Publications by authors named "Minoru Yoshida"

433 Publications

The growth potential and patency of free right internal thoracic arteries verified by CT angiography.

Ann Thorac Surg 2021 Jan 20. Epub 2021 Jan 20.

Department of Cardiovascular Surgery, IMS Tokyo Katsushika General Hospital, Tokyo Japan.

Background: The use of the left internal thoracic artery (LITA) is a golden standard in coronary artery bypass grafting (CABG). Multi-arterial grafting for CABG is being increasingly emphasized for CABG. This study aimed to solve the utility of the right ITA (RITA) for multiple CABG as "free" RITA and described new evidence.

Methods: One hundred sixty-three patients received solo CABG with bilateral ITAs between 2005 and 2018. The RITA was used as in situ RITA (Group-A, n=62) and or the composite graft created and saphenous vein graft (SVG) (Group-B, n=101). The patency rate and graft size of the composite 'free' RITA and SVG were examined by coronary computed tomographic angiography (CTA).

Results: The average number of distal anastomoses per patient was 3.4±1.0 in Group-A, and 4.2±1.1 in Group-B (P<0.001). The sequential grafting with free RITA was in 86 patients. The patency rate of both LITA and RITA was similar in both groups. In Group-B, 40 patients received late CTA at a mean of 46 months (17-175 months). The late patency rate was 95.1% in LITA, and 96.9% in free RITA. The diameter of free RITA increased from 2.06±0.34 to 2.37±0.23 mm (P=0.036); that of in situ LITA increased from 2.08±0.51 to 2.44±0.49 mm (P=0.047), and that of composite SVG decreased from 4.1± 0.9 to 2.6± 0.7 mm (P<0.001).

Conclusions: Multiple bypass grafting can be sufficiently achieved with LITA and free RITA. The growth potential of free RITA and in situ LITA might be the important role of expected long-term patency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2021.01.015DOI Listing
January 2021

Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors.

Int J Biol Macromol 2021 Feb 27;170:415-423. Epub 2020 Dec 27.

Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Aβ, which acts as a potential seed for the aggregation of full length Aβ. Preventing the formation of pGlu-Aβ through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC = 34 μM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijbiomac.2020.12.118DOI Listing
February 2021

Identification of a Selective RelA Inhibitor Based on DSE-FRET Screening Methods.

Int J Mol Sci 2020 Nov 30;21(23). Epub 2020 Nov 30.

Department of Cellular and Molecular Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

Nuclear factor-κB (NF-κB) is an important transcription factor involved in various biological functions, including tumorigenesis. Hence, NF-κB has attracted attention as a target factor for cancer treatment, leading to the development of several inhibitors. However, existing NF-κB inhibitors do not discriminate between its subunits, namely, RelA, RelB, cRel, p50, and p52. Conventional methods used to evaluate interactions between transcription factors and DNA, such as electrophoretic mobility shift assay and luciferase assays, are unsuitable for high-throughput screening (HTS) and cannot distinguish NF-κB subunits. We developed a HTS method named DNA strand exchange fluorescence resonance energy transfer (DSE-FRET). This assay is suitable for HTS and can discriminate a NF-κB subunit. Using DSE-FRET, we searched for RelA-specific inhibitors and verified RelA inhibition for 32,955 compounds. The compound A55 (2-(3-carbamoyl-6-hydroxy-4-methyl-2-oxopyridin-1(2H)-yl) acetic acid) selectively inhibited RelA-DNA binding. We propose that A55 is a seed compound for RelA-specific inhibition and could be used in clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21239150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734590PMC
November 2020

Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations.

Nat Chem Biol 2021 Mar 9;17(3):335-343. Epub 2020 Nov 9.

Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science (CSRS), Saitama, Japan.

Mitochondrial DNA (mtDNA) mutations are the major cause of mitochondrial diseases. Cells harboring disease-related mtDNA mutations exhibit various phenotypic abnormalities, such as reduced respiration and elevated lactic acid production. Induced pluripotent stem cell (iPSC) lines derived from patients with mitochondrial disease, with high proportions of mutated mtDNA, exhibit defects in maturation into neurons or cardiomyocytes. In this study, we have discovered a small-molecule compound, which we name tryptolinamide (TLAM), that activates mitochondrial respiration in cybrids generated from patient-derived mitochondria and fibroblasts from patient-derived iPSCs. We found that TLAM inhibits phosphofructokinase-1 (PFK1), which in turn activates AMPK-mediated fatty-acid oxidation to promote oxidative phosphorylation, and redirects carbon flow from glycolysis toward the pentose phosphate pathway to reinforce anti-oxidative potential. Finally, we found that TLAM rescued the defect in neuronal differentiation of iPSCs carrying a high ratio of mutant mtDNA, suggesting that PFK1 represents a potential therapeutic target for mitochondrial diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41589-020-00676-4DOI Listing
March 2021

A real-world prospective observational study on the efficacy and safety of liposomal amphotericin B in 426 patients with persistent neutropenia and fever.

J Infect Chemother 2021 Feb 24;27(2):277-283. Epub 2020 Oct 24.

Pharmacovigilance, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan. Electronic address:

Introduction: Invasive fungal diseases are crucial causes of morbidity and mortality among patients with febrile neutropenia (FN). Though liposomal amphotericin B (L-AMB) is one of the agents recommended for first-line empirical antifungal therapy in patients with FN, large-scale clinical studies have not been performed in Japan.

Methods: An open-label prospective multi-center study was carried out to evaluate the safety and efficacy of L-AMB in Japanese patients with FN suspected of having fungal infection.

Results: Of the 426 patients registered, safety and efficacy evaluations were conducted for 424 and 399, respectively. By clinical response criteria using 5 composite endpoints, the response rate was 46.6% (186/399). The response rate by age were 54.5% (child: 30/55), 47.5% (adult: 97/204), 42.1% (elderly: 59/140) respectively. Regarding the composite endpoints, resolution of fever was observed in 61.2% (244/399), no breakthrough fungal infection in 99.0% (395/399), survival for 7 days or longer after the completion of treatment in 83.7% (334/399), no discontinuation of treatment due to toxicity or lack of efficacy in 60.9% (243/399), and successful treatment of any baseline fungal infection in 10/18. Adverse drug reactions (ADRs) developed in 61.1% (259/424), and frequent ADRs were hypokalemia, kidney dysfunction, and liver dysfunction, as previously reported.

Conclusions: The safety and efficacy profile of L-AMB in Japanese patients with FN suspected of having fungal infection were elucidated for the first time, through the analysis of a large number of cases including pediatric patients under real-world clinical settings collected in this nationwide study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jiac.2020.10.005DOI Listing
February 2021

Winners of the 2019 JA Ōmura Awards for excellence.

J Antibiot (Tokyo) 2020 11 27;73(11):737-738. Epub 2020 Oct 27.

RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41429-020-00370-6DOI Listing
November 2020

Mortality associated with new risk classification of developing refeeding syndrome in critically ill patients: A cohort study.

Clin Nutr 2020 Aug 5. Epub 2020 Aug 5.

Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan. Electronic address:

Background & Aims: Although refeeding syndrome (RFS) has been recognized as a potentially fatal metabolic complication, the definition of RFS has remained unclear. Recently, European researchers suggested an evidence-based and consensus-supported algorithm that consisted of a new RFS risk classification and treatment strategies for medical inpatients. The classification was based on the National Institute for Health and Clinical Excellence (NICE) criteria for patients at risk of developing RFS. In this study, we aimed to investigate the frequency of each applied new risk group and the association between the new classification and mortality in critically ill patients.

Methods: This cohort study was conducted at a Japanese metropolitan tertiary-care university hospital from December 2016 to December 2018. We included critically ill adult patients who were admitted to the intensive care unit (ICU) via the emergency department and who stayed in the ICU for 24 h or longer. We applied the new risk classification based on the NICE RFS risk factors on ICU admission. The main exposure was risk classification of RFS: no risk, low risk, high risk, or very high risk. The primary outcome was in-hospital mortality censored at day 30 after ICU admission. We performed a multivariable analysis using Cox proportional hazard regression.

Results: We analyzed 542 patients who met the eligibility criteria. The prevalence of the four RFS risk classification groups was 25.8% for no risk, 25.7% for low risk, 46.5% for high risk, and 2.0% for very high risk. The 30-day mortality was 5.0%, 7.2%, 16.3%, and 27.3%, respectively (log-rank trend test: p < 0.001). In the multivariable Cox regression, adjusted hazard ratios with no risk group as a reference were 1.28 (95% CI 0.48-3.38) for low risk, 2.81 (95% CI 1.24-6.35) for high risk, and 3.17 (95% CI 0.78-12.91) for very high risk.

Conclusions: Approximately half the critically ill patients were categorized as high or very high risk based on the new risk classification. Furthermore, as the risk categories progressed, the 30-day in-hospital mortality increased. Early recognition of patients at risk of developing RFS may improve patient outcomes through timely and optimal nutritional treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnu.2020.07.034DOI Listing
August 2020

Structure activity study of S-trityl-cysteamine dimethylaminopyridine derivatives as SIRT2 inhibitors: Improvement of SIRT2 binding and inhibition.

Bioorg Med Chem Lett 2020 10 2;30(19):127458. Epub 2020 Aug 2.

Department of Drug Discovery, Science Farm Ltd., 1-7-30-805 Kuhonji, Chuo-ku, Kumamoto 8620976, Japan; Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 8620973, Japan. Electronic address:

Sirtuin proteins are a highly conserved class of nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases. The pleiotropic human isoform 2 of Sirtuins (SIRT2) has been engaged in the pathogenesis of cancer in a plethora of reports around the globe. Thus, SIRT2 modulation is deemed as a promising approach for pharmaceutical intervention. Previously, we reported S-Trityl-l-Cysteine (STLC)-ornamented dimethylaminopyridine chemical entity named STC4 with a significant SIRT2 inhibitory capacity; this was separate from the conventional application of STLC scaffold as a kinesin-5 inhibitor. An interactive molecular docking study of SIRT2 and STC4 showed interaction between Asn168 of SIRT2 and the methyl ester of STC4, that appears to hinder STC4 to reach the selective pocket of the protein unlike strong SIRT2 inhibitor SirReal2. To improve its activity, herein, we utilized S-trityl cysteamine pharmacophore lacking the methyl ester. Nine compounds were synthesized and assayed affording three biopertinent SIRT2 inhibitors, and two of them, STCY1 and STCY6 showed higher inhibitory activity than STC4. These compounds have pronounced anti-proliferative activities against different cancer cell lines. A molecular docking study was executed to shed light on the supposed binding mode of the lead compound, STCY1, into the selective pocket of SIRT2 by interaction of the nitrogen of pyridine ring of the compound and Ala135 of the protein. The outcome of the study exposes that the active compounds are effective intermediates to construct more potent biological agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127458DOI Listing
October 2020

Peanut skin extract ameliorates the symptoms of type 2 diabetes mellitus in mice by alleviating inflammation and maintaining gut microbiota homeostasis.

Aging (Albany NY) 2020 07 22;12(14):13991-14018. Epub 2020 Jul 22.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China.

In this study, mice with type 2 diabetes mellitus (T2DM) induced by high-fat diet were used to investigate the antidiabetic effect and mechanism of action of peanut skin extract (PSE). Results revealed that the fasting blood glucose, body weight, and food intake of mice with T2DM significantly decreased after they were given PSE. The effects of 80 mg/kg PSE were similar to those of 140 mg/kg metformin (MET). The glucose tolerance and insulin sensitivity of the mice also improved. The composition of intestinal microflora in the mice significantly changed after PSE administration. In particular, no was detected in the PSE-treated group, and the ratio of to was remarkably reduced. PSE also increased the abundance of gut microbiota involved in fatty acid biosynthesis, lipid biosynthesis, and sucrose metabolism. The abundance of gut microbiota related to aminoacyl-tRNA biosynthesis also decreased. Lipopolysaccharide, interleukin (IL)-6, IL-1β and tumor necrosis factor-α in the blood, liver and adipose tissue were reduced by PSE. Similarly, the mRNA expression levels of IkappaB kinase and nuclear factor kappaB in the hypothalamus were reduced by PSE. These results suggested that PSE and MET elicited significant antidiabetic effects by maintaining gut microbiota and inhibiting inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.103521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425515PMC
July 2020

A novel GSK3 inhibitor that promotes self-renewal in mouse embryonic stem cells.

Biosci Biotechnol Biochem 2020 Oct 8;84(10):2113-2120. Epub 2020 Jul 8.

Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science (CSRS) , Saitama, Japan.

Small molecules that regulate cell stemness have the potential to make a major contribution to regenerative medicine. In the course of screening for small molecules that affect stemness in mouse embryonic stem cells (mESCs), we discovered that NPD13432, an aurone derivative, promoted self-renewal of mESCs. Normally, mESCs start to differentiate upon withdrawal of 2i/LIF. However, cells treated with the compound continued to express endogenous Nanog, a pluripotency marker protein essential for sustaining the undifferentiated state, even in the absence of 2i/LIF. Biochemical characterization revealed that NPD13432 inhibited GSK3α and GSK3β with IC values of 92 nM and 310 nM, respectively, suggesting that the compound promotes self-renewal in mESCs by inhibiting GSK3. The chemical structure of the compound is unique among known molecules with this activity, providing an opportunity to develop new inhibitors of GSK3, as well as chemical tools for investigating cell stemness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09168451.2020.1789445DOI Listing
October 2020

Independent lung ventilation with use of a double-lumen endotracheal tube for refractory hypoxemia and shock complicating severe unilateral pneumonia: A case report.

Respir Med Case Rep 2020 7;30:101084. Epub 2020 May 7.

Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Background: The indications for independent lung ventilation (ILV) in critical care settings have not been fully clarified, especially because extracorporeal membrane oxygenation (ECMO) is being used increasingly in cases of severe respiratory failure.

Case Report: A 90-year-old man presented with severe unilateral pneumonia, and despite conventional mechanical ventilation management with use of a single lumen endotracheal tube and high positive endo-expiratory pressure (PEEP), oxygenation and hemodynamics deteriorated. We then performed ILV using a double-lumen endotracheal tube (DLT) and two ventilators, each set at a different respiratory mode. With continuous administration of a neuromuscular blocking agent, the ventilator for the left lung (non-affected lung) was set to pressure-controlled ventilation (PCV) mode, whereas the ventilator for the right lung (affected lung) was set to bi-level mode, 1 breath/min, and high PEEP. ILV and the high PEEP applied to the affected lung prevented hyperinflation of the non-affected lung and increased pulmonary blood perfusion on the non-affected side. Thus, ILV immediately improved oxygenation and hemodynamics by correcting ventilation/perfusion mismatch.

Discussion: Although ECMO is a valid treatment option for patients with severe respiratory failure, it is highly invasive intervention. ILV performed with use of a DLT is less invasive and more useful than ECMO. Thus, ILV should be kept in mind as a treatment option, especially in cases of refractory respiratory failure and circulatory failure in which the pathophysiology of the left and right lungs differs markedly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmcr.2020.101084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229276PMC
May 2020

Rolling-Circle Replication in Mitochondrial DNA Inheritance: Scientific Evidence and Significance from Yeast to Human Cells.

Genes (Basel) 2020 05 6;11(5). Epub 2020 May 6.

Chemical Genetics Research Group, RIKEN Center for Sustainable Resource Science, Hirosawa 2-1, Wako, Saitama 351-0198, Japan.

Studies of mitochondrial (mt)DNA replication, which forms the basis of mitochondrial inheritance, have demonstrated that a rolling-circle replication mode exists in yeasts and human cells. In yeast, rolling-circle mtDNA replication mediated by homologous recombination is the predominant pathway for replication of wild-type mtDNA. In human cells, reactive oxygen species (ROS) induce rolling-circle replication to produce concatemers, linear tandem multimers linked by head-to-tail unit-sized mtDNA that promote restoration of homoplasmy from heteroplasmy. The event occurs ahead of mtDNA replication mechanisms observed in mammalian cells, especially under higher ROS load, as newly synthesized mtDNA is concatemeric in hydrogen peroxide-treated human cells. Rolling-circle replication holds promise for treatment of mtDNA heteroplasmy-attributed diseases, which are regarded as incurable. This review highlights the potential therapeutic value of rolling-circle mtDNA replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11050514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288456PMC
May 2020

Genome-wide Survey of Ribosome Collision.

Cell Rep 2020 05;31(5):107610

Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan; RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan. Electronic address:

Ribosome movement is not always smooth and is rather often impeded. For ribosome pauses, fundamental issues remain to be addressed, including where ribosomes pause on mRNAs, what kind of RNA/amino acid sequence causes this pause, and the physiological significance of this attenuation of protein synthesis. Here, we survey the positions of ribosome collisions caused by ribosome pauses in humans and zebrafish using modified ribosome profiling. Collided ribosomes, i.e., disomes, emerge at various sites: Pro-Pro/Gly/Asp motifs; Arg-X-Lys motifs; stop codons; and 3' untranslated regions. The electrostatic interaction between the charged nascent chain and the ribosome exit tunnel determines the eIF5A-mediated disome rescue at the Pro-Pro sites. In particular, XBP1u, a precursor of endoplasmic reticulum (ER)-stress-responsive transcription factor, shows striking queues of collided ribosomes and thus acts as a degradation substrate by ribosome-associated quality control. Our results provide insight into the causes and consequences of ribosome pause by dissecting collided ribosomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.107610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746506PMC
May 2020

LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells.

Blood 2020 08;136(6):684-697

Department of Hematology and Oncology.

The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-κB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage-induced cell death and is a suitable therapeutic target for B-cell lymphomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019002654DOI Listing
August 2020

Serine catabolism produces ROS, sensitizes cells to actin dysfunction, and suppresses cell growth in fission yeast.

J Antibiot (Tokyo) 2020 08 20;73(8):574-580. Epub 2020 Apr 20.

Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.

Serine is an essential component in organisms as a building block of biomolecules, a precursor of metabolites, an allosteric regulator of an enzyme, etc. This amino acid is thought to be a key metabolite in human diseases including cancers and infectious diseases. To understand the consequence of serine catabolism, we screened natural products to identify a fungal metabolite chaetoglobosin D (ChD) as a specific inhibitor of fission yeast cell growth when cultivated with serine as a sole nitrogen source. ChD targets actin, and actin mutant cells showed severe growth defect on serine medium. ROS accumulated in cells when cultivated in serine medium, while actin mutant cells showed increased sensitivity to oxidative stress. ROS production is a new aspect of serine metabolism, which might be involved in disease progression, and actin could be the drug target for curing serine-dependent symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41429-020-0305-6DOI Listing
August 2020

Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer.

J Med Chem 2020 04 1;63(8):4183-4204. Epub 2020 Apr 1.

Department of Biotechnology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.

Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and β-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00045DOI Listing
April 2020

Publisher Correction: Integrating yeast chemical genomics and mammalian cell pathway analysis.

Acta Pharmacol Sin 2020 05;41(5):729

The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41401-019-0355-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471429PMC
May 2020

Exploratory Observational Study of Extracorporeal Cardiopulmonary Resuscitation for Nonshockable Out-Of-Hospital Cardiac Arrest Occurring After an Emergency Medical Services Arrival: SOS-KANTO 2012 Study Report.

J Emerg Med 2020 Mar 28;58(3):375-384. Epub 2020 Jan 28.

Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.

Background: The outcomes of patients with nonshockable out-of-hospital cardiac arrest (OHCA) are poor, but may be improved by extracorporeal cardiopulmonary resuscitation (E-CPR).

Objective: To examine the effects of veno-arterial extracorporeal membranous oxygenation (ECMO) as E-CPR in patients with nonshockable OHCA after emergency medical services (EMS) arrival for whom satisfactory cardiopulmonary resuscitation (CPR) was immediately performed.

Methods: Among 16,452 patients enrolled in the SOS-KANTO 2012 study, we examined data on 531 patients aged ≥ 18 years who performed activities of daily living (ADL) well or had moderate disability before the onset of cardiac arrest (CA) and those with normal spontaneous respiration or pulse palpation upon EMS arrival. CPR was performed immediately after CA onset, and advanced life support was provided upon hospital arrival for these patients. We divided patients into ECMO and non-ECMO groups. We retrospectively analyzed background factors and clinical outcomes.

Results: E-CPR was performed on 38 (7.2%) patients. In the univariate analysis, the mean age of the ECMO group was lower, ADL function before onset was more favorable, mean body weight was higher, and the mean interval from onset until hospital arrival was shorter than those in the non-ECMO group. One-to 3-month survival or favorable cerebral function outcome rates were higher in the ECMO group than in the non-ECMO group. In the multivariate analysis, ECMO use and the interval from onset until hospital arrival were independent prognostic factors for favorable cerebral functional outcomes at 1 and 3 months.

Conclusion: E-CPR may be associated with favorable outcomes in carefully selected patients with nonshockable OHCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jemermed.2019.12.004DOI Listing
March 2020

Clinical outcomes of urinary tract infection caused by extended spectrum beta-lactamase producing Enterobacteriaceae: a retrospective observational study comparing patients with and without systemic inflammatory response syndrome.

Acute Med Surg 2020 Jan-Dec;7(1):e472. Epub 2019 Dec 5.

Department of Emergency and Critical Care Medicine St. Marianna University School of Medicine Kawasaki Japan.

Aim: In severe urinary tract infection (UTI), susceptible antibiotics should be given. With the recent increase of multidrug-resistant bacteria, especially extended spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E), broad-spectrum antibiotics, such as carbapenems, are used more frequently, which could lead to a further increase of multidrug-resistant bacteria. We aimed to analyze the relationship between initial empirical antibiotic appropriateness and clinical outcomes in UTI, especially in patients with systemic inflammatory response syndrome (SIRS) and ESBL-E.

Methods: A retrospective observational study from 2012 to 2017.

Results: Among urine culture-positive cases with ≥10 colony-forming units/mL ( = 1,880), true UTI cases were extracted ( = 844) and divided into the SIRS group ( = 336 [ESBL-E12.8% (43/336)]) and non-SIRS group ( = 508 [ESBL-E12.6% (64/508)]). In the SIRS ESBL-E group, the initial antibiotics were susceptible in 55.8% (24/43), among which 91.7% (22/24) improved and 8.3% (2/24) deteriorated or died. The initial antibiotics were resistant in 44.2% (19/43), among which 47.4% (9/19) improved with the initial antibiotics, 47.4% (9/19) improved after escalating antibiotics, and 5.3% (1/19) deteriorated or died. In the SIRS group, 14 cases had true bacteremia with ESBL-E. Seven cases were initiated with inappropriate antibiotics; four cases showed improvement before or without antibiotic change and three cases improved after antibiotic escalation.

Conclusion: Initiation of narrow-spectrum antibiotics in septic UTI with ESBL-E might not deteriorate the clinical outcome if promptly escalated on clinical deterioration or with ESBL-E culture results. Further investigation is warranted to guide judicious use of initial antibiotics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ams2.472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971456PMC
December 2019

An internet-based survey exploring the awareness of febrile neutropenia in patients with malignant lymphoma.

Support Care Cancer 2020 Sep 17;28(9):4509-4516. Epub 2020 Jan 17.

Fourth Department of Internal Medicine, Teikyo University School of Medicine, Mizonokuchi hospital, 5-1-1 Futago, Takatsu-ku, Kawasaki, 213-8507, Japan.

Purpose: Febrile neutropenia (FN) is associated with infection-related mortality and a reduction of relative dose intensity during chemotherapy of malignant lymphoma. To prevent deaths and recover the attenuated efficacy of chemotherapies caused by FN, guidelines for the management of FN are published. The aim of this study is to clarify the degree to how much patients understand the FN.

Methods: An internet-based survey was employed to investigate the awareness of FN in Japanese patients who had received chemotherapies for malignant lymphoma.

Results: A total of 105 subjects were enrolled, of whom 64 (61.0%) received ambulatory treatment and 41 (39.0%) received primarily inpatient services. Sixty-four (61.0%) remembered receiving explanations of FN and 61 (95.3%) understood FN very well or almost well. Respondents who reported understanding received explanations from multiple medical staff that were similar to those from single medical staff. A total of 31 (29.5%) experienced FN and 17 of them developed FN at home. Only 8 (47.1%) visited or made contact with their hospitals within 3 h after onset at home.

Conclusions: Explanatory procedures need to be addressed, since subjects' levels of understanding were not proportionate to the number of elucidators. Although medical professionals made preliminary explanations, in fact, no more than half of those respondents who developed FN at home had made contact to their hospitals immediately. In conclusion, these results suggest that medical professionals should make more effort to lead patients to an understanding of the proper correspondences in case of FN onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-019-05231-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378043PMC
September 2020

Leptin and Adiponectin Signaling Pathways Are Involved in the Antiobesity Effects of Peanut Skin Extract.

Oxid Med Cell Longev 2019 14;2019:2935315. Epub 2019 Oct 14.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Excessive food intake and metabolic disorder promote obesity and diabetes. In China, peanut skin is used as a herbal medicine to treat hemophilia, thrombocytopenic purpura, and hepatic hemorrhage. In the present study, we demonstrated that peanut skin extract (PSE) safely reduced appetite, body weight, fat tissue, plasma TG and TC, and blood glucose level in mice with diet-induced obesity (DIO). Moreover, the leptin/leptin receptor/neuropeptide Y (NPY) and adiponectin signaling pathways involved in the antiobesity effects of PSE are confirmed through leptin and adiponectin overexpression and leptin receptor silencing in mice. PSE consisted of oligosaccharide and polyphenol in a mass ratio of 45 : 55, and both parts were important for the antiobesity function of PSE. Our results suggested that PSE can be developed as functional medical food to treat metabolic disorders and obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/2935315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815585PMC
May 2020

Intraspecies cell-cell communication in yeast.

FEMS Yeast Res 2019 11;19(7)

Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

Although yeasts are unicellular microorganisms that can live independently, they can also communicate with other cells, in order to adapt to the environment. Two yeast species, the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe, engage in various kinds of intraspecies cell-cell communication using peptides and chemical molecules that they produce, constituting a sort of 'language'. Cell-cell communication is a fundamental biological process, and its ultimate purpose is to promote survival by sexual reproduction and acquisition of nutrients from the environment. This review summarizes what is known about intraspecies cell-cell communication mediated by molecules including mating pheromones, volatile gases, aromatic alcohols and oxylipins in laboratory strains of S. cerevisiae and S. pombe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/femsyr/foz071DOI Listing
November 2019

Winners of the 2018 JA Ōmura Awards for excellence.

J Antibiot (Tokyo) 2019 11 28;72(11):783-784. Epub 2019 Oct 28.

RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41429-019-0233-5DOI Listing
November 2019

Antiproliferative -Trityl-l-Cysteine -Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement.

Molecules 2019 Sep 10;24(18). Epub 2019 Sep 10.

Department of Drug Discovery, Science Farm Ltd., 1-7-30-805 Kuhonji, Chuo-Ku, Kumamoto 8620976, Japan.

-trityl-l-cysteine () is a well-recognized lead compound known for its anticancer activity owing to its potent inhibitory effect on human mitotic kinesin Eg5. contains two free terminal amino and carboxyl groups that play pivotal roles in binding to the Eg5 pocket. On the other hand, such a zwitterion structure complicates the clinical development of because of the solubility issues. Masking either of these radicals reduces or abolishes activity against Eg5. We recently identified and characterized a new class of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of sirtuin protein (SIRT2) inhibitors that can be utilized as cytotoxic agents based on an -trityl-l-histidine scaffold. Herein, we propose new -derived compounds that possess pronounced SIRT2 inhibition effects. These derivatives contain modified amino and carboxyl groups, which conferred with bioactivity, representing an explicit repurposing approach. Compounds and exhibited half maximal inhibitory concentration values of 10.8 ± 1.9 and 9.5 ± 1.2 μM, respectively, against SIRT2. Additionally, introduction of the derivatizations in this study addressed the solubility limitations of free , presumably due to interruption of the zwitterion structure. Therefore, we could obtain drug-like derivatives that work by a new mechanism of action. The new derivatives were designed, synthesized, and their structure was confirmed using different spectroscopic approaches. In vitro and cellular bioassays with various cancer cell lines and in silico molecular docking and solubility calculations of the synthesized compounds demonstrated that they warrant attention for further refinement of their bioactivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24183295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766826PMC
September 2019

Mechanism of Action of Prethioviridamide, an Anticancer Ribosomally Synthesized and Post-Translationally Modified Peptide with a Polythioamide Structure.

ACS Chem Biol 2019 08 31;14(8):1819-1828. Epub 2019 Jul 31.

Chemical Genomics Research Group , RIKEN Center for Sustainable Resource Science , Saitama 351-0198 , Japan.

Thioviridamide, prethioviridamide, and JBIR-140, which are ribosomally synthesized and post-translationally modified peptides (RiPPs) possessing five thioamide bonds, induce selective apoptosis in various cancer cells, especially those expressing the adenovirus oncogene E1A. However, the target protein of this unique family of bioactive compounds was previously unknown. To investigate the mechanism of action, we adopted a combined approach of genome-wide shRNA library screening, transcriptome profiling, and biochemical identification of prethioviridamide-binding proteins. An shRNA screen identified 63 genes involved in cell sensitivity to prethioviridamide, which included translation initiation factors, aminoacyl tRNA synthetases, and mitochondrial proteins. Transcriptome profiling and subsequent analysis revealed that prethioviridamide induces the integrated stress response (ISR) through the GCN2-ATF4 pathway, which is likely to cause cell death. Furthermore, we found that prethioviridamide binds and inhibits respiratory chain complex V (FFo-ATP synthase) in mitochondria, suggesting that inhibition of complex V leads to activation of the GCN2-ATF4 pathway. These results imply that the members of a unique family of RiPPs with polythioamide structure target mitochondria to induce the ISR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.9b00410DOI Listing
August 2019

Antiviral and virucidal activities against herpes simplex viruses of umesu phenolics extracted from Japanese apricot.

Microbiol Immunol 2019 Sep 22;63(9):359-366. Epub 2019 Aug 22.

Division of Food and Nutrition, Wakayama Shin-Ai Women's Junior College, Wakayama, Japan.

Umesu phenolics were obtained from the salt extracts of Japanese apricot (Nanko-mume cultivar of Prunus mume Sieb. et Zucc.) as purified phenolics. The antiviral activities of umesu phenolics obtained were then examined against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), enveloped DNA viruses. The phenolics inhibited the multiplication of these viruses when added to the culture media of the infected cells. This inhibition occurred at phenolic concentrations at which they showed no severe cytotoxicity. One-step growth experiments showed that the eclipse period in the HSV-1 multiplication process was extended in the presence of umesu phenolics and that the addition of phenolics after the completion of viral DNA replication did not affect their multiplication. More drastic effects were observed on virucidal activities against HSV-1 and HSV-2; the infectivity decreased to 0.0001 when infected cells were incubated with 3 mg/ml phenolics at 30°C for 5 min. These results demonstrate the antiviral and virucidal activities of umesu phenolics and suggest a potential pharmacological use for these phenolics as a sanitizing or preventive medicine against superficial HSV infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1348-0421.12729DOI Listing
September 2019

[Situation and Problems of Activities for Cancer Cooperative Treatment in Kumamoto].

Gan To Kagaku Ryoho 2019 Jul;46(7):1151-1157

Dept. of Medical Oncology, National Hospital Organization Kumamoto Medical Center.

The Consultation Support and Information Providing Committee, which is a subsidiary organization of the Kumamoto Cancer Medical Cooperation Council, created a critical path called"my medical chart,"which is used in Kumamoto prefecture jointly. The path was implemented in 2009 at designated cancer hospitals. For promoting cancer consultation support centers and nurturing cancer counselors, the Cancer Special Counselor Working Group was formed, and activities were initiated. These activities of the Committee resulted in an increased number of patients visiting the designated cancer hospitals. The number of medical cooperations using"my medical chart"exceeded 4,800. A disparity was also observed in cancer treatment, such as surgery, radiotherapy, and chemotherapy. We investigate the situation of cancer treatment and report current problems and future issues.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2019

Identification of ryuvidine as a KDM5A inhibitor.

Sci Rep 2019 07 9;9(1):9952. Epub 2019 Jul 9.

Nagahama Inst. Bio-Sci. & Tech., 1266 Tamura, Nagahama, Shiga, 526-0829, Japan.

KDM5 family members (A, B, C and D) that demethylate H3K4me3 have been shown to be involved in human cancers. Here we performed screening for KDM5A inhibitors from chemical libraries using the AlphaScreen method and identified a battery of screening hits that inhibited recombinant KDM5A. These compounds were further subjected to cell-based screening using a reporter gene that responded to KDM5A inhibition and 6 compounds were obtained as candidate inhibitors. When further confirmation of their inhibition activity on cellular KDM5A was made by immunostaining H3K4me3 in KDM5A-overexpressing cells, ryuvidine clearly repressed H3K4me3 demethylation. Ryuvidine prevented generation of gefitinib-tolerant human small-cell lung cancer PC9 cells and also inhibited the growth of the drug-tolerant cells at concentrations that did not affect the growth of parental PC9 cells. Ryuvidine inhibited not only KDM5A but also recombinant KDM5B and C; KDM5B was the most sensitive to the inhibitor. These results warrant that ryuvidine may serve as a lead compound for KDM5 targeted therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46346-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616564PMC
July 2019

Cucurbitacin B Exerts Antiaging Effects in Yeast by Regulating Autophagy and Oxidative Stress.

Oxid Med Cell Longev 2019 2;2019:4517091. Epub 2019 Jun 2.

College of Pharmaceutical Sciences, Zhejiang University, 866 Yu Hang Tang Road, Hangzhou, China.

The budding yeast has been used as a model organism for the basic mechanism of aging, which provides useful assay systems for measuring both replicative and chronological lifespans. In the course of our screening program for substances that extend replicative lifespan, cucurbitacin B (CuB) was found as a hit compound from a compound library, which contains cerebrosides, phenols, sesquiterpenoid, triterpenoids, and sterols isolated from natural products by our research group. Importantly, it prolonged not only the replicative lifespan but also the chronological lifespan in yeast. CuB increased gene expression, suggesting that CuB induces autophagy. Indeed, the GFP signal generated from the cleavage of GFP-Atg8, which is a signature of autophagy, was increased upon CuB treatment. On the other hand, CuB failed to increase the chronological lifespans when either or , essential autophagy genes, was deleted, indicating that the lifespan extension by CuB depends on autophagy induction. Furthermore, CuB significantly increased superoxide dismutase (Sod) activity and the survival rate of yeast under oxidative stress, while it decreased the amount of reactive oxygen species (ROS) and malondialdehyde (MDA) production, indicating that CuB has activity to antagonize oxidative stress. Additionally, CuB did not affect replicative lifespans of , , , and mutants with the K6001 background, indicating that aging-related genes including , , , and participate in the antiaging effect of CuB. These results suggest that CuB exerts antiaging activity by regulating autophagy, ROS, antioxidative ability, and aging-related genes. Finally, we discuss the possible intracellular targets of CuB based on the phenotypic comparison between the CuB and global gene deletion databases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/4517091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589324PMC
February 2020

A unique kinesin-like protein, Klp8, is involved in mitosis and cell morphology through microtubule stabilization.

Cytoskeleton (Hoboken) 2019 05 17;76(5):355-367. Epub 2019 Jul 17.

Department of Life Science, Gakushuin University, Tokyo, Japan.

Kinesins are microtubule (MT)-based motors involved in various cellular functions including intracellular transport of vesicles and organelles, and dynamics of chromosomes during cell division. The fission yeast Schizosaccharomyces pombe expresses nine kinesin-like proteins (klps). Klp8 is one of them and has not been characterized yet though it has been reported to localize at the division site. Here, we studied function and localization of Klp8 in S. pombe cells. The gene klp8 was not essential for both viability and cytoskeletal organization. Klp8-YFP was concentrated as medial cortical dots during interphase, and organized into a ring at the division site during mitosis. The Klp8 ring seemed to be localized in the space between the actomyosin contractile ring and the plasma membrane. The Klp8 ring shrank as cytokinesis proceeded. In klp8-deleted (Δ) cells, the speed of spindle elongation during anaphase B was slowed down. Overproduction of Klp8 caused bent or elongated cells, in which MTs were abnormally elongated and less dynamic than those in normal cells. Deletion of klp8 gene suppressed the delay in mitotic entry in blt1Δ cells. These results suggest that Klp8 is involved in mitosis and cell morphology through MT stabilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cm.21551DOI Listing
May 2019