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Ikuta N.,Kobe University | Chikamoto K.,Kanazawa University | Asano Y.,Kanazawa University | Yasui Y.,Kanazawa University | And 4 more authors.
Journal of Medicinal Food | Year: 2017

Alpha-lipoic acid (LA) is a powerful antioxidant. LA has two enantiomers, R(+)-LA (R-LA) and S(-)-LA (S-LA). Of these, R-LA is naturally occurring and an essential cofactor in energy metabolism. R-LA treatment has been reported to affect glucose metabolism in rat hepatoma cells. This study analyzed the time course of metabolite levels in LA-treated cultured H4IIEC3 rat hepatoma cells, including a specific evaluation of the effect of R-LA and the enantioselectivity of LA. Principal component analysis showed that this experiment was well designed to observe enantioselectivity. R-LA treatment was found to inhibit the glycolysis and Thr-Gly-Ser pathways, as well as lactic acid production, leading to the inhibition of gluconeogenesis in starved H4IIEC3 cells. This study may provide mechanistic insight into how R-LA induces apoptosis in hepatoma cells. © Copyright 2017, Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition 2017.


PubMed | CycloChem Bio Co., Kobe Women's University, Kyoto Pharmaceutical University and Kobe University
Type: Journal Article | Journal: Journal of clinical biochemistry and nutrition | Year: 2014

In recent years, the number of patients suffering from diabetes mellitus has been increasing worldwide. In particular, type 2 diabetes mellitus, a lifestyle-related disease, is recognized as a serious disease with various complications. Many types of pharmaceutics or specific health foods have been used for the management of diabetes mellitus. At the same time, the relationship between diabetes mellitus and -lipoic acid has been recognized for many years. In this study, we found that the -lipoic acid -cyclodextrin complex exhibited an HbA1c lowering effect for treating type 2 diabetes mellitus in animal models. Moreover, in this study, we investigated the activation of phosphorylation of AMP-activated protein kinase, which plays a role in cellular energy homeostasis, in the liver of KKA(y) mice by using -lipoic acid and the -lipoic acid -cyclodextrin complex. Our results show that the -lipoic acid -cyclodextrin complex strongly induced the phosphorylation of AMP-activated protein kinase. Thus, we concluded that intake of the -lipoic acid -cyclodextrin complex exerted an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia as well as doing exercise.


Nikolai S.,University of Kiel | Huebbe P.,University of Kiel | Metges C.C.,Leibniz Institute for Farm Animal Biology | Schloesser A.,University of Kiel | And 6 more authors.
Nutrition | Year: 2014

Objective: A high-fat diet (HFD) affects energy expenditure in laboratory rodents. R-α lipoic acid cyclodextrin (RALA-CD) complex is a stable form of lipoic acid (LA) and may improve energy expenditure. The aim of this study was to determine the effect of RALA-CD on energy expenditure and underlying molecular targets in female laboratory mice. Methods: Female C57BL/6J mice were fed a HFD containing 0.1% LA for about 16 wk. The effects on energy expenditure, gene and protein expression were assessed using indirect calorimetry, real-time reverse transcriptase polymerase chain reaction, and Western blot, respectively. Results: Supplementing mice with RALA-CD resulted in a significant increase in energy expenditure. However, both RALA per se (without γ-cyclodextrin) and S-α lipoic acid cyclodextrin did not significantly alter energy expenditure. Furthermore RALA-CD changed expression of genes encoding proteins centrally involved in energy metabolism. Transcriptional key regulators sirtuin 3 and peroxisome proliferator-activated receptor-γ, coactivator 1 alpha, as well as thyroid related enzyme type 2 iodothyronine deiodinase were up-regulated in brown adipose tissue (BAT) of RALA-CD-fed mice. Importantly, mRNA and/or protein expression of downstream effectors uncoupling protein (Ucp) 1 and 3 also were elevated in BAT from RALA-CD-supplemented mice. Conclusion: Overall, present data suggest that RALA-CD is a regulator of energy expenditure in laboratory mice. © 2014 Elsevier Inc.


PubMed | Kanazawa University, University of Kiel, CycloChem Bio Co and Leibniz Institute for Farm Animal Biology
Type: Journal Article | Journal: Nutrition (Burbank, Los Angeles County, Calif.) | Year: 2013

A high-fat diet (HFD) affects energy expenditure in laboratory rodents. R- lipoic acid cyclodextrin (RALA-CD) complex is a stable form of lipoic acid (LA) and may improve energy expenditure. The aim of this study was to determine the effect of RALA-CD on energy expenditure and underlying molecular targets in female laboratory mice.Female C57BL/6J mice were fed a HFD containing 0.1% LA for about 16 wk. The effects on energy expenditure, gene and protein expression were assessed using indirect calorimetry, real-time reverse transcriptase polymerase chain reaction, and Western blot, respectively.Supplementing mice with RALA-CD resulted in a significant increase in energy expenditure. However, both RALA per se (without -cyclodextrin) and S- lipoic acid cyclodextrin did not significantly alter energy expenditure. Furthermore RALA-CD changed expression of genes encoding proteins centrally involved in energy metabolism. Transcriptional key regulators sirtuin 3 and peroxisome proliferator-activated receptor-, coactivator 1 alpha, as well as thyroid related enzyme type 2 iodothyronine deiodinase were up-regulated in brown adipose tissue (BAT) of RALA-CD-fed mice. Importantly, mRNA and/or protein expression of downstream effectors uncoupling protein (Ucp) 1 and 3 also were elevated in BAT from RALA-CD-supplemented mice.Overall, present data suggest that RALA-CD is a regulator of energy expenditure in laboratory mice.


Ikuta N.,Kanazawa University | Ikuta N.,CycloChem Bio Co. | Sugiyama H.,Kanazawa University | Shimosegawa H.,Kanazawa University | And 8 more authors.
International Journal of Molecular Sciences | Year: 2013

R(+)-alpha lipoic acid (RALA) is one of the cofactors for mitochondrial enzymes and, therefore, plays a central role in energy metabolism. RALA is unstable when exposed to low pH or heat, and therefore, it is difficult to use enantiopure RALA as a pharma- and nutra-ceutical. In this study, we have aimed to stabilize RALA through complex formation with cyclodextrins (CDs). α-CD, β-CD and γ-CD were used for the formation of these RALA-CD complexes. We confirmed the complex formation using differential scanning calorimetry and showed by using HPLC analysis that complexed RALA is more stable than free RALA when subjected to humidity and high temperature or acidic pH conditions. Scanning electron microscopy studies showed that the particle size and shape differed depending on the cyclodextrin used for complexation. Further, the complexes of CD and RALA showed a different particle size distribution pattern compared with that of CD itself or that of the physical mixture of RALA and CD. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


PubMed | CycloChem Bio Co., Kobe University, University of Kiel and Kanazawa University
Type: | Journal: Oxidative medicine and cellular longevity | Year: 2015

Brain aging is accompanied by a decrease in mitochondrial function. In vitro studies suggest that tocotrienols, including - and -tocotrienol (T3), may exhibit neuroprotective properties. However, little is known about the effect of dietary T3 on mitochondrial function in vivo. In this study, we monitored the effect of a dietary T3/-cyclodextrin complex (T3CD) on mitochondrial membrane potential and ATP levels in the brain of 21-month-old mice. Mice were fed either a control diet or a diet enriched with T3CD providing 100mg T3 per kg diet for 6 months. Dietary T3CD significantly increased mitochondrial membrane potential and ATP levels compared to those of controls. The increase in MMP and ATP due to dietary T3CD was accompanied by an increase in the protein levels of the mitochondrial transcription factor A (TFAM). Furthermore, dietary T3CD slightly increased the mRNA levels of superoxide dismutase, -glutamyl cysteinyl synthetase, and heme oxygenase 1 in the brain. Overall, the present data suggest that T3CD increases TFAM, mitochondrial membrane potential, and ATP synthesis in the brains of aged mice.


PubMed | CycloChem Bio Co., Kobe University and Tokyo University of Science
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2015

-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R--lipoic acid (RLA) and S--lipoic acid (SLA) mixed at the ratio of 50:50) to rats, RLA showed higher plasma concentration than SLA, and its area under the plasma concentration-time curve from time zero to the last (AUC) was significantly about 1.26 times higher than that of SLA. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C), AUC, and half-life (T1/2) of the enantiomers were not significantly different. After oral and intraduodenal administration of the racemic mixture to pyrolus-ligated rats, the AUCs of RLA were significantly about 1.24 and 1.32 times higher than that of SLA, respectively. In addition, after intraportal administration the AUC of RLA was significantly 1.16 times higher than that of SLA. In conclusion, the enantioselective pharmacokinetics of LA in rats arose from the fraction absorbed multiplied by gastrointestinal availability (FaFg) and hepatic availability (Fh), and not from the total clearance.


PubMed | CycloChem Bio Co., Tokyo University of Science and Kobe University
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2016

R--lipoic acid (R-LA) is a cofactor of mitochondrial enzymes and a very strong antioxidant. R-LA is available as a functional food ingredient but is unstable against heat or acid. Stabilized R-LA was prepared through complexation with -cyclodextrin (CD), yielding R-LA/CD. R-LA/CD was orally administered to six healthy volunteers and showed higher plasma levels with an area under the plasma concentration-time curve that was 2.5 times higher than that after oral administration of non-complexed R-LA, although the time to reach the maximum plasma concentration and half-life did not differ. Furthermore, the plasma glucose level after a single oral administration of R-LA/CD or R-LA was not affected and no side effects were observed. These results indicate that R-LA/CD could be easily absorbed in the intestine. In conclusion, -CD complexation is a promising technology for delivering functional but unstable ingredients like R-LA.


PubMed | CycloChem Bio Co., Kobe University and Tokyo University of Science
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2016

-Lipoic acid (LA) contains a chiral carbon and exists as two enantiomers (R--lipoic acid (RLA) and S--lipoic acid (SLA)). We previously demonstrated that oral bioavailability of RLA is better than that of SLA. This difference arose from the fraction absorbed multiplied by gastrointestinal availability (F(a) F(g)) and hepatic availability (F(h)) in the absorption phase. However, it remains unclear whether F(a) and/or F(g) are involved in enantioselectivity. In this study, Caco-2 cells and Madin-Darby canine kidney strain II cells were used to assess the enantioselectivity of membrane permeability. LA was actively transported from the apical side to basal side, regardless of the differences in its steric structure. Permeability rates were proportionally increased in the range of 10-250 g LA/mL, and the permeability coefficient did not differ significantly between enantiomers. Hence, we conclude that enantioselective pharmacokinetics arose from the metabolism (F(h) or F(g) F(h)), and definitely not from the membrane permeation (F(a)) in the absorption phase.


Ikeda H.,Tokyo Institute of Technology | Ikuta N.,Kobe University | Nakata D.,CycloChemBio Co. | Ishida Y.,CycloChemBio Co. | Terao K.,CycloChemBio Co.
Bulletin of the Chemical Society of Japan | Year: 2015

The structures of inclusion complexes of (R)-α-lipoic acid with α-, β-, and γ-cyclodextrin (CD) were constructed using restraints derived from ROESY spectra and MMFF94 molecular mechanics calculations. (R)-α-lipoic acid and α-CD generate a single stable inclusion complex, in which the 1,2-dithiolane ring of the (R)-α-lipoic acid is oriented toward the secondary hydroxy side of the α-CD. NMR data suggests that β-CD produces two kinds of inclusion complexes with α-lipoic acid. Finally, γ-CD yields 1:1 and 1:2 host/guest complexes with (R)-α-lipoic acid. The estimated structure of the 1:1 γ-CD inclusion complex has the 1,2-dithiolane ring oriented toward the primary hydroxy side of the γ-CD. © 2015 The Chemical Society of Japan.

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