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Marine organisms ingest microplastics directly from water and indirectly from food sources. Ingesting microplastics can lead to the accumulation of plastic-derived chemicals. However, the relative contributions of the two exposure routes to the accumulation of plastic-derived chemicals in organisms are unknown. Using microplastics containing two brominated flame retardants (BFRs; BDE209 and DBDPE) and three UV stabilizers (UVSs; UV-234, UV-327, and BP-12), we performed exposure experiments to compare chemical accumulation patterns in fish (Myoxocephalus brandti) between exposure from water and prey (Neomysis spp.). We found significantly higher concentrations of BFRs in fish fed microplastic-contaminated prey than fish exposed to microplastics in the water. However, we observed similar concentrations of UVSs in fish exposed to both sources. As BFRs are more hydrophobic than UVSs, the differences may reflect the hydrophobic nature of the additives. Our findings indicate that both exposure routes are crucial to understanding the accumulation of plastic additives in fish., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masahiro Nakaoka reports financial support was provided by Japan Society for the Promotion of Science. Hideshige Takada reports financial support was provided by Environmental Restoration and Conservation Agency. Masahiro Nakaoka reports financial support was provided by Environmental Restoration and Conservation Agency., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Compared with CysLT 1 receptors, the functional role of CysLT 2 receptors in asthma has not been clarified. The purpose of this study was to determine 1) whether CysLT 2 receptors are expressed in the lung of mice and if expression increases in asthmatic mice, and 2) whether CysLT 2 receptors are involved in allergic leukocyte infiltration into the lung and in the development of airway remodeling in asthmatic mice. BALB/c mice were sensitized with ovalbumin (OVA) + Al(OH) 3 , and intratracheally challenged with OVA 4 times. Lung tissue was isolated before and after the 4th OVA challenge for detection of CysLT 2 receptors by immunohistochemistry and flow cytometry. The effect of a CysLT 2 receptor antagonist BayCysLT 2 RA on multiple antigen challenge-induced leukocyte infiltration into the lung and the development of airway remodeling was evaluated. Even in non-challenged mice, CysLT 2 receptors were expressed in bronchial smooth muscle. After multiple challenges, expression was also observed in leukocytes infiltrating into alveolar spaces. CysLT 2 R + leukocytes included alveolar macrophages, conventional dendritic cells, and eosinophils. BayCysLT 2 RA significantly inhibited multiple antigen challenge-induced increases in eosinophils and mononuclear cells in the lung. The development of airway remodeling was tended to be suppressed by CysLT 2 receptor antagonist. In conclusion, CysLT 2 receptors were constitutively expressed in the lung, and expression was strengthened in asthmatic mice. Activation of CysLT 2 receptors was functionally involved in allergic leukocyte infiltration into the lung. The CysLT 2 receptor can be a molecular target for the development of new pharmacotherapies for asthma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although the effectiveness of CysLT 1 receptor antagonists on asthma has been clinically established, the effects of CysLT 2 receptor antagonists are still unclear. The purpose of this study was to develop a new CysLT 1 and CysLT 2 receptors-mediated anaphylaxis guinea pig model using S-hexyl GSH, a γ-glutamyl transpeptidase (GTP) inhibitor, to suppress conversion of LTC 4 to LTD 4 . Actively sensitized guinea pigs were challenged with OVA in the absence or presence of S-hexyl GSH, and survival rate following anaphylactic response was monitored. OVA-induced fatal anaphylaxis in the absence of S-hexyl GSH was almost completely inhibited by montelukast, a CysLT 1 receptor antagonist, but not by the CysLT 2 receptor antagonist BayCysLT 2 RA. However, under treatment with S-hexyl-GSH, the inhibitory effect of motelukast was dramatically diminished, whereas that of BayCysLT 2 RA was markedly increased. The dual CysLT 1/2 receptor antagonist ONO-6950 effectively inhibited anaphylactic response in both S-hexyl GSH-treated and non-treated animals. LC/MS/MS analysis revealed that S-hexyl GSH treatment actually inhibited LTC 4 metabolism in the blood and lung tissues. Using S-hexyl GSH, we developed a novel CysLT 1 and CysLT 2 receptors-mediated anaphylaxis guinea pig model that can be useful for not only screening both CysLT 2 and CysLT 1/2 receptors antagonists, but also for functional analysis of CysLT 2 receptors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

CysLT 1 receptors are known to be involved in the pathogenesis of asthma. However, the functional roles of CysLT 2 receptors in this condition have not been determined. The purpose of this study is to develop an experimental model of CysLT 2 receptor-mediated LTC 4 -induced lung air-trapping in guinea pigs and use this model to clarify the mechanism underlying response to such trapping. Because LTC 4 is rapidly converted to LTD 4 by γ-glutamyltranspeptidase (γ-GTP) under physiological conditions, S-hexyl GSH was used as a γ-GTP inhibitor. In anesthetized artificially ventilated guinea pigs with no S-hexyl GSH treatment, i.v. LTC 4 -induced bronchoconstriction was almost completely inhibited by montelukast, a CysLT 1 receptor antagonist, but not by BayCysLT 2 RA, a CysLT 2 receptor antagonist. The inhibitory effect of montelukast was diminished by treatment with S-hexyl GSH, whereas the effect of BayCysLT 2 RA was enhanced with increasing dose of S-hexyl GSH. Macroscopic and histological examination of lung tissue isolated from LTC 4 -/S-hexyl-GSH-treated guinea pigs revealed air-trapping expansion, particularly at the alveolar site. Inhaled LTC 4 in conscious guinea pigs treated with S-hexyl GSH increased both airway resistance and airway hyperinflation. On the other hand, LTC 4 -induced air-trapping was only partially suppressed by treatment with the bronchodilator salmeterol. Although montelukast inhibition of LTC 4 -induced air-trapping was weak, treatment with BayCysLT 2 RA resulted in complete suppression of this air-trapping. Furthermore, BayCysLT 2 RA completely suppressed LTC 4 -induced airway vascular hyperpermeability. In conclusion, we found in this study that CysLT 2 receptors mediate LTC 4 -induced bronchoconstriction and air-trapping in S-hexyl GSH-treated guinea pigs. It is therefore believed that CysLT 2 receptors contribute to asthmatic response involving air-trapping., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Rectourethral fistulais a relatively rare complication of radical prostatectomy but is extremely difficult to treat. We report a case with post-laparoscopic radical prostatectomy rectourethral fistula, treated with only endoscopic shielding.A 75-year-old man had undergone laparoscopic radical prostatectomy for prostate cancer, cT2cN0M0. Although there was no finding of rectal injury during the operation, pneumaturia, pyuria and diarrhea appeared at postoperative day 21 and diagnosed rectourethral fistula by colonoscopy and amidotrizoic acid enema. The fistula did not close spontaneously. Four months after the prostatectomy, we treated with endoscopic shielding by use of polyglycolic acid sheets and fibrin glue. The fistula have not recurred for 20 months after the endoscopic procedure.This method is simple and less-invasive for patients. We think it is worth trying this method before surgical management for narrow rectourethral fistula following radical prostatectomy.

A previously healthy 74-year-old Japanese female was hospitalized with fever and high C-reactive protein. She developed palatal herpangina-like aphthous ulcers, localized intestinal wall thickening, terminal ileum ulcers, and an erythematous acneiform rash; thus Behçet's disease-like illness was suspected. Significant peripheral blood acute monocytosis developed during her hospitalization and acute monocytic leukemia (FAB M5b) with normal karyotype was diagnosed. By immunostaining, the infiltrating cells in the skin and the terminal ileum were identified as monocytic leukemic cells. This case exhibited a unique initial presentation of Behçet's disease-like illness associated with acute monocytic leukemia.

We assessed in this study the anti-asthmatic effects of ONO-6950, a novel cysteinyl leukotriene 1 (CysLT1) and 2 (CysLT2) receptors dual antagonist, in normal and S-hexyl glutathione (S-hexyl GSH)-treated guinea pigs, and compared these effects to those of montelukast, a CysLT1 selective receptor antagonist. Treatment with S-hexyl GSH reduced animals LTC4 metabolism, allowing practical evaluation of CysLT2 receptor-mediated airway response. ONO-6950 antagonized intracellular calcium signaling via human and guinea pig CysLT1 and CysLT2 receptors with IC50 values of 1.7 and 25 nM, respectively (human receptors) and 6.3 and 8.2 nM, respectively (guinea pig receptors). In normal guinea pigs, both ONO-6950 (1 or 0.3 mg/kg, p.o.) and the CysLT1 receptor antagonist montelukast (0.3 or 0.1 mg/kg, p.o.) fully attenuated CysLT1-mediated bronchoconstriction and airway vascular hyperpermeability induced by LTD4. On the other hand, in S-hexyl GSH-treated guinea pigs ONO-6950 at 3 mg/kg, p.o. or more almost completely inhibited bronchoconstriction and airway vascular hyperpermeability elicited by LTC4, while montelukast showed only partial or negligible inhibition of these airway responses. In ovalbumin sensitized guinea pigs, treatment with S-hexyl GSH on top of pyrilamine and indomethacin rendered antigen-induced bronchoconstriction sensitive to both CysLT1 and CysLT2 receptor antagonists. ONO-6950 strongly inhibited this asthmatic response to the level attained by combination therapy with montelukast and BayCysLT2RA, a selective CysLT2 receptor antagonist. These results clearly demonstrate that ONO-6950 is an orally active dual CysLT1/LT2 receptor antagonist that may provide a novel therapeutic option for patients with asthma., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The expression and functional role of CysLT2 receptors in asthma have not been clarified. In this study, we evaluated CysLT2 receptors expression, and effects of CysLT2-and CysLT1/2-receptor antagonists on antigen-induced bronchoconstriction using isolated lung tissues from both asthma and non-asthma subjects., Methods: CysLT1 and CysLT2 receptors expression in asthma and non-asthma lung tissue preparations was examined in immunohistochemistry experiments, and their functional roles in antigen-induced bronchoconstriction were assessed using ONO-6950, a dual CysLT1/2-receptor antagonist, montelukast, a CysLT1 receptor antagonist, and BayCysLT2RA, a CysLT2 receptor-specific antagonist., Results: CysLT1 receptors were expressed on the bronchial smooth muscle and epithelium, and on alveolar leukocytes in 5 in 5 non-asthma subjects and 2 in 2 asthma subjects. On the other hand, although degrees of CysLT2 receptors expression were variable among the 5 non-asthma subjects, the expression in the asthma lung was detected on bronchial smooth muscle, epithelium and alveolar leukocytes in 2 in 2 asthma subjects. In the non-asthma specimens, antagonism of CysLT2 receptors did not affect antigen-induced bronchial contractions, even after pretreatment with the CysLT1-receptor specific antagonist, montelukast. However, in the bronchus isolated from one of the 2 asthma subjects, antagonism of CysLT2 receptors suppressed contractions, and dual antagonism of CysLT1 and CysLT2 receptors resulted in additive inhibitory effect on anaphylactic contractions., Conclusions: CysLT2 receptors were expressed in lung specimens isolated from asthma subjects. Activation of CysLT2 receptors may contribute to antigen-induced bronchoconstriction in certain asthma population., (Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.

Cysteinyl leukotrienes act through G-protein-coupled receptors termed cysteinyl leukotriene 1 (CysLT1) and cysteinyl leukotriene 2 (CysLT2) receptors. However, little is known about the pathophysiological role of CysLT2 receptors in asthma. To elucidate the possible involvement of CysLT2 receptors in bronchoconstriction and airway vascular hyperpermeability, we have established a novel guinea pig model of asthma. In vitro study confirmed that CHO-K1 cells, expressing guinea pig CysLT2 and CysLT1 receptors are selectively stimulated by LTC4 and LTD4, respectively. However, when LTC4 was intravenously injected to guinea pigs, the resulting bronchoconstriction was fully abrogated by montelukast, a CysLT1 receptor antagonist, indicating rapid metabolism of LTC4 to LTD4 in the lung. We found that treatment with S-hexyl glutathione (S-hexyl GSH), an inhibitor of gamma-glutamyl transpeptidase, significantly increased LTC4 content and LTC4/(LTD4 plus LTE4) ratio in the lung. Under these circumstances, LTC4-induced bronchoconstriction became resistant to montelukast, but sensitive to Compound A, a CysLT2 receptor antagonist, depending on the dose of S-hexyl GSH. Combination with montelukast and Compound A completely abrogated this spasmogenic response. Additionally, we confirmed that LTC4 elicits airway vascular hyperpermeability via CysLT2 receptors in the presence of high dose of S-hexyl GSH as evidenced by complete inhibition of LTC4-induced hyperpermeability by Compound A, but not montelukast. These results suggest that CysLT2 receptors mediate bronchoconstriction and airway vascular hyperpermeability in guinea pigs and that the animal model used in this study may be useful to elucidate the functional role of CysLT2 receptors in various diseases, including asthma., (Copyright © 2015 Elsevier B.V. All rights reserved.)