Effects of Microbial Products on Glucose Consumption and Morphology of Macrophages

Magae, Junji; Munemura, Kazuko; Ichikawa, Chiyo; Osada, Kazuko; Hanada, Toshihiko; Tsuji, Ryohei; Yamashita, Masahiro; Hino, Ayako; Horiuchi, Tatsuo; Uramoto, Masakazu; Yamasaki, Makari; Endō, Toyoshige; Nagai, Kazuo

doi:10.1271/bbb.57.1628

Cited by 18 publications

(24 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8,9 Ascochlorin and ascofuranone, one of its derivatives, inhibit oxidative phosphorylation by hindering ubiquinone-dependent electron transport in isolated mitochondria, 10-12 and it has been suggested that the antiviral activity of ascochlorin and macrophage activation by ascofuranone are a result of this inhibitory activity on mitochondrial respiration. 10,11,13 These compounds also modulate the activity of nuclear hormone receptors, 14 which suggests that mechanisms other than those involving the respiratory chain contribute to their physiological activities.Ascochlorin-related compounds show profound antitumor activity against a variety of transplantable tumors and suppress the metastasis of melanomas and lung carcinomas in murine animal models. 8,9 Because pretreatment with ascofuranone before tumor implantation is as effective as treatment after tumor implantation, the antitumor activity of ascofuranone must be mediated, at least in part, by activation of a host defense mechanism against tumors.…”

mentioning

confidence: 99%

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

Jeong

Nakajima

Magae

et al. 2009

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins. ' UICCKey words: AP-1; p53; mitochondrial respiration; ascochlorin; ATM; ATR Ascochlorin and ascofuranone ( Fig. 1) are prenylphenol antifungal antibiotics isolated from an incomplete fungus, Ascochyta viciae. Although originally reported to be an antiviral antibiotic, 1-3 ascochlorin and its derivatives exhibit a large variety of physiological activities including hypolipidemic activity, 2 suppression of hypertension, 4 amelioration of types I and II diabetes, 5,6 immunomodulation 7 and antitumor activity. 8,9 Ascochlorin and ascofuranone, one of its derivatives, inhibit oxidative phosphorylation by hindering ubiquinone-dependent electron transport in isolated mitochondria, 10-12 and it has been suggested that the antiviral activity of ascochlorin and macrophage activation by ascofuranone are a result of this inhibitory activity on mitochondrial respiration. 10,11,13 These compounds also modulate the activity of nuclear hormone receptors, 14 which suggests that mechanisms other than those involving the respiratory chain contribute to their physiological activities.Ascochlorin-related compounds show profound antitumor activity against a variety of transplantable tumors and suppress the metastasis of melanomas and lung carcinomas in murine animal models. 8,9 Because pretreatment with ascofuranone before tumor implantation is as effective as treatment after tumor implantation, the antitumor activity of ascofuranone must be mediated, at least in part, by activation of a host defense mechanism against tumors. We recently found that ascochlorin and ascofuranone selectively suppress the AP-1 activity of human renal carcinoma cells, as well as its downstream targets such as matrix metalloproteinase-9, through suppression of the Erk1/2 signaling pathway, 15,16 suggesting that ascochlorin directly suppresses tumor malignancy by this mechanism. We also found that human breast cancer cell lines that are devoid of es...

show abstract

mentioning

confidence: 99%

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

Jeong

Nakajima

Magae

et al. 2009

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…36 It is also possible that ascochlorin derivatives directly participate in a cellular oxidative reaction because they react with the electron transport chain in mitochondria. [23][24][25] Finally, we could not exclude the trivial possibility that a suppression of food intake might reduce hyperglycemia and gluosuria, because higher doses of MAC and AS-6 significantly reduced body weight, whereas a low dose of AS-6 and pioglitazone rather increased weight gain. Although the administration of AS-6 and MAC by mixing in the diet could not determine the exact doses, we could not detect significant efficacy by direct administration methods.…”

Section: Discussionmentioning

confidence: 99%

“…20 A proteome analysis of ascochlorin-treated human osteosarcoma cells shows a decrease in the expression of several genes in the mitogen-activated protein kinase (MAPK)-signaling cascade, including epidermal growth factor receptor and ERK-1/2. 21 Ascochlorin and ascofuranone moderate oxidative phosphorylation by inhibiting ubiquinone-dependent electron transport in isolated mitochondria, [22][23][24] and it is suggested that the antiviral activity of ascochlorin and the macrophage activation of ascofuranone result from this inhibitory activity on mitochondrial respiration. 22,23,25 These compounds also modulate the activity of nuclear hormone receptors.…”

Section: Introductionmentioning

confidence: 99%

“…21 Ascochlorin and ascofuranone moderate oxidative phosphorylation by inhibiting ubiquinone-dependent electron transport in isolated mitochondria, [22][23][24] and it is suggested that the antiviral activity of ascochlorin and the macrophage activation of ascofuranone result from this inhibitory activity on mitochondrial respiration. 22,23,25 These compounds also modulate the activity of nuclear hormone receptors. Ascochlorin activates human ER, suggesting that mechanisms other than those involving the respiratory chain contribute to their physiological activities.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Relationship between peroxisome proliferator-activated receptor-γ activation and the ameliorative effects of ascochlorin derivatives on type II diabetes

Magae

Tsuruga²,

Maruyama

et al. 2009

J Antibiot

Self Cite

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor-c (PPAR-c) is a crucial factor in the development of insulin resistance associated with type II diabetes. We previously found that 4-O-carboxymethyl ascochlorin, a derivative of ascochlorin, ameliorates diabetes and activates PPAR-c. Here, we compared the relationship between the amelioration of type II diabetes in db/db mice lacking leptin receptor, and PPAR-c activation by 4-O-carboxymethyl-ascochlorin, as well as by 4-O-methyl-ascochlorin, a derivative that does not activate PPAR-c. Administration of these compounds significantly reduces blood glucose in a dose-dependent manner, whereas blood cholesterol is significantly elevated in 4-O-carboxymethyl-ascochlorin-treated mice but is significantly decreased in 4-O-methyl-ascochlorin-treated mice. Pioglitazone, a potent PPAR-c agonist with a thiazolidinedione structure, reduces glucose but elevates cholesterol blood levels. These results suggest that ascochlorin derivatives ameliorate diabetes through a mechanism that is probably independent of PPAR-c activation, although PPAR-c activation could be partially involved in the ameliorative effect in certain derivatives.

show abstract

“…Ascochlorin and its derivative, ascofuranone, inhibit oxidative phosphorylation by inhibiting ubiquinone-dependent electron transport in isolated mitochondria [23ϳ25]. It has been suggested that the anti-viral activity of ascochlorin and the macrophage activation by ascofuranone are caused by the inhibition of mitochondria respiration [23,24,26]. Some ascochlorin derivatives also modulate the activity of nuclear hormone receptors.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive Activity of 4-O-Methylascochlorin

Tsuruga¹,

Nakajima

Magae³

2007

J Antibiot

Self Cite

View full text Add to dashboard Cite

A major strategy for suppressing immune responses is the elimination of antigen-reactive lymphocytes through apoptosis. 4-O-Methylascochlorin (MAC) is a methylated derivative of a prenyl-phenol antibiotic, ascochlorin. MAC induces apoptosis in various lymphocyte cell lines. We found that MAC strongly suppressed killer T-cell activity induced by allogenic skin grafts. MAC did not suppress the killer T-cell activity induced by intraperitoneal injection of live allogenic tumor cells bearing both class I and II MHC. MAC suppressed IL-2 production of splenocytes from allogenic skin-implanted mice when induced by specific spleen adherent cells, but not by antibodies for T-cell receptor e . These results suggest that MAC suppresses the antigen presentation process of alloantigen that is mediated by professional antigen presenting cells. MAC significantly increased the survival time of allogenic skin implanted on the flank mice. These results suggest that MAC may be clinically useful as an immunosuppressant that targets the antigen presentation process. Keywords ascochlorin, MAC, CTL, immunosuppressant, graft rejection IntroductionImmunosuppressants affect T lymphocytes by two general mechanisms, namely by transcription suppression and by direct toxicity. Some of them suppress the transcription of T-cell lymphokines, including interleukin-2 (IL-2) and interferon-g . Cyclosporin A (CsA) and FK506 inhibit lymphokine transcription through the formation of drugbinding protein complexes that suppress cytoplasmic calcineurin, a protein phosphatase required for nuclear translocation of the regulatory domain of the nuclear factor of activated T cells, a major transcription factor for T-cell lymphokines [1ϳ5]. Other immunosuppressants eliminate activated lymphocytes by direct toxicity. Methotrexate and cyclophosphamide induce apoptosis of T lymphocytes [6]. Azathiopurine and mycophenolic acid inhibit DNA synthesis by inhibiting the purine synthesis pathway [7,8]. Glucocorticoid hormones and FTY720 induce apoptosis of lymphocytes [9,10]. Rapamycin suppresses lymphocyte proliferation by interfering with the target of rapamycin signal transduction pathway of growth factors [11].Ascochlorin ( Fig. 1) is a prenyl-phenol antibiotic that was originally isolated as an antiviral agent produced by an incomplete fungus, Ascochyta visiae [12,13], and synthesized in racemic and optically active form [14]. Ascochlorin and its derivatives exhibit various physiological activities including hypolipidemic activity [15,16], suppression of hypertension [17], amelioration of type I and II diabetes [18,19], immunomodulation [20,21], and anti-tumor activity [21,22]

show abstract

Effects of Microbial Products on Glucose Consumption and Morphology of Macrophages

Cited by 18 publications

References 7 publications

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

Ascochlorin activates p53 in a manner distinct from DNA damaging agents

Relationship between peroxisome proliferator-activated receptor-γ activation and the ameliorative effects of ascochlorin derivatives on type II diabetes

Immunosuppressive Activity of 4-O-Methylascochlorin

Contact Info

Product

Resources

About