DHC Corporation Laboratories

Japan

DHC Corporation Laboratories

Japan
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Kimura K.,Osaka Prefecture University | Takada M.,Osaka Prefecture University | Ishii T.,University of Shizuoka | Tsuji-Naito K.,DHC Corporation Laboratories | Akagawa M.,Osaka Prefecture University
Free Radical Biology and Medicine | Year: 2012

Pyrroloquinoline quinone (PQQ), a redox cofactor for bacterial dehydrogenases, has been implicated to be an important nutrient in mammals functioning as a potent growth factor. However, the underlying molecular mechanisms have not been elucidated. The present study revealed that PQQ induces the activation (tyrosine autophosphorylation) of epidermal growth factor receptor (EGFR) and its downstream signaling in a ligand-independent manner, leading to increased cellular proliferation in an epithelial cell line A431. PQQ inhibited protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the EGFR signaling by tyrosine dephosphorylation, to oxidatively modify the catalytic cysteine through its redox cycling activity to generate H 2O2. PQQ-inducible intracellular ROS production and EGFR activation were significantly suppressed by the pre-treatment with antioxidants. The intracellular redox state regulates the EGFR signaling through the redox-sensitive catalytic cysteine of PTP1B and modulates cell proliferation. Our data suggest that PQQ may stimulate epithelial cell proliferation by activating EGFR by oxidation and subsequent inactivation of PTP1B via its redox cycling. Our results provide novel insight into the mechanisms by which PQQ may function as a growth factor to contribute to mammalian growth. © 2012 Elsevier Inc.


Negishi T.,DHC Corporation | Denpo K.,DHC Corporation | Kamohara S.,DHC Corporation | Nakashima N.,DHC Corporation Laboratories | Kageyama M.,DHC Corporation Laboratories
Japanese Pharmacology and Therapeutics | Year: 2015

Objectives: We evaluate efficacy of a dietary supplement containing bovine alpha S1-casein tryptic hydrolysate, Hemerocallis flower extract, Arginin, and Ornithine on sleep disorders among Japanese adults. Methods: Ten subjects with sleep disorders were provided dietary supplement for two weeks. Each subject ingested every night during the treatment period. We evaluated sleep quality by using PSQI (Pittsburgh sleep quality index), OSA-MA (OSA sleep inventory MA version), and portable physiological signal recorder. Subjects completed the PSQI and OSA-MA before treatment, after two weeks, and after the cooling-up one week. Results: The result of this study provided evidence that improvement due to this supplement was observed for the sleep quality score. After two weeks treatment, sleep quality, daytime dysfunction, sleep disturbance, initiation and maintenance of sleep, sleepiness on rising, sleep length, and refreshing were improved. And these improvements did not remain after following one week. Conclusions: Bovine alpha S1-casein tryptic hydrolysate and Hemerocallis flower extract were effective for sleep disorders. Arginin and Ornithine have the helpful effect for improvement of sleep quality.


Tsuji-Naito K.,DHC Corporation Laboratories | Jack R.W.,Seperex Nutritionals Hong Kong Ltd.
Bioscience, Biotechnology and Biochemistry | Year: 2012

Concentrated fractions of low molecular weight whey proteins (1-30 kDa), that is concentrated bovine milk whey active proteins (CBP), have been found to enhance bone formation in both in vivo and clinical studies, but the underlying mechanisms are poorly understood. In this study, we found that CBP promoted osteoblastic differentiation in normal human osteoblasts, and determined the involvement of the c-jun NH 2-terminal kinase (JNK)-activating transcription factor 4 (ATF4) pathway. We observed that alkaline phosphatase activity and mineralization were significantly induced by CBP treatment. In addition, mRNA expression of ATF4 was intensely elevated in CBP-treated osteoblasts, indicating that the late-phase events of differentiation were promoted. We found that CBP activated the phosphorylation of JNK and extracellular signal-regulated kinase (ERK). Furthermore, pathway analyses using the various signaling pathway-specific inhibitors revealed that JNK activation, but not ERK activation, is essential for CBP-induced mineralization and ATF4 expression. Our results indicate that the JNK-mediated ATF4 pathway is required for CBP-promotive osteogenesis.


Kudo M.,DHC Corporation Laboratories | Katayoshi T.,DHC Corporation Laboratories | Kobayashi-Nakamura K.,DHC Corporation Laboratories | Akagawa M.,Osaka Prefecture University | Tsuji-Naito K.,DHC Corporation Laboratories
Biochemical and Biophysical Research Communications | Year: 2016

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. © 2016 DHC corporation.


Takasao N.,Osaka Prefecture University | Tsuji-Naito K.,DHC Corporation Laboratories | Ishikura S.,DHC Corporation Laboratories | Tamura A.,DHC Corporation Laboratories | Akagawa M.,Osaka Prefecture University
Journal of Agricultural and Food Chemistry | Year: 2012

The breakdown of collagenous networks with aging results in hypoactive changes in the skin. Accordingly, reviving stagnant collagen synthesis can help protect dermal homeostasis against aging. We searched for type I collagen biosynthesis-inducing substances in various foods using human dermal fibroblasts and found that cinnamon extract facilitates collagen biosynthesis. Cinnamon extract potently up-regulated both mRNA and protein expression levels of type I collagen without cytotoxicity. We identified cinnamaldehyde as a major active component promoting the expression of collagen by HPLC and NMR analysis. Since insulin-like growth factor-I (IGF-I) is the most potent stimulator of collagen biosynthesis in fibroblasts, we examined the effect of cinnamaldehyde on IGF-I signaling. Treatment with cinnamaldehyde significantly increased the phosphorylation levels of the IGF-I receptor and its downstream signaling molecules such as insulin receptor substrate-1 and Erk1/2 in an IGF-I-independent manner. These results suggested that cinnamon extract is useful in antiaging treatment of skin. © 2012 American Chemical Society.


Kamikubo R.,Osaka Prefecture University | Kai K.,Osaka Prefecture University | Tsuji-Naito K.,DHC Corporation Laboratories | Akagawa M.,Osaka Prefecture University
Molecular Nutrition and Food Research | Year: 2016

Scope: Nonalcoholic fatty liver disease is currently the most common chronic liver disease worldwide, characterized by excessive hepatic lipid accumulation without significant ethanol consumption. We have performed a screening for medicinal foods that inhibit hepatocytic lipid accumulation through activation of AMP-activated protein kinase (AMPK), which is a critical regulator of the hepatic lipid metabolism. Methods and results: We found that clove (Syzygium aromaticum), which is commonly used as a spice, markedly inhibits palmitate-inducible lipid accumulation in human HepG2 hepatocytes. Analyses of the clove extracts found that β-caryophyllene, an orally-active cannabinoid, is the principal suppressor of the lipid accumulation, and stimulates the phosphorylation of AMPK and acetyl-CoA carboxylase 1 (ACC1). Our data also showed that β-caryophyllene prevents the translocation of sterol regulatory element-binding protein-1c (SREBP-1c) into the nucleus and forkhead box protein O1 (FoxO1) into the cytoplasm through AMPK signaling, and consequently, induces a significant downregulation of fatty acid synthase (FAS) and upregulation of adipose triglyceride lipase, respectively. Moreover, we demonstrated that the β-caryophyllene-induced activation of AMPK could be mediated by the cannabinoid type 2 receptor-dependent Ca2+ signaling pathway. Conclusion: Our results suggest that β-caryophyllene has the potential efficacy in preventing and ameliorating nonalcoholic fatty liver disease and its associated metabolic disorders. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


PubMed | Osaka Prefecture University and DHC Corporation Laboratories
Type: Journal Article | Journal: Molecular nutrition & food research | Year: 2016

Nonalcoholic fatty liver disease is currently the most common chronic liver disease worldwide, characterized by excessive hepatic lipid accumulation without significant ethanol consumption. We have performed a screening for medicinal foods that inhibit hepatocytic lipid accumulation through activation of AMP-activated protein kinase (AMPK), which is a critical regulator of the hepatic lipid metabolism.We found that clove (Syzygium aromaticum), which is commonly used as a spice, markedly inhibits palmitate-inducible lipid accumulation in human HepG2 hepatocytes. Analyses of the clove extracts found that -caryophyllene, an orally-active cannabinoid, is the principal suppressor of the lipid accumulation, and stimulates the phosphorylation of AMPK and acetyl-CoA carboxylase 1 (ACC1). Our data also showed that -caryophyllene prevents the translocation of sterol regulatory element-binding protein-1c (SREBP-1c) into the nucleus and forkhead box protein O1 (FoxO1) into the cytoplasm through AMPK signaling, and consequently, induces a significant downregulation of fatty acid synthase (FAS) and upregulation of adipose triglyceride lipase, respectively. Moreover, we demonstrated that the -caryophyllene-induced activation of AMPK could be mediated by the cannabinoid type 2 receptor-dependent CaOur results suggest that -caryophyllene has the potential efficacy in preventing and ameliorating nonalcoholic fatty liver disease and its associated metabolic disorders.


Kosehira M.,Omnica Co. | Kageyama M.,DHC Corporation Laboratories | Kamohara S.,Health Science University | Kitaichi N.,Health Sciences University of Hokkaido
Japanese Pharmacology and Therapeutics | Year: 2015

Objective We wanted to verify clinically the relationship between absorption of anthocyanins (those plasma concentrations) and eye fatigue by using Standardized Bilberry Extract (SBE). Methods We performed a placebo-controlled, double-blind, randomized, and crossover clinical trial. Subjects were healthy males and females from 20 to 44 years old. Either 180 mg of SBE or placebo per day was administered orally for 7 days. The wash-out period for the crossover trial was 13days. At the end of the 7-day trial, subjects wore an eye mask for 10 minutes before playing a video game (tetris) an a smartphone for 30 minutes to induce VDT stress. It was evaluated HFC-1 values as an objective index, and questionnaire as a subjective index. The day after the consecutive 7-day trial, the subjects plasma concentration of anthocyanins was measured 1 hr after a administration of SBE or placebo. Result HFC-1 values of the subjects administered SBE showed significant improvement (P= 0.012) compared with those administered placebo. Moreover, plasma concentration of anthocyanins were correlated with HFC-1 values (r=-0.369), and subjective index by questionnaire (r=-0.530). Conclusion Administration of SBE for 7 days increase plasma concentration of anthocyanins, and improved the eye fatigue induced by VDT stress and/or nearsighted work.


Ishikura-Kinoshita S.,DHC Corporation Laboratories | Saeki H.,DHC Corporation Laboratories | Tsuji-Naito K.,DHC Corporation Laboratories
Journal of Investigative Dermatology | Year: 2012

Collagen fibers, structural elements responsible for mechanical strength in skin, are synthesized constitutively in response to cytokines such as IGF-I. However, little is known about their intracellular trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus during synthesis. We demonstrate herein that the BBF2 human homolog on chromosome 7 (BBF2H7)-mediated Sec23A pathway is involved in regulation of intracellular procollagen trafficking. The mRNA and protein expression of BBF2H7, Sec23A, and type I and III collagen (COL1 and COL3) was induced by IGF-I stimulation. In addition, the cleaved form of BBF2H7 was detected in IGF-I-treated cultures, indicating that activation occurs concurrently with its expression. Knockdown with small interfering RNAs targeting BBF2H7 caused a significant reduction in the expression of COL1 and COL3, regardless of IGF-I treatment. Both mitogen-activated protein kinase and phosphatidylinositol-3 kinase pathways via IGF-I receptor activation were required for BBF2H7 induction. Using immunofluorescence microscopy, we showed that Golgi apparatus dysmorphology is due to coat protein complex II vehicle hypoplasia caused by the absence of BBF2H7 and Sec23A. The BBF2H7-mediated Sec23A pathway was required for ER-to-Golgi procollagen trafficking to promote collagen synthesis. This role of growth factors such as IGF-I, which to our knowledge is previously unreported, suggests antiaging strategies. © 2012 The Society for Investigative Dermatology.


PubMed | DHC Corporation Laboratories
Type: Journal Article | Journal: The Journal of investigative dermatology | Year: 2012

Collagen fibers, structural elements responsible for mechanical strength in skin, are synthesized constitutively in response to cytokines such as IGF-I. However, little is known about their intracellular trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus during synthesis. We demonstrate herein that the BBF2 human homolog on chromosome 7 (BBF2H7)-mediated Sec23A pathway is involved in regulation of intracellular procollagen trafficking. The mRNA and protein expression of BBF2H7, Sec23A, and type I and III collagen (COL1 and COL3) was induced by IGF-I stimulation. In addition, the cleaved form of BBF2H7 was detected in IGF-I-treated cultures, indicating that activation occurs concurrently with its expression. Knockdown with small interfering RNAs targeting BBF2H7 caused a significant reduction in the expression of COL1 and COL3, regardless of IGF-I treatment. Both mitogen-activated protein kinase and phosphatidylinositol-3 kinase pathways via IGF-I receptor activation were required for BBF2H7 induction. Using immunofluorescence microscopy, we showed that Golgi apparatus dysmorphology is due to coat protein complex II vehicle hypoplasia caused by the absence of BBF2H7 and Sec23A. The BBF2H7-mediated Sec23A pathway was required for ER-to-Golgi procollagen trafficking to promote collagen synthesis. This role of growth factors such as IGF-I, which to our knowledge is previously unreported, suggests antiaging strategies.

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