Proceedings for Annual Meeting of The Japanese Pharmacological Society
Online ISSN : 2435-4953
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Greeting
Plenary Lecture
  • Daniel Hoyer
    Session ID: 94_2-PL
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The physiopathological roles of orexins/hypocretins are supported by preclinical and clinical studies. Orexin A and B (hypocretins 1 and 2) and their two receptors (OX1R and OX2R) affect arousal, sleep/wake regulation, reward and stress. The absence of orexin producing cells in the lateral hypothalamus (LH) and of orexin in the CSF, results in narcolepsy with cataplexy (narcolepsy type I). Orexin KO or double OX1R / OX2R KO mice display narcolepsy/cataplexy, whereas OX2R KO and OX1R KO mice have moderate or no sleep phenotype. These features triggered drug discovery programmes for the treatment of insomnia and other disorders. Dual OX1R / OX2R antagonists (DORAs) are close to or marketed. Suvorexant (Belsomra®) and Lemborexant (Dayvigo®) are the first registered orexin hypnotics. DORAs promote sleep primarily by increasing REM (rapid eye movement) sleep, with little effect on NREM (non-rapid eye movement), especially slow wave sleep (SWS), although the primary target mediating sleep by DORAs and other OXR antagonists is the OX2R. We shall briefly review preclinical and clinical data of OXR antagonists and agonists in various neuropsychiatric diseases. REM sleep enhancement by DORAs provides opportunities to treat specific neurological disorders, whereas OX2R antagonists such as Seltorexant (JNJ-54717793), have broader applications, by promoting balanced sleep and antidepressant effects, whereas OX1R antagonists may be indicated in panic/anxiety or addiction. The development of OXR agonists is in very early stages. In preclinical models, OXR agonists produce arousal and have anti narcolepsy/cataplexy effects as expected. In the clinic, only peptide agonists have been tested so far, with very limited success. In summary, OXR antagonists and agonists represent an exciting new class of neuropsychiatric treatments.

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Special Lectures
  • Yoshio Goshima
    Session ID: 94_1-SL1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    L-3,4-dihydroxyphenyalanine (L-DOPA) has been believed as merely a precursor of dopamine (DA), and its therapeutic and/or untoward effects mainly occur through its conversion to dopamine. In 1986, we proposed that L-DOPA by itself acts as a neuroactive substance or neurotransmitter. L-DOPA produced pre- and postsynaptic actions even under the inhibition of aromatic L-amino acid decarboxylase (AADC). L-DOPA was released in a transmitter-like manner, in vitro and in vivo from the striatum, the nucleus accumbens and the lower brain stem nuclei such as the nucleus tractus solitarii (NTS). In the NTS, there were tyrosine hydroxylase (TH)-positive, AADC-negative; L-DOPA-positive and DA-negative-neurons i.e. neurons that may contain L-DOPA as an end product. Recently, GPR143, a gene product of ocular albinism 1, was identified as an L-DOPA receptor. Surprisingly, in Gpr-143 gene-deficient (GPR143-KO) mice, responsiveness to phenylephrine (iv), an a1-adrenoceptor (AR) agonist, was attenuated when compared to wild type (wt) mice. We found that GPR143 expressed in vascular smooth muscle cells coupled with a1-AR and enhanced pressor response to sympathetic nerve activities. We also found GPR143-immunoreactivities in Levy's body in the brains of Parkinson's disease (PD) patients, although further studies are needed to elucidate the significance of L-DOPA and its receptor GPR143 in L-DOPA therapy and in pathogenesis of PD.

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  • Yuichi Sugiyama
    Session ID: 94_1-SL2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Recently, many studies on genetic polymorphisms (PGx) in drug transporters and transporter-mediated drug-drug interactions(DDI) have been published, and these are part of mechanisms of interindividual difference in drug response. It is important to predict such interindividual difference at early stage of drug development. With a PBPK model, the effect of changes in transporter function on the Pharmacokinetics (PK),and, ultimately, the Pharmacodynamics (PD) and/or Toxicodynamics (TD) will be predicted. I will focus on the following subjects. Recent reports provided quantitative predictions for OATP1Bs-mediated DDIs between statins and cyclosporine A(CsA)/rifampicin(RIF) based on PBPK models. In the process of the analyses, the in vitro?in vivo discrepancies in the Ki values for OATPs were suggested. I will share with you our approach to make the bottom-up prediction possible. Finally, it should be also challenging to reproduce the inter-individual variabilities by considering the mean value and deviation of each PK parameter in a certain population with PBPK model (so-called "virtual clinical study").

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  • Yasushi Okuno
    Session ID: 94_1-SL3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    In recent years, artificial intelligence (AI) has been attracting attention as a technology that discovers knowledge and creates new value from big data that is increasing in all fields. In the fields of drug discovery and life sciences as well, various AI researches using a wide variety of and enormous amounts of big data are being developed, and it is expected that the AIs will dramatically improve the efficiency of drug development.

    We have been also developing artificial intelligence and machine learning technologies for drug discovery, for example AIs for target biomolecules identification and for drug screening and optimization. Furthermore, in November 2016, we established the Life Intelligence Consortium (LINC), which aims to develop pharmaceutical AIs in collaboration with academia and pharmaceutical and IT companies. LINC has developed about 30 types of AI technologies from upstream to downstream of drug development.

    In my talk, I would like to introduce our research of AIs for drug development and discuss the impact of AI on the pharmaceutical industry.

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  • Bernard Balleine
    Session ID: 94_1-SL4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The cognitive control of action reflects our ability to extract and encode causal relationships from the environment to guide choice between different courses of action. To investigate this process at both a psychological and a neural level we have adopted a model of cognitive control in rodents in which the influence of predictive learning on action selection is assessed in an instrumental choice situation: the Pavlovian-instrumental transfer paradigm. Over the last several years we have systematically investigated the core neural systems and cellular circuits that mediate transfer effects of various kinds and, in this presentation, I will describe: the behavioural background to this research project; the psychological theories that best account for these kinds of effect; and our most recent findings at a neural level, focusing on neurochemistry of amygdala-striatal interactions and specific modulatory processes within the striatum that enhance motor output via a pallido-thalamic feedback circuit. As a consequence of this latter research, we have uncovered what appears to be a form of GPCR-based ‘memory' process in the nucleus accumbens that encodes specific Pavlovian associations for later use in the control of choice between actions.

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  • Takanori Takebe
    Session ID: 94_2-SL5
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Organoids are multicellular structures that can be derived from adult organs or pluripotent stem cells. Early versions of organoids range from simple epithelial structures to complex, disorganized tissues with large cellular diversity. The current challenge is to engineer cellular complexity into organoids in a controlled manner that results in organized assembly and acquisition of tissue function. These efforts have relied on studies of organ assembly during embryonic development and have resulted in development of organoids with multilayer tissue complexity and higher order functions. Coupled with patient-derived stem cells, my group studied the mechanisms of human hepatic diseases that includes viral hepatitis, steatohepatitis, recently extended to drug induced liver injury (DILI), wherein organoid modelled the clinical phenotype and genotype are correlated. Here I will summarize the next generation of organoid by design, and discuss its promise and impact to elucidate personalized disease mechanisms and understand drug reactions underlying individual variations in humans.

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  • Kenya Honda
    Session ID: 94_2-SL6
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The mammalian alimentary tract harbors hundreds of species of commensal microbes that critically influence a multitude of host physiological functions. Unfavorable alterations of the gut microbiota composition often correlate with several negative health outcomes. Thus, the amelioration of microbiota dysfunction is a promising route for future therapeutics for several diseases. We have been aiming to understand the features and functions, particularly immunological attributes, of the microbiota, and trying to identify responsible bacterial species and factors for shaping the immune system. We have succeeded in isolation of human and mouse gut-associated commensal bacterial strains that specifically affect the development and function of Th17 cells, Treg cells, Th1 cells or CD8 T cells. In addition, we have identified trypsin-degrading bacterial species. Our findings would allow for designing bacterial consortia that activate or suppress specific adaptive immune programs, potentially resulting in development of better therapeutics for numerous diseases involving the immune system, including infectious disease, autoimmunity, allergy, and cancer.

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  • Haruhiko Bito
    Session ID: 94_2-SL7
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    In a population of neurons activated by plastic stimuli triggered during memory formation, synaptic inputs cause CREB-dependent transcriptional activation in the nucleus. We first showed that synaptic input not only induces neuroplasticity signals at the synaptic site, but also co-activates activity-dependent neuroplasticity mechanisms linking the synapse and the nucleus, thereby controlling long-term memory and long-term plasticity. Furthermore, by deciphering the synapses-nucleus communication, we have revealed multiple CREB pathways from the synapses to the nucleus and an inverse synaptic tagging mechanism governed by a CREB-target gene Arc. These biological discoveries led to the identification of genomic and protein structural module information responsible for the mechanism of bidirectional coupling between synaptic plasticity and Arc transcriptional plasticity. This led to a technological breakthrough that helped create the next-generation Ca2+ indicator suite XCaMP, which can record rapid action potential kinetics, and a synthetic promoter, E-SARE, which labels activated neuronal populations. These innovations in neural circuit measurement and labeling technologies, triggered by the elucidation of Ca2+ signaling, now contributes to further elucidating novel in vivo mechanisms of brain function regulation.

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  • Masahiro Nishibori
    Session ID: 94_2-SL8
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    High mobility group box-1 (HMGB1) is a chromatin DNA-binding protein localized in nuclei. HMGB1, secreted or released from cells through cytosolic compartment by stress stimuli or injuries, exerts neurite outgrowth-promoting and pro-inflammatory activities. These features of HMGB1 on dynamics and biological activities are quite unique and distinct from those of known bioactive molecules. We raised anti-HMGB1 monoclonal antibody (mAb), validated the involvement of HMGB1 in different brain injuries and evaluated the efficacy of the mAb treatment. We found that the systemic injection of anti-HMGB1 mAb protected BBB disruption common to brain ischemia, hemorrhage, trauma and epilepsy, and reduced the inflammatory responses in the brain. We identified a plasma protein histidine-rich glycoprotein (HRG) as a HMGB1-binding protein. HRG plays a very important role in the homeostasis of blood cells, vascular endothelial cells and coagulation/fibrinolysis system. We proposed not only a novel hypothesis on septic cascade starting from a dramatic decrease in plasma HRG leading to immunothrombus formation but also a supplementary therapy with purified HRG. We identified CLEC1A as a novel receptor for HRG, and analyzed the regulation of HMGB1 mobilization by HRG. The translational research and drug development beginning with the target validation represent one of the directions in pharmacology.

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  • Hiroaki Ueno
    Session ID: 94_3-SL9
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The environment surrounding the pharmaceutical industry is changing drastically. For example, the progress of aging in developed countries, the worsening of medical finance, the rise of new technologies such as genomic medicine and AI, and the diversification of health and medical needs of patients and people.Under these changes, what should we do to contribute to the extension of healthy life expectancy? JPMA issued "Policy recommendations 2019" in 2019. We should not only create drugs for the treatment of diseases but also engage in R & D for prevention and preemptive medicine. To this end, it is essential to create innovation that incorporates innovative technologies such as health care big data, AI, and genomic medicine.With these changes, the form of open innovation has been expanding from one-one-one collaborative research to many-to-many collaborative research. In order to create innovation in the future, we need an ecosystem constructed by a wide range of stakeholders from industry, academia, and government.In this lecture, I would like to introduce examples of open innovation that has been conducted in the pharmaceutical industry and discuss the direction of future open innovation.

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Education Lecture
  • Sadao Kuromitsu
    Session ID: 94_2-EL
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Acute myeloid leukemia (AML) is one of blood cancer categories characterized by the clonal growth of immature hematopoietic stem cells or progenitor cells. Genetic mutations of fms-like tyrosine kinase 3 (FLT3) such as ITD; Intrernal Tandem Duplication and TKD; Tyrosine Kinase Domain mutations are known to be the most frequently observed in AML patients. The mutant FLT3 is constitutively activated in a ligand-independent manner and causes the abnormal growth. Gilteritinib was synthesized in the ALK inhibitor research and developed for the treatment of FLT3 mutation-positive AML because of its FLT3 inhibitory effects found in the drug discovery studies. Gilteritinib was approved two years ago for the first drug for the treatment of relapsed or refractory AML with FLT3 mutation in Japan and the U.S. after a global phase III study. This presentation will highlight the pathogenesis of AML, the role of FLT3 in AML, and non-clinical pharmacological data on Gilteritinib.

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JPS-ASCEPT Lecture
  • Denise Wootten
    Session ID: 94_2-JAL
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    G protein-coupled receptors (GPCRs) are the largest family of cell surface drug targets. Consequently, there is high interest in understanding the structure of members of this receptor superfamily and the molecular detail of how ligands and transducer proteins interact with them. Our laboratory has been applying single particle cryo-EM to determination of active GPCR structures, using minimally modified receptors. Our work has been principally focused on the class B GPCR subfamily that bind large peptide hormones and are well established clinical targets for the treatment of major disease, including migraine, irritable bowel syndrome, diabetes, obesity and neurodegeneration. Combining novel structural information with molecular pharmacology, biophysical studies and molecular dynamics simulations, we are gaining substantial insights into how ligands and accessory proteins interact with this receptor family to facilitate G protein coupling and downstream signaling.

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The 36th Encouragement of Young Investigator Award Lecture
  • Ichiro Kawahata
    Session ID: 94_1-YAL1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The increase in Parkinson's disease is a social problem in the face of an aging society; however, no fundamental therapeutics has been developed. To approach the etiology of Parkinson's disease and develop therapeutics, we elucidated the mechanism of dopaminergic neurodegeneration as well as a novel regulatory system for neuronal function and conducted a pharmacological analysis of therapeutics using novel drug targets. In detail, we revealed a novel mechanism that tyrosine hydroxylase, a rate-limiting enzyme of dopamine biosynthesis, is lost in dopaminergic neuron selectively and discovered novel drug targets to recover the reduced-dopamine biosynthesis. We further unveiled a mechanism for the α-synuclein uptake into dopaminergic neurons and its propagation, the pathogenesis of Parkinson's disease. These findings suggest preventive and therapeutic applications for Parkinson's disease. Based on these discoveries, we will introduce the overcoming of Lewy body diseases, including Parkinson's disease, and research updates for drug discovery also perspectives.

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  • Junichi Kikuta
    Session ID: 94_1-YAL2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    We originally established an advanced imaging system to visualize living bone tissues using intravital two-photon microscopy, and revealed the dynamics of osteoclastic bone resorption which was finely regulated by cell-cell contact with bone-forming osteoblasts. By means of this system, we could grasp the real mode of actions of active vitamin D and parathyroid hormone (PTH) on bone metabolism. Furthermore, intravital imaging revealed that various biologic DMARDs acted at specific therapeutic points during bone destruction, with different efficacies. This technique facilitates investigation of cellular dynamics in the physiology and pathogenesis of bone disorders in vivo, and would thus be useful for evaluating the efficacy of novel anti-bone resorptive drugs currently developed in the world.

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  • Hiroshi Nomura
    Session ID: 94_1-YAL3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Memory retrieval is impaired due to the passage of a long time or neuronal degeneration. However, it is thought that the memory traces remain in the brain, as the forgotten memories are occasionally recollected spontaneously. Histamine neurons are located in the tuberomammillary nucleus, project to wide areas of the brain, and are involved in cognitive function, arousal, and food intake. Using multidisciplinary methods including mouse behavior analysis, manipulation and imaging of neuronal activity, and human clinical trials and demonstrated that activation of the brain histamine system restores retrieval of forgotten memories. Histamine promotes reactivation of perirhinal cortex neurons that are engaged in the initial learning. These findings contribute to development of new drugs treating cognitive impairments. In this presentation, I would like to introduce our recent findings and future directions using in vivo manipulation and imaging of neuronal activity.

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Symposium
  • Yasushi Okuno
    Session ID: 94_1-S01-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The expansion of COVID-19 in the world has not ended yet, and the situation in Japan is still unpredictable. Under these circumstances, the development of SARS-CoV-2 treatments such as vaccines and medicines is still underway. Since April of this year, we have been conducting research on the drug screening for SARS-CoV-2 using the supercomputer "Fugaku". In my talk, I would like to talk about the impact of the supercomputer "Fugaku" on drug discovery, by exemplifying the in silico drug screening for SARS-CoV-2.

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  • Yumiko Imai
    Session ID: 94_1-S01-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The clinical manifestations of COVID-19 vary from mild or almost asymptomatic to severe ones that require intensive cares such as mechanical ventilation and ECMO in the ICU. In humans with such complex genetic or environmental factors, multi-layered omics networks on the viral and the host side are involved in the formation of various pathologies across all organs. Precision medicine, which provides appropriate medical cares to individual patients based on the omics information including genomic one, is a key to control COVID-19 in humans with diverse biological backgrounds. We construct the multi-layer omics data generation / analysis platform, in which time-series multi-layered omics data of the virus and host, which are linked to medical information, are stored. Those our generating and public data, could be useful for clarifying the complex biological network of COVID-19, and the prediction of disease progression, complications, and effects of interventions for individual patients.

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  • Kato Yuri, Motohiro Nishida
    Session ID: 94_1-S01-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    A new pandemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged and its severe and prognostic symptoms have become a social problem. SARS-CoV-2 infection is mainly initiated by binding of its surface Spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane followed by internalization via endocytosis-mediated pathway. We eventually found that ACE2 expression levels were upregulated by the exposure to epidemiologically reported risk factors for COVID-19 severity; cigarette side-stream smoke, anti-cancer drug, diabetes and obesity, through formation of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2 on the rodent myocardial plasma membrane. We thus used 20 already approved drugs that has previously reported to have potency to attenuate the formation of TRPC3-Nox2 protein complex and evaluated the inhibitory effect on Spike protein-induced ACE2-GFP internalization in HEK293 cells. We found that several TRPC3-Nox2 complex inhibitors also have potency to inhibit the Spike protein-induced ACE2 internalization, and finally identified one drug that has the most potency to prevent SARS-CoV-2-induced infection and proliferation in TMPRRS2-expressing VeroE6 cells, and fluorescence-labeled S protein-induced pseudo infection in human iPS cardiomyocytes. These results provide a new concept that the inhibition of TRPC3-Nox2 complex formation will be a novel strategy to improve COVID-19 aggravation and sequelae by suppressing ACE2-mediated infection pathway.

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  • Yasunari Kanda, Hiroshi Asakura
    Session ID: 94_1-S01-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The pandemic of COVID-19 presents an urgent need for effective treatments. To date, there are limited therapies that are proven to be effective against COVID-19. Several potential candidates or repurposed drugs are under investigation, including drugs that inhibit SARS-CoV-2 replication and block infection via its receptor ACE2. The most promising therapy is remdesivir, which is approved by US Food and Drug Administration (FDA) for emergency use in adults and children hospitalized with severe suspected COVID-19. In addition, because SARS-CoV-2 may induce long COVID-19 symptoms, such as heart failure and myocarditis, safety issues of anti-COVID-19 drugs including cardiotoxicity are important for patients. Here we show currently available pharmacological strategies, that are based on our understanding of COVID-19. In particular, we have used iPSC-based models to investigate the efficacy and safety of drug candidates for COVID-19. We found several drug candidates which inhibit SARS-CoV-2 replication. These drugs have not shown any cardiotoxicities using iPSC-cardiomyocytes. In the symposium, we would like to discuss our challenge and future perspectives against COVID-19 drugs.

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  • Yuki Kambe, Takashi Kurihara, Atsuro Miyata
    Session ID: 94_1-S02-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Although depression has a very high lifetime incidence rate of 10%, the remission rate of existing antidepressants is low, and the discovery of new drug targets is urgently needed. On the other hand, large-scale genome-wide association study analysis revealed Sirt1 as a genomic region associated with depression, and because Sirt1 is a factor involved in the regulation of mitochondrial activity, we focused on mitochondria in the present study to examine their relevance to depression. Mice showed depressed- and anxiety-like behaviors when subjected to chronic restraint stress. These mouse brain mitochondrial specimens had significantly reduced oxygen consumption rates and expression of electron transfer chain proteins. Furthermore, mitochondria-specific unfolded protein stress responses (UPRmt) was significantly correlated with the depression-like behavior of mice. Antibiotics that inhibit protein synthesis have been reported to induce UPRmt. We found that doxycycline had antidepressant- and anxiolytic-like effects in mice when it was chronically applied to them. These results indicate that UPRmt may be involved in depressive- and anxiety-like behaviors in mice.

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  • Takayoshi Masuoka, Junsuke Uwada, Takaharu Ishibashi, Ikunobu Muramats ...
    Session ID: 94_1-S02-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Acetylcholine is crucial for regulation of synaptic transmission in the hippocampus and the cortex, the center of learning and memory. Released acetylcholine from cholinergic terminals is thought to act on muscarinic and nicotinic acetylcholine receptors on plasma membrane, and is subsequently hydrolyzed by cholinesterase. Previous experiments by our group have shown that muscarinic acetylcholine receptor subtype M1 (M1-mAChR) in the brain is highly distributed on intracellular organelles of neurons, such as endoplasmic reticulum and Golgi apparatus, and activates signaling cascades distinct from those of plasma membrane receptor. The intracellular M1-mAChRs is activated by endogenous acetylcholine following its uptake via a putative transport system without degradation, which facilitates long-term potentiation in the hippocampal CA1 synapses. In addition, the cholinergic synaptic regulation through intracellular M1-mAChR in the hippocampus disappeared after chronic physical stress. In this symposium, we demonstrate the function of intracellular M1-mAChR in the brain and discuss about possible contribution to stress and neuropsychiatric disorder.

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  • Fusako Kagitani, Sae Uchida
    Session ID: 94_1-S02-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The ovary is innervated by autonomic nerves in addition to being under the control of hormones. In this symposium, we will introduce our studies on regulation of ovarian estradiol secretion and ovarian blood flow by sympathetic adrenergic innervation in relation to physical stress.

    In rats, sympathetic nerves reach the ovary by two routes: the superior ovarian nerve (SON) in the suspensory ligament and ovarian nerve plexus (ONP) along the ovarian artery. Of the two pathways, stimulation of the SON, but not the ONP, reduces estradiol secretion via activation of alpha2-adrenoceptors, whereas stimulation of the either nerves reduces ovarian blood flow via activation of alpha1-adrenoceptors. Reflex activation of ovarian sympathetic nerves by noxious physical stress (noxious cutaneous stimulation of a hindpaw) causes ovarian vasoconstriction and inhibition of ovarian estradiol secretion. The ovarian vasoconstrictive response is produced via reflex activation of the SON and ONP, whereas inhibition of ovarian estradiol secretion occurs as a result of reflex activation of the SON only. These results suggest that reflex activation of sympathetic nerves to the ovary by stressful physical stimulation, for example, noxious stimulation, may be involved in rapid inhibition of ovarian function in emergencies. Rapid and direct regulation of ovarian function by the autonomic nerves may be an important adaptation of female reproductive function to either internal or external environmental changes.

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  • Takahiro Shimizu, Shogo Shimizu, Youichirou Higashi, Motoaki Saito
    Session ID: 94_1-S02-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The sympatho-adrenomedullary (SA) system is one of the body's principal responses to stress stimuli. In contrast, dysregulation of the system in response to excessive stress can contribute to the development of various diseases including essential hypertension and other cardiovascular events, gastrointestinal diseases and certain disorders of immune function. Therefore, to establish "fundamental" approaches for treatment of these stress-related diseases, we have to elucidate regulatory mechanisms that control the SA outflow focusing on the brain, which plays a key role in responses to stress. We have investigated a relationship between brain 2-arachodonoylglycerol (2-AG) and central regulation mechanisms for the SA outflow. 2-AG has been recognized as an endogenous ligand for cannabinoid CB receptors (endocannabinoid), which plays an inhibitory role in synaptic neurotransmission via presynaptic CB1 receptors. On the other hand, 2-AG is hydrolyzed by monoacylglycerol lipase to arachidonic acid, a precursor of prostanoids. In this symposium, we will introduce our data indicating bidirectional roles of brain 2-AG as an endocannabinoid and as a precursor of prostanoids in central regulation of the SA outflow.

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  • Kazuhide Inoue
    Session ID: 94_1-S03-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Purinergic receptors are nucleoside receptors, adenosine receptors (A1, A2A, B, A3), and nucleotide receptors, P2X and P2Y receptors. Burnstock proposed calling the former the P1 receptor and the latter the P2 receptor(1978), and further subdividing the P2 receptor into ion channel-typed P2X and G protein-coupled P2Y(1985). P2X and P2Y are collectively called ATP receptors. Adenosine-3'-phosphate (ATP) is an agonist of P2X receptors. P2X molecules form a trimer acting as a single non-selective cation channel (Na+, K+, Ca2+). Seven types from P2X1 to P2X7 have been reported. All subunit molecules form homomer receptors, and some P2X molecules can form heteromers (P2X1 with P2X5, P2X2 with P2X3 or P2X6, and P2X4 with P2X6 or P2X7). Various subtypes are expressed in all tissues in the body, and utilize the difference in sensitivity (1 million times difference from nM to mM) to play an important individual physiological functions.

    It's already been 61 years since Holton pointed out the relationship between ATP and pain (1959). Today, ATP is involved in a variety of nociceptive transmission through ATP receptor subtypes that are variously expressed in dorsal root ganglion (DRG) neurons, dorsal root ganglion neurons, spinal microglia, and the upper central nervous system.

    Currently, drug discovery targeting ATP receptors is being carried out all over the world.

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  • Jiang-Fan Chen
    Session ID: 94_1-S03-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    In this memorial lecture, I will review the long drug development history and belated US FDA approval of the adenosine A2A receptor (A2AR) antagonist istradefylline for treatment of Parkinson's disease (PD) and its implications. The A2AR has been long considered as the leading drug target for PD treatment for its highly concentrated expression in the striatopallidal neurons and its colocalization and functional antagonistic interact ion with dopamine D2 receptors in this neuron type. Since the early 1990s, mounting experimental findings have demonstrated the motor enhancement effect of A2AR antagonists, alone or synergizing with L-DOPA in rodents and non-human primates. Since 2001, more than 25 clinical trials were conducted to evaluate the safety and clinical efficacy of A2AR antagonists in PD patients. After more than two decades of preclinical and clinical studies, on August 27, 2019, the U.S. Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist Nourianz (istradefylline) developed by Kyowa Hakko-Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes. This milestone achievement represent is the first A2AR therapeutic drug and the first non-dopaminergic drug for PD treatment approved by US FDA in the last two decades. This approval provides an important lessons to be remembered, namely the selection of defined patients subpopulations who are most responsive to the tested drug is critical for a successful demonstration of the clinical efficacy of the drug. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A2A receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases. As a pioneer, Professor Geoff Burnstock established the purinergic signaling field against all the odds more than 50 years ago and thus set up the stage for us to pursuit and achieve many milestone like this in near future.

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  • Fusao Kato
    Session ID: 94_1-S03-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Molecular identification of purine receptors, particularly the P2X receptor channels of several types, in the late 90's lead researchers to identify their roles in the brain because many subtypes were found there. Except for the first identification of the fast excitatory synaptic transmission mediated by ATP in the medial habenula of rats (Edwards et al., 1992), such demonstration in the mammalian brain remained highly limited, mostly due to the extremely rapid breakdown of ATP to adenosine. In the brain slice preparation, we found that ATP (presumably released from astrocytes) triggers Ca-dependent action potential-independent release by activating presynaptic P2X2/3 receptors, which is followed by reduction of action potential-dependent release through activating presynaptic adenosine A1 receptors (Kato & Shigetomi, 2001; Shigetomi & Kato, 2004). We proposed that spatially limited colocalization of P2X and A1 receptors and ectonucleotidase enables ATP to exert dual functions and dubbed this system "purine signaling complex in the brain synapses," which later found in many brain structures (Kawamura et al., 2004) and also in non-mammalian species (Wakisaka et al., 2017).

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  • Schuichi Koizumi
    Session ID: 94_1-S03-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The molecular pathogenesis of depression is often explained by the catecholaminetheory. However, there are many cases of so-called refractory depression thatare resistant to existing noradrenergic and serotonin activating drugs, so thetrue molecular pathogenesis of depression needs to be elucidated. Asdemonstrated by Prof Burnstock, ATP is not a merely energy currency but is animportant intercellular signaling molecule that mediates information betweenneurons and glial cells in the central nervous system. Animal studies havereported that "ATP" is the most universally altered intercellular signalingmolecule in depressive symptoms, and that a decrease in this extracellular ATPcauses depressive symptoms (Nat Med 2013). However, its molecular and regulatorymechanisms remain unclear. In the present study, we tested this ATP hypothesisand elucidated the molecular mechanism of this ATP hypothesis using fluoxetine(FLX), a typical SSRI antidepressant, which increased extracellular ATP (ATPo)in the hippocampal brain in a dose-dependent manner. This ATPo increase wasdependent on astrocytes rather than neurons, and the molecular mechanism of thisincrease was found to be an enhancement of the ATP exocytosis. We found thatreleased ATP acts as ATP and degraded adenosine on P2Y11 and A2b receptors,respectively, to enhance the cAMP-CREB system and that this signal enhancementleads to BDNF expression. Very interestingly, the sequence of responses fromATP/adenosine to BDNF production was induced in astrocytes, but not in neurons.We further discuss the importance of astrocytes as a prime target fordepression.

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  • Masato Tsutsui, Kaori Kato, Takaaki Ogoshi, Shingo Noguchi, Kazuhiro Y ...
    Session ID: 94_1-S04-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    We investigated the roles of nitric oxide synthases (NOSs) in the pathogenesis of lung diseases by using our triple n/i/eNOSs-/- mice. Bleomycin treatment resulted in pulmonary fibrosis (PF) in wild-type (WT), single nNOS-/-, iNOS-/-, and eNOS-/-, and triple n/i/eNOSs-/- mice as compared with saline treatment. PF was exacerbated only in triple NOSs-/- mice, but not in any single NOS-/- mice, as compared with WT mice, suggesting a protective role of NOSs in the development of PF(Respir Res 2014). Hypoxic exposure led to pulmonary hypertension (PH) in all WT, single NOS-/-, and triple NOSs-/- mice as compared with normoxic exposure. PH was aggravated in triple NOSs-/- mice and, to a lesser extent, in single eNOS-/- mice as compared with WT mice, again suggesting a protective role of NOSs in the development of PH (AJRCCM 2018). In contrast, ovalbumin-induced bronchial asthmatic changes (BA) were markedly mitigated in triple NOSs-/- than in WT mice, suggesting an opposing injurious role of NOSs in the development of BA(Lung 2016). We recently found that spontaneous development of pulmonary emphysematous changes (PE) was noted only in triple n/i/eNOSs-/- mice, suggesting a preventive role of NOSs in the development of PE. Taken together, our findings demonstrate diversity of the roles of NOSs in the pathogenesis of lung diseases.

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  • Hiroshi Watanabe
    Session ID: 94_1-S04-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Pulmonary arterial hypertension (PAH) is a chronic and life-threatening disease characterised by progressive vascular remodelling that leads to increased pulmonary vascular resistance, right ventricular heart failure and death. PAH is defined by >25 mmHg increase in pulmonary arterial blood pressure and a pulmonary capillary wedge pressure of 15 mmHg. If left untreated PAH is fatal; it has a survival rate of just 34 % after 5 years. Current therapies for PAH include stimulating the nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) axis, improving the prostacyclin pathway or inhibiting the endothelin pathway. Although the causal relationship remains unproven, the NO–sGC–cGMP axis is ultimately a critical factor in the development of PAH because the condition is associated with endothelial dysfunction, impaired NO synthesis and insufficient stimulation of the NO–sGC–cGMP pathway. NO activates sGC, resulting in the synthesis of cGMP, which is a key mediator of pulmonary arterial vasodilatation that may also inhibit vascular smooth muscle proliferation and platelet aggregation. Dysregulation of the NO–sGC–cGMP axis results in pulmonary vascular inflammation, thrombosis and constriction, and ultimately leads to PAH. Therapeutic options targeting the NO–sGC–cGMP axis include phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil and tadalafil, and the sGC stimulator riociguat. In this session, I would like to introduce the importance of NO-cGMP-PKG Axis in PAH and discuss the similarities and differences between PDE5 inhibitors and sGC stimulator and considers which is better for the treatment of PAH.

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  • Kazuhiro Yatera
    Session ID: 94_1-S04-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Coronavirus is a type of single-stranded RNA virus with a lipid bilayer called an envelope on the outside, and it looks like a corona under an electron microscope. It cannot self-regenerate, attaches to and enters human cells via ACE2 receptors, and proliferates within the human cells. There have been some coronaviral diseases such as SARS, MERS and "normal" human coronaviruses (HCoV) that cause common colds.

    The "new coronavirus" was named as SARS coronavirus-2 (SARS-CoV-2), and new coronavirus infectious disease caused by SARS-CoV-2 was named as COVID-19 short for "corona-virus disease discovered in 2019". SARS-CoV-2 infection spreads before the symptom onset, and prophylactic actions such as wearing masks and social or physical distancing are very important and critical.

    Treatment is mainly general respiratory management with various therapeutic agents including approved or nonapproved antiviral drugs for treating new coronavirus infection such as remdesivir, favipiravir in combination with corticosteroids (dexamethasone) and other expected agents for treating COVID-19 such as inhaled corticosteroid (ciclesonide), ivermectin, anticoagulants, antimicrobials and the treatment of comorbid illnesses. Therapeutic methods and agents are selected at the hospital based on the latest information such as treatment results and side effects of each regimen.

    In this symposium, I would like to talk about current knowledge of the diagnosis and management of COVID-19 in Japan.

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  • Yuichi Hattori, Kohshi Hattori
    Session ID: 94_1-S04-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Acute bacterial or viral infections responsible for pneumonia or sepsis cause severe inflammatory damage to the lungs, leading to the development of acute lung injury (ALI) in critically ill patients. ALI is characterized by high permeability pulmonary edema as well as refractory hypoxemia and diffuse pulmonary infiltrates. Our previous study has shown that the inducible NO synthase inhibition or the histamine H1-receptor blockade significantly but incompletely inhibited LPS-induced lung vascular permeability in mice, suggesting that NO and histamine may also be partly responsible for mediating increased lung vascular leak following LPS challenge. The involvement of histamine in lung vascular leak has also been demonstrated using histidine decarboxylase gene knockout mice. Furthermore, treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced the LPS lung hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. We thus assume that several vascular permeability molecules, including NO, histamine, and VEGF, can be excessively produced and thereby actually contribute to the development of pulmonary edema in ALI.

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  • Naoki Aizawa
    Session ID: 94_1-S05-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Men with benign prostatic hyperplasia (BPH) often experience symptoms of overactive bladder (OAB), and bladder outlet obstruction (BOO) is one of cause of BPH. It has been suggested that bladder myogenic microcontractions or micromotions may partly contribute to the development of urgency (bladder sensory (afferent) hypersensitivity) in OAB related to BOO. We have investigated the direct effects of drugs (anticholinergics, β3-adrenoceptor agonists, α1-adrenoceptor antagonists, PDE type5 inhibitors, etc.) on the bladder afferent function in rodents. In our results, almost all drugs may act on the bladder afferent function, and some of drug (e.g. mirabegron) inhibits the afferent activities through the suppression of the bladder myogenic microcontractions in normal or pathophysiological conditions.

    Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes long-standing pain and/or storage symptoms including storage symptoms, such as urgency and frequency. It has been reported that CP/CPPS is possibly overlapping with symptoms in BPH.

    In this symposium, I will introduce our recent studies using pathophysiological animal models with BOO or CP/CPPS.

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  • Yuji Hotta, Kazunori Kimura
    Session ID: 94_1-S05-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Erection is initiated by the production and release of nitric oxide (NO) via NO synthase upon sexual stimulation. NO relaxes the penile corpus cavernosum smooth muscle, which increases the inflow of blood into the penile corpus cavernosum and compresses the veins, thereby preventing blood loss. This increases the intracavernous pressure in the penile corpus cavernosum to induce erection. Phosphodiesterase 5 (PDE5) inhibitors, which target the NO/cyclic guanosine monophosphate (cGMP) pathway, are currently used to treat erectile dysfunction (ED). PDE5 inhibitors are useful drugs in the general population with ED; however, these inhibitors are not necessarily useful for ED due to diabetes complications or neurogenic conditions after radical prostatectomy. One reason for this low effectiveness is inadequate production of NO in these conditions. Therefore, NO replacement may be an effective ED treatment, but it has been difficult to achieve to date due to systemic side effects.

    To overcome this limitation, we focused on the development of light-controlled NO donors, which can produce NO in response to light, thus producing NO only in localized, light-exposed areas. Light-controlled NO donors can also control the onset and end of drug effects because they can produce NO only for the duration of light exposure. We modified the compound and recently succeeded in developing a red light-responsive NO donor termed "NORD-1" with high tissue permeability.

    In this symposium, we introduce the results of an in vivo study on the enhancement of erectile response with NORD-1 and the effectiveness of the ED model.

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  • Gen L. Takei
    Session ID: 94_1-S05-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Mammalian sperm activate their motility upon ejaculation, but sperm motility needs further change to whiplash-like motility to penetrate and fertilize the egg. This specialized motility is called "hyperactivation". It was reported that extracellular Na+ is involved in regulation of hyperactivation. Na+/K+ ATPase (NKA) plays a major role in the regulation of cellular Na+ homeostasis. The catalytic subunit of NKA is an α subunit, and there are α1 and α4 subunits in sperm. The sensitivity of these two α subunits to ouabain, a specific NKA inhibitor, is quite different, that is, 10-6 M ouabain inhibits NKA α4 while >10-5 M ouabain inhibits both the α1 and α4. Therefore, this difference of sensitivity enables us to distinguish the physiological role of NKA α subunits on sperm function by pharmacological approach. In this symposium, I will introduce my latest study which showed, by utilizing this pharmacological property of ouabain, that the NKA α1 subunits is necessary for the maintenance of motility while the α4 subunit is necessary for the hyperactivation-associated change in flagellar movement. These results suggest that NKA α4 subunit is an attractive target for the male contraception.

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  • Yokonishi Tetsuhiro
    Session ID: 94_1-S05-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Spermatogonial stem cell (SSCs) proliferate and differentiate to sperm in seminiferous tubules. SSCs are under well-organized control of germ cell niche composed of Sertoli cells, Leydig cells, peritubular myoid cells (PMCs) and vasculature. Thus, Sertoli cell dysfunction causes spermatogenic failure. Recently we discovered benzalkonium Chloride (BC) ablates Sertoli cells selectively. We tried manipulating mouse germ cell niche by seminiferous transplantation into BC treated testis. FACS sorted donor Sertoli cells colonize and support recipient spermatogenesis. When we transplanted whole testicular cells into Sertoli-depleted testis, donor SSCs, Sertoli, Leydig and PMCs colonize and reconstruct donor testis in recipient testis. BC has been used clinically for decades and ablates mouse and canine Sertoli cells, suggesting that this novel method of drug-induced Sertoli cell elimination followed by replacement may be useful for male infertility patients with Sertoli cell disorder. Using this novel technique, we can reorganize mouse germ cell niche. This might achieve human testis reconstruction in mouse testis and can be a strategy of fertility preservation for young cancer patients.

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  • Yoshiyuki Takahashi
    Session ID: 94_1-S06-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    In 2020, the number of universities teaching nursing in Japan reached 274. In recent years, increasing social demand has been seen for nurses who can cope with Japan's declining population, advances in medical care, and community-based integrated care systems. Therefore, the expectations of recipients of a bachelor's degree in nursing education have been rising. In 2017, the Ministry of Education, Culture, Sports, Science and Technology of Japan published the "Model Core Curriculum for Nursing Education in Japan" and established learning goals that each university can refer to when organizing the curriculum. In October 2020, the "Regulation for Enforcement of the Act on Public Health Nurses, Midwives, and Nurses" was revised and the total number of credits was increased, and one unit was added to enhance the foundation of clinical judgment when applying pharmacological knowledge. The revision of this regulation provides a good opportunity for universities to revise their own curriculums. It is important both to consider carefully how a curriculum is organized at the basic education stage within a limited period and to create one that attracts students.

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  • Akiko Matsuda
    Session ID: 94_1-S06-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Elderly patients who take multiple types of medication have been increasing. Such patient often taking supplements and traditional Chinese medicine. A number of medication errors by nurses have been reported in Japan.

    The model core curriculum for nursing education, which was established in 2017, claimed the importance of pharmacology education in nursing education. Produce the desired pharmacology education in science of nursing. We would like to have discussions, for pharmacology education in science of nursing the purpose of produce of nursing practice ability.

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  • Takeshi Unoki
    Session ID: 94_1-S06-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    I have experienced for clinical practice in the intensive care unit for more than 10 years and am working as a professor in nursing school. In this symposium, I will talk about pharmacology education for nursing student and clinical nurses based on my experience.

    The point of our opinion is pharmacology in nursing curriculum at this time is just pharmacology, not but pharmacology for nursing or nurses. Off course, pharmacology is pharmacology, however, its education should be changed depending on medical profession and it should contribute to knowledge in terms practice. It is time for transition from pharmacology education for pharmacology to pharmacology education for specifically nursing students and clinical nurses.

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  • Toshihiko Yanagita, Maki Kanaoka, Yumiko Kinoshita, Ryu Takeya
    Session ID: 94_1-S06-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Two active learning programs of practical pharmacotherapy for nursing students have been performed in school of nursing, University of Miyazaki; (1) pharmacotherapy role-play for interprofessional education (IPE) and (2) practical excise for Kampo medicine.

    Pharmacotherapy role-play for IPE was performed as joint lecture both medical students and nursing students. This pharmacotherapy role-play is named Case & Communication based approach (C&C approach), since it is studied through communication between physicians, nurses and patients based on cases presented beforehand. In the practical excise for Kampo medicine, nursing students studied Kampo medicines and tried to taste 9 frequently used Kampo medicines. These active-learning programs in nursing pharmacology education may be effective for better understanding of pharmacotherapy, patient's feeling, and improvement of students' awareness and motivation as a nurse.

    In this symposium, we would like to show the detail of these programs and possibility of contribution to nursing education.

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  • Hiroyuki Sugiyama
    Session ID: 94_1-S07-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    COVID-19 therapeutics currently under development can be broadly divided into two categories. The first is an antiviral drug with in vitro antiviral activity that inhibits the growth of the virus in infected organs in the body. Second, they do not act directly on the virus, but act on the body to ameliorate cytokine storms and acute respiratory distress syndrome (ARDS) caused by an overactive defense response to infection. For an entirely new drug, the safety of the drug has to be confirmed in pre-clinical animal studies, and the safety and dosing of the drug in humans must be established in Phase I and Phase II studies. However, if the drug has already been administered to humans through drug repositioning, the initial steps in development can be shortened. Antiviral drugs include remdesivir, favipiravir, ciclesonide, nelfinavir, nafamostat and ivermectin. On the other hand, bioactive agents include dexamethasone, tocilizumab, baricitinib, and eritran. These drugs and other candidates and others are summarized and briefly presented in this section.

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  • Yasuhisa Fujita
    Session ID: 94_1-S07-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Countries around the world are currently fighting the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a betacoronavirus, belonging to the same genus as severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV. Currently, there are no proven antiviral therapies for COVID-19. Numerous clinical trials have been initiated to identify an effective treatment. One leading candidate is remdesivir (GS-5734), a broad-spectrum antiviral that was initially developed for the treatment of Ebola virus, has been provisionally approved for COVID-19. Remdesivir is a nucleotide analogue that delays replication of viral RNA. It comes in the form of a prodrug which is metabolized to the active form (remdesivir triphosphate) once it enters cells. In vitro and preclinical studies have shown that it has antiviral activity against SARS-CoV-2. There have been several studies of remdesivir in patients with COVID-19. These have included a compassionate use program, placebo-controlled trials and dosing trials. The results present here.

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  • Kappei Tsukahara
    Session ID: 94_1-S07-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Eritoran (E5564) is Eisai's in-house discovered and developed investigational TLR4 (Toll-Like Receptor 4) antagonist created with natural product organic synthesis technology. It is a structural analogue of Lipid A, which is an activator of endotoxins of bacteria. It has been previously observed to be safe in 14 clinical studies including a large Phase 3 randomized trial in severe sepsis. We are participating in the international network REMAP-CAP-COVID (Randomized, Embedded, Multi-factorial, Adaptive Platform-Community Acquired Pneumonia COVID) which aims for novel coronavirus medicine development through drug repurposing, and began an international collaborative clinical trial in October 2020 which is designated for confirmed novel coronavirus patients who are hospitalized and are in a progressing disease state. It is hoped that through suppressing the most upstream TLR4 activity which controls production of multiple cytokines, the cytokine storm in patients can be suppressed and pneumonia can thus be prevented from becoming severe.

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  • Norihisa Shindo, Hiroyoshi Toyoshiba
    Session ID: 94_1-S07-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Although months have passed since WHO declared COVID-19 a global pandemic, only a limited number of clinically effective drugs are available, and the development of drugs to treat COVID-19 has become an urgent issue worldwide. The pace of new research on COVID-19 is extremely high and it is impossible to read every report. In order to tackle these problems, we leveraged our artificial intelligence (AI) system, Concept Encoder, to accelerate the process of drug repositioning. The Concept Encoder is a patented AI system based on natural language processing technology and by deep learning papers on COVID-19, the system identified a large group of genes implicated in COVID-19 pathogenesis. The AI system then generated a molecular linkage map for COVID-19, connecting the genes by deep learning the molecular relationship. By thoroughly reviewing the resulting map and list of the genes with rankings, we found potential key players for disease progression and existing drugs that might improve COVID-19 survival. Here, we focus on potential targets and discuss the perspective of our approach.

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  • Hirotaka Nagai, Tomoyuki Furuyashiki
    Session ID: 94_1-S08-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Excessive or chronic social stress induces emotional and cognitive disturbancesand is a risk for mental illness. Reduced neuronal activity in the medialprefrontal cortex (mPFC) underlies these behavioral abnormalities. However, thesubcellular origin and process of this neuronal change remain elusive. Here weexamined ultrastructural alterations of mPFC neurons after social defeat stressin mice by serial electron microscopy and expansion microscopy. Social stresscaused the loss of dendritic branches as well as morphological abnormality ofsubcellular structures, including mitochondria in remaining dendrites withvaricosity-like membrane deformation. Social stress induced synaptic shrinkageselectively at mitochondria-containing synapses. Furthermore, multi-omics andfunctional analyses revealed that social stress deteriorated mitochondrialfunctions with decreased mitochondrial proteins at synapses. Pharmacologicalmanipulation targeting mitochondria attenuated the synaptic shrinkage anddepression-related behaviors. Together, these findings illustrate the importanceof synaptic subcellular organelle in the synaptic pathology underlying stressand depression.

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  • Misaki Niu, Atsushi Kasai, Kaoru Seiriki, Hitoshi Hashimoto
    Session ID: 94_1-S08-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    The processing of stress responses involves brain-wide communication among cortical and subcortical regions. Although considerable effort has been made to discover these brain regions, hypothesis-free and unbiased approaches to identify previously unknown neural elements have been limited until recently due to technical limitations. Here, we performed whole-brain activation mapping and machine learning-based analyses to identify previously uncharacterized brain regions and neuronal ensembles implicated in stress, and found that the claustrum (CLA) most prominently contributes to discrimination in stressed brains. Activity-dependent genetic labeling in TRAP2 mice subjected to social defeat stress revealed reciprocal connection of the CLA with fos-tagged neurons in brain-wide areas, including the basolateral amygdala and medial prefrontal cortex. Chemogenetic reactivation of the fos-tagged CLA neuronal ensemble reproduced anxiety-like behaviors and brain-wide neuronal activation, while its silencing attenuated anxiety-like behaviors induced by acute social defeat stress and increased resistance to chronic social defeat stress. The CLA thus controls stress-induced emotional responses bidirectionally through brain-wide networks, and its inactivation can be a preventative measure that increases stress resilience.

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  • Takuya Sasaki
    Session ID: 94_1-S08-3
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Stress experiences induce diverse psychiatric symptoms. While stress experiences themselves are terminated within short time periods at a time scale of seconds or minutes, the stress-induced mood changes subsequently last for days or even a lifetime. This fact means that physiological activity not only during onsite stress episodes but also during post-stress periods may be crucial to facilitate stress-induced psychiatric changes. We hypothesized that this effect is mediated by memory processing mechanisms in the brain. A well-established theory of memory suggests that learned memory traces need to be consolidated into neuronal circuits for a long-term memory storage. Especially, the ventral part of the HC (vHC) is especially considered a crucial brain region for emotion- and sociality-related information processing and for memory consolidation. We tested this idea, mice were subjected to social defeat (SD) stress. Defeated mice showed deficits in social interactions. This reduction was suppressed by vHC inactivation, suggesting that vHC neuronal activity after stress experiences is especially crucial to induce social behavior deficit. To further examine detailed hippocampal activity patterns, we recorded spike patterns of vHC CA1 neurons using tetrode assemblies. Stress-encoding neurons in the vHC were continuously reactivated for several hours after SD experiences, which likely underlies the long-lasting effects of SD stress on social behavior. To further examine the causal of vHC activity in stress-induced behavioral changes, closed-loop feedback stimulation was applied to the vHC when synchronized reactivations of neuronal population in the vHC were detected. This manipulation abolished the stress-induced reductions in social interaction deficits, suggesting the importance of synchronized reactivation of vHC neurons for subsequent psychiatric responses. The vHC-specific activity patterns may serve as a biomarker and a therapeutic target in stress-induced mood disorders.

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  • Shusaku Uchida
    Session ID: 94_1-S08-4
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Although stressful events predispose individuals to psychiatric disorders, such as depression, not all people who encounter a stressful life experience become depressed, suggesting that gene-environment interactions (GxE) determine depression risk. Accumulating evidence has implicated that stress-induced aberrant synaptic and structural plasticity may be key underlying mechanisms of stress susceptibility. Recent evidence has provided key insights into the biological significance of epigenetic regulation of gene expression in synaptic plasticity and behavioral response to chronic stress. The medial prefrontal cortex (mPFC) is vulnerable to damage from a variety of psychosocial stressors and aberrant structural and functional changes in this brain structure have been implicated in depression. However, little is known about the role of epigenetic mechanisms within the mPFC in chronic stress-induced aberrant neuronal plasticity and depression-like behavior. In this symposium, I will focus on causal and mechanistic evidence implicating altered functions and connectivity of the mPFC circuits in the establishment and the maintenance of stress resilience and susceptibility. I also touch upon recent findings suggesting a role for epigenetic mechanisms in these processes and briefly discuss promising avenues of future investigation.

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  • Mitsuru Ishikawa, Hideyuki Okano
    Session ID: 94_1-S09-1
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    It has already become a powerful tool for generating neural cells from human induced-pluripotent stem cells (iPSCs) to mimic neurophysiological functions, for instance, by constructing brain organoids. In particular, recent studies using disease-specific iPSCs cells have also been required to utilize a large number of samples, including sporadic diseases. In addition, it becomes important to validate pathological conditions and drug screening in a rapid manner. However, required long period culture, highly cellular heterogeneity and highly clonal diversity make analysis of brain organoids difficult. Therefore, an application of alternative rapid and accurate method has been needed, so target-specific neuronal induction by transient expression of bHLH-type proneural factors and other transcription factors in iPSCs can be very useful.

    We have improved this tool based on using TetO-Neurog2 or TetO-Ascl1 system and developed a platform for stable generation and functional analysis of target neuronal cells. In this symposium, we will introduce our new platform and report the results of the studies on Alzheimer's disease and various psychiatric and neurodevelopmental disorders. We believe that our platform will enable us to selectively generate numerous subtype-specific neuronal cells and provide a rapid pathophysiological or drug screening system.

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  • Takahiro A. Kato
    Session ID: 94_1-S09-2
    Published: 2021
    Released: March 21, 2021
    CONFERENCE PROCEEDINGS OPEN ACCESS

    Microglia have been highlighted to understand the underlying pathophysiology of various neuropsychiatric disorders. Postmortem brain analysis and PET imaging analysis are two major methods to estimate microglial activation in humans, however only a limited aspect of microglial activation can be measured by these methods. Dynamic analysis using fresh microglia in human brain is an ideal method, however technological and ethical considerations have limited the ability to conduct research using fresh brain microglia.

    To overcome this limitation, we have originally developed a technique to create directly induced microglia-like (iMG) cells from fresh human peripheral blood monocytes adding GM-CSF and IL-34 for 2 weeks, instead of brain biopsy (Sci Rep 2014). Using the iMG cells, dynamic morphological and molecular-level analyses such as real-time cell differentiation, phagocytosis and cytokine releases are applicable.

    We have used the iMG cells as surrogate cells of human brain microglia, and revealed previously-unknown dynamic pathophysiology of microglia in patients with Nasu-Hakola disease (Sci Rep 2014), fibromyalgia (Sci Rep 2017) and rapid-cycling bipolar disorder (Front Immunology 2017).

    In addition, we have recently shown microglia-related pathophysiology using plasma such as human metabolome analysis focusing on the tryptophan-kynurenine pathway and neuron-related exosome analysis.

    We believe that these indirect methods using human bloods shed new light on clarifying dynamic molecular pathologies of microglia in a variety of neuropsychiatric disorders.

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