iPSC screening for drug repurposing identifies anti‐RNA virus agents modulating host cell susceptibility

RNAウイルスの感染を阻害する既存薬の同定 --複数の異なるRNAウイルスに対して宿主細胞の感受性を下げることにより感染を抑制する薬剤--. 京都大学プレスリリース. 2021-04-07.iPS cells in drug screenings for COVID-19. 京都大学プレスリリース. 2021-04-07.Human pathogenic RNA viruses are threats to public health because they are prone to escaping the human immune system through mutations of genomic RNA, thereby causing local outbreaks and global pandemics of emerging or re‐emerging viral diseases. While specific therapeutics and vaccines are being developed, a broad‐spectrum therapeutic agent for RNA viruses would be beneficial for targeting newly emerging and mutated RNA viruses. In this study, we conducted a screen of repurposed drugs using Sendai virus (an RNA virus of the family Paramyxoviridae), with human‐induced pluripotent stem cells (iPSCs) to explore existing drugs that may present anti‐RNA viral activity. Selected hit compounds were evaluated for their efficacy against two important human pathogens: Ebola virus (EBOV) using Huh7 cells and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) using Vero E6 cells. Selective estrogen receptor modulators (SERMs), including raloxifene, exhibited antiviral activities against EBOV and SARS‐CoV‐2. Pioglitazone, a PPARγ agonist, also exhibited antiviral activities against SARS‐CoV‐2, and both raloxifene and pioglitazone presented a synergistic antiviral effect. Finally, we demonstrated that SERMs blocked entry steps of SARS‐CoV‐2 into host cells. These findings suggest that the identified FDA‐approved drugs can modulate host cell susceptibility against RNA viruses

Identification of novel orthonairoviruses from rodents and shrews in Gabon, Central Africa

In Africa, several emerging zoonotic viruses have been transmitted from small mammals such as rodents and shrews to humans. Although no clinical cases of small mammal-borne viral diseases have been reported in Central Africa, potential zoonotic viruses have been identified in rodents in the region. Therefore, we hypothesized that there may be unrecognized zoonotic viruses circulating in small mammals in Central Africa. Here, we investigated viruses that have been maintained among wild small mammals in Gabon to understand their potential risks to humans. We identified novel orthonairoviruses in 24.6 % of captured rodents and shrews from their kidney total RNA samples. Phylogenetic analysis revealed that the novel viruses, Lamusara virus (LMSV) and Lamgora virus, were closely related to Erve virus, which was previously identified in shrews of the genus Crocidura and has been suspected to cause neuropathogenic diseases in humans. Moreover, we show that the LMSV ovarian tumour domain protease, one of the virulence determination factors of orthonairoviruses, suppressed interferon signalling in human cells, suggesting the possible human pathogenicity of this virus. Taken together, our study demonstrates the presence of novel orthonairoviruses that may pose unrecognized risks of viral disease transmission in Gabon

Rasとカルシウムのシグナルは、Raf1においてShoc2を介して合流する

京都大学0048新制・論文博士博士(医学)乙第12541号論医博第2022号新制||医||987(附属図書館)28839(主査)教授 野田 亮, 教授 成宮 周, 教授 楠見 明弘学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDA

Drastic change in selectivity caused by addition of oxygen to the hydrogen stream for the hydrogenation of nitrite in water over a supported platinum catalyst

In the present study, we investigated the influence of the addition of O₂ to the H₂ reactant stream during the hydrogenation of NO₂⁻ in water on the catalytic performances of Al₂O₃-supported precious metal catalysts including Pd, Pt, Ir, Rh, and Ru with 0.3 mmol g-¹ of the metal. Pd/Al₂O₃ showed high selectivity for N₂ irrespective of the presence and absence of O₂, and Rh and Ru/Al₂O₃ were inactive towards the hydrogenation of NO₂⁻ even in the absence of O₂. In contrast, while Pt/Al₂O₃ showed high selectivity for NH₃ (90%) in the absence of O₂ (P-H2 = 0.2 atm and P-O2 = 0 atm), the product drastically changed to N₂ with 93% selectivity when O₂ was added (P-H2 = 0.2 atm and P-O2 = 0.1 atm). Since Pt/Al₂O₃ was completely inactive towards the oxidation of NH₃ with O₂ in water under the reaction conditions, oxidative decomposition of the formed NH₃ was not the reason for the high selectivity for N₂ in the presence of O₂. Kinetic analysis of the reaction in the absence and presence of O₂ and studies on the effects of the Pt size suggested that hydrogen atoms activated on the Pt particles were mainly consumed by O₂ upon H₂O formation in the presence of O₂. We concluded that the inactivation of the Pt sites active for NH₃ formation and furthermore the change in the function of the sites to N₂ formation caused by the O₂ addition lead to the drastic change in the selectivity from NH₃ to N₂ in the presence of O₂

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: study protocol for a multicenter randomized phase II trial (the OCUU-CRPC study)

Abstract Background Enzalutamide is an oral androgen receptor targeted agent that has been shown to improve survival in PREVAIL trials and has been approved for patients with chemo-naïve metastatic castration-resistant prostate cancer (CRPC). Meanwhile, flutamide is a non-steroidal oral anti-androgen that was commonly used before the approval of bicalutamide. The objective of the OCUU-CRPC study is to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative anti-androgen therapy (AAT) after combined androgen blockade (CAB) therapy that included bicalutamide in patients with CRPC. Methods A total of 100 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day, 4 × 40 mg capsules once daily) and flutamide (375 mg/day; 3 × 125 mg tablets thrice daily) groups. The primary endpoint for the drug efficacy is the response rate of prostate-specific antigen (PSA) (i.e., the ratio of patients whose PSA declined by ≥50% from baseline) at 3 months. Meanwhile, the secondary endpoints are PSA progression rate at 3 and 6 months, PSA response rate at 6 months, change in quality of life, PSA progression-free survival, and safety. The patient registration started in January 2015 and will end in March 2018, and the follow-up period is 6 months after the last patient registration. The main result will be reported in March 2019. Discussion In the OCUU-CRPC study, we compare the efficacy and safety of enzalutamide or alternative AAT with flutamide in participants with CRPC who were previously treated with a CAB therapy with bicalutamide. The expected results of this study will be that enzalutamide is superior to flutamide in terms of PSA response. A longer time to disease progression with enzalutamide over flutamide may translate to better overall survival. However, flutamide may be more accessible for patients owing to its lower cost than enzalutamide. Trial registration The OCUU-CRPC study was prospectively registered at clinicaltrials.gov (NCT02346578, January 2015) and University Hospital Medical Information Network (UMIN000016301, January 2015)