Publications by authors named "Michiko Kudo"

9 Publications

  • Page 1 of 1

Alternate expression of PEPT1 and PEPT2 in epidermal differentiation is required for NOD2 immune responses by bacteria-derived muramyl dipeptide.

Biochem Biophys Res Commun 2020 01 19;522(1):151-156. Epub 2019 Nov 19.

DHC Corporation, Fundamental Research Laboratory, Division 2, 2-42 Hamada, Mihama-ku, Chiba, 261-0025, Japan. Electronic address:

Peptide transporters 1 and 2 (PEPT1 and PEPT2) are proton-coupled oligopeptide transporter members of the solute carrier 15 family and play a role in the cellular uptake of di/tri-peptides and peptidomimetics. Our previous work showed that PEPT2 is predominantly expressed within undifferentiated keratinocytes. Here we show that PEPT2 expression decreases as keratinocyte differentiation progresses and that PEPT1 alternately is expressed at later stages. Absolute quantification using quantitative polymerase chain reaction revealed that the expression level of PEPT1 is about 17 times greater than that of PEPT2. Immunohistochemical study of human skin provided evidence of PEPT1 in the epidermis. The uptake of glycylsarcosine into keratinocytes was significantly blocked by PEPT inhibitors, including nateglinide and glibenclamide. Moreover, we found that PEPT1 knockdown in differentiated keratinocytes significantly suppressed the influence of a bacterial-derived peptide, muramyl dipeptide (MDP), on the production of proinflammatory cytokine interleukin-8, implying that bacteria-derived oligopeptides can be transported by PEPT1 in advanced differentiated keratinocytes. Taken together, PEPT1 and PEPT2 may concertedly play an important role in MDP-NOD2 signaling in the epidermis, which provides new insight into the mechanisms of skin homeostasis against microbial pathogens.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.044DOI Listing
January 2020

Tomatidine Reduces Palmitate-Induced Lipid Accumulation by Activating AMPK via Vitamin D Receptor-Mediated Signaling in Human HepG2 Hepatocytes.

Mol Nutr Food Res 2019 11 10;63(22):e1801377. Epub 2019 Sep 10.

Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, 599-8531, Japan.

Scope: Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide, defined by hepatic over-accumulation of lipids without significant ethanol consumption. Pharmacological or bioactive food ingredients that suppress hepatic lipid accumulation through AMP-activated protein kinase (AMPK) signaling, which plays a critical role in the regulation of lipid metabolism, are searched.

Methods And Results: It is found that tomatidine, the aglycone of α-tomatine abundant in green tomatoes, significantly inhibits palmitate-provoked lipid accumulation and stimulates phosphorylation of AMPK and acetyl-CoA carboxylase 1 (ACC1) in human HepG2 hepatocytes. The results also indicate that tomatidine can enhance triglyceride turnover and decline in lipogenesis by upregulating adipose triglyceride lipase (ATGL) and downregulating fatty acid synthase (FAS) via the AMPK signaling-dependent regulation of transcription factors, element-binding protein-1c (SREBP-1c) and forkhead box protein O1 (FoxO1). Furthermore, mechanistic studies demonstrate that tomatidine-stimulated AMPK phosphorylation is due to CaMKKβ activation in response to an increase in intracellular Ca concentration. Finally, it is discovered that tomatidine functions as an agonist for vitamin D receptor to elicit AMPK-dependent suppression of lipid accumulation.

Conclusion: The in vitro study suggests the potential efficacy of tomatidine as a preventive and therapeutic treatment in obesity-related fatty liver diseases.
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http://dx.doi.org/10.1002/mnfr.201801377DOI Listing
November 2019

Bifunctional effects of O-methylated flavones from Scutellaria baicalensis Georgi on melanocytes: Inhibition of melanin production and intracellular melanosome transport.

PLoS One 2017 9;12(2):e0171513. Epub 2017 Feb 9.

Fundamental Research Laboratory, Fundamental Research Department, DHC Corporation, Chiba, Japan.

The growing interest in skin lightening has recently renewed attention on the esthetic applications of Chinese herbal medicine. Although Scutellaria baicalensis Georgi is used for antipyretic and antiinflammatory purposes, its whitening effect remains unclear. This study reports three major findings: (1) S. baicalensis has a potent inhibitory effect on melanogenesis; (2) wogonin and its glycoside are the active components of S. baicalensis; and (3) O-methylated flavones from S. baicalensis, such as wogonin, inhibit intracellular melanosome transport. Using a melanin quantification assay, we showed that S. baicalensis potently inhibits melanogenesis in B16F10 cells. Componential analyses revealed that the main components of S. baicalensis are baicalin, wogonoside, baicalein, wogonin, and oroxylin A. Among these five flavones, wogonin and wogonoside consistently inhibited melanogenesis in both B16F10 melanoma cells and primary melanocytes. Wogonin exhibited the strongest inhibition of melanin production and markedly lightened the color of skin equivalents. We identified microphthalmia-associated transcription factor and tyrosinase-related proteins as potential targets of wogonin- and wogonoside-induced melanogenesis suppression. In culture, we found that the melanosomes in wogonin-treated B16F10 cells were localized to the perinuclear region. Immunoblotting analyses revealed that wogonin significantly reduced in melanophilin protein, which is required for actin-based melanosome transport. Other actin-based melanosome transport-related molecules, i.e., Rab27A and myosin Va, were not affected by wogonin. Cotreatment with MG132 blocked the wogonin-induced decrease in melanophilin, suggesting that wogonin promotes the proteolytic degradation of melanophilin via the calpain/proteasomal pathway. We determined that the structural specificities of the mono-O-methyl group in the flavone A-ring and the aglycone form were responsible for reducing melanosome transport. Furthermore, wogonin and two wogonin analogs, mono-O-methyl flavones, strongly suppressed melanosome transport. Our findings suggest the applicability of S. baicalensis in the esthetic field. Thus, we propose a novel pharmacologic approach for the treatment of hyperpigmentation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300169PMC
August 2017

H(+)/peptide transporter (PEPT2) is expressed in human epidermal keratinocytes and is involved in skin oligopeptide transport.

Biochem Biophys Res Commun 2016 07 20;475(4):335-41. Epub 2016 May 20.

DHC Corporation Laboratories, Division 2, 2-42 Hamada, Mihama-ku, Chiba 261-0025, Japan. Electronic address:

Peptide transporter 2 (PEPT2) is a member of the proton-coupled oligopeptide transporter family, which mediates the cellular uptake of oligopeptides and peptide-like drugs. Although PEPT2 is expressed in many tissues, its expression in epidermal keratinocytes remains unclear. We investigated PEPT2 expression profile and functional activity in keratinocytes. We confirmed PEPT2 mRNA expression in three keratinocyte lines (normal human epidermal keratinocytes (NHEKs), immortalized keratinocytes, and malignant keratinocytes) by reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time RT-PCR. In contrast to PEPT1, PEPT2 expression in the three keratinocytes was similar or higher than that in HepG2 cells, used as PEPT2-positive cells. Immunolocalization analysis using human skin showed epidermal PEPT2 localization. We studied keratinocyte transport function by measuring the oligopeptide content using liquid chromatography/tandem mass spectrometry. Glycylsarcosine uptake in NHEKs was pH-dependent, suggesting that keratinocytes could absorb small peptides in the presence of an inward H(+) gradient. We also performed a skin-permeability test of several oligopeptides using skin substitute, suggesting that di- and tripeptides pass actively through the epidermis. In conclusion, PEPT2 is expressed in keratinocytes and involved in skin oligopeptide uptake.
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http://dx.doi.org/10.1016/j.bbrc.2016.05.093DOI Listing
July 2016

Caspase-independent apoptosis induction of quorum-sensing autoinducer analogs against chronic myeloid leukemia K562.

Invest New Drugs 2012 Jun 5;30(3):862-9. Epub 2011 Jan 5.

Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan.

Quorum sensing is defined as the ability of microorganisms to sense their population density via the release of signaling molecules called autoinducers (AIs). Various types of AI analogs were prepared and their antitumor properties against chronic myeloid leukemia (CML) K562 cells were investigated. Two AI analogs induced progressive apoptosis with JNK activation and p21 induction. In addition, this induction of apoptosis is not related to bcr-abl kinase, which sustains CML proliferation. However, the progression of apoptosis was not inhibited by a caspase family inhibitor. These results suggested that AI analogs could induce caspase-independent apoptosis in CML K562.
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http://dx.doi.org/10.1007/s10637-010-9623-zDOI Listing
June 2012

Interactions between antitumor drugs and vault RNA.

Nucleic Acids Symp Ser (Oxf) 2008 (52):217-8

Supramolecular Biology, International Graduate School of Arts and Sciences, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.

It is supposed that ribonucleoprotein particle vault is involved in detoxification processes and thus is related to multidrug resistance. The vault is composed of three proteins and three vault RNAs, hvg-1, -2 and -3. The direct interactions between vault components and drugs were not reported. Recently, we revealed the interactions between vault RNAs and mitoxantrone. Here, we examined the interactions between hvg-2 and six antitumor drugs by a chemical shift perturbation method of NMR. It was found that in addition to mitoxantrone, hvg-2 can interact with two drugs basically in the same way using the same site. The difference in the affinity was also noticed among three drugs. Hvg-2 did not bind to the other three drugs. It is suggested that the common or closely related chemical structure of the positive three drugs is recognized by vault RNA.
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http://dx.doi.org/10.1093/nass/nrn110DOI Listing
November 2010

Structure of RNA aptamer complexed with an RNA-binding peptide of Tat with aid of residue-specific 13C, 15N labeling.

Nucleic Acids Symp Ser (Oxf) 2005 (49):69-70

Supramolecular Biology, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.

An RNA aptamer containing two binding sites of HIV Tat exhibits extremely high affinity to Tat. We have determined the structure of the aptamer complexed with an RNA-binding peptide of Tat. The analysis was made feasible by the use of several peptides in which a single arginine residue was specifically 13C, 15N-labeled. Residue specific labeling of the peptide enhanced the identification of intermolecular contacts, which are otherwise hard to identify due to spectral overlapping. The structure of the complex has revealed the origin of the high affinity of the aptamer to Tat.
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http://dx.doi.org/10.1093/nass/49.1.69DOI Listing
June 2007

Structure of RNA aptamer for HIV Tat complexed with Tat-derived peptide.

Nucleic Acids Symp Ser (Oxf) 2004 (48):111-2

Department of Environment and Natural Sciences, Graduate School of Environment and Information Sciences, Yokohama National University, 79-7 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan.

An RNA aptamer containing two binding sites exhibits extremely high affinity to the HIV Tat protein. We previously reported the structure of the aptamer complexed with argininamide as the simplest analogue of Tat. Here, we have analyzed the structure of the aptamer complexed with the partial peptide of Tat, RKKRR. The profile of chemical sift perturbations for the aptamer upon complex formation with RKKRR revealed that RKKRR can be a realistic analogue of Tat to address the interactions between the arginine-rich motif of Tat and the aptamer. It was suggested that the aptamer interacts with different arginine residues of RKKRR simultaneously at the two binding sites, which can explain the extremely high affinity to Tat.
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http://dx.doi.org/10.1093/nass/48.1.111DOI Listing
July 2007

Potential candidates for cardiac resynchronization therapy in Japanese patients with idiopathic dilated cardiomyopathy--a Niigata multicenter study of DCM--.

Circ J 2004 Dec;68(12):1104-9

First Department of Internal Medicine, Division of Cardiology, Niigata University School of Medicine, Asahimachi, Niigata, Japan.

Background: The purpose of this study was to assess the candidates suitable for cardiac resynchronization therapy (CRT) and to examine the significance of the QRS duration in Japanese patients with idiopathic dilated cardiomyopathy (DCM).

Methods And Results: The study population consisted of 357 patients. The selection criteria for candidates suitable for CRT were QRS duration =130 ms, left ventricular ejection fraction (LVEF) =35% and New York Heart Association (NYHA) functional class III or IV by ACC/AHA/NASPE 2002 guidelines. We divided the study population into 2 groups: group A with a QRS duration <130 ms, and group B with a QRS duration =130 ms. In 25 of the 375 patients (7.0%), all the criteria were fulfilled. Group B had a significantly larger left ventricular diameter end-diastole and end-systole than group A (P<0.0001). Group B had a lower LVEF (P<0.0001). There was a fair inverse correlation (r=-0.58, P<0.0001) between the length of the QRS duration and LVEF.

Conclusion: Approximately 7% of the Japanese patients with DCM are CRT candidates. In the present study, we found that prolonged QRS duration was associated with poor systolic function.
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http://dx.doi.org/10.1253/circj.68.1104DOI Listing
December 2004
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