients with MPM is dismal. RNA interference (RNAi) technology has been considered as an effective tool to substantially enhance the therapeutic efficacy of chemotherapeutic agents in many preclinical and clinical settings. In this study, therefore, we investigated whether non-viral anti-thymidylate synthase RNAi embedded liposome (TS shRNA lipoplex) would effectively guide the downregulation of TS in human malignant mesothelioma MSTO-211H cells. Consequently, it enhanced the antitumor effect of PMX both in vitro and in vivo. TS shRNA effectively enhanced the in vitro cell growth inhibition upon treatment with PMX via downregulating TS expression in the MSTO-211H cell line. In in vivo orthotopic tumor model, the combined treatment of PMX and TS shRNA lipoplex efficiently combated the progression of orthotopic thoracic tumors and as a result prolonged mouse survival, compared to each single treatment. Our findings emphasize the pivotal relevance of RNAi as an effective tool for increasing the therapeutic efficacy of PMX, a cornerstone in the treatment regimens of MPM, and thereby, raising the possibility for the development of a novel therapeutic strategy, combination therapy of TS-shRNA and PMX, that can surpass many of the currently applied, but less effective, therapeutic regimens against lethal MPM.
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http://dx.doi.org/10.3892/ijo.2016.3367DOI Listing
April 2016

Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed.

J Control Release 2015 Dec 18;220(Pt A):29-36. Epub 2015 Oct 18.

Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan; Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan. Electronic address:

Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non-Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non-Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the "fluid" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM.
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http://dx.doi.org/10.1016/j.jconrel.2015.10.019DOI Listing
December 2015

Time-resolved infrared detection of the proton and protein dynamics during photosynthetic oxygen evolution.

Biochemistry 2012 Apr 4;51(15):3205-14. Epub 2012 Apr 4.

Division of Material Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan.

Photosynthetic oxygen evolution by plants and cyanobacteria is performed by water oxidation at the Mn(4)CaO(5) cluster in photosystem II. The reaction is known to proceed via a light-driven cycle of five intermediates called S(i) states (i = 0-4). However, the detailed reaction processes during the intermediate transitions remain unresolved. In this study, we have directly detected the proton and protein dynamics during the oxygen-evolving reactions using time-resolved infrared spectroscopy. The time courses of the absorption changes at 1400 and 2500 cm(-1), which represent the reactions and/or interaction changes of carboxylate groups and the changes in proton polarizability of strong hydrogen bonds, respectively, were monitored upon flash illumination. The results provided experimental evidence that during the S(3) → S(0) transition, drastic proton rearrangement, most likely reflecting the release of a proton from the catalytic site, takes place to form a transient state before the oxidation of the Mn(4)CaO(5) cluster that leads to O(2) formation. Early proton movement was also detected during the S(2) → S(3) transition. These observations reveal the common mechanism in which proton release facilitates the transfer of an electron from the Mn(4)CaO(5) cluster in the S(2) and S(3) states that already accumulate oxidizing equivalents. In addition, relatively slow rearrangement of carboxylate groups was detected in the S(0) → S(1) transition, which could contribute to the stabilization of the S(1) state. This study demonstrates that time-resolved infrared detection is a powerful method for elucidating the detailed molecular mechanism of photosynthetic oxygen evolution by pursuing the reactions of substrate and amino acid residues during the S-state transitions.
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http://dx.doi.org/10.1021/bi300294nDOI Listing
April 2012

Nano-strip grating lines self-organized by a high speed scanning CW laser.

Nanotechnology 2011 Apr 16;22(17):175307. Epub 2011 Mar 16.

Kanagawa Industrial Technology Center, Kanagawa Prefectural Government, 705-1 Shimo-Imaizumi, Ebina, Kanagawa 243-0435, Japan.

After a laser annealing experiment on Si wafer, we found an asymmetric sheet resistance on the surface of the wafer. Periodic nano-strip grating lines (nano-SGLs) were self-organized along the trace of one-time scanning of the continuous wave (CW) laser. Depending on laser power, the nano-trench formed with a period ranging from 500 to 800 nm with a flat trough between trench structures. This simple method of combining the scanning laser with high scanning speed of 300 m min(-1) promises a large area of nanostructure fabrication with a high output. As a demonstration of the versatile method, concentric circles were drawn on silicon substrate rotated by a personal computer (PC) cooling fan. Even with such a simple system, the nano-SGL showed iridescence from the concentric circles.
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http://dx.doi.org/10.1088/0957-4484/22/17/175307DOI Listing
April 2011

Sonothrombolysis for intraocular fibrin formation in an animal model.

Ultrasound Med Biol 2009 Nov 20;35(11):1845-53. Epub 2009 Aug 20.

Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima 890-8520, Japan.

Vascular diseases such as diabetic retinopathy or retinal arterial occlusion are always associated with retinal and/or choroidal vasculopathy and intravascular thrombosis is commonly found. The ultrasound (US) therapy is a recently developed technique to accelerate fibrinolysis and it is being applied to some clinical fields. The present study was to observe the effects of extraocular US exposure on intraocular fibrin, which is a deteriorating factor in various ocular diseases. Tubes containing human blood (2 mL) in the following groups were irradiated with US; US alone, US with tissue plasminogen activator (tPA), tPA alone, and saline (control). Fibrinolysis was quantified by measuring D-dimer after 2h. In rat eyes, intracameral fibrin (fibrin formation in the anterior chamber of the eye) was induced by YAG-laser-induced iris bleeding. Then, eyes in the following groups were irradiated with US; US alone, subconjunctival tPA alone, US and subconjunctival tPA, control. Intracameral fibrin was scored on day 3 (3+ maximum to 0). The temperatures of rat eyes were measured by infrared thermography. Histologic evaluation was also performed. D-dimer was increased by US with statistical significance (p <0.05) or tPA (p <0.01). D-dimer in US with tPA group was significantly higher than either US alone or tPA alone group (p <0.01). In rat eyes, the average intracameral fibrin score on day 3 was 1.4 in control group and 1.2 in subconjunctival tPA alone group; however, it decreased significantly in the US alone group (0.75; p <0.05, vs. control), US and subconjunctival tPA group (0.71; p <0.01, vs. control). The temperature was less than 34 degrees C after US exposure. No histologic damage was observed. US irradiation from outside accelerated intracameral fibrinolysis without causing apparent tissue damage. This noninvasive method might have therapeutic value for intraocular fibrin.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2009.05.023DOI Listing
November 2009

Inhibitory effects of sesquiterpene lactones isolated from Eupatorium chinense L. on IgE-mediated degranulation in rat basophilic leukemia RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice.

Bioorg Med Chem 2009 Apr 5;17(8):3189-97. Epub 2009 Mar 5.

Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan.

Sesquiterpene lactones (SQTLs) have been shown to suppress the degranulation as inferred by histamine release in rat basophilic leukemia RBL-2H3 cells. In this study, we isolated the 9 kinds of SQTLs from Eupatorium chinense L. and examined the effects of these SQTLs on the degranulation in RBL-2H3 cells. The chemical structures of two novel compounds (SQTL-3 and 8) were determined. All the SQTLs suppressed the degranulation from Ag-stimulated RBL-2H3 cells. To disclose the inhibitory mechanism of degranulation by SQTLs, we examined the activation of intracellular signaling molecules such as Lyn, Syk, and PLCgammas and intracellular free Ca(2+) concentration ([Ca(2+)]i). None of these SQTLs showed the activation of Syk and PLCgammas. The intracellular free Ca(2+) concentration ([Ca(2+)]i) was elevated by Fc epsilonRI activation, but SQTLs treatment reduced the elevation of [Ca(2+)]i by suppressing Ca(2+) influx. Thus, it was suggested that the suppression of Ag-stimulated degranulation by these SQTLs is mainly due to the decreased Ca(2+) influx. Furthermore, in order to clarify the in vivo effect of SQTL-rich extract, we administered SQTL-rich extract to the type I allergic model mice and measured the passive cutaneous anaphylaxis (PCA) reaction induced by IgE-antigen complex. The SQTLs remarkably suppressed PCA reaction in a dose-dependent manner. Thus, it was suggested that SQTLs would be a candidate as an anti-allergic agent.
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http://dx.doi.org/10.1016/j.bmc.2009.02.062DOI Listing
April 2009

On the respiratory mechanism during underwater oviposition in a damselfly Calopteryx cornelia Selys.

J Insect Physiol 2006 May 6;52(5):499-505. Epub 2006 Mar 6.

Biodiversity Conservation Research Group, National Institute for Environmental Studies, Tsukuba 305-8506, Japan.

Calopteryx cornelia females oviposit almost exclusively underwater in forest streams. Field observation showed that the duration of uninterrupted submerged oviposition ranged between 20 and 120 min and the number of eggs laid was linearly related to the time spent underwater. By holding a damselfly under water in a small jar, we measured the maximum 'submergence potential', which was defined as the time elapsed between placing the insect underwater and asphyxiation. A series of experiments showed that there was no gender difference in the submergence potential. This was about 120 min if a damselfly was allowed to change its position while under water. The submergence potential was shorter if the damselflies were kept motionless, if air bubbles trapped on the wing surfaces were removed by coating with Vaseline or if the water was hypoxic. By contrast, submergence potential was longer if a part of the wings were kept above the water surface, or if the water was agitated using a magnetic stirrer. These results suggest that ovipositing C. cornelia females depend for oxygen on the physical-gill action of the thin air layer trapped on the body and wing surfaces. Respiration capacity under water is not likely to be a limiting factor for ovipositing females during the production of a single clutch.
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http://dx.doi.org/10.1016/j.jinsphys.2006.01.009DOI Listing
May 2006

Motility recovery during the process of regeneration in freshwater planarians.

Behav Brain Res 2004 Apr;150(1-2):9-14

Graduate School of Mathematics, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan.

Planarians are phylogenetically considered to be the most primitive animals to have acquired a central nervous system and a bilateral symmetry. However, very little is known about the relationship between planarian brain integration and motility. A behavioural and histological study was therefore undertaken in an aspect of planarian motility recovery during its process of regeneration. Quantitative analysis showed that the tail-regenerates recovered their motility gradually as the new heads reformed, while the non-head reforming tail fragments showed no signs of recovery. The head fragments recovered their motility soon after cutting. The cephalic margin was not a function of the motility. The brain regenerated back to its original form in approximately two weeks, the same amount of time it took for the decapitated tails to recover their motility to initial levels. This study provides quantitative evidence that the planarian motility recovered in relation to the head formation during its process of regeneration. Our results reinforce the view that the brain plays a functional part in activating planarian motility.
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http://dx.doi.org/10.1016/j.bbr.2003.06.001DOI Listing
April 2004