冠動脈攣縮治療戦略とカリウムチャネル開口薬

第86回日本薬理学会年会一般演題//J Pharmacol Sci 2013;121 Suppl 1:85

Molecular characterization and validation of commercially available methods for haptoglobin measurement in bottlenose dolphin

AbstractHaptoglobin (Hp) is a positive acute-phase protein and a valuable marker of inflammation in both human and veterinary medicine. The aim of this study was to validate the molecular characterization of Hp in dolphins and to validate commercially available Hp measurement methods such as Hp-ELISA (originally designed for pigs) and Hp–hemoglobin (Hb) binding assay. The dolphin Hp (dHp) amino acid sequence appeared most similar to pig Hp by sequence homology and phylogenetic clustering. Amino acid sequence analysis revealed that dHp comprises the Hp1 form of α1 and β chains. The anti-pig Hp antibody cross-reacted with both recombinant dHp, expressed by Escherichia coli, and dHp from serum. The intra- and inter-assay levels of imprecision of pig Hp-ELISA and the Hp–Hb binding assay were found to be tolerable for the determination of Hp in dolphin, and there was no significant discrepancy between the two determination methods. The ability of the assay to differentiate between healthy and inflammation groups was investigated, and a significant increase in Hp concentration was detected in inflammatory conditions. Thus, Hp is a useful inflammation marker for dolphin, and the Hp concentration in dolphin serum samples can be reliably measured using commercially available pig Hp-ELISA and Hp–Hb binding assay

Vasopressin-independent renal urinary concentration: Increased rBSC1 and enhanced countercurrent multiplication

Vasopressin-independent renal urinary concentration: Increased rBSC1 and enhanced countercurrent multiplication.BackgroundA close association between the expression of the sodium transporter, rat bumetanide sensitive cotransporter (rBSC), in thick ascending limb of Henle and urinary concentration has been reported. However, direct evidence for this association and the mechanism of rBSC1 expression are still to be elucidated.MethodsBrattleboro (BB) rats weighing approximately 200g were dehydrated by water restriction for 4 hours, which induced around a 5% body weight reduction. Although plasma arginine vasopressin (AVP) was undetectable even after the water restriction, BB rats concentrated urine from 182 ± 23 (mean ± SD) at baseline to 404 ± 65 mOsm/kg · H2O.ResultsUrinary volume was reduced from 5.8 ± 1.8 to 1.4 ± 0.6mL/h. This treatment significantly increased sodium and urea accumulation in the renal medulla and reduced urinary sodium excretion. rBSC1 signals for both mRNA and protein were increased in dehydrated rats, although aquaporin type 2 (AQP2) expression was not enhanced in dehydrated BB rats. Subcutaneous infusion of desmopressin acetate (DDAVP) intensified rBSC1 signals of BB rats more than those in dehydrated condition.ConclusionDehydration increased rBSC1 expression and enhanced countercurrent multiplication even in AVP deficiency. These results supply strong evidence for the association between rBSC1 expression and urinary concentration, and indicate the presence of an AVP-independent mechanism for urine concentration

Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice

The oxytocin receptor (OXTR) and its ligand, oxytocin (OXT), regulate reproductive physiology (i.e., parturition and lactation) and sociosexual behaviors. To define the essential functions of OXTR, we generated mice with a null mutation in the Oxtr gene (Oxtr-/-) and compared them with OXT-deficient (Oxt-/-) mice. Oxtr-/- mice were viable and had no obvious deficits in fertility or reproductive behavior. Oxtr-/- dams exhibited normal parturition but demonstrated defects in lactation and maternal nurturing. Infant Oxtr-/- males emitted fewer ultrasonic vocalizations than wild-type littermates in response to social isolation. Adult Oxtr-/- males also showed deficits in social discrimination and elevated aggressive behavior. Ligand Oxt-/- males from Oxt-/- dams, but not from Oxt+/- dams, showed similar high levels of aggression. These data suggest a developmental role for the OXT/OXTR system in shaping adult aggressive behavior. Our studies demonstrate that OXTR plays a critical role in regulating several aspects of social behavior and may have important implications for developmental psychiatric disorders characterized by deficits in social behavior

Characterization of the K2-19 Multiple-Transiting Planetary System via High-Dispersion Spectroscopy, AO Imaging, and Transit Timing Variations

K2-19 (EPIC201505350) is an interesting planetary system in which two transiting planets with radii ~ 7 $R_{Earth}$ (inner planet b) and ~ 4 $R_{Earth}$ (outer planet c) have orbits that are nearly in a 3:2 mean-motion resonance. Here, we present results of ground-based follow-up observations for the K2-19 planetary system. We have performed high-dispersion spectroscopy and high-contrast adaptive-optics imaging of the host star with the HDS and HiCIAO on the Subaru 8.2m telescope. We find that the host star is relatively old (>8 Gyr) late G-type star ($T_{eff}$ ~ 5350 K, $M_s$ ~ 0.9 $M_{Sun}$, and $R_{s}$ ~ 0.9 $R_{Sun}$). We do not find any contaminating faint objects near the host star which could be responsible for (or dilute) the transit signals. We have also conducted transit follow-up photometry for the inner planet with KeplerCam on the FLWO 1.2m telescope, TRAPPISTCAM on the TRAPPIST 0.6m telescope, and MuSCAT on the OAO 1.88m telescope. We confirm the presence of transit-timing variations, as previously reported by Armstrong and coworkers. We model the observed transit-timing variations of the inner planet using the synodic chopping formulae given by Deck & Agol (2015). We find two statistically indistinguishable solutions for which the period ratios ($P_{c}/P_{b}$) are located slightly above and below the exact 3:2 commensurability. Despite the degeneracy, we derive the orbital period of the inner planet $P_b$ ~ 7.921 days and the mass of the outer planet $M_c$ ~ 20 $M_{Earth}$. Additional transit photometry (especially for the outer planet) as well as precise radial-velocity measurements would be helpful to break the degeneracy and to determine the mass of the inner planet

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial