Folia Pharmacologica Japonica
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
Volume 156, Issue 5
Displaying 1-13 of 13 articles from this issue
Reviews: Technique Succession of Animal Experiments on Pharmacological Research and Practice
  • Koichiro Wada
    2021 Volume 156 Issue 5 Pages 255-258
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    Recently, cellular and molecular research techniques are rapidly progressed, while pathological models and animal experimental techniques are avoided. The International Union of Basic and Clinical Pharmacology has made proposal for the development of leaders of technology, and The Japanese Pharmacological Society has also started the various efforts about the issues of technique succession of animal experiments on pharmacological research and practice. Furthermore, the problem of succession of animal research techniques has become a problem not only in The Pharmacological Society but also in The Japanese Association for Experimental Animal Technologists, and it seems that cross-society measures will be required in the future.

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  • Motoaki Saito, Shogo Shimizu, Youichirou Higashi, Takahiro Shimizu
    2021 Volume 156 Issue 5 Pages 259-264
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    The use of animals for scientific purposes is still a subject of debate. The current regulatory position in most western countries allows regulated animal use to occur because of the perceived benefits in generating new knowledge. The use of animals for scientific purposes engenders a wide range of ethical perspectives, with some people looking for the complete termination of animal use, and others strongly support their continued use. Although regulatory systems vary from country to country, in most jurisdictions, research and teaching institutions are required to ensure that staff and students using animals for scientific purposes are appropriately trained, that animals are well cared for, and that the ethical review process for projects is robust. In the curriculum of the Kochi Medical School, it is mandatory for all medical students to perform laboratory exercises in the class of Pharmacology. For the purpose of this experimental class it is common to use small animals in these exercises. However, in recent years in many countries, alternative methods to replace the use of small animals have been introduced. Such methods are experiment simulations with the use of computers and they have been used in some medical schools. In this manuscript, I will make an introduction on how we perform pharmacological laboratory exercises with the use of small animals in Kochi Medical School. Additionally, I would like to discuss the necessity of the use of small animals in exercises as part of the training of medical students.

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  • Norio Yata
    2021 Volume 156 Issue 5 Pages 265-269
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    In recent years, civil society has begun to waver in its trust in the basic principle of ensuring reproducibility in scientific research. In particular, “standardization of techniques” has become an issue in many fields related to laboratory animals and animal experiments, which are premised on the existence of animal lives that are injured, pained, and sacrificed for the sake of scientific research. We, laboratory animal technicians, are always the closest to laboratory animals. We always have practiced breeding management, pre- and post-operative care, experimental treatment etc. by making the best use of our knowledge and techniques. That bring accurate experimental results. It is our significance. Technology is only meaningful if passed down to the next generation. In this report, I would like to introduce the technical seminars conducted by the Japan Association for Laboratory Animal Technicians, a national organization of laboratory animal technicians, and the pursuit of “skills to pass on” in these sessions.

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Reviews: New Horizon for Clinical Application and Drug Discovery from Basic Science
  • Hideyuki Yamawaki, Yasu-Taka Azuma
    2021 Volume 156 Issue 5 Pages 270
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS
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  • Takashi Iezaki, Eiichi Hinoi
    2021 Volume 156 Issue 5 Pages 271-274
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    Vertebral bone and limb bone are formed by endochondral ossification, which is replaced with bone tissue by osteoblasts after cartilage formation. Bone growth is regulated by the balance between epiphyseal chondrocyte proliferation and ossification. We attempted to elucidate the mechanism of chondrocyte differentiation and maturation regulated by the Extracellular-signal-regulated kinase 5 (Erk5) signal. Erk5 is a serine/threonine kinase belonging to the mitogen-activated protein kinase (MAPK) family, which includes Erk1/2, JNK, and p38. Mesenchymal stem cell-specific Erk5-deficient mice exhibited the phenotype of deformities of the metatarsal bones, enlargement of the long bones in limbs, and overgrowth of cartilage tissue. Based on this result, we searched for factors that directly phosphorylate Erk5, and We demonstrated that Erk5 directly phosphorylates and activates Smurf2 (a ubiquitin E3 ligase) at Thr249 to activate its function and promotes ubiquitination-mediated degradation. The TGF-β-Smad signal suppresses the proliferation of many cells and regulates the production of extracellular matrix. Our findings may lead to the development of novel drugs targeting TGF-β associated diseases. In this paper, we investigated the function of Smurf2Thr249 phosphorylation and the possibility as new therapeutic target for various diseases.

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  • Haru Yamamoto, Tatsuya Usui, Kazuaki Sasaki
    2021 Volume 156 Issue 5 Pages 275-281
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    Nonalcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease, with the increased prevalence of obesity, type 2 diabetes, and metabolic disorders in recent years. As the disease progresses, it leads to hepatic fibrosis, which may progress to hepatocellular carcinoma, but there is still no cure for severe hepatic fibrosis. Currently, in order to develop drugs for the treatment of NASH, the effects of candidate drugs are evaluated by a long-term administration to mice and rats that are fed a high-fat or methionine-deficient diet to reproduce the pathology of fatty liver and liver fibrosis. Since drug development using these experimental animals is time-consuming and costly, in vitro models that reproduce the pathology of NASH have recently been developing. In this review, we will outline the current issues in the diagnosis and treatment of NASH, and introduce our research for the discovery of early diagnostic markers and the development of new therapeutic agents using liver organoid cultures derived from mouse models of NASH.

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  • Akira Sugiyama, Muneyoshi Okada, Kosuke Otani, Hideyuki Yamawaki
    2021 Volume 156 Issue 5 Pages 282-287
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    Basement membrane is a dense sheet-like extracellular matrix (ECM), which separates cells from surrounding interstitium. Type IV collagen is a major component of basement membrane and three of six α chains (namely α1-α6 chains) form a triple-helix structure. Recently, endogenous bioactive factors called “matricryptins” or “matrikines”, which are produced by degrading and cleaving C-terminal domain of type IV collagen, attract attentions as a novel therapeutic target or a candidate for biomarkers. In all type IV collagens, matricryptins called arresten (α1 chain), canstatin (α2), tumstatin (α3), tetrastatin (α4), pentastatin (α5), and hexastatin (α6), have been identified. The type IV collagen-derived matricryptins have been previously studied as new therapeutic targets for neoplastic diseases since they exert anti-angiogenic and/or anti-tumor effects. On the other hand, we have recently demonstrated the cardioprotective effects of matricryptins in addition to the altered expression levels in cardiac diseases. In this review, we introduce the results of fundamental studies for the type IV collagen-derived matricryptins in various diseases, such as neoplastic diseases and cardiac diseases, and discuss the potential clinical application as novel therapeutic agents and biomarkers.

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  • Naoshige Ono, Yasu-Taka Azuma
    2021 Volume 156 Issue 5 Pages 288-291
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    Interleukin-19 (IL-19) is a member of the IL-10 family and is an anti-inflammatory cytokine produced mainly by macrophages, epithelial cells, and vascular smooth muscle cells. In addition, receptors for IL-19, IL-20 receptor 1 and IL-20 receptor 2, are also expressed in the cells mentioned above. The last 10 years from the finding of IL-19, investigations underline the anti-inflammatory role of IL-19 in the human diseases such as psoriasis, asthma, arteriosclerosis, and inflammatory bowel disease. If it is a pro-inflammatory cytokine, therapeutic applications may include the use of neutralizing antibodies, however, because IL-19 exhibits anti-inflammatory effects, recombinant products may be useful in therapeutic applications. However, the therapeutic applications of IL-19 for human disease have not yet been developed. In this review, we present the new findings on the preventive and therapeutic effects of IL-19 on various mouse disease models. Increasing knowledge about mouse disease models will increase the feasibility of future human disease applications.

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Award Lecture
  • Hiroshi Nomura
    2021 Volume 156 Issue 5 Pages 292-296
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    Histamine is a biological amine that functions as a neurotransmitter in the brain to regulate arousal, appetite, and cognitive functions. Many pharmacological studies using histamine receptor agonists and antagonists have found that histamine promotes memory consolidation and retrieval. More recently, we have revealed that the activation of the brain histaminergic system by H3R antagonists/inverse agonists restores retrieval of forgotten long-term memory in mice and humans. The recovery of memory retrieval may involve histamine-induced excitatory effects. Histamine may increase neuronal excitability throughout the neural circuit, including both neurons that are and are not recruited into the memory trace, similar to noise added to the neural circuits for memory retrieval. Stochastic resonance can explain how adding noise to the circuit enhances memory retrieval. Memory is processed not only by consolidation and retrieval, but also by various processes such as maintenance, reconsolidation, extinction, and reinstatement. Further studies that separately analyze the memory processes are needed to elucidate the whole picture of the effects of histamine on learning and memory. Regarding the human histaminergic system, alterations in histamine signaling have been reported in several neuropsychiatric disorders, and these changes have been suggested to be involved in cognitive dysfunction in patients with the neuropsychiatric disorders. Therefore, the drugs that modulate histamine signaling, including H3R antagonists/inverse agonists, may be effective in the treatment of cognitive dysfunction, including Alzheimer’s disease.

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Review: New Trends in Drug Discovery Research
  • Takashi Yoshinaga
    2021 Volume 156 Issue 5 Pages 297-302
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL FREE ACCESS

    Safety pharmacology studies have been clearly defined through discussions at the International Council for Harmonization of Pharmaceutical Regulations (ICH), and are conducted as non-clinical studies according to the ICH S7A and S7B to ensure the safety of subjects participating in clinical studies. The representative of in vitro studies of cardiovascular system is hERG assay, but CiPA recommendations by FDA/HESI (multi-ion channel assays, simulation with in silico model using the multi-ion channel data, human iPS cell-derived cardiomyocyte assay), a new clinical risk prediction strategy that makes effective use of non-clinical data is being established. In addition, regarding the risk of heart failure that induced by anticancer drugs, which are attracting attention as a social problem, technology development has been made centering on human iPS cell-derived cardiomyocytes. There are many issues to be solved, but active challenges are being taken globally to bridge the gap between clinical and non-clinical.

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Review on New Drug
  • Tsuyoshi Osaka, Naoya Yamaguchi, Takahito Hara
    2021 Volume 156 Issue 5 Pages 303-311
    Published: 2021
    Released on J-STAGE: September 01, 2021
    JOURNAL OPEN ACCESS

    Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, and AXL, among others. This drug is considered to exert excellent antitumor effects by inhibiting these targets simultaneously. Significant improvement in the primary endpoint (overall survival or PFS) were observed in patients on CAB in comparison with controls in a phase-III study in patients with renal cell carcinoma, progressed after treatment with anti-angiogenic agents, and in another phase-III study in patients with previously treated, advanced hepatocellular carcinoma. These results led to the approval of CAB in Japan in 2020 as a therapeutic agent for unresectable or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma progressed after cancer chemotherapy, under the trade name of CABOMETYX® (20 mg, and 60 mg tablets). It has been suggested that CAB may modulate the immune system in favor of antitumor immunity and combined use with PD-1 checkpoint inhibitors may exert a synergistic effect. In a phase-III study that examined the efficacy of combination therapy with CAB and nivolumab in treatment-naive patients with advanced renal cell carcinoma, progression-free survival was significantly increased in patients on combination therapy over patients on sunitinib monotherapy. Three global phase-III clinical studies of combination therapy with atezolizumab and CAB in patients with non-small cell lung cancer, castration-resistant prostate cancer, and renal cell carcinoma, are in progress to confirm the efficacy of CAB.

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