Contents

• Preface
• I. Basic Research for Innovative Medicine
  • Diverting Glycolysis to Combat Oxidative Stress
    Edouard Mullarky and Lewis C. Cantley.
    • Chemical Definition and Sources of ROS
    • Physiology of ROS
    • Biochemical Mechanisms that Preserve Redox Homeostasis
    • Metabolic Adaptations to ROS
    • Conclusion
    • Acknowledgments
    • References
  • Metabolic Regulation by Nuclear Receptors
    Sihao Liu, Michael Downes, and Ronald M. Evans.
    • Introduction
    • NR Endogenous Ligands Are Dietary Sensors
    • Gut and Gut Microbiota
    • De Novo Lipogenesis
    • Integrative Physiology—Nuclear Receptor-Mediated Crosstalk
    • Fibroblast Growth Factors
    • Lipids
    • Concluding Remarks
    • References
  • Fighting Fire with Fire in Cancer
    Thorsten Berger, Mary E. Saunders, and Tak W. Mak.
    • Introduction
    • Boosting the Immune System
    • Targeting Cancer Cell Metabolism
    • Targeting Reactive Oxygen Species
    • Exploiting Cancer Cell Aneuploidy
    • Conclusion
    • References
  • Linear Polyubiquitination: A Crucial Regulator of NF-κB Activation
    Kazuhiro Iwai.
    • The Ubiquitin Conjugation System
    • The Canonical NF-κB Activation Pathways
    • The Linear Ubiquitin Chains and Their Roles in NF-κB Activation
    • Mechanism Underlying Linear Ubiquitin Chain-Mediated NF-κB Activation
    • Perspectives
    • References
  • VCP, a Major ATPase in the Cells, as a Novel Drug Target for Currently Incurable Disorders
    Akira Kakizuka.
    • Background
    • VCP in Neurodegenerative Disorders
    • Development of Novel Inhibitors (KUSs) of VCP ATPase Activity That Do Not Block VCP Cellular Functions
    • KUSs Protected Cells Under ER Stress-Inducing Conditions
    • KUSs or Exogenous ATP Prevented ER Stress in Cultured Cells
    • KUSs Mitigated Pathologies of rd10, a Mouse Model of Retinitis Pigmentosa
    • Discussion
    • References
  • Roles of E-cadherin in Hepatocarcinogenesis
    Shin Maeda and Hayato Nakagawa.
    • Introduction
    • Results
    • Discussion
    • References
  • The Hippo Signaling Pathway: A Candidate New Drug Target for Malignant Tumors
    Miki Nishio, Hiroki Goto, Miki Suzuki, Aya Fujimoto, Koshi Mimori, and Akira Suzuki.
    • Introduction
    • Loss of Hippo Signaling in the Liver
    • Loss of Hippo Signaling in the Pancreas
    • Loss of Hippo Signaling in the Intestine
    • Loss of Hippo Signaling in the Lung
    • Loss of Hippo Signaling in the Skin
    • Loss of Hippo Signaling in T Lymphocytes
    • Loss of Hippo Signaling in Salivary Glands
    • Loss of Hippo Signaling in Neurons
    • Loss of Hippo Signaling in Bone
    • Concluding Remarks
    • Acknowledgments
    • References
  • Inhibitory Immunoreceptors on Mast Cells in Allergy and Inflammation
    Akira Shibuya, Chigusa Nakahashi-Oda, and Satoko Tahara-Hanaoka.
    • Introduction
    • Allergin-1
    • CD300a
    • Conclusion
    • References
  • Doxycycline-Inducible Autoimmune Blistering Skin Disease Model
    Wataru Nishie and Hiroshi Shimizu.
    • Bullous Pemphigoid (BP), The Most Common Autoimmune Blistering Disease
    • BP Models Produced by “Humanization of Autoantigen”
    • Perspectives
    • References
  • T Cell Senescence and Autoimmunity
    Nagahiro Minato, Professor.
    • Introduction: Immune Aging and Senescence-Associated T Cells
    • SA-T Cells Represent an Endogenously Arising Follicular T Cell Population with Age
    • SA-T Cells Increase Robustly in Bone Fide Lupus-Prone Mice
    • SA-T Cells Show Typical Signs and Features of Cellular Senescence
    • SA-T Cells Are Activated in Response to Autologous GC B Cells to Produce OPN that Protects Against B Cell Apoptosis in GCs
    • Involvement of SA-T Cells in the Expansion of GCs and Autoimmunity in Lupus
    • Conclusion and Perspectives
    • References
• II. Translational Research for Innovative Medicine
  • IL-6: A New Era for the Treatment of Autoimmune Inflammatory Diseases
    Tadamitsu Kishimoto, Sujin Kang, and Toshio Tanaka.
    • Introduction
    • Pleiotropic Function of IL-6
    • IL-6 Signaling Systems
    • Regulatory Mechanisms of IL-6 Synthesis
    • Pathological Role of IL-6 in Autoimmune Inflammatory Diseases
    • IL-6-Targeting Strategies: A New Era for the Treatment of Autoimmune Inflammatory Diseases
    • Concluding Remarks
    • Conflict of Interest
    • References
  • Pathogenesis of Non-alcoholic Steatohepatitis and Its Potential Therapeutic Strategies
    Yoshihiro Ogawa, Takayoshi Suganami, Michiko Itoh, and Miyako Tanaka.
    • Introduction
    • Interaction Between Adipocytes and Macrophages in Obese Adipose Tissue
    • Development of a Novel Rodent Model of NASH
    • Identification of Hepatic Crown-Like Structure (hCLS)
    • Macrophage-Induced C-Type Lectin (Mincle)
    • Role of Mincle in Adipose Tissue Remodeling and Ectopic Fat Accumulation
    • Summary
    • Acknowledgments
    • References
  • Multifaceted Translational Approach to Major Mental Illness
    Akira Sawa.
    • Introduction
    • Major Mental Illness Caused by a Combination of Multiple Genetic Risk Factors and Environmental Stressors in the Pathological Trajectory
    • Research Infrastructure That Allows a Multifaceted Translational Approach to Major Mental Illness
    • Two Representative Studies that Use the Research Infrastructure
    • Acknowledgments
    • References
  • Translational Research of Leptin in Lipodystrophy and Its Related Diseases
    Ken Ebihara and Kazuwa Nakao, Professor.
    • Introduction
    • Transgenic Mice Overexpressing Leptin
    • Crossbreeding Experiment of LepTg Mice with A-ZIPTg Mice
    • Leptin Replacement Therapy in Japanese Patients with Lipodystrophy
    • Significance of Hepatic AMPK in the Metabolic Action of Leptin
    • fMRI Analysis of Food-Related Brain Activity in Patients with Lipodystrophy
    • Conclusions
    • References
  • Translational Research of the Activation of the C-Type Natriuretic Peptide (CNP)-Guanylyl Cyclase-B Pathway for Skeletal Dysplasia
    Akihiro Yasoda and Kazuwa Nakao, Professor.
    • Introduction
    • Skeletal Phenotypes of the CNP/GC-B System in Genetically Engineered Mice
    • Importance of CNP/GC-B Signaling in Endochondral Bone Growth in Humans: Lessons from Rare Congenital Skeletal Disorders
    • Translational Research into Activation of CNP/GC-B Signaling for Skeletal Dysplasias
    • Conclusions and Future Prospects
    • Acknowledgments
    • References
  • Clarity and Challenges in Tissue Fibrosis
    Scott L. Friedman.
    • Introduction
    • Liver Fibrosis
    • Genomics of Fibrosis
    • Framework for Antifibrotic Therapies
    • Summary
    • References
  • TRP Channels: Their Function and Potentiality as Drug Targets
    Motohiro Nishida, Koichiro Kuwahara, Daisuke Kozai, Reiko Sakaguchi, and Yasuo Mori.
    • Introduction
    • Modulation of Trpa1 Channel Activity
    • TRPC Channels as Therapeutic Targets for Heart Failure
    • Conclusion
    • References
  • Autophagic Cell Death and Cancer Chemotherapeutics
    Shigeomi Shimizu.
    • Apoptosis and Other Types of Cell Death
    • Autophagy
    • Alternative Macroautophagy
    • Autophagic Cell Death
    • Cancer and Autophagic Cell Death
    • Autophagic Cell Death and Cancer Chemotherapeutics
    • References
  • Adrenomedullin as a Potential Therapeutic Agent for Refractory Ulcerative Colitis
    Kazuo Kitamura, Shinya Ashizuka, Haruhiko Inatsu, and Toshihiro Kita.
    • Introduction
    • Basic Characteristics of AM
    • Pathophysiological Roles of AM in Inflammation
    • Preclinical Pharmacological Effect of AM in Experimental Model of Colitis
    • Exploratory Clinical Study of AM as a Therapeutic Agent for Refractory Ulcerative Colitis
    • Conclusion
    • Acknowledgments
    • References
  • RNA Activation
    X. Y. Zhao, J. Voutila, Nagy A. Habib, and Vikash Reebye.
    • Introduction
    • Molecular Mechanism
    • Application of saRNA
    • Concluding Remarks
    • References
• III. New Technology for Innovative Medicine
  • Proceedings of the Uehara Memorial Foundation. Innovative Medicine: Basic Research and Development. Cardiac Reprogramming for Heart Repair
    Masaki Ieda.
    • Introduction
    • Cell Fate Conversion by Transcription Factors
    • Direct Reprogramming of Mouse Fibroblasts into Cardiomyocytes in Vitro
    • Cardiac Reprogramming in Vivo by Gene Transfer of Defined Factors
    • Gata4/Mef2c/Tbx5/Myocd/Mesp1 Reprogram Human Fibroblasts into Cardiomyocyte-Like Cells
    • MiR-133 Promotes Cardiac Reprogramming by Repressing Snai1 and Silencing the Fibroblast Profile
    • Perspectives and Challenges of Cardiac Reprogramming for Clinical Applications
    • Conclusions
    • Acknowledgments
    • References
  • Development of a New In Vivo Optical Probe for Biological Diagnosis and Therapy
    Michitaka Ozaki, Takeaki Ozawa, and Yuma Yamada.
    • Introduction
    • An Optical Probe for In Vivo Imaging of Caspase-3 Activity
    • An Optical Probe for In Vivo Imaging of the Hepatic Redox State
    • Optical Imaging of Deeper Lesions in the Living Body
    • Development of an In Vivo Optical Probe for Antigen-Specific Imaging Inside/Outside Cells
    • Conclusion
    • References
  • Introduction of Mesenchymal Stem Cells for Liver Surgery (Hepatectomy and Transplantation)
    Shinji Uemoto, Professor, Yasuhiro Fujimoto, Takumi Teratani, Hiroyuki Kanazawa, Junji Iwasaki, Zhao Xiangdong, Yuki Masano, Shintaro Yagi, Koichiro Hata, and Eiji Kobayashi.
    • Clinical Liver Transplantation: Deceased Donor vs. Living Donor
    • Mesenchymal Stem Cells
    • Mesenchymal Stem Cells for Rat Hepatectomy
    • Mesenchymal Stem Cells for Pig Ischemia/Reperfusion Injury
    • Mesenchymal Stem Cells for Rat Whole Liver Transplantation with a Long Preservation Period
    • Experimental Models for Clinical Application
    • Future Perspectives
    • Conclusion
    • References
  • Synaptic and Axonal Plasticity Induction in the Human Cerebral Cortex
    Yoshikazu Ugawa.
    • Introduction
    • What Is QPS?
    • Mechanisms Underlying QPS
    • Dopamine/Dopamine Agonists and Plasticity
    • Meta-plasticity
    • Sensory Cortical Plasticity [
    • Axonal Plasticity in the Human Motor Cortex
    • Future Projects for QPS
    • References
  • TIM-3 Is a Novel Therapeutic Target for Eradicating Acute Myelogenous Leukemia Stem Cells
    Koichi Akashi.
    • Introduction
    • Search for Surface Antigens Specific to AML LSCs
    • TIM-3 Expression and Functions in Normal Hematopoiesis
    • TIM-3 Is a Marker of Malignant Stem Cells in Human AML
    • Targeting AML-LSCs by Monoclonal Anti-TIM-3 Killing Antibodies in a Xenograft Model
    • TIM-3 Is a Functional Molecule for AML LSC Maintenance
    • Conclusion
    • References
  • TGF-β LAP Degradation Products, a Novel Biomarker and Promising Therapeutic Target for Liver Fibrogenesis
    Mitsuko Hara, Tomokazu Matsuura, and Soichi Kojima.
    • Introduction of Liver Fibrogenesis
    • Activation of Hepatic Stellate Cells
    • TGF-β and Its Activation Reaction
    • TGF-β LAP-DP Serves as a Surrogate Marker for Its Activation Reaction
    • Conclusion and Future Subjects
    • Acknowledgments
    • References
  • Cell-Based Regenerative Therapy for Liver Disease
    Kenichi Horisawa and Atsushi Suzuki.
    • The Liver and Disease
    • Expectations for Cell-Based Regenerative Therapies
    • Pluripotent Stem Cell–Based Approaches to Treat Liver Failure
    • Direct Reprogramming
    • Conclusions
    • References