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Fukuyama K.,Tohoku University | Ohrui H.,Tohoku University | Ohrui H.,Yokohama University of Pharmacy | Kuwahara S.,Tohoku University
Organic Letters | Year: 2015

An efficient enantioselective total synthesis of EFdA, a remarkably potent anti-HIV nucleoside analogue with various favorable pharmacological profiles, has been achieved in 37% overall yield from diacetone-d-glucose by a 14-step sequence that features a highly diastereoselective installation of the tetrasubstituted stereogenic center at the C4′ position, direct oxidative cleavage of an acetonide-protected diol derivative to an aldehyde, and one-pot 2′-deoxygenation of a ribonucleoside intermediate. © 2015 American Chemical Society. Source


Nakazawa Y.,Keio University | Oka M.,Keio University | Oka M.,Yokohama University of Pharmacy | Bando M.,Keio University | Takehana M.,Keio University
Molecular Vision | Year: 2015

Purpose: This study investigated the ability of hesperetin, a natural flavonoid, to prevent selenite-induced cataracts in a rat model. Methods: Animals were divided into four treatment groups: G1 (control group), G2 (hesperetin-treated group), G3 (selenite-induced cataract group), and G4 (hesperetin-treated selenite cataract group). Animals in the G1 and G3 groups were injected with vehicle alone, while those in the G2 and G4 groups received a subcutaneous injection of hesperetin (0.4 μg/g bodyweight on days 0, 1, and 2, corresponding to P13, P14, and P15). Sodium selenite (20 μmol/g bodyweight given 4 h after the hesperetin injection on day 0) was administered to rats in the G3 and G4 groups to induce cataract formation. Lenses were observed with slit-lamp microscopy, and filensin degradation and the decreased glutathione (GSH) and ascorbic acid levels in the lens were measured on day 6. Results: Lenses in the G3 group showed mature central opacity, while some lenses in the G4 group lacked central opacity and had lower-grade cataracts. All lenses in the G1 and G2 groups were transparent. Expression of the 94 kDa and 50 kDa forms of filensin was significantly decreased in the lenses in the G3 group compared with those in the G1 and G2 groups. Interestingly, these forms of filensin rescued the rat lenses in the G4 group. In the G3 group lenses, the GSH and ascorbic acid levels were lower than in the control group but were normalized in the G4 group lenses. Conclusions: The results suggest that hesperetin can prevent selenite-induced cataract formation. © 2015 Molecular Vision. Source


Mukai M.,Okayama University | Isobe T.,Yokohama University of Pharmacy | Okada K.,Yokohama University of Pharmacy | Murata M.,Yokohama University of Pharmacy | And 2 more authors.
Pharmazie | Year: 2015

Propofol (2,6-diisopropylphenol) is a short-acting anesthetic commonly used in clinical practice, and is rapidly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT). In the present study, propofol glucuronidation was examined in the liver microsomes of male and female humans, monkeys, rats, and mice. The kinetics of propofol glucuronidation by liver microsomes fit the substrate inhibition model for humans and mice, the Hill model for monkeys, and the isoenzyme (biphasic) model for rats. The Km, Vmax, and CLint values of human liver microsomes were 50μM, 5.6 nmol/min/mg protein, and 110μL/min/mg protein, respectively, for males, and 46μM, 6.0 nmol/min/mg protein, and 130μL/min/mg protein, respectively, for females. The rank order of the CLint or CLmax (in vitro clearance) values of liver microsomes was mice «humans > monkeys > rats (high-affinity phase)» rats (low-affinity phase) in both males and females. Although no significant sex differences were observed in the values of kinetic parameters in any animal species, the in vitro clearance values of liver microsomes were males < females in humans, males = females in rats (low-affinity phase), and males > females in monkeys, rats (high-affinity phase), and mice. These results demonstrated that the kinetic profile of propofol glucuronidation by liver microsomes markedly differed among humans, monkeys, rats, and mice, and suggest that species and sex differences exist in the roles of UGT isoform(s), including UGT1A9, involved in its metabolism. Source


Miyake Y.,Okayama University | Hirose R.,Okayama University | Isobe T.,Yokohama University of Pharmacy | Hanioka N.,Yokohama University of Pharmacy
Xenobiotica | Year: 2016

1. UDP-glucuronosyltransferase 1A6 (UGT1A6) plays important roles in the glucuronidation of numerous drugs, environmental pollutants, and endogenous substances. Minipigs have been used as experimental animals in pharmacological and toxicological studies because many of their physiological characteristics are similar to those of humans. The aim of the present study was to examine similarities and differences in the enzymatic properties of UGT1A6 between humans and minipigs. 2. Minipig UGT1A6 (mpUGT1A6) cDNA was cloned by the RACE method, and the corresponding proteins were expressed in insect cells. The enzymatic function of mpUGT1A6 was analyzed by the kinetics of serotonin glucuronidation. 3. Amino acid homology between human UGT1A6 (hUGT1A6) and mpUGT1A6 was 79.9%. The kinetics of serotonin glucuronidation by recombinant hUGT1A6 and mpUGT1A6 enzymes fit the Michaelis-Menten equation. The Km, Vmax, and CLint values of hUGT1A6 were 10.5 mM, 4.04 nmol/min/mg protein, and 0.39 μL/min/mg protein, respectively. The Km value of mpUGT1A6 was similar to that of hUGT1A6, whereas the Vmax and CLint values of mpUGT1A6 were approximately 2-fold higher than those of hUGT1A6. 4. These results suggest that the enzymatic properties of UGT1A6 enzymes are moderately different between humans and minipigs. © 2015 Informa UK Ltd. Source


Nakazawa Y.,Keio University | Oka M.,Yokohama University of Pharmacy | Tamura H.,Keio University | Takehana M.,Keio University | Takehana M.,Yokohama University of Pharmacy
Open Medicine (Poland) | Year: 2016

Background. Chaperone activity of α-crystallin in the lens works to prevent protein aggregation and is important to maintain the lens transparency. This study evaluated the effect of hesperetin on lens chaperone activity in selenite-induced cataracts. Methodology. Thirteen-day-old rats were divided into four groups. Animals were given hesperetin (groups G2 and G4) or vehicle (G1 and G3) on Days 0, 1, and 2. Rats in G3 and G4 were administered selenite subcutaneously 4 hours after the first hesperetin injection. On Days 2, 4, and 6, cataract grades were evaluated using slit-lamp biomicroscopy. The amount of a-crystallin and chaperone activity in water-soluble fraction were measured after animals sacrificed. Results. G3 on day 4 had developed significant cataract, as an average cataract grading of 4.6 ± 0.2. In contrast, G4 had less severe central opacities and lower stage cataracts than G3, as an average cataract grading of 2.4 ± 0.4. The a-crystallin levels in G3 lenses were lower than in G1, but the same as G4. Additionally, chaperone activity was weaker in G3 lenses than G1, but the same as in G4. Conclusions. Our results suggest that hesperetin can prevent the decreasing lens chaperone activity and a-crystallin water solubility by administered of selenite. © Yosuke Nakazawa et al published by De Gruyter Open 2016. Source

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