Folia Pharmacologica Japonica
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
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Volume 122, Issue 4
Displaying 1-9 of 9 articles from this issue
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Reviews: Roles of PPARγ: From Physiological Functions to Drug Development
  • The mechanisms by which PPARγ and adiponectin regulate glucose and lipid metabolism
    Junji KAMON, Toshimasa YAMAUCHI, Yasuo TERAUCHI, Naoto KUBOTA, Takashi ...
    Article type: Reviews
    2003 Volume 122 Issue 4 Pages 294-300
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.294
    JOURNAL FREE ACCESS
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    Obesity, a state of increased adipose tissue mass, is a major cause for type 2 diabetes, hyperlipidemia, and hypertension, resulting in clustering of risk factors for atherosclerosis. Heterozygous PPARγ knockout mice and KKAy mice administered with a PPARγ antagonist were protected from high-fat diet-induced adipocyte hypertrophy and insulin resistance. Moderate reduction of PPARγ activity prevented adipocyte hypertrophy, thereby diminution of TNFα, resistin, and FFA and upregulation of adiponectin and leptin. These alterations led to reduction of tissue TG content in muscle/liver, thereby ameliorating insulin resistance. Insulin resistance in the lipoatrophic mice and KKAy mice were ameliorated by replenishment of adiponectin. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes, but not the obesity of ob/ob mice. Furthermore, targeted disruption of the adiponectin gene caused moderate insulin resistance and glucose intolerance. In muscle, adiponectin activated AMP kinase and PPARγ pathways, thereby increasing β-oxidation of lipids, leading to decreased TG content, which ameliorated muscle insulin resistance. In the liver, adiponectin also activated AMPK, thereby downregulating PEPCK and G6Pase, leading to decreased glucose output from the liver. In conclusion, PPARγ plays a central role in the regulation of adipocyte hypertrophy and insulin sensitivity. The upregulation of the adiponectin pathway by PPARγ may play a role in the increased insulin sensitivity of heterozygous PPARγ knockout mice, and activation of adiponectin pathway may provide novel therapeutic strategies for obesity-linked disorders such as type 2 diabetes and metabolic syndrome.
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  • Role of PPARγ in the development of the central nervous system
    Koichiro WADA, Yoshinori KAMISAKI
    Article type: Reviews
    2003 Volume 122 Issue 4 Pages 301-308
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.301
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    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that plays a central role in adipocyte differentiation and insulin sensitivity. Recently, a diversity of the action of PPARγ on many other cell types or organs is indicated. We summarize here the possible role of PPARγ in the development of the murine central nervous system. Expressions of PPARγ in newborn or adult mouse brain are extremely low, but high in embryo or fetal mouse brain. Furthermore, we investigated the role of PPARγ in proliferation or differentiation of neural stem cells (NSCs) isolated from murine embryonic brains, because NSCs are considered to be a major source of neurons in developmental brains. Administrations of PPARγ-specific ligands on the NSCs from wild-type mice resulted in the stimulation of cell growth. On the other hand, administration of PPARγ-antagonist showed the cell death and apoptosis of NSCs. These results may indicate that PPARγ plays an important role during the early stage of the development of the central nervous system.
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  • PPARγ-gene therapy using an adenovirus vector for inflammatory bowel disease
    Atsushi NAKAJIMA, Kazufumi KATAYAMA, Tadanori MAYUMI
    Article type: Reviews
    2003 Volume 122 Issue 4 Pages 309-316
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.309
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    Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the nuclear receptors that plays a central role in adipocyte differentiation and insulin sensitivity. Recently, PPARγ has also been recognized as a suppressive regulator of inflammation in the gastrointestinal tract. We summarize here the therapeutic benefits of PPARγ-gene therapy using a replication-deficient adenovirus vector expressing PPARγ (AdRGD-PPARγ). We demonstrate that PPARγ- protein levels are decreased in dextran sodium sulfate-induced colitis and restored in this model by intraperitoneal administration of the AdRGD-PPARγ. Treatment with AdRGD-PPARγ and PPARγ-specific ligands resulted in a marked amelioration of tissue inflammation associated with the colitis, including reduction in intercellular adhesion molecule-1, cyclooxygenase-2, and tumor necrosis factor-alpha expression. Our results suggest that gene delivery of PPARγ may open up a novel therapeutic approach for inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.
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  • The role of PPARγ in the onset of type 2 diabetes
    Kazuo HARA, Toshimasa YAMAUCHI, Naoto KUBOTA, Kazuyuki TOBE, Tsutomu Y ...
    Article type: Reviews
    2003 Volume 122 Issue 4 Pages 317-324
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.317
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    We have investigated the role of PPARγ and its related genes on the pathogenesis of type 2 diabetes. Heterozygous PPARγ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARγ agonist treatment. Moreover, a Pro12Ala polymorphism in the human PPARγ 2 gene, which has been reported to cause a reduction in the PPARγ activity, was associated with decreased risk of type 2 diabetes in Japanese. The protective effect of this polymorphism against type 2 diabetes has been confirmed by meta-analysis using reports in various ethnic groups. Taken together with these results, PPARγ is a thrifty gene mediating type 2 diabetes both in mice and humans. Indeed, pharmacological inhibitors of PPARγ/RXR ameliorates high-fat diet-induced insulin resistance in animal models of type 2 diabetes.
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  • Role of PPARγ in inflammatory response related to mast cells
    Kazutaka MAEYAMA, Maiko EMI, Kazuyasu CHIHARA
    Article type: Reviews
    2003 Volume 122 Issue 4 Pages 325-330
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.325
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    The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors. The activation of PPARγ regulates lipid and glucose homeostasis and its agonists have been developed as novel antidiabetic drugs. Recently, it has been reported that PPARγ plays roles in inflammatory and immunological responses. Especially in monocyte/macrophage system, the expression of PPARγ and the negative regulation of cytokine production has been reported. Mast cells are derived from stem cells in bone marrow, and their proliferation and differentiation are regulated by stimulation of stem cell factor from fibroblasts and/or IL-3 from T lymphocytes. Recently, it was reported that PPARγ is expressed in mast cells, but its roles remain uncertain. After antigen stimulation, mast cells produce and release prostaglandin D2 which is metabolized to 15-deoxy Δ12,14-prostaglandin J2 (15d-PGJ2). Because 15d-PGJ2 acts potently as an endogenous PPARγ agonist, mast cells might play roles in inflammation and immunological responses via the PPARγ pathway. In this paper we will discuss PPARγ function in mast cells using cultured bone marrow derived mast cells obtained from heterozygous PPARγ-deficient mice.
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Technical Note
  • Identification of intracellular regulatory protein for ion channel using yeast two-hybrid system
    Naohiko ANZAI, Hiroki MIYAZAKI, Shinichi SAKAMOTO
    Article type: Technical Note
    2003 Volume 122 Issue 4 Pages 331-337
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.331
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    Many proteins including ion channels mediate a variety of biological activities of cells through forming large molecular assemblies via protein-protein interactions. Hence, to understand the function of a particular protein, it is often useful to identify other proteins with which it associates. The two-hybrid system is a widely used yeast-based genetic approach for detecting protein-protein interactions and provides a powerful way of isolating ion channel-associated proteins in an in vivo setting without purifying both proteins. This system is thought to be one of the important techniques for “Proteome” analysis in the post-genomic era. In this article, we describe the yeast two-hybrid assay we have used to identify proteins binding to asic-sensing ion channel ASIC3 and urate transporter 1 (URAT1) and discuss some general and specific considerations about using ion channel proteins in the two-hybrid system.
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Review on New Drug
  • Antifungal activity and clinical efficacy of micafungin sodium (Funguard®)
    Fumiaki IKEDA
    Article type: Review on New Drug
    2003 Volume 122 Issue 4 Pages 339-344
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.339
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    Micafungin sodium (MCFG) is a new lipopeptide antifungal agent of the echinocandin class. MCFG inhibits 1,3-β-glucan synthesis in C. albicans and A. fumigatus in a non-competitive manner and has antifungal activity against both Aspergillus and Candida species. In neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis, the efficacy of MCFG was superior to that of fluconazole and itroconazole, but comparable to that of amphotericin B. The efficacy and safety of MCFG were investigated in 70 patients with deep-seated mycosis caused by Candida and Aspergillus species. The overall clinical response rates were 57.1% in aspergillosis and 78.6% in candidiasis. The incidence of adverse events related to micafungin was 17.9 %, and there was no dose-related occurrence of any adverse events. The results from this study indicated that micafungin was effective against aspergillosis and candidiasis, with no tolerability problems.
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  • Pharmacological and clinical profile of exemestane (Aromasin®), a novel irreversible aromatase inhibitor
    Makoto TAHARA, Shunji NOMURA, Munehiro HASHIMOTO
    Article type: Review on New Drug
    2003 Volume 122 Issue 4 Pages 345-354
    Published: 2003
    Released on J-STAGE: September 19, 2003
    DOIhttps://doi.org/10.1254/fpj.122.345
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    Aromatase is the rate-limiting enzyme playing a role at the final step of estrogen biosynthesis, which is attracting attention as the target enzyme of hormone therapy of postmenopausal breast cancer. Exemestane (Aromasin®) is a novel steroidal irreversible aromatase inhibitor that was approved in Japan as a therapeutic drug for postmenopausal breast cancer. Exemestane selectively inhibits aromatase activity in vitro, in a time-dependent and irreversible manner, suggesting the mechanism of action that exemestane covalently binds to aromatase as a pseudo-substrate and inactivates the enzyme. In vivo studies show the inhibitory effect of exemestane on the ovarian aromatase activity and plasma estradiol level of PMSG-primed rats. In studies using DMBA-induced rat mammary tumor models, exemestane shows antitumor activity in both conventional (premenopausal) and ovariectomized, testosterone-treated postmenopausal models. Despite its steroidal structure, exemestane does not have hormonal or anti-hormonal activity, except for a slight androgenic activity. In the early and late phase II clinical trials conducted in Japan on postmenopausal breast cancer patients who received 25 mg/day of exemestane, the response rates were 31.4% and 24.2%, respectively. Blood estrogen levels were also markedly reduced. These results confirmed the clinical relevance of non-clinical study results, as well as the possibility of extrapolation to foreign trial data.
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