Publications by authors named "Ayaka Yamamoto"

22 Publications

  • Page 1 of 1

Ethanolamine Plasmalogen Suppresses Apoptosis in Human Intestinal Tract Cells by Attenuating Induced Inflammatory Stress.

ACS Omega 2021 Feb 22;6(4):3140-3148. Epub 2021 Jan 22.

Department of Life and Food Sciences, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.

Ethanolamine plasmalogen (PlsEtn) is a subtype of ethanolamine glycerophospholipids (EtnGpl). Recently, PlsEtn has attracted increasing research interest due to its beneficial effects in health and disease; however, its functional role in colonic health has not been well established. This study was conducted to determine the mechanism underlying the antiapoptotic effect of PlsEtn in human intestinal tract cells under induced inflammatory stress. Lipopolysaccharide induced apoptosis of differentiated Caco-2 cells, which was suppressed by EtnGpl in a dose-dependent manner. Cells treated with ascidian muscle EtnGpl containing high levels of PlsEtn demonstrated a lower degree of apoptosis, and downregulated TNF-α and apoptosis-related proteins compared to those treated with porcine liver EtnGpl containing low PlsEtn. This indicates that PlsEtn exerted the observed effects, which provided protection against induced inflammatory stress. Overall, our results suggest that PlsEtn with abundant vinyl ether linkages is potentially beneficial in preventing the initiation of inflammatory bowel disease and colon cancer.
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http://dx.doi.org/10.1021/acsomega.0c05545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860056PMC
February 2021

Absorption Kinetics of Ethanolamine Plasmalogen and Its Hydrolysate in Mice.

J Oleo Sci 2021 Feb 15;70(2):263-273. Epub 2021 Jan 15.

Food and Biotechnology Platform Promoting Project, New Industry Creation Hatchery Center (NICHe), Tohoku University.

Ethanolamine plasmalogen (PlsEtn), a subclass of ethanolamine glycerophospholipid (EtnGpl), has been reported to have many biological and dietary functions. In terms of PlsEtn absorption, some studies have reported that PlsEtn is re-esterized at the sn-2 position using lymph cannulation and the everted jejunal sac model. In this study, we aimed to better understand the uptake kinetics of PlsEtn and increase its absorption. We thus compared the uptake kinetics of PlsEtn with that of the lyso-form, in which the fatty acid at the sn-2 position was hydrolyzed enzymatically. Upon administration of EtnGpl (extracted from oysters or ascidians, 75.4 mol% and 88.4 mol% of PlsEtn ratio, respectively), the plasma PlsEtn species in mice showed the highest levels at 4 or 8 hours after administration. In the contrast, administration of the EtnGpl hydrolysate, which contained lysoEtnGpl and free fatty acids, markedly increased the plasma levels of PlsEtn species at 2 h after administration. The area under the plasma concentration-time curve (AUC), especially the AUC of PlsEtn species, was higher with hydrolysate administration than that with EtnGpl administration. These results indicate that EtnGpl hydrolysis accelerated the absorption and metabolism of PlsEtn. Consequently, using a different experimental approach from that used in previous studies, we reconfirmed that PlsEtn species were absorbed via hydrolysis at the sn-2 position, suggesting that hydrolysis in advance could increase PlsEtn uptake.
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http://dx.doi.org/10.5650/jos.ess20223DOI Listing
February 2021

Dietary PlsEtn Ameliorates Colon Mucosa Inflammatory Stress and ACF in DMH-Induced Colon Carcinogenesis Mice: Protective Role of Vinyl Ether Linkage.

Lipids 2021 03 29;56(2):167-180. Epub 2020 Sep 29.

Department of Life and Food Sciences, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, 080-8555, Japan.

Ethanolamine plasmalogen (PlsEtn), a sub-class of ethanolamine glycerophospholipids (EtnGpl), is a universal phospholipid in mammalian membranes. Several researchers are interested in the relationship between colon carcinogenesis and colon PlsEtn levels. Here, we evaluated the functional role of dietary purified EtnGpl from the ascidian muscle (87.3 mol% PlsEtn in EtnGpl) and porcine liver (7.2 mol% PlsEtn in EtnGpl) in 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) in vivo, and elucidated the possible underlying mechanisms behind it. Dietary EtnGpl-suppressed DMH-induced aberrant crypt with one foci (AC1) and total ACF formation (P < 0.05). ACF suppression by dietary ascidian muscle EtnGpl was higher compared with dietary porcine liver EtnGpl. Additionally, dietary EtnGpl decreased DMH-induced oxidative damage, overproduction of TNF-α, and expression of apoptosis-related proteins in the colon mucosa. The effect of dietary ascidian muscle EtnGpl showed superiority compared with dietary porcine liver EtnGpl. Our results demonstrate the mechanisms by which dietary PlsEtn suppress ACF formation and apoptosis. Dietary PlsEtn attained this suppression by reducing colon inflammation and oxidative stress hence a reduction in DMH-induced intestinal impairment. These findings provide new insights about the functional role of dietary PlsEtn during colon carcinogenesis.
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http://dx.doi.org/10.1002/lipd.12283DOI Listing
March 2021

Food Additives (Hypochlorous Acid Water, Sodium Metabisulfite, and Sodium Sulfite) Strongly Affect the Chemical and Biological Properties of Vitamin B in Aqueous Solution.

ACS Omega 2020 Mar 10;5(11):6207-6214. Epub 2020 Mar 10.

The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori City, Tottori 680-8553, Japan.

Food additives, such as hypochlorous acid water, sodium metabisulfite, and sodium sulfite, strongly affect the chemical and biological properties of vitamin B (cyanocobalamin) in aqueous solution. When cyanocobalamin (10 μmol/L) was treated with these compounds, hypochlorous acid water (an effective chlorine concentration of 30 ppm) rapidly reacted with cyanocobalamin. The maximum absorptions at 361 and 550 nm completely disappeared by 1 h, and vitamin B activity was lost. There were no significant changes observed in the absorption spectra of cyanocobalamin for 0.01% (w/v) sodium metabisulfite; however, a small amount of the reaction product was formed within 48 h, which was subsequently identified as sulfitocobalamin through high-performance liquid chromatography. Similar results were shown for sodium sulfite. The effects of these food additives on the vitamin B content of red shrimp and beef meats were determined, revealing no significant difference in vitamin B content of shrimp and beef meats with or without the treatment even in hypochlorous acid water. The results suggest that these food additives could not react with food vitamin B in food, as most of this vitamin present in food is its protein-bound form rather than the free form.
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http://dx.doi.org/10.1021/acsomega.0c00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097994PMC
March 2020

Identification and characterization of oligomeric proanthocyanidins with significant anti-cancer activity in adzuki beans ().

Heliyon 2019 Oct 23;5(10):e02610. Epub 2019 Oct 23.

Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minami-minowa Kami-ina, Nagano, 399-4598, Japan.

The aim of the present study was to characterize and evaluate the anti-cancer activity of proanthocyanidin-enriched fractions from adzuki beans. For this purpose, we concentrated proanthocyanidins from adzuki beans () into five fractions using Amberlite XAD-1180N, Toyopearl HW40F, and Sepacore C-18 reverse-phase flash column chromatography. Proanthocyanidin-enriched fractions were characterized as (epi)catechin hexamer, heptamer, and octamer, epigallocatechin-(epi)catechin pentamer, and epigallocatechin-(epi)catechin hexamer using electrospray ionization time-of-flight mass spectrometry and thiolytic degradation. These fractions showed significant anti-cancer activity against the human PC-3 prostate cancer cell line. They also significantly suppressed the expression of the fatty acid-binding protein 5 gene, which plays critical roles in cell growth and metastasis in prostate cancer.
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http://dx.doi.org/10.1016/j.heliyon.2019.e02610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820087PMC
October 2019

Catechin and caffeine contents in green tea at different harvest periods and their metabolism in miniature swine.

Food Sci Nutr 2019 Aug 28;7(8):2769-2778. Epub 2019 Jul 28.

Department of Food Science & Biotechnology, Faculty of Agriculture Kagoshima University Kagoshima Japan.

The catechin content in green tea leaves varies according to cultivation conditions such as intensity of solar radiation, temperature, and precipitation, and thus, there is ambiguity about the best harvest time for obtaining optimal functional effects. In this study, the Yabukita (ordinary) and Benifuki varieties, which contain methylated catechin, were used to determine the difference in green tea catechins according to harvest times and tea manufacturing processes. Caffeine determination was also carried out to provide information about green tea intake for all age-groups of children and pregnant women. Determining the quantity of each catechin was difficult because of degradation, polymerization, and isomerization that had occurred during heat-drying in the refining process. In addition, the absorption of catechin compounds was tested using miniature swine because of their functional and physiological similarity to humans. Benifuki tea leaves contained epigallocatechin-3-(3"-O-methyl) gallate (EGCg3"Me) instead of epigallocatechin-3-(4"-O-methyl) gallate (EGCg4"Me). However, EGCg4"Me was detected during the entire intake period, but EGCg3"Me was not detected in the blood of miniature swine fed Benifuki tea. It is possible that the position of the methyl group was modified by the pig metabolism. Furthermore, caffeine from both Yabukita and Benifuki tea varieties was found to be easily accumulated in miniature swine. These results suggest that nonrefined September-October picking tea (autumn and winter tea) of the Benifuki variety is preferable over the Yabukita variety for consumption by children and pregnant women owing to its lower caffeine content and higher content of methylated catechin.
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http://dx.doi.org/10.1002/fsn3.1143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694591PMC
August 2019

Isolation and characterization of a novel oligomeric proanthocyanidin with significant anti-cancer activities from grape stems (Vitis vinifera).

Sci Rep 2019 08 19;9(1):12046. Epub 2019 Aug 19.

Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minami-minowa Kami-ina, Nagano, 399-4598, Japan.

Novel proanthocyanidin fractions from grape stem extracts were purified using Amberlite XAD-1180N, Sephadex-LH-20, Toyopearl HW40F and reverse phase high-performance liquid chromatography. Two key compounds were estimated as epigallocatechin-(epicatechin) gallate using electron-spray ionization time-of-flight mass spectrometry. Epigallocatechin-(epicatechin) gallate (compound 1) showed significant anti-cancer activity in PC-3 prostate cancer cells. In particular, compound 1 suppressed the gene expression of fatty acid-binding protein 5 (FABP5), which is involved in promoting cell proliferation and metastasis in prostate cancer cells.
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http://dx.doi.org/10.1038/s41598-019-48603-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700121PMC
August 2019

Synergistic Effects of Olaparib and DNA-damaging Agents in Oesophageal Squamous Cell Carcinoma Cell Lines.

Anticancer Res 2019 Apr;39(4):1813-1820

Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.

Background/aim: Chemotherapy is an important first-line treatment for oesophageal squamous cell carcinoma (ESCC). However, there are few secondary options. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, enhances the cytotoxicity of various anticancer drugs and has been used to treat advanced ovarian and breast cancers. This study examined the effect of olaparib on the cytotoxicity of anticancer drugs in ESCC cell lines.

Materials And Methods: ESCC KYSE70 and KYSE140 cells were grown in Dulbecco's modified Eagle's medium and treated with 5-fluorouracil (5-FU), cisplatin, docetaxel, doxorubicin, SN-38, or temozolomide without or with olaparib.

Results: Olaparib enhanced the cytotoxicity of all tested anticancer drugs and increased the effects of cisplatin, doxorubicin, SN-38, and temozolomide synergistically. These anticancer drugs caused the accumulation of phospho-histone H2AX Ser139 (γH2AX), a biomarker of DNA damage, and olaparib increased this accumulation.

Conclusion: PARP inhibitors may potentiate the anticancer activity of DNA-damaging agents in ESCC patients synergistically.
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http://dx.doi.org/10.21873/anticanres.13288DOI Listing
April 2019

Mllt10 knockout mouse model reveals critical role of Af10-dependent H3K79 methylation in midfacial development.

Sci Rep 2017 09 20;7(1):11922. Epub 2017 Sep 20.

Laboratory of Developmental Neurobiology, Graduate School of Brain Science, Doshisha University, Kyoto, Japan.

Epigenetic regulation is required to ensure the precise spatial and temporal pattern of gene expression that is necessary for embryonic development. Although the roles of some epigenetic modifications in embryonic development have been investigated in depth, the role of methylation at lysine 79 (H3K79me) is poorly understood. Dot1L, a unique methyltransferase for H3K79, forms complexes with distinct sets of co-factors. To further understand the role of H3K79me in embryogenesis, we generated a mouse knockout of Mllt10, the gene encoding Af10, one Dot1L complex co-factor. We find homozygous Mllt10 knockout mutants (Mllt10-KO) exhibit midline facial cleft. The midfacial defects of Mllt10-KO embryos correspond to hyperterolism and are associated with reduced proliferation of mesenchyme in developing nasal processes and adjacent tissue. We demonstrate that H3K79me level is significantly decreased in nasal processes of Mllt10-KO embryos. Importantly, we find that expression of AP2α, a gene critical for midfacial development, is directly regulated by Af10-dependent H3K79me, and expression AP2α is reduced specifically in nasal processes of Mllt10-KO embryos. Suppression of H3K79me completely mimicked the Mllt10-KO phenotype. Together these data are the first to demonstrate that Af10-dependent H3K79me is essential for development of nasal processes and adjacent tissues, and consequent midfacial formation.
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http://dx.doi.org/10.1038/s41598-017-11745-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607342PMC
September 2017

Effect of oral theaflavin administration on body weight, fat, and muscle in healthy subjects: a randomized pilot study.

Biosci Biotechnol Biochem 2017 Feb 19;81(2):311-315. Epub 2016 Oct 19.

a R&D Division , Yaizu Suisankagaku Industry Co., Ltd. , Shizuoka , Japan.

Theaflavins are reddish-colored polyphenols in black tea. To test the efficacy of theaflavin administration on body fat and muscle, we performed a randomized, double-blind, placebo-controlled study and investigated the effect of theaflavins administration on the body composition using of healthy subjects. In this study, 30 male and female Japanese were enrolled and participants were randomly allocated to receive placebo, theaflavin (50 or 100 mg/day), or catechin (400 mg/ml) for 10 weeks. The effects were evaluated using body weight, body fat percentage, subcutaneous fat percentage, and skeletal muscle percentage. Theaflavin administration significantly improved body fat percentage, subcutaneous fat percentage, and skeletal muscle percentage when compared to with the placebo. In contrast, there was no significant difference in all measured outcomes between the catechin and the placebo groups. The results indicate that oral administration of theaflavin had a beneficial effect on body fat and muscle in healthy individuals.
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http://dx.doi.org/10.1080/09168451.2016.1246170DOI Listing
February 2017

Effects of conventional anticonvulsant drugs on generalized tonic-clonic seizures in Noda epileptic rats.

Epilepsy Res 2014 Sep 21;108(7):1158-67. Epub 2014 May 21.

Laboratory of Veterinary Physiology II, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.

Noda epileptic rats (NERs) present with clinico-pathological manifestations reminiscent of human generalized tonic-clonic epilepsy. Thus, this strain of rat has been a model of primary, generalized, tonic-clonic epilepsy. However, the infrequency of seizures in these rats makes the assessment of antiepileptic drugs (AEDs) difficult. Therefore, traditional AEDs have only been tested in NERs against audiogenic seizures evoked by weekly acoustic priming from 3 to 22 weeks of age or by using the kindling procedure in adult animals. Adult NERs are susceptible to changes in their environment, such as bedding replacement or unpleasant sensory stimuli. In the present study, traditional AEDs-phenobarbital (PB) and sodium valproate (VPA)-were evaluated against seizures evoked by strong environmental stimuli in mature NERs that had not been previously primed. The number of animals presenting with seizures decreased in a dose-dependent manner following administration of either PB (dose range 1.0-5.0mg/kg) or VPA (50 and 100mg/kg). Consequently, the utility of NERs as a model of generalized tonic-clonic epilepsy was confirmed. This type of protocol can be used to further evaluate AEDs and test effects of chronic administration of AEDs.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.05.004DOI Listing
September 2014

Efficient DNA fingerprinting based on the targeted sequencing of active retrotransposon insertion sites using a bench-top high-throughput sequencing platform.

DNA Res 2014 Oct 16;21(5):491-8. Epub 2014 Jun 16.

Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan

In many crop species, DNA fingerprinting is required for the precise identification of cultivars to protect the rights of breeders. Many families of retrotransposons have multiple copies throughout the eukaryotic genome and their integrated copies are inherited genetically. Thus, their insertion polymorphisms among cultivars are useful for DNA fingerprinting. In this study, we conducted a DNA fingerprinting based on the insertion polymorphisms of active retrotransposon families (Rtsp-1 and LIb) in sweet potato. Using 38 cultivars, we identified 2,024 insertion sites in the two families with an Illumina MiSeq sequencing platform. Of these insertion sites, 91.4% appeared to be polymorphic among the cultivars and 376 cultivar-specific insertion sites were identified, which were converted directly into cultivar-specific sequence-characterized amplified region (SCAR) markers. A phylogenetic tree was constructed using these insertion sites, which corresponded well with known pedigree information, thereby indicating their suitability for genetic diversity studies. Thus, the genome-wide comparative analysis of active retrotransposon insertion sites using the bench-top MiSeq sequencing platform is highly effective for DNA fingerprinting without any requirement for whole genome sequence information. This approach may facilitate the development of practical polymerase chain reaction-based cultivar diagnostic system and could also be applied to the determination of genetic relationships.
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http://dx.doi.org/10.1093/dnares/dsu015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195495PMC
October 2014

Fatty acid-bearing albumin but not fatty acid-depleted albumin induces HIF-1 activation in human renal proximal tubular epithelial cell line HK-2.

Biochem Biophys Res Commun 2014 Jul 9;450(1):476-81. Epub 2014 Jun 9.

Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

Recently, we found that albumin overload induces expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) protein and several HIF-1 target genes in human renal proximal tubular epithelial cell line HK-2. In this study, the role of albumin-bound fatty acids in the albumin-induced HIF-1 activation was studied. The enhancing effect of fatty acid-bearing human serum albumin [FA(+)HSA] treatment on HIF-1α protein expression was much greater than that of fatty acid-depleted human serum albumin [FA(-)HSA] treatment. The FA(+)HSA treatment induced HIF-1 target gene mRNAs such as those of glucose transporter 1 (GLUT1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and breast cancer resistance protein (BCRP) in concentration-dependent manners, while FA(-)HSA caused no significant increases in these mRNAs. Consistent with increased GLUT1 mRNA, GLUT1 protein expression and GLUT inhibitor cytochalasin B-sensitive d-[(3)H]glucose uptake activity were significantly enhanced by treatment with FA(+)HSA, but not with FA(-)HSA. These findings indicate that fatty acids bound to albumin play a crucial role in albumin-induced HIF-1 activation followed by changes in HIF-1 target gene expression and protein product activity.
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http://dx.doi.org/10.1016/j.bbrc.2014.05.146DOI Listing
July 2014

Albumin overload induces expression of hypoxia-inducible factor 1α and its target genes in HK-2 human renal proximal tubular cell line.

Biochem Biophys Res Commun 2013 May 12;434(3):670-5. Epub 2013 Apr 12.

Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

The aim of this study was to investigate the effect of human serum albumin (HSA) overload on the expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) in human renal proximal tubular cell line HK-2. First, the cell viability and cytotoxic activity were examined to assess the cellular conditions in HK-2 cells with HSA treatment employed in this study. HSA treatment for 48h decreased the cell viability and increased the leakage of lactate dehydrogenase (LDH) into the medium in a concentration-dependent manner, but the toxicity was relatively mild. Western Blot analysis revealed that HSA treatment induced the expression of HIF-1α protein in a concentration-dependent manner without a change in β-actin protein expression. Confocal microscopy analysis revealed that HIF-1α protein was predominantly localized in the nucleus but was also observed in the cytoplasm. The HIF-1 target gene mRNAs, glucose transporter 1 and glyceraldehyde 3-phosphate dehydrogenase, were up-regulated by HSA treatment, leading to the increases in the protein expression levels. In addition, the mRNA of HIF-1α was increased by HSA treatment. In conclusion, albumin loading induces HIF-1α in HK-2 cells, resulting in the increases in the expression of proteins of its target genes.
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http://dx.doi.org/10.1016/j.bbrc.2013.03.140DOI Listing
May 2013

PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction.

Clin Cancer Res 2013 Mar 22;19(6):1363-74. Epub 2013 Jan 22.

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

Purpose: Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be expressed in cancer cells. The purpose of this study is to elucidate the function of PD-L1 in peritoneal dissemination.

Experimental Design: Ovarian cancer cases were studied by microarray and immunohistochemistry. PD-L1 expression in mouse ovarian cancer cell line in various conditions was assessed by flow cytometry. PD-L1-overexpression cell line and PD-L1-depleted cell line were generated, and cytolysis by CTLs was analyzed, and alterations in CTLs were studied by means of timelapse and microarray. These cell lines were injected intraperitoneally to syngeneic immunocompetent mice.

Results: Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and peritoneal positive cytology. PD-L1 expression in mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and coculture with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression inhibited gathering and degranulation of CTLs. Gene expression profile of CTLs caused by PD-L1-overexpressing ovarian cancer was associated with CTLs exhaustion. In mouse models, PD-L1 depletion resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival.

Conclusion: PD-L1 expression in tumor cell promotes peritoneal dissemination by repressing CTL function. PD-L1-targeted therapy is a promising strategy for preventing and treating peritoneal dissemination.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2199DOI Listing
March 2013

Alanine scanning analyses of the three major loops in domain II of Bacillus thuringiensis mosquitocidal toxin Cry4Aa.

Appl Environ Microbiol 2010 Feb 30;76(3):860-5. Epub 2009 Nov 30.

Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-Naka, Okayama-Shi, Okayama 700-8530, Japan.

Cry4Aa produced by Bacillus thuringiensis is a dipteran-specific toxin and is of great interest for developing a bioinsecticide to control mosquitoes. Therefore, it is very important to characterize the functional motif of Cry4Aa that is responsible for its mosquitocidal activity. In this study, to characterize a potential receptor binding site, namely, loops 1, 2, and 3 in domain II, we constructed a series of Cry4Aa mutants in which a residue in these three loops was replaced with alanine. A bioassay using Culex pipiens larvae revealed that replacement of some residues affected the mosquitocidal activity of Cry4Aa, but the effect was limited. This finding was partially inconsistent with previous results which suggested that replacement of the Cry4Aa loop 2 results in a significant loss of mosquitocidal activity. Therefore, we constructed additional mutants in which multiple (five or six) residues in loop 2 were replaced with alanine. Although the replacement of multiple residues also resulted in some decrease in mosquitocidal activity, the mutants still showed relatively high activity. Since the insecticidal spectrum of Cry4Aa is specific, Cry4Aa must have a specific receptor on the surface of the target tissue, and loss of binding to the receptor should result in a complete loss of mosquitocidal activity. Our results suggested that, unlike the receptor binding site of the well-characterized molecule Cry1, the receptor binding site of Cry4Aa is different from loops 1, 2, and 3 or that there are multiple binding sites that work cooperatively for receptor binding.
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http://dx.doi.org/10.1128/AEM.02175-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813026PMC
February 2010

LAMP-2 positive vacuolar myopathy with dilated cardiomyopathy.

Intern Med 2007 1;46(11):757-60. Epub 2007 Jun 1.

Department of Neurology, National Hospital Organization, Miyazaki Higashi Hospital.

We report a 46-year-old male patient with late-onset vacuolar myopathy and dilated cardiomyopathy. Acid maltase activity of the muscle was normal, but the biopsied muscle specimen stained for lysosome-associated membrane protein-2 (LAMP-2), which has recently been reported to be deficient in muscles of patients with Danon disease. The clinical features of the patient are distinct from X-linked myopathy with excessive autophagy, infantile autophagic vacuolar myopathy and autophagic vacuolar myopathy with late-onset and multiorgan involvement (Kaneda).
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http://dx.doi.org/10.2169/internalmedicine.46.6265DOI Listing
July 2007

Subsequent exposure to the choline uptake enhancer MKC-231 antagonizes phencyclidine-induced behavioral deficits and reduction in septal cholinergic neurons in rats.

Eur Neuropsychopharmacol 2007 Sep 30;17(9):616-26. Epub 2007 Apr 30.

Department of Neuropsychiatry, Faculty of Medicine, Tottori University, Tottori, Japan.

This study examined the effects of subsequent, subchronic, treatment with choline uptake enhancer MKC-231 on the behavioral and cellular deficits induced by repeated PCP exposure in rats. Prior subchronic PCP exposure resulted in increased locomotion following an acute PCP or cocaine challenge, but resulted in decreased locomotor activity in response to a carbachol-challenge. MKC-231 significantly antagonized the alterations in the locomotor responses to cocaine and carbachol, but not to PCP. In the novel object recognition test, repeated PCP exposure caused cognitive deficits in rats, and the PCP-induced cognitive deficits were antagonized by MKC-231. In contrast, no effects of PCP exposure were shown in the repeated passive avoidance test. Furthermore, repeated PCP exposure decreased a number of choline acetyltransferase (ChAT)-positive cells in the medial septum and increased dynorphin A expression in the ventral striatum. Moreover, MKC-231 significantly antagonized the changes in septal ChAT-positive cells, but not the changes in ventrostriatal dynorphin A expression. These results suggest that MKC-231 could be a therapeutic drug for the treatment of schizophrenia.
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http://dx.doi.org/10.1016/j.euroneuro.2007.02.011DOI Listing
September 2007

Infusion of neuropeptide Y into CA3 region of hippocampus produces antidepressant-like effect via Y1 receptor.

Hippocampus 2007 ;17(4):271-80

Department of Neuropsychiatry, Faculty of Medicine, Tottori University, Yonago, Japan.

A couple of papers indicate that patients with depression show a decrease in serum neuropeptide Y (NPY). To study the role of NPY in depression, we examined the effects of infusion of NPY into the hippocampus of learned helplessness (LH) rats (an animal model of depression). Infusion of NPY into the cerebral ventricle of LH rats showed antidepressant-like effects. Infusion of NPY into the CA3 region, but not the dentate gyrus (DG), produced antidepressant-like effects in the LH paradigm. Infusion of NPY did not affect locomotor activity or aversive learning ability. Coadministration of BIBO3304 (a Y1 receptor antagonist) with NPY to the CA3 region blocked the antidepressant-like effects of NPY, whereas coadministration of NPY with BIIE0246 (a Y2 receptor antagonist) to the CA3 region failed to block antidepressant-like effects. Furthermore, infusions of [Leu(31) Pro(34)]PYY (a Y1 and Y5 receptor agonist) alone and BIIE0246 alone into the CA3 region produced the antidepressant-like effects in LH rats. These results suggest that infusion of NPY into the CA3 region of hippocampus of LH rats produces antidepressant-like activity through Y1 receptors and attenuating effects through Y2 receptors.
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http://dx.doi.org/10.1002/hipo.20264DOI Listing
June 2007

A study of a dendritic marker, microtubule-associated protein 2 (MAP-2), in rats neonatally treated neurosteroids, pregnenolone and dehydroepiandrosterone (DHEA).

Neurosci Lett 2005 Oct;386(3):145-9

Department of Neuropsychiatry, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.

Neurosteroids administered during the neonatal period affect the development of several brain systems. We examined the effects of neonatal treatment with pregnenolone and dehydroepiandrosterone (DHEA) on a marker of neuronal dendrites, microtubule-associated protein 2 (MAP-2), in rat brain. Neonatal treatment with pregnenolone and DHEA increased the expression of MAP-2 in the hippocampus and nucleus accumbens but not in the prefrontal cortex, striatum or amygdala in adulthood.
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http://dx.doi.org/10.1016/j.neulet.2005.06.004DOI Listing
October 2005

Characterization of Danon disease in a male patient and his affected mother.

Neuromuscul Disord 2003 Nov;13(9):708-11

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, 187-8502, Tokyo, Japan.

Danon disease, primary lysosome-associated membrane protein-2 (LAMP-2) deficiency, is histologically characterized by unusual vacuoles bound by membranes with sarcolemmal features in skeletal muscle. We studied skeletal muscle specimens from a male patient with genetically confirmed Danon disease who had two muscle biopsies, at age 20 months and 16 years, and from his mother with cardiomyopathy but without clinically apparent skeletal myopathy. In the patient, the number of vacuoles increased over the 14-year interval between biopsies, suggesting that the number of vacuolated fibers increases with age, and correlates with the development of muscle symptoms. In contrast, in the muscle biopsy from the mother there were no vacuoles even though she had decreased LAMP-2.
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http://dx.doi.org/10.1016/s0960-8966(03)00105-6DOI Listing
November 2003

Germline mosaicism of a novel mutation in lysosome-associated membrane protein-2 deficiency (Danon disease).

Ann Neurol 2002 Jul;52(1):122-5

Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.

We identified a family with lysosome-associated membrane protein-2 deficiency (Danon disease) associated with a novel 883 ins-T mutation in the lysosome-associated membrane protein-2 gene located at Xq24. Although the affected son and daughter carried the same mutation, it was not detected in their mother's peripheral blood or buccal cells; this indicated germline mosaicism. This is the first molecular evidence for germline mosaicism in Danon disease and has important implications for genetic counseling.
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http://dx.doi.org/10.1002/ana.10235DOI Listing
July 2002