23 results on '"Yoshitomo Suhara"'
Search Results
2. Effect of lonidamine derivatives on the inhibition of transformed cell area expansion
- Author
-
Megumi Aoyama, Taiki Homma, Ryohto Koharazawa, Yoshitomo Suhara, and Kentaro Semba
- Subjects
Transformed cell ,Cancer cells ,Lonidamine ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Expansion of transformed cell area is regulated by the surrounding nontransformed cells. Lonidamine (LND) was recently found to regulate transformed cell area expansion through suppressing the cell motility of nontransformed cells; however, the structure–activity relationship between LND and this inhibitory activity has yet to be elucidated. We synthesized several LND derivatives and evaluated their inhibitory activity against the expansion of transformed cell area and found that the halogenation pattern on the benzene ring moiety, the carboxylic acid moiety, and the overall hydrophobicity of the molecule were correlated with inhibition activity. We also found that the localization of the tight junction protein, zonula occludens-1 (ZO-1), in nontransformed cells was significantly altered after treatment with the LND derivatives that displayed inhibitory activity. Further studies with LND derivatives and monitoring the localization of ZO-1 may help to develop more active compounds for suppressing transformed cell area expansion and lead to new anticancer treatments.
- Published
- 2023
- Full Text
- View/download PDF
3. Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice.
- Author
-
Yoshihisa Hirota, Kimie Nakagawa, Keigo Isomoto, Toshiyuki Sakaki, Noboru Kubodera, Maya Kamao, Naomi Osakabe, Yoshitomo Suhara, and Toshio Okano
- Subjects
Medicine ,Science - Abstract
Calcium (Ca) absorption from the intestinal tract is promoted by active vitamin D (1α,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1α,25D3 plays an important role in osteogenesis, vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis. While it is known that, in contrast to ALF, ELD is an active ligand that directly acts on bone, the reason for its superior osteogenesis effects is unknown. Cyp27b1-knockout mice (Cyp27b1-/-mice) are congenitally deficient in 1α,25D3 and exhibit marked hypocalcemia and high parathyroid hormone levels, resulting in osteodystrophy involving bone hypocalcification and growth plate cartilage hypertrophy. However, because the vitamin D receptor is expressed normally in Cyp27b1-/-mice, they respond normally to 1α,25D3. Accordingly, in Cyp27b1-/-mice, the pharmacological effects of exogenously administered active vitamin D derivatives can be analyzed without being affected by 1α,25D3. We used Cyp27b1-/-mice to characterize and clarify the superior osteogenic effects of ELD on the bone in comparison with ALF. The results indicated that compared to ALF, ELD strongly induces ECaC2, calbindin-D9k, and CYP24A1 in the duodenum, promoting Ca absorption and decreasing the plasma concentration of 1α,25D3, resulting in improved osteogenesis. Because bone morphological measurements demonstrated that ELD has stronger effects on bone calcification, trabecular formation, and cancellous bone density than ALF, ELD appears to be a more effective therapeutic agent for treating postmenopausal osteoporosis, in which cancellous bone density decreases markedly. By using Cyp27b1-/-mice, this study was the first to succeed in clarifying the osteogenic effect of ELD without any influence of endogenous 1α,25D3. Furthermore, ELD more strongly enhanced bone mineralization, trabecular proliferation, and cancellous bone density than did ALF. Thus, ELD is expected to show an effect on postmenopausal osteoporosis, in which cancellous bone mineral density decreases markedly. In the future, this study may enable the development of next-generation active vitamin D derivatives with higher affinity for bone than ELD.
- Published
- 2018
- Full Text
- View/download PDF
4. Comparison of the sympathetic stimulatory abilities of B-type procyanidins based on induction of uncoupling protein-1 in brown adipose tissue (BAT) and increased plasma catecholamine (CA) in mice.
- Author
-
Yuta Nakagawa, Kana Ishimura, Satomi Oya, Masaki Kamino, Yasuyuki Fujii, Fumio Nanba, Toshiya Toda, Takeshi Ishii, Takahiro Adachi, Yoshitomo Suhara, and Naomi Osakabe
- Subjects
Medicine ,Science - Abstract
OBJECTIVES:We previously found that elevated energy expenditure following a single oral dose of flavan 3-ols (FL), a mixture of catechins and B type procyanidins, is caused by sympathetic nerve activation. In the present study, we compared the activity of the FL components (-)-epicatechin (EC; monomer), procyanidin B2 (B2; dimer), procyanidin C1 (C1; trimer), cinnamtannin A2 (A2; tetramer), and more than pentamer fraction (P5). METHODS:Male ICR mice were treated with a single oral dose of FL, EC, B2, C1, A2, or P5. The animals were sacrificed and blood and brown adipose tissue (BAT) sampled. The plasma catecholamine (CA) levels and BAT uncoupling protein (UCP)-1 mRNA expression were determined. RESULTS:A single dose of 10 mg/kg FL significantly increased plasma CA and UCP-1 mRNA levels. B2, C1, and A2, but not EC and P5 (all at 1 mg/kg), significantly increased plasma adrenaline levels. Plasma noradrenaline was significantly elevated by B2 and A2, but not by EC, C1, or P5. UCP-1 mRNA levels were significantly increased by C1 and P5. In the dose response study of A2, 10-3 mg/kg A2 increased UCP-1 mRNA levels significantly, but not 10-2 and 10-1 mg/kg A2. In addition, combination treatment with 10-1 mg/kg A2 and yohimbine, an α2 adrenalin blocker, remarkably increased UCP-1 mRNA levels. CONCLUSION:These results suggest that FL and its components, except EC, increase UCP-1 mRNA and plasma CA with varying efficacy.
- Published
- 2018
- Full Text
- View/download PDF
5. Elucidation of the Interaction between Flavan-3-ols and Bovine Serum Albumin and Its Effect on Their In-Vitro Cytotoxicity
- Author
-
Yasuyuki Fujii, Yoshitomo Suhara, Yusuke Sukikara, Tomohiro Teshima, Yoshihisa Hirota, Kenjiro Yoshimura, and Naomi Osakabe
- Subjects
flavan-3-ols ,bovine serum albumin ,docking simulation ,b-type procyanidin ,cytotoxicity ,Organic chemistry ,QD241-441 - Abstract
Flavan-3-ols (FLs), specifically catechin and its oligomer B-type procyanidins, are suggested to potently bind to bovine serum albumin (BSA). We examined the interaction between BSA and FLs by fluorescence quenching and found the following order of binding activities to BSA: cinnamtannin A2 (A2; tetramer) > procyanidin C1 (C1; trimer) ≈ procyanidin B2 (B2, dimer) > (−)epicatechin (EC, monomer). Docking simulations between BSA and each compound at the binding site showed that the calculated binding energies were consistent with the results of our experimental assay. FLs exerted cytotoxicity at 1000 μg/mL in F11 cell culture with fetal bovine serum containing BSA. In culture containing serum-free medium, FLs exhibited significant cell proliferation at 10−4 μg/mL and cytotoxicity was observed at concentrations greater than 10 μg/mL. Results of this study suggest that interactions between polyphenols and BSA should be taken into account when evaluating procyanidin in an in vitro cell culture system.
- Published
- 2019
- Full Text
- View/download PDF
6. New Aspects of Vitamin K Research with Synthetic Ligands: Transcriptional Activity via SXR and Neural Differentiation Activity
- Author
-
Yoshihisa Hirota and Yoshitomo Suhara
- Subjects
vitamin K ,ã-glutamyl carboxylase (GGCX) ,steroid and xenobiotic receptor (SXR) ,neural differentiation action ,UBIAD1 ,derivatives research ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Vitamin K is classified into three homologs depending on the side-chain structure, with 2-methyl-1,4-naphthoqumone as the basic skeleton. These homologs are vitamin K1 (phylloquinone: PK), derived from plants with a phythyl side chain; vitamin K2 (menaquinone-n: MK-n), derived from intestinal bacteria with an isoprene side chain; and vitamin K3 (menadione: MD), a synthetic product without a side chain. Vitamin K homologs have physiological effects, including in blood coagulation and in osteogenic activity via γ-glutamyl carboxylase and are used clinically. Recent studies have revealed that vitamin K homologs are converted to MK-4 by the UbiA prenyltransferase domain-containing protein 1 (UBIAD1) in vivo and accumulate in all tissues. Although vitamin K is considered to have important physiological effects, its precise activities and mechanisms largely remain unclear. Recent research on vitamin K has suggested various new roles, such as transcriptional activity as an agonist of steroid and xenobiotic nuclear receptor and differentiation-inducing activity in neural stem cells. In this review, we describe synthetic ligands based on vitamin K and exhibit that the strength of biological activity can be controlled by modification of the side chain part.
- Published
- 2019
- Full Text
- View/download PDF
7. UBIAD1 Plays an Essential Role in the Survival of Pancreatic Acinar Cells
- Author
-
Kimie Nakagawa, Kiyomi Fujiwara, Akihiro Nishimura, Chinami Murakami, Kanaha Kawamoto, Chihiro Ichinose, Yumi Kunitou, Yoshitomo Suhara, Toshio Okano, and Hiroshi Hasegawa
- Subjects
UBIAD1 ,MK-4 ,tamoxifen ,knockout mice ,pancreas ,acinar cells ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K2 biosynthetic enzyme. We previously showed the lethality of this enzyme in UBIAD1 knockout mice during the embryonic stage. However, the biological effects of UBIAD1 deficiency after birth remain unclear. In the present study, we used a tamoxifen-inducible systemic UBIAD1 knockout mouse model to determine the role of UBIAD1 in adult mice. UBIAD1 knockout resulted in the death of the mice within about 60 days of administration of tamoxifen. The pancreas presented with the most prominent abnormality in the tamoxifen-induced UBIAD1 knockout mice. The pancreas was reduced remarkably in size; furthermore, the pancreatic acinar cells disappeared and were replaced by vacuoles. Further analysis revealed that the vacuoles were adipocytes. UBIAD1 deficiency in the pancreatic acinar cells caused an increase in oxidative stress and autophagy, leading to apoptotic cell death in the tamoxifen-induced UBIAD 1 knockout mice. These results indicate that UBIAD1 is essential for maintaining the survival of pancreatic acinar cells in the pancreas.
- Published
- 2019
- Full Text
- View/download PDF
8. Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1.
- Author
-
Yoshihisa Hirota, Kimie Nakagawa, Natsumi Sawada, Naoko Okuda, Yoshitomo Suhara, Yuri Uchino, Takashi Kimoto, Nobuaki Funahashi, Maya Kamao, Naoko Tsugawa, and Toshio Okano
- Subjects
Medicine ,Science - Abstract
UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a significant role in vitamin K2 (MK-4) synthesis. We investigated the enzymological properties of UBIAD1 using microsomal fractions from Sf9 cells expressing UBIAD1 by analysing MK-4 biosynthetic activity. With regard to UBIAD1 enzyme reaction conditions, highest MK-4 synthetic activity was demonstrated under basic conditions at a pH between 8.5 and 9.0, with a DTT ≥0.1 mM. In addition, we found that geranyl pyrophosphate and farnesyl pyrophosphate were also recognized as a side-chain source and served as a substrate for prenylation. Furthermore, lipophilic statins were found to directly inhibit the enzymatic activity of UBIAD1. We analysed the aminoacid sequences homologies across the menA and UbiA families to identify conserved structural features of UBIAD1 proteins and focused on four highly conserved domains. We prepared protein mutants deficient in the four conserved domains to evaluate enzyme activity. Because no enzyme activity was detected in the mutants deficient in the UBIAD1 conserved domains, these four domains were considered to play an essential role in enzymatic activity. We also measured enzyme activities using point mutants of the highly conserved aminoacids in these domains to elucidate their respective functions. We found that the conserved domain I is a substrate recognition site that undergoes a structural change after substrate binding. The conserved domain II is a redox domain site containing a CxxC motif. The conserved domain III is a hinge region important as a catalytic site for the UBIAD1 enzyme. The conserved domain IV is a binding site for Mg2+/isoprenyl side-chain. In this study, we provide a molecular mapping of the enzymological properties of UBIAD1.
- Published
- 2015
- Full Text
- View/download PDF
9. A Single Oral Administration of Theaflavins Increases Energy Expenditure and the Expression of Metabolic Genes.
- Author
-
Naoto Kudo, Yasunori Arai, Yoshitomo Suhara, Takeshi Ishii, Tsutomu Nakayama, and Naomi Osakabe
- Subjects
Medicine ,Science - Abstract
Theaflavins are polyphenols found in black tea, whose physiological activities are not well understood. This study on mice evaluated the influence of a single oral administration of theaflavins on energy metabolism by monitoring the initial metabolic changess in skeletal muscle and brown adipose tissue (BAT). Oxygen consumption (VO2) and energy expenditure (EE) were increased significantly in mice treated with theaflavin rich fraction (TF) compared with the group administered vehicle alone. There was no difference in locomotor activity. Fasting mice were euthanized under anesthesia before and 2 and 5, 20-hr after treatment with TF or vehicle. The mRNA levels of uncoupling protein-1 (UCP-1) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in BAT were increased significantly 2-hr after administration ofTF. The levels of UCP-3 and PGC-1α in the gastrocnemius muscle were increased significantly 2 and 5-hr after administration of TF. The concentration of phosphorylated AMP-activated protein kinase (AMPK) 1α was also increased significantly in the gastrocnemius 2 and 5-hr after treatment with TF. These results indicate that TF significantly enhances systemic energy expenditure, as evidenced by an increase in expression of metabolic genes.
- Published
- 2015
- Full Text
- View/download PDF
10. Substitution at the C-3 Position of Catechins Has an Influence on the Binding Affinities against Serum Albumin
- Author
-
Masaki Ikeda, Manabu Ueda-Wakagi, Kaori Hayashibara, Rei Kitano, Masaya Kawase, Kunihiro Kaihatsu, Nobuo Kato, Yoshitomo Suhara, Naomi Osakabe, and Hitoshi Ashida
- Subjects
catechin ,serum albumin ,interaction ,docking study ,fluorescence analysis ,Organic chemistry ,QD241-441 - Abstract
It is known that catechins interact with the tryptophan (Trp) residue at the drug-binding site of serum albumin. In this study, we used catechin derivatives to investigate which position of the catechin structure strongly influences the binding affinity against bovine serum albumin (BSA) and human serum albumin (HSA). A docking simulation showed that (−)-epigallocatechin gallate (EGCg) interacted with both Trp residues of BSA (one at drug-binding site I and the other on the molecular surface), mainly by π–π stacking. Fluorescence analysis showed that EGCg and substituted EGCg caused a red shift of the peak wavelength of Trp similarly to warfarin (a drug-binding site I-specific compound), while 3-O-acyl-catechins caused a blue shift. To evaluate the binding affinities, the quenching constants were determined by the Stern–Volmer equation. A gallate ester at the C-3 position increased the quenching constants of the catechins. Against BSA, acyl substitution increased the quenching constant proportionally to the carbon chain lengths of the acyl group, whereas methyl substitution decreased the quenching constant. Against HSA, neither acyl nor methyl substitution affected the quenching constant. In conclusion, substitution at the C-3 position of catechins has an important influence on the binding affinity against serum albumin.
- Published
- 2017
- Full Text
- View/download PDF
11. Vitamin K2 biosynthetic enzyme, UBIAD1 is essential for embryonic development of mice.
- Author
-
Kimie Nakagawa, Natsumi Sawada, Yoshihisa Hirota, Yuri Uchino, Yoshitomo Suhara, Tomoka Hasegawa, Norio Amizuka, Tadashi Okamoto, Naoko Tsugawa, Maya Kamao, Nobuaki Funahashi, and Toshio Okano
- Subjects
Medicine ,Science - Abstract
UbiA prenyltransferase domain containing 1 (UBIAD1) is a novel vitamin K2 biosynthetic enzyme screened and identified from the human genome database. UBIAD1 has recently been shown to catalyse the biosynthesis of Coenzyme Q10 (CoQ10) in zebrafish and human cells. To investigate the function of UBIAD1 in vivo, we attempted to generate mice lacking Ubiad1, a homolog of human UBIAD1, by gene targeting. Ubiad1-deficient (Ubiad1(-/-)) mouse embryos failed to survive beyond embryonic day 7.5, exhibiting small-sized body and gastrulation arrest. Ubiad1(-/-) embryonic stem (ES) cells failed to synthesize vitamin K2 but were able to synthesize CoQ9, similar to wild-type ES cells. Ubiad1(+/-) mice developed normally, exhibiting normal growth and fertility. Vitamin K2 tissue levels and synthesis activity were approximately half of those in the wild-type, whereas CoQ9 tissue levels and synthesis activity were similar to those in the wild-type. Similarly, UBIAD1 expression and vitamin K2 synthesis activity of mouse embryonic fibroblasts prepared from Ubiad1(+/-) E15.5 embryos were approximately half of those in the wild-type, whereas CoQ9 levels and synthesis activity were similar to those in the wild-type. Ubiad1(-/-) mouse embryos failed to be rescued, but their embryonic lifespans were extended to term by oral administration of MK-4 or CoQ10 to pregnant Ubiad1(+/-) mice. These results suggest that UBIAD1 is responsible for vitamin K2 synthesis but may not be responsible for CoQ9 synthesis in mice. We propose that UBIAD1 plays a pivotal role in embryonic development by synthesizing vitamin K2, but may have additional functions beyond the biosynthesis of vitamin K2.
- Published
- 2014
- Full Text
- View/download PDF
12. Recent Advances in the Medicinal Chemistry of Vitamin K Derivatives: An Overview (2000–2021)
- Author
-
Shinya Fujii, Yoshitomo Suhara, and Hiroyuki Kagechika
- Abstract
In recent decades, many physiological and pharmacological functions of vitamin K other than its role as the cofactor of γ-glutamyl carboxylase (GGCX) have been identified, and consequently, many vitamin K derivatives and related congeners, including putative metabolites, have been designed and synthesized. Their biological activities include antitumor activity, anti-inflammatory activity, neuroprotective effects, neural differentiation-inducing activity, and modulating potency toward the nuclear steroid and xenobiotic receptor (SXR). These activities make vitamin K and its derivatives attractive candidates for drug discovery. In this chapter, an overview of recent advances in the medicinal chemistry of vitamin K, focusing especially on SXR modulation, neural differentiation, and antitumor activities, was provided.
- Published
- 2022
13. Elucidation of the Interaction between Flavan-3-ols and Bovine Serum Albumin and Its Effect on Their In-Vitro Cytotoxicity
- Author
-
Yoshihisa Hirota, Yasuyuki Fujii, Yusuke Sukikara, Tomohiro Teshima, Naomi Osakabe, Kenjiro Yoshimura, and Yoshitomo Suhara
- Subjects
Pharmaceutical Science ,01 natural sciences ,Catechin ,Culture Media, Serum-Free ,Analytical Chemistry ,Anthocyanins ,chemistry.chemical_compound ,Drug Discovery ,B-type procyanidin ,Bovine serum albumin ,Cytotoxicity ,skin and connective tissue diseases ,Procyanidin B2 ,0303 health sciences ,biology ,Molecular Structure ,Serum Albumin, Bovine ,musculoskeletal system ,Molecular Docking Simulation ,Chemistry (miscellaneous) ,Molecular Medicine ,cytotoxicity ,Procyanidin C1 ,Protein Binding ,musculoskeletal diseases ,Serum albumin ,Article ,Flavan-3-ols ,Cell Line ,lcsh:QD241-441 ,03 medical and health sciences ,Tetramer ,lcsh:Organic chemistry ,docking simulation ,bovine serum albumin ,Animals ,Biflavonoids ,Proanthocyanidins ,Physical and Theoretical Chemistry ,030304 developmental biology ,Cell Proliferation ,Flavonoids ,Chromatography ,Binding Sites ,010405 organic chemistry ,Organic Chemistry ,0104 chemical sciences ,Rats ,chemistry ,Cell culture ,biology.protein ,Cattle ,Fetal bovine serum - Abstract
Flavan-3-ols (FLs), specifically catechin and its oligomer B-type procyanidins, are suggested to potently bind to bovine serum albumin (BSA). We examined the interaction between BSA and FLs by fluorescence quenching and found the following order of binding activities to BSA: cinnamtannin A2 (A2, tetramer) >, procyanidin C1 (C1, trimer) &asymp, procyanidin B2 (B2, dimer) >, (&minus, )epicatechin (EC, monomer). Docking simulations between BSA and each compound at the binding site showed that the calculated binding energies were consistent with the results of our experimental assay. FLs exerted cytotoxicity at 1000 &mu, g/mL in F11 cell culture with fetal bovine serum containing BSA. In culture containing serum-free medium, FLs exhibited significant cell proliferation at 10&minus, 4 &mu, g/mL and cytotoxicity was observed at concentrations greater than 10 &mu, g/mL. Results of this study suggest that interactions between polyphenols and BSA should be taken into account when evaluating procyanidin in an in vitro cell culture system.
- Published
- 2019
14. UBIAD1 Plays an Essential Role in the Survival of Pancreatic Acinar Cells
- Author
-
Hiroshi Hasegawa, Chihiro Ichinose, Kanaha Kawamoto, Kiyomi Fujiwara, Yoshitomo Suhara, Chinami Murakami, Kimie Nakagawa, Toshio Okano, Akihiro Nishimura, and Yumi Kunitou
- Subjects
acinar cells ,Neutrophils ,Apoptosis ,Vacuole ,medicine.disease_cause ,lcsh:Chemistry ,Mice ,Adipocytes ,pancreas ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,Mice, Knockout ,tamoxifen ,Vitamin K2 ,General Medicine ,Immunohistochemistry ,Computer Science Applications ,Cell biology ,medicine.anatomical_structure ,Phenotype ,Neutrophil Infiltration ,Knockout mouse ,MK-4 ,Female ,Pancreas ,medicine.drug ,Genotype ,Cell Survival ,Biology ,Catalysis ,Article ,Cell Line ,Inorganic Chemistry ,medicine ,Autophagy ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,Organic Chemistry ,Mesenchymal Stem Cells ,Dimethylallyltranstransferase ,Oxidative Stress ,Enzyme ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Genes, Lethal ,Atrophy ,UBIAD1 ,Oxidative stress ,Tamoxifen ,knockout mice - Abstract
UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K2 biosynthetic enzyme. We previously showed the lethality of this enzyme in UBIAD1 knockout mice during the embryonic stage. However, the biological effects of UBIAD1 deficiency after birth remain unclear. In the present study, we used a tamoxifen-inducible systemic UBIAD1 knockout mouse model to determine the role of UBIAD1 in adult mice. UBIAD1 knockout resulted in the death of the mice within about 60 days of administration of tamoxifen. The pancreas presented with the most prominent abnormality in the tamoxifen-induced UBIAD1 knockout mice. The pancreas was reduced remarkably in size, furthermore, the pancreatic acinar cells disappeared and were replaced by vacuoles. Further analysis revealed that the vacuoles were adipocytes. UBIAD1 deficiency in the pancreatic acinar cells caused an increase in oxidative stress and autophagy, leading to apoptotic cell death in the tamoxifen-induced UBIAD 1 knockout mice. These results indicate that UBIAD1 is essential for maintaining the survival of pancreatic acinar cells in the pancreas.
- Published
- 2019
15. Comparison of the sympathetic stimulatory abilities of B-type procyanidins based on induction of uncoupling protein-1 in brown adipose tissue (BAT) and increased plasma catecholamine (CA) in mice
- Author
-
Toshiya Toda, Masaki Kamino, Naomi Osakabe, Yasuyuki Fujii, Yuta Nakagawa, Kana Ishimura, Satomi Oya, Yoshitomo Suhara, Fumio Nanba, Takeshi Ishii, and Takahiro Adachi
- Subjects
Male ,0301 basic medicine ,Physiology ,Administration, Oral ,Adipose tissue ,lcsh:Medicine ,Biochemistry ,chemistry.chemical_compound ,Catecholamines ,Adipose Tissue, Brown ,Brown adipose tissue ,Blood plasma ,Medicine and Health Sciences ,Amines ,lcsh:Science ,Procyanidin B2 ,Uncoupling Protein 1 ,Liquid Chromatography ,Mice, Inbred ICR ,Multidisciplinary ,Organic Compounds ,Ingestion ,Chromatographic Techniques ,Neurochemistry ,Neurotransmitters ,Thermogenin ,Body Fluids ,Yohimbine ,Chemistry ,Blood ,medicine.anatomical_structure ,Adipose Tissue ,Physical Sciences ,Seeds ,Brown Adipose Tissue ,Anatomy ,Research Article ,medicine.drug ,Procyanidin C1 ,Biogenic Amines ,medicine.medical_specialty ,Epinephrine ,Materials by Structure ,Materials Science ,Research and Analysis Methods ,Blood Plasma ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Proanthocyanidins ,RNA, Messenger ,030102 biochemistry & molecular biology ,Organic Chemistry ,lcsh:R ,Chemical Compounds ,Biology and Life Sciences ,Hormones ,High Performance Liquid Chromatography ,Gastrointestinal Tract ,Biological Tissue ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,chemistry ,Oligomers ,Catecholamine ,lcsh:Q ,Soybeans ,Physiological Processes ,Digestive System ,Neuroscience - Abstract
Objectives We previously found that elevated energy expenditure following a single oral dose of flavan 3-ols (FL), a mixture of catechins and B type procyanidins, is caused by sympathetic nerve activation. In the present study, we compared the activity of the FL components (-)-epicatechin (EC; monomer), procyanidin B2 (B2; dimer), procyanidin C1 (C1; trimer), cinnamtannin A2 (A2; tetramer), and more than pentamer fraction (P5). Methods Male ICR mice were treated with a single oral dose of FL, EC, B2, C1, A2, or P5. The animals were sacrificed and blood and brown adipose tissue (BAT) sampled. The plasma catecholamine (CA) levels and BAT uncoupling protein (UCP)-1 mRNA expression were determined. Results A single dose of 10 mg/kg FL significantly increased plasma CA and UCP-1 mRNA levels. B2, C1, and A2, but not EC and P5 (all at 1 mg/kg), significantly increased plasma adrenaline levels. Plasma noradrenaline was significantly elevated by B2 and A2, but not by EC, C1, or P5. UCP-1 mRNA levels were significantly increased by C1 and P5. In the dose response study of A2, 10−3 mg/kg A2 increased UCP-1 mRNA levels significantly, but not 10−2 and 10−1 mg/kg A2. In addition, combination treatment with 10−1 mg/kg A2 and yohimbine, an α2 adrenalin blocker, remarkably increased UCP-1 mRNA levels. Conclusion These results suggest that FL and its components, except EC, increase UCP-1 mRNA and plasma CA with varying efficacy.
- Published
- 2018
16. Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1
- Author
-
Natsumi Sawada, Toshio Okano, Yuri Uchino, Naoko Okuda, Naoko Tsugawa, Maya Kamao, Yoshihisa Hirota, Kimie Nakagawa, Yoshitomo Suhara, Nobuaki Funahashi, and Takashi Kimoto
- Subjects
Insecta ,Molecular Sequence Data ,Protein domain ,Protein Prenylation ,Gene Expression ,Mevalonic Acid ,lcsh:Medicine ,Sequence alignment ,Biology ,Cell Line ,chemistry.chemical_compound ,Prenylation ,EVH1 domain ,Dimethylallyltranstransferase ,Microsomes ,Animals ,Humans ,Point Mutation ,Amino Acid Sequence ,Binding site ,lcsh:Science ,Multidisciplinary ,Geranyl pyrophosphate ,lcsh:R ,Vitamin K 2 ,Biosynthetic Pathways ,Protein Structure, Tertiary ,Cholesterol ,Biochemistry ,chemistry ,Protein prenylation ,lcsh:Q ,Sequence Alignment ,Research Article - Abstract
UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a significant role in vitamin K2 (MK-4) synthesis. We investigated the enzymological properties of UBIAD1 using microsomal fractions from Sf9 cells expressing UBIAD1 by analysing MK-4 biosynthetic activity. With regard to UBIAD1 enzyme reaction conditions, highest MK-4 synthetic activity was demonstrated under basic conditions at a pH between 8.5 and 9.0, with a DTT ≥0.1 mM. In addition, we found that geranyl pyrophosphate and farnesyl pyrophosphate were also recognized as a side-chain source and served as a substrate for prenylation. Furthermore, lipophilic statins were found to directly inhibit the enzymatic activity of UBIAD1. We analysed the aminoacid sequences homologies across the menA and UbiA families to identify conserved structural features of UBIAD1 proteins and focused on four highly conserved domains. We prepared protein mutants deficient in the four conserved domains to evaluate enzyme activity. Because no enzyme activity was detected in the mutants deficient in the UBIAD1 conserved domains, these four domains were considered to play an essential role in enzymatic activity. We also measured enzyme activities using point mutants of the highly conserved aminoacids in these domains to elucidate their respective functions. We found that the conserved domain I is a substrate recognition site that undergoes a structural change after substrate binding. The conserved domain II is a redox domain site containing a CxxC motif. The conserved domain III is a hinge region important as a catalytic site for the UBIAD1 enzyme. The conserved domain IV is a binding site for Mg2+/isoprenyl side-chain. In this study, we provide a molecular mapping of the enzymological properties of UBIAD1.
- Published
- 2015
17. Substitution at the C-3 Position of Catechins Has an Influence on the Binding Affinities against Serum Albumin
- Author
-
Rei Kitano, Hitoshi Ashida, Nobuo Kato, Kaori Hayashibara, Kunihiro Kaihatsu, Masaki Ikeda, Yoshitomo Suhara, Naomi Osakabe, Masaya Kawase, and Manabu Ueda-Wakagi
- Subjects
0301 basic medicine ,Models, Molecular ,Stereochemistry ,serum albumin ,Serum albumin ,Molecular Conformation ,Pharmaceutical Science ,interaction ,01 natural sciences ,Article ,Catechin ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,chemistry.chemical_compound ,fluorescence analysis ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Bovine serum albumin ,catechin ,docking study ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Nucleophilic acyl substitution ,Tryptophan ,Serum Albumin, Bovine ,Gallate ,Human serum albumin ,0104 chemical sciences ,030104 developmental biology ,Chemistry (miscellaneous) ,Docking (molecular) ,biology.protein ,Molecular Medicine ,Cattle ,Acyl group ,medicine.drug ,Protein Binding - Abstract
It is known that catechins interact with the tryptophan (Trp) residue at the drug-binding site of serum albumin. In this study, we used catechin derivatives to investigate which position of the catechin structure strongly influences the binding affinity against bovine serum albumin (BSA) and human serum albumin (HSA). A docking simulation showed that (−)-epigallocatechin gallate (EGCg) interacted with both Trp residues of BSA (one at drug-binding site I and the other on the molecular surface), mainly by π–π stacking. Fluorescence analysis showed that EGCg and substituted EGCg caused a red shift of the peak wavelength of Trp similarly to warfarin (a drug-binding site I-specific compound), while 3-O-acyl-catechins caused a blue shift. To evaluate the binding affinities, the quenching constants were determined by the Stern–Volmer equation. A gallate ester at the C-3 position increased the quenching constants of the catechins. Against BSA, acyl substitution increased the quenching constant proportionally to the carbon chain lengths of the acyl group, whereas methyl substitution decreased the quenching constant. Against HSA, neither acyl nor methyl substitution affected the quenching constant. In conclusion, substitution at the C-3 position of catechins has an important influence on the binding affinity against serum albumin.
- Published
- 2017
18. Synthetic Small Molecules Derived from Natural Vitamin K Homologues that Induce Selective Neuronal Differentiation of Neuronal Progenitor Cells.
- Author
-
Yoshitomo Suhara, Yoshihisa Hirota, Norika Hanada, Shun Nishina, Sachiko Eguchi, Rie Sakane, Kimie Nakagawa, Akimori Wada, Kazuhiko Takahashi, Hiroaki Tokiwa, and Toshio Okano
- Subjects
- *
PROGENITOR cells , *CELL differentiation , *VITAMIN synthesis , *VITAMIN K2 , *IN vitro studies - Abstract
We synthesized new vitamin K2 analogues with ω-terminal modifications of the side chain and evaluated their selective differentiation of neuronal progenitor cells into neurons in vitro. The result of the assay showed that the menaquinone-3 analogue modified with the m-methylphenyl group had the most potent activity, which was twice as great as the control. This finding indicated that it is possible to obtain much more potent compounds with modification of the structure of vitamin K2. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
19. Cytochrome P450-Dependent Catabolism of Vitamin K: ω-Hydroxylation Catalyzed by Human CYP4F2 and CYP4F11.
- Author
-
Edson, Katheryne Z., Prasad, Bhagwat, Unadkat, Jashvant D., Yoshitomo Suhara, Toshio Okano, Peter Guengerich, F., and Rettie, Allan E.
- Published
- 2013
- Full Text
- View/download PDF
20. Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women.
- Author
-
Naoko Tsugawa, Masataka Shiraki, Yoshitomo Suhara, Maya Kamao, Reo Ozaki, Kiyoshi Tanaka, and Toshio Okano
- Subjects
BONE injuries ,BLOOD plasma ,BONE fractures ,ISOPENTENOIDS - Abstract
Abstract  It has been reported that vitamin K supplementation effectively prevents fractures and sustains bone mineral density in osteoporosis. However, there are only limited reported data concerning the association between vitamin K nutritional status and bone mineral density (BMD) or fractures in Japan. The objectives were to evaluate the association between plasma phylloquinone (K1) or menaquinone (MK-4 and MK-7) concentration and BMD or fracture in Japanese women prospectively. A total of 379 healthy women aged 30â88 years (mean age, 63.0 years) were consecutively enrolled. Plasma K1, MK-4, MK-7, and serum undercarboxylated osteocalcin (ucOC) concentrations, BMD, and incidence of vertebral fractures were evaluated. In stepwise multiple linear regression analyses, L2â4 BMD and a bone turnover marker, log K1, concentrations were independently correlated with vertebral fracture incidence. When subjects were divided into low and high K1 groups by plasma K1 concentration, the incidence of vertebral fracture in the low K1 group (14.4%) was significantly higher than that in the high K1 group (4.2%), and its age-adjusted RR was 3.58 (95% CI, 3.26â3.93). L2â4 BMD was not different between the two groups. These results suggest that subjects with vitamin K1 insufficiency in bone have increased susceptibility for vertebral fracture independently from BMD. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
21. Vitamin K status of healthy Japanese women: age-related vitamin K requirement for γ-carboxylation of osteocalcin.
- Author
-
Naoko Tsugawa, Masataka Shiraki, Yoshitomo Suhara, Maya Kamao, Kiyoshi Tanaka, and Toshio Okano
- Abstract
Background: Vitamin K deficiency is associated with low bone mineral density and increased risk of bone fracture. Phylloquinone (K1) and menaquinone 4 (MK-4) and 7 (MK-7) are generally observed in human plasma; however, data are limited on their circulating concentrations and their associations with bone metabolism or with γ-carboxylation of the osteocalcin molecule. Objectives: The objectives were to measure the circulating concentrations of K
1 , MK-4, and MK-7 in women and to ascertain whether each form of vitamin K is significantly associated with bone metabolism. Design: Plasma concentrations of K1 , MK-4, MK-7, undercarboxylated osteocalcin (ucOC; measured by using the new electrochemiluminescence immunoassay), intact osteocalcin (iOC), calcium, and phosphorus; bone-derived alkaline phosphatase activity; and concentrations of urinary creatinine, N-terminal telopeptide, and deoxypyridinoline were measured in healthy women (n = 396). Results: On average, MK-7 and MK-4 were the highest and lowest, respectively, of the 3 vitamers in all age groups. K1 and MK-7 correlated inversely with ucOC, but associations between nutritional basal concentration of MK-4 and ucOC were not observed. Multiple regression analysis indicated that not only K1 and MK-7 concentrations but also age were independently correlated with ucOC concentration and the ratio of ucOC to iOC. The plasma K1 or MK-7 concentration required to minimize the ucOC concentration was highest in the group aged ⩾70 y, and it decreased progressively for each of the younger age groups. Conclusions: The definite role of ucOC remains unclear. However, if submaximal γ-carboxylation is related to the prevention of fracture or bone mineral loss, circulating vitamin K concentrations in elderly people should be kept higher than those in young people. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
22. Menadione (Vitamin K3) Is a Catabolic Product of Oral Phylloquinone (Vitamin K1) in the Intestine and a Circulating Precursor of Tissue Menaquinone-4 (Vitamin K2) in Rats.
- Author
-
Yoshihisa Hirota, Naoko Tsugawa, Kimie Nakagawa, Yoshitomo Suhara, Kiyoshi Tanaka, Yuri Uchino, Atsuko Takeuchi, Natsumi Sawada, Maya Kamao, Akimori Wada, Takashi Okitsu, and Toshio Okano
- Subjects
- *
MENADIONE , *VITAMIN K , *FAT-soluble vitamins , *METABOLISM , *VITAMIN K2 - Abstract
Mice have the ability to convert dietary phylloquinone (vitamin K1) intomenaquinone-4 (vitamin K2) and store the latter in tissues. A prenyltransferase enzyme, UbiA prenyltransferase domain-containing 1 (UBIAD1), is involved in this conversion. There is evidence that UBIAD1 has a weak side chain cleavage activity for phylloquinone but a strong prenylation activity for menadione (vitamin K3), which has long been postulated as an intermediate in this conversion. Further evidence indicates that when intravenously administered in mice phylloquinone can enter into tissues but is not converted further to menaquinone-4. These findings raise the question whether phylloquinone is absorbed and delivered to tissues in its original form and converted tomenaquinone-4 or whether it is converted to menadione in the intestine followed by delivery of menadione to tissues and subsequent conversion to menaquinone-4. To answer this question, we conducted cannulation experiments using stable isotope tracer technology in rats. We confirmed that the second pathway is correct on the basis of structural assignments and measurements of phylloquinone-derived menadione using high resolution MS analysis and a bioassay using recombinant UBIAD1 protein. Furthermore, high resolution MS and H¹ NMR analyses of the product generated from the incubation of menadione with recombinant UBIAD1 revealed that the hydroquinone, but not the quinone form of menadione, was an intermediate of the conversion. Taken together, these results provide unequivocal evidence that menadione is a catabolic product of oral phylloquinone and a major source of tissue menaquinone-4. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
23. Functional and Structural Analysis of Influenza Virus Neuraminidase N3 Offers Further Insight into the Mechanisms of Oseltamivir Resistance.
- Author
-
Qing Li, Jianxun Qi, Yan Wu, Hiromasa Kiyota, Kosuke Tanaka, Yoshitomo Suhara, Ohrui, Hiroshi, Suzuki, Yasuo, Vavricka, Christopher J., and Gao, George F.
- Subjects
- *
INFLUENZA viruses , *NEURAMINIDASE , *AMINO acids , *OSELTAMIVIR , *SEROTYPES , *COMPARATIVE studies - Abstract
The influenza virus neuraminidase H274Y substitution is a highly prevalent amino acid substitution associated with resistance to the most heavily used influenza drug, oseltamivir. Previous structural studies suggest that the group specific 252 residue (Y252 in group 1 and T252 in group 2) might be a key factor underlying H274Y resistance. However, H274Y has only been reported in N1 subtypes, which indicates that there must be additional key residues that determine H274Y resistance. Furthermore, we found that members of NA serotype N3 also possess Y252, raising the key question as to whether or not H274Y resistance may also be possible for some group 2 NAs. Here, we demonstrate that the H274Y substitution results in mild oseltamivir resistance for N3. Comparative structural analysis of N3, N1, and their 274Y variants indicates that the interaction of residue 296 (H in N1 and nonaromatic for other serotypes) with conserved W295 is another important determinant of oseltamivir resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.