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Saitama, Japan

Hosoya T.,Josai International University | Hosoya T.,Chiba University | Hosoya T.,Fuji Yakuhin Co. | Matsumoto K.,Josai International University | And 6 more authors.
Neurogastroenterology and Motility | Year: 2014

Background: Transient receptor potential channel melastatin 8 (TRPM8) is activated by cold temperatures and cooling agents (menthol and icilin). Recent studies showed TRPM8 is expressed in visceral organs and peripheral sensory pathways. However, the role of TRPM8 in visceral hyperalgesia is poorly understood in pathological states such as inflammatory bowel disease. Hence, we investigated the distribution of TRPM8 and its involvement in visceral hyperalgesia in experimental colitis mice. Methods: TRPM8 immunoreactivity was detected using immunohistochemical staining with fluorescein-conjugated tyramide amplification. Visceral hyperalgesia was measured by the intracolonic administration of TRPM8 agonist, WS-12, in control and dextran sodium sulfate (DSS)-induced colitis mice. Key Results: TRPM8 immunoreactivity in the distal colon was much higher than in the transverse and proximal colon under physiological conditions. TRPM8 immunoreactivity markedly increased in the distal colon mucosa of DSS-induced colitis mice compared with control mice. The number of TRPM8 nerve fibers in mucosa of DSS- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis model mice drastically increased compared with control mice. TRPM8 immunoreactivities colocalized with the calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in the mucosa. Intracolonic administration of WS-12 induced behavioral visceral pain-like responses. The numbers of these responses in the colitis model mice were 3 times higher than in control mice, and were decreased by pretreatment with the TRPM8 channel blocker AMTB. Conclusions & Inferences: Increased expression of TRPM8 may contribute to the visceral hyperalgesia of experimental colitis. © 2014 John Wiley & Sons Ltd. Source

Background: Chronic kidney disease (CKD) is highly prevalent in hyperuricemic patients. Cardiovascular events/kidney failure are more frequent in CKD patients than in patients without albuminuria. Topiroxostat, a selective xanthine oxidase inhibitor, has been reported to reduce the serum urate level and urinary albumin/creatinine ratio (ACR) in Japanese hyperuricemic patients with stage 3 CKD. We further assessed the effect of topiroxostat on the serum urate and albuminuria. Methods: This is a post-hoc, sub-group analysis of data obtained from the previously reported multicenter, randomized, placebo-controlled, double-blind, parallel-group, 22-week study comparing the efficacy and safety of topiroxostat versus placebo in Japanese hyperuricemic stage 3 CKD patients with or without gout. We conducted sub-group analyses of the effects of topiroxostat on the serum urate, ACR, estimated glomerular filtration rate and blood pressure. Results: Both in patients receiving/not receiving renin-angiotensin-aldosterone (RAA) inhibitors/lipid-lowering drugs, the serum urate level decreased more in the topiroxostat group than in the placebo group. The percent change of the ACR was also significantly lower in the topiroxostat group than in the placebo group in patients receiving RAA inhibitors/lipid-lowering drugs. In the subgroup analysis of patients with nephrosclerosis, the percent change of the ACR was significantly lower in the topiroxostat group than in the placebo group. Also in the patients with diabetic nephropathy, the percent change of the ACR tended to be lower in the topiroxostat group than in the placebo group (P=0.059 vs. placebo). Conclusion: The efficacy of topiroxostat in reducing the serum urate and ACR was maintained when it was administered concomitantly with RAA-blocking agents/lipid-lowering agents. Source

Matsumoto K.,Josai International University | Matsumoto K.,Kyoto Pharmaceutical University | Hosoya T.,Chiba University | Hosoya T.,Fuji Yakuhin Co. | And 6 more authors.
Histochemistry and Cell Biology | Year: 2014

Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a role in esophageal function. However, the distribution of TRPV1 nerve fibers in the esophagus is currently not well understood. In the present study, we investigated the distribution of TRPV1 and neurotransmitters released from TRPV1 nerve fibers in the mouse lower esophagus. Furthermore, we investigated changes in the presence of TRPV1 in the mouse model of esophagitis. Numerous TRPV1-immunoreactive nerve fibers were seen in both the submucosal layer and myenteric plexus of the lower esophagus and colocalized with calcitonin gene-related peptide (CGRP). TRPV1 colocalized with substance P in axons in the submucosal layer and myenteric plexus. TRPV1 colocalized with neuronal nitric oxide synthase in the myenteric plexus. We observed some colocalization of CGRP with the vesicular acetylcholine (ACh) transporter, packaging of ACh into synaptic vesicles after its synthesis in terminal cytoplasm, in the submucosal layer and myenteric plexus. In the esophagitis model, the number of the TRPV1 nerve fibers did not change, but their immunoreactive intensity increased compared with sham-operated mice. Inhibitory effect of exogenous capsaicin on electrically stimulated twitch contraction significantly increased in esophagitis model compared with the effect in sham-operated mice. Overall, these results suggest that TRPV1 nerve fibers projecting to both the submucosal and muscle layer of the esophagus are extrinsic spinal and vagal afferent neurons. Furthermore, TRPV1 nerve fibers contain CGRP, substance P, nitric oxide, and ACh. Therefore, acid influx-mediated TRPV1 activation may play a role in regulating esophageal relaxation. © 2014, Springer-Verlag Berlin Heidelberg. Source

Isogai Y.,Toyama Prefectural University | Nakayama K.,Toyama Prefectural University | Nakayama K.,Fuji Yakuhin Co.
Protein Engineering, Design and Selection | Year: 2015

The antibiotic acylases belonging to the N-terminal nucleophile hydrolase superfamily are key enzymes for the industrial production of antibiotic drugs. Cephalosporin acylase (CA) and penicillin G acylase (PGA) are two of the most intensively studied enzymes that catalyze the deacylation of β-lactam antibiotics. On the other hand, aculeacin A acylase (AAC) is known to be an alternative acylase class catalyzing the deacylation of echinocandin or cyclic lipopeptide antibiotic compounds, but its structural and enzymatic properties remain to be explored. In the present study, 3D homology models of AAC were constructed, and docking simulation with substrate ligands was performed for AAC, as well as for CA and PGA. The docking models of AAC with aculeacin A suggest that AAC has the deep narrow binding pocket for the long-chain fatty acyl group of the echinocandin molecule. To confirm this, CA mutants have been designed to form the binding pocket for the long acyl chain. Experimentally synthesized mutant enzymes exhibited lower enzymatic activity for cephalosporin but higher activity for aculeacin A, in comparison with the wild-type enzyme. The present results have clarified the difference in mechanisms of substrate selection between the β-lactam and echinocandin acylases and demonstrate the usefulness of the computational approaches for engineering the enzymatic properties of antibiotic acylases. © 2015 The Author 2015. Source

To provide crystal polymorphs of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile, which is a useful pharmaceutical, and a production method therefor. Through purification of a corresponding salt, recrystallization, or storage under humidified conditions, three different crystal forms; i.e., crystalline polymorphs of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile are produced.

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