Folia Pharmacologica Japonica
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
Volume 154, Issue 2
Displaying 1-7 of 7 articles from this issue
Reviews: A New Twist in Researches of Lifestyle-related Diseases and Cancer for Extension of Healthy Life Expectancy
  • Tatsuya Usui, Kazuaki Sasaki
    2019 Volume 154 Issue 2 Pages 50-55
    Published: 2019
    Released on J-STAGE: August 10, 2019
    JOURNAL FREE ACCESS

    Colorectal cancer is a disease with high unmet medical needs. An increase in the number of cancer patients who are resistant to anti-cancer drugs is one of factors that increase the number of fatalities. Since there was no suitable experimental model to recapitulate the tumor environment in which various cells in the tissues exist, it was extremely difficult to develop a medicine that overcomes the anti-cancer drug resistance in each colorectal cancer patient. In this review, we describe the current status and problems of drug therapy for colorectal cancer patients, and introduce our study to develop the new targeting drugs using human colon tissue-derived air liquid interface organoid culture method.

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  • Masashi Mukohda
    2019 Volume 154 Issue 2 Pages 56-60
    Published: 2019
    Released on J-STAGE: August 10, 2019
    JOURNAL FREE ACCESS

    Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand activated transcription factor known to regulate fatty acid metabolism. Thiazolidinediones (TZDs), PPARγ synthetic agonists, currently used to treat patients with type 2 diabetes, have been shown to lower the blood pressure and protect against vascular diseases such as atherosclerosis. In line with these findings, it has been reported that individuals with loss-of-function mutations of PPARγ developed sever early-onset hypertension in addition to metabolic abnormalities. Accumulating evidences suggest PPARγ in the vasculature has protective effects on cardiovascular disease despite unclear mechanism. Because of ubiquitous expression of PPARγ, TZDs are well-known to be associated with serious side effects such as weight gain, fluid retention, and bone fractures. Thus identification of mechanisms on tissue-specific PPARγ activity may lead to the development of targeted treatment which is characterized by no deleterious effects. This review discusses role of PPARγ in cardiovascular disease.

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  • Machi Atarashi, Takeshi Izawa, Mitsuru Kuwamura, Jyoji Yamate
    2019 Volume 154 Issue 2 Pages 61-65
    Published: 2019
    Released on J-STAGE: August 10, 2019
    JOURNAL FREE ACCESS

    Non-alcoholic steatohepatitis (NASH), one of the most common chronic liver diseases (CLD), is getting the most important cause of cirrhosis and hepatocellular carcinoma. Iron is an essential micronutrient for organisms. Once excess iron is accumulated in vital organs, dysfunctions of these organs can occur via the generation of reactive oxygen species. Hepatic iron overload is often seen in CLD patients. In NASH patients, iron accumulation in the liver is positively correlated with histological severity. Thus iron overload can contribute to progression of nonalcoholic fatty liver disease (NAFLD) to NASH. In a rat model of NASH, feeding of high-fat and high-iron diet increases hepatic inflammation with increased hepatic cytokine expression compared with feeding of high-fat diet only. In this model, iron is intensely accumulated in Kupffer cells/macrophages within the lesion, raising the possibility that iron-laden Kupffer cells/macrophages can play a key role in the enhancement of hepatic inflammation in NASH condition. On the other hand, in a rat model of liver cirrhosis, dietary iron overload clearly abrogates the development and progression of liver cirrhosis induced by repeated administration of thioacetamide (TAA). These findings suggest that iron overload can promote or suppress chronic liver diseases depending on the tissue microenvironment. Here we review and introduce the recent findings on the pathological roles of iron overload in the development and progression of NAFLD/NASH.

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  • Yasuyuki Fujimoto, Yasu-Taka Azuma
    2019 Volume 154 Issue 2 Pages 66-71
    Published: 2019
    Released on J-STAGE: August 10, 2019
    JOURNAL FREE ACCESS

    Cytokine signal is essential for the biological function including development, maintenance of homeostasis and progression of disease. There are growing evidences that signaling via pro-inflammatory cytokines underlie a variety of immunological diseases such as psoriasis, atopic dermatitis, inflammatory bowel disease, and metabolic syndromes, in which cytokine signals are known as a potential therapeutic target of antibody drugs. In contrast, anti-inflammatory cytokines, which is represented by IL-10, largely contribute to suppression of inflammation and restoration of injured tissues. IL-19 is a member of IL-10 cytokine family, which comprises IL-20 cytokine subfamily with IL-20, IL-22, IL-24, and IL-26. IL-19 is produced by myeloid and epithelial cells with stimulation of bacterial components and cytokines. Although IL-19 has been originally recognized as a potential Th2-related cytokine, in recent researches, it has been reported that this cytokine upregulates Th17 response to reflect and promote progression of Th17-related disease including psoriasis. On the other hand, IL-19 has anti-inflammatory effects on inflammatory diseases such as infectious skin disease, inflammatory bowel disease, and cardiovascular disease. Therefore, IL-19 may exert pleiotropic effects dependent on the pathological mechanism of inflammatory diseases. In this review, we summarize recent studies about IL-19 and introduce the pathophysiological and therapeutic role of IL-19 in inflammatory diseases.

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Review: New Trends in Drug Discovery Research
  • Takahiro Iwao, Tamihide Matsunaga
    2019 Volume 154 Issue 2 Pages 72-77
    Published: 2019
    Released on J-STAGE: August 10, 2019
    JOURNAL FREE ACCESS

    In drug disposition, the liver and small intestine are very important as tissues involving in drug metabolism, absorption, and excretion. Thus, in drug development studies, it is necessary to evaluate the pharmacokinetics in these tissues accurately including the contributions of drug-metabolizing enzymes and drug transporters. Currently, all kinds of evaluation systems have been used for the pharmacokinetic prediction; however, there are some issues in these systems. Therefore, the researches for the development of human induced pluripotent stem (iPS) cell-derived hepatocytes and enterocytes, as novel systems besides existing ones, are being advanced. Because human iPS cells have abilities of pluripotency and almost infinite proliferation, it is thought to be possible to stably provide the high-quality cells that have similar characteristics to human normal tissue cells by using human iPS cells. In this review, we describe current status of differentiation studies of human iPS cell-derived hepatocytes and enterocytes and the functional characteristics of these cells centered on pharmacokinetic functions.

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Review: New Trends in Drug Discovery Research
  • Toshio Tanaka, Junko Koiwa
    2019 Volume 154 Issue 2 Pages 78-83
    Published: 2019
    Released on J-STAGE: August 10, 2019
    JOURNAL FREE ACCESS

    Even after entering the era of genomic drug discovery in the 21st century, development of a breakthrough therapeutic drug (first-in-class) for intractable diseases (unmet medical needs) has been extremely difficult, but to the US FDA 62% of the approved first-in-class drugs are found by phenotypic screening. The next-generation zebrafish drug discovery enables high-throughput quantitative live in vivo phenotypic screening, and has been impacting global drug discovery strategies now. Compared to severe immunodeficient mice, zebrafish is expected to become a true individualized medical tool as a clinical ex vivo diagnostic system because of the high efficiency and speed of engraftment of patient-derived cancer xenotransplantation. Phenomics-based personalized medicine with the patient-derived cancer xenograft zebrafish in addition to conventional omics platform of individualized medicine is a true next-generation precision medicine to utilize for selection of therapeutic drugs and decision of their doses for the patient, and emerging paradigm shift is realizing in this century.

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