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κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820.

The microminipig is one of the smallest minipigs that has emerged as a possible experimental animal model, because it shares many anatomical and/or physiological similarities with humans, including the coronary artery distribution in the heart, the digestive physiology, the kidney size and its structure, and so on. However, information on gene expression profiles, including those on drug-metabolizing phase I and II enzymes, in the microminipig is limited. Therefore, the aim of the present study was to identify transcripts in microminipig livers and to determine gene expression profiles. De novo assembly and expression analyses of microminipig transcripts were conducted with liver samples from three male and three female microminipigs using parallel long-read and short-read sequencing technologies. After unique sequences had been automatically aligned by assembling software, the mean contig length of 50843 transcripts was 707 bp. The expression profiles of cytochrome P450 (P450) 1A2, 2C, 2E1 and 3A genes in livers in microminipigs were similar to those in humans. Liver carboxylesterase (CES) precursor, liver CES-like, UDP-glucuronosyltransferase (UGT) 2C1-like, amine sulfotransferase (SULT)-like, N-acetyltransferases (NAT8) and glutathione S-transferase (GST) A2 genes, which are relatively unknown genes in pigs and/or humans, were expressed strongly. Furthermore, no significant gender differences were observed in the gene expression profiles of phase I enzymes, whereas UGT2B17, SULT1E1, SULT2A1, amine SULT-like, NAT8 and GSTT4 genes were different between males and females among phase II enzyme genes under the present sample conditions. These results provide a foundation for mechanistic studies and the use of microminipigs as model animals for drug development in the future. Copyright © 2016 John Wiley & Sons, Ltd.

Dolastatin 10 (1) is a highly potent cytotoxic microtubule inhibitor (cytotoxicity IC50

The microminipig is one of the smallest minipigs that has emerged as a possible experimental animal model, because it shares many anatomical and/or physiological similarities with humans, including the coronary artery distribution in the heart, the digestive physiology, the kidney size and its structure, and so on. However, information on gene expression profiles, including those on drug-metabolizing phase I and II enzymes, in the microminipig is limited. Therefore, the aim of the present study was to identify transcripts in microminipig livers and to determine gene expression profiles. De novo assembly and expression analyses of microminipig transcripts were conducted with liver samples from three male and three female microminipigs using parallel long-read and short-read sequencing technologies. After unique sequences had been automatically aligned by assembling software, the mean contig length of 50843 transcripts was 707 bp. The expression profiles of cytochrome P450 (P450) 1A2, 2C, 2E1 and 3A genes in livers in microminipigs were similar to those in humans. Liver carboxylesterase (CES) precursor, liver CES-like, UDP-glucuronosyltransferase (UGT) 2C1-like, amine sulfotransferase (SULT)-like, N-acetyltransferases (NAT8) and glutathione S-transferase (GST) A2 genes, which are relatively unknown genes in pigs and/or humans, were expressed strongly. Furthermore, no significant gender differences were observed in the gene expression profiles of phase I enzymes, whereas UGT2B17, SULT1E1, SULT2A1, amine SULT-like, NAT8 and GSTT4 genes were different between males and females among phase II enzyme genes under the present sample conditions. These results provide a foundation for mechanistic studies and the use of microminipigs as model animals for drug development in the future. Copyright © 2016 John WileySons, Ltd.

Mammalian oocytes acquire their intrinsic ability in a stepwise manner through ovarian folliculogenesis, ultimately becoming competent to undergo complete oocyte maturation at the final stage of the Graafian follicle. The fully-grown oocyte is tightly surrounded by compact layers of specialized granulosa cells (cumulus cells) known as the cumulus-oocyte complex. Oocyte maturation consists of the nuclear and the cytoplasmic maturation. Dynamic morphological changes such as cumulus expansion, chromosome alignment, and spindle formation are observed during the oocyte maturation. Mounting evidence that oocyte quality profoundly affects fertilization and subsequent embryo development drives the continued search for reliable predictors of oocyte developmental competence. It is necessary to understand the phenomenon and the molecular mechanisms active during oocyte maturation to obtain high-quality oocytes for in vitro maturation. In the present paper, we summarize the actions of the molecules that pla...

To ascertain whether metaphase II (MII) spindle shape influences oocyte competence, we examined the meiotic spindle organization in in vivo ovulated (IVO) oocytes and in spontaneously matured or follicle stimulating hormone (FSH)-induced oocytes.FSH-induced oocytes matured in Waymouth's MB752/1 or human tubal fluid (HTF) media and oocytes matured spontaneously in the basal medium were obtained, and spindles were detected by immunofluorescence. To evaluate the fertilization-associated differences in spindle morphology, we performed in vitro fertilization and analysed integrin mRNA expression.The distance between the pericentriolar materials (PCMs) in oocytes matured under all conditions was initially more, but it reduced gradually and increased again thereafter. Therefore, oocytes exhibiting a reduction in the distance between PCMs had the highest development rate to blastocyst in each condition.These results indicate that the 'maturation competence' of MII oocytes can be evaluated on the basis of the distance between PCMs.