著者

今井 由美子

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-ES-4, 2020 (Released:2020-03-18)

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The respiratory virus infection COVID-19 caused by the new coronavirus SARS-CoV2 has been reported in China since December 2019. It has been reported that COVID-19 tends to be more severe in the elderly and in patients with underlying diseases including diabetes, heart disease, and chronic lung disease. In severe cases, patients require intensive cares including mechanical ventilation in the ICUs. So far, no biomarker that predicts the severity, or no therapeutic strategies to prevent the development of severe diseases has been established. Pathology of severe COVID-19 has two aspects: viral overgrowth and excess pulmonary inflammation. For the former, clinical trials using existing drugs such as remdesivir (nucleic acid drug), lopinavir/ritonavir combination drug (protease inhibitor), favipravir (polymerase inhibitor), and interferon (antiviral drugs) are being conducted in patients with severe COVID-19 in China. Furthermore the interest has been focused on immune globulin preparations enriched with pathogen-specific antibodies collected from the plasma of recovered patients. For the latter, clinical studies using tocilizumab (IL-6 receptor antibody) and ACE2 protein have been conducted with the purpose of reducing excessive inflammation of the lung. In addition, single cell analysis of immune cells and comprehensive repertoire analysis of TCR/BCR using patient blood are in progress overseas, which are useful to elucidate the mechanism of the severe disease progression and identify the useful biomarkers for it.

著者

竹田 誠

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-ES-1, 2020 (Released:2020-03-18)

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In December 2019 a pneumonia outbreak by the novel coronavirus, SARS-CoV-2, occurred in Wuhan City, China. The disease was named as COVID-19. Information on the SARS-CoV-2 genomic sequence was first released on 10 January 2020. We urgently started development of genetic diagnostic methods for SARS-CoV-2. On 14 January, soon after receiving the prototype designed primers, we have received the first clinical specimens suspected for COVID-19. We urgently started assessment of the primers and the laboratory diagnosis testing for SARS-CoV-2 in a parallel way. After the nightlong assessment/testing, the first COVID19 case in Japan was confirmed. The patient was a returnee from Wuhan. Until 22 January, we have established the nested RT-PCR diagnostic method/protocol for SARS-CoV-2, and urgently distributed the primer set/protocol to ~ 80 prefectural public health laboratories (PHLs) nationwide, because the Chun Jie holidays starts in China on 24 January and many Chinese tourists visit Japan. As we concerned, sporadic COVID-19 cases with an epidemiological linkage to Wuhan have detected in Tokyo, Aichi, Nara, Hokkaido, and Osaka prefectures after 24 January. Following the nested RT-PCR method, we have established the real-time RT-PCR diagnostic methods for SARS-CoV-2, and distributed the primer/probe set to ~ 80 PHLs on 30–31 January. However, the laboratory workload increased dramatically, because Japan has started to accept 829 returnees (15 were shown to be SARS-CoV-2-positive later) from Wuhan using government chartered flights on 29 January and screen ~3,500 passengers and crew (>600 were shown to be SARS-CoV-2-positive later) on a cruise ship quarantined in Yokohama for SARS-CoV-2. About one month and a half has passed, a significant number of COVID-19 cases via unknown infection route are currently detected in many prefectures in Japan (total 239 cases, as of 2 March 2020).

著者

森谷 美穂 橋本 璃乃 前田 桜 松木 亨 関 健二郎

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.3-P-293, 2020 (Released:2020-03-18)

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Re-experiencing trauma by overgeneralization is a hallmark of PTSD which is high comorbidity with depression. We thus studied the relation from overgeneralization to depression. Mice were subjected to context A with electric shock as a conditioning which was followed by unconditioned context B using a different, but similar box in 3h on Day1 and was followed by re-exposure to context A (Group ABA) or B (Group ABB) on Day2. Group ABA and ABB mice exhibited the longer freezing in context A and B on Day2. However, the mice which was not exposed to context B on Day1 (Group A-B) showed the shorter freezing time in context B on Day2, indicating that the overgeneralization was induced by experiencing the context B after the conditioning in 3 h. Group ABB mice exhibited the longer immobility time of tail suspension test (TST) than Group ABA and A-B. Freezing time in the first half of the test in context B and immobility time of TST in Group ABB were negatively correlated with the staying time of center zone in the box during the context B on Day1. In contrast, the freezing and immobility time of TST in Group ABA have positive correlation with the time of center zone during context B on Day1. These results suggest that the PTSD and depression may depend on the coping style during unconditioned context within a few hours after the trauma.

著者

久場 敬司 湊 隆文 韮澤 悟 佐藤 輝紀 山口 智和 渡邊 博之 今井 由美子 高橋 砂織

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.3-P-314, 2020 (Released:2020-03-18)

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Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system, critically involved in blood pressure regulation, heart function, lung injury, or fibrotic kidney disease. Recombinant human ACE2 protein (rhACE2), currently clinically evaluated to treat acute lung failure, is a glycosylated protein, requiring time- and cost-consuming protein production in mammalian cells. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is a novel ACE2-like enzyme to decrease angiotensin II levels in mice. Comparative analysis of protein 3D structures revealed that B38-CAP homologue shares structural similarity to mammalian ACE2 without any apparent sequence identity, containing the consensus HEXXH amino acid sequence of the M32 peptidase family. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1-7, as well as other known ACE2 target peptides, with the same potency and kinetics as human ACE2. Treatment with B38-CAP reduced plasma angiotensin II levels and suppressed angiotensin II-induced hypertension, cardiac hypertrophy and fibrosis in mice. Moreover, continuous infusion of B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice, without any overt toxicity of liver and kidney. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, which exhibits ACE2-like functions in vitro and in vivo. These results indicate that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure.

著者

山元 ひかり 入鹿山 容子 石川 有紀子 滑川 由紀子 根本 剛 田中 大夢 高橋 元樹 柳沢 正史

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-SS-05, 2020 (Released:2020-03-18)

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Loss of orexin-producing neurons in the lateral hypothalamus causes the chronic sleep disorder narcolepsy-cataplexy. Narcoleptic humans suffer from two major symptoms, excessive sleepiness and cataplexy in the active phase, and these symptoms in mouse models are manifested as sleep/wakefulness fragmentation and SOREMs (direct transitions from wakefulness to REM sleep), respectively. The neuropeptides orexin-A (OXA) and orexin-B (OXB) act on two receptors orexin type-1 receptor (OX1R) and orexin type-2 receptor (OX2R). Orexin receptor agonists are expected to be of potential value for treating human narcolepsy. Here, to confirm the fundamental strategy aimed at improving narcoleptic symptoms, we examined the association between orexin receptor subtypes and these symptoms by intracerebroventricular (ICV) administration of the OX2R-selective agonist [Ala11, D-Leu15]-OXB in orexin knockout mice. OXA and [Ala11, D-Leu15]-OXB similarly decreased the number of SOREMs. Further, transition frequencies between NREM sleep and wake states in narcoleptic model mice were similarly decreased. We confirmed in vivo that [Ala11, D-Leu15]-OXB did not activate OX1R-expressing LC noradrenergic neurons by Fos staining. Therefore, OX2R-selective agonism is sufficient to ameliorate narcoleptic symptoms, both cataplexy and fragmentation of wakefulness in model mice. Activation of LC noradrenaline neurons expressing OX1R are not essential for suppression of these symptoms.

著者

恒枝 宏史 前田 貴大 髙田 慎治郎 大塚 小由希 今 寛太 和田 努 笹岡 利安

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-O-050, 2020 (Released:2020-03-18)

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Non-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease induced by obesity. So far, no therapeutic drug is available against NASH, because the pathogenic mechanism remains unclear. Since hypothalamic orexin system is a main regulator of energy homeostasis, we investigated the role of orexin against NASH under obese conditions, using orexin knockout (ORX-KO) mice fed high fat diet (HFD). ORX-KO mice showed severer obesity and glucose intolerance on HFD, compared to wild-type controls. Also, remarkable NASH-like phenotypes were observed in the liver of ORX-KO mice, such as the accumulation of triglyceride and the increase in the levels of biomarkers for endoplasmic reticulum (ER) stress (phosphorylation of eIF2α, etc.), chronic inflammation (Tnfα mRNA, etc.), and hepatic fibrosis (Tgfβ mRNA, etc.). When the HFD-fed ORX-KO mice were treated with orexin A (i.c.v.), the hepatic ER stress and chronic inflammation were improved, whereas body weight was not altered. These results indicate that the central action of orexin is required to prevent the development of NASH by reducing ER stress and chronic inflammation in the liver under the obese condition. Hypothalamic orexin system may be a crucial therapeutic target to promote the brain-liver network functions for preventing the progression of NASH.