Activation of Phosphoinositide 3-Kinase, Protein Kinase C, and Extracellular Signal-Regulated Kinase Is Required for Oridonin-Enhanced Phagocytosis of Apoptotic Bodies in Human Macrophage-Like U937 Cells

Li, Yanqiu; You, Song; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1254/jphs.fpj05005x

Cited by 31 publications

(32 citation statements)

References 33 publications

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“…These include PKCα in Fcγ receptormediated phagocytosis (Breton 2000) and in the IgG-stimulated respiratory burst (Larsen 2000), PKCβ in the phagocytosis of latex particles (Dieter 2000), and PKCβ and PKCδ in the phagocytosis of L. monocytogenes and translocation of PKCβ to early endosomes during bacterial escape from phagocytic vesicles (Wadsworth 2002). Novel PKCs δ and ε have also been linked to IgG-stimulated phagocytosis (Larsen 2000), and the phagocytosis of apoptotic cells by monocytes/macrophages requires PKC activity (Liu 2005). IL-4 induction of CD36 is blocked by PKC inhibition (Feng 2000), and IL-4 or IL-13 induces the activation of PKCδ and PKCζ (Ikizawa 2001).…”

Section: Introductionmentioning

confidence: 99%

Foreign body-type multinucleated giant cell formation requires protein kinase C β, δ, and ζ

McNally

MacEwan

Anderson

2008

Experimental and Molecular Pathology

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Multinucleated giant cells are a classic cellular feature of chronic inflammation, although the mechanism of macrophage fusion leading to their formation is not well understood. Here, we investigate the participation of protein kinase C (PKC) in the interleukin (IL)-4-induced fusion of human monocyte-derived macrophages and foreign body giant cell (FBGC) formation in vitro. The PKC inhibitors H-7 and calphostin C attenuated macrophage fusion, whereas H-8, which is more selective for PKA and PKG, did not. Macrophage fusion was also prevented by the phospholipase C inhibitor, Et-18-OCH 3 , the PKC isoform inhibitors GO6983 or rottlerin and by peptide inhibitors for PKC (20-28), PKCβ, or PKCζ but not by HBDDE or peptide inhibitors for PKCε or PKA. In cultures of fusing macrophages/FBGC, we detected only PKCα, β, δ, and ζ by immunoprecipitation and immunoblotting, and we also observed strong expression of these isoforms by immunocytochemistry. Our collective results suggest that the γ, ε, η, μ, θ, or ι PKC isoforms are not required in the mechanism of IL-4-induced macrophage fusion; whether PKCα is required is unclear. However, new evidence is provided that FBGC formation is supported by PKCβ, PKCδ, and PKCζ in combined diacylglycerol-dependent (PKCβ and PKCδ) and -independent (PKCζ) signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Foreign body-type multinucleated giant cell formation requires protein kinase C β, δ, and ζ

McNally

MacEwan

Anderson

2008

Experimental and Molecular Pathology

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“…this suggests that rrE may have affected the immune response to the xenografts by recruiting immune cells to the tumor site. Supporting a possible involvement of oridonin in regulating immune cells and immune system, a previous study showed that oridonin enhanced the phagocytosis of apoptotic u937 cells by macrophage-like u937 cells through the release of tnF-α and il-1β (22).…”

Section: Discussionmentioning

confidence: 78%

Genomic and in vivo evidence of synergy of a herbal extract compared to its most active ingredient: Rabdosia rubescens vs. oridonin

Wong

Zhang

Kesler

et al. 2010

Experimental and Therapeutic Medicine

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Abstract. Rabdosia rubescens is a herbal root extract of traditional Chinese medicine (TCM) used to treat inflammatory diseases and oral cancers. a key principle of tcm is that multiple ingredients in a plant extract are more effective and less toxic than a single purified active ingredient or a purified drug derived from a plant product. Rabdosia rubescens extract (RRE) contains terpenoids and flavonoids, but the most active ingredient within the extract attributed to the inhibition of cancer is the kaurene diterpene, oridonin. in order to research synergy with a complete plant extract, the effects of rrE on the inhibition of prostate cancer cell proliferation were compared to the effects of pure oridonin alone in vitro. three groups of 8 Scid mice bearing human prostate cancer xenografts (lapc-4) were administered either rrE containing 0.02 mg/g oridonin, pure oridonin at a dose of 0.02 mg/g, or pure oridonin at a dose of 0.1 mg/g, by gavage for 5 days/week for 4 weeks. rrE and pure oridonin at 0.1 mg/g inhibited tumor growth to a similar extent, while oridonin at a dose of 0.02 mg/g did not. Therefore, in comparison to RRE, five times more pure oridonin was required to obtain equivalent prostate xenograft growth inhibition. Since the nuclear factor-κB signaling pathway and inflammation are implicated in prostate carcinogenesis, gene microarray analysis was conducted and demonstrated activation of genes by rrE that was not evident with oridonin treatment alone. this study demonstrated that genomic methods and xenograft studies are capable of demonstrating the benefits of the synergy of whole plant extracts rather than active ingredients isolated and purified as drugs. IntroductionBotanical extracts are used for the prevention and treatment of common conditions by 80% of the world's population according to estimates made by the World health Organization (1). drugs are produced from botanical sources by isolation and purification of the most active ingredients, while other substances in the raw fraction are separated. Synergistic interactions of mixtures of bioactive constituents and related substances or analogs in plant extracts have been proposed to occur with the most active ingredient. these interactions help explain the improved effectiveness of extracts containing multiple ingredients compared to drugs developed from single constituents.We previously studied the action and metabolism of chinese red yeast rice (Monascus purpureus Went) (crYr), a dietary supplement containing monacolins, one of which (monacolin K) is identical in structure to the statin drug lovastatin, and to unsaturated fatty acids and phytosterols capable of lowering low-density lipoprotein (ldl) cholesterol in humans (2-5). the apparent bioactivity of crYr containing 6 mg of Monacolin K was equivalent to 20 mg of purified lovastatin. moreover, crYr is well tolerated in patients who are intolerant to statin drugs (6), suggesting that the lower amounts of active substances, enhanced action and more complete metabolism in comparison to a d...

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“…Oridonin has been demonstrated to be able to cause ERK activation (12)(13)(14)(15) and p38 inactivation (13,15) in human macrophage-like U937 cells, murine fibrosarcoma L929 cells and human melanoma A375-S2 cells without affecting JNK activity (12,13,15). Other reports claimed that oridonin could inactivate JNK (15) in L929 cells, and inactivate ERK (11,16) but activate p38 and JNK (11) in human osteosarcoma cells and epidermoid carcinoma A431 cells.…”

Section: Discussionmentioning

confidence: 99%

Oridonin induces G2/M cell cycle arrest and apoptosis through MAPK and p53 signaling pathways in HepG2 cells

et al. 2010

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Abstract. Oridonin, the main active constituent of Isodon rubescen, has antihepatocarcinoma activity in experimental and clinical settings. The aims of the study were to explore the anticancer effect of oridonin in HepG2 cells and to investigate the underlying mechanisms. Results showed that oridonin treatment for 24 or 48 h resulted in a marked decrease in cell viability time-and dose-dependently. IC 50 values were determined as 38.86 μM and 24.90 μM for 24-h and 48-h treatments, respectively. Flow cytometric analysis showed that a 24-h treatment of 40 μM oridonin induced G2/M cell cycle arrest and apoptosis. Typical apoptotic nucleus alterations were observed with fluorescence microscope after DAPI staining. Immunoblot analysis demonstrated that oridonin treatment increased expression levels of p-JNK, p-p38, p-p53 and p21, elevated the level of cyclin B1/p-Cdc2 (Tyr15) complex, and inhibited the expression of p-ERK. Moreover, oridonin treatment activated caspase-9 and caspase-3. In conclusion, oridonin induced G2/M cell cycle arrest and apoptosis in HepG2 cells through MAPK and p53 pathways, which advances our understanding on the molecular mechanisms of oridonin in hepatocarcinoma management.

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Activation of Phosphoinositide 3-Kinase, Protein Kinase C, and Extracellular Signal-Regulated Kinase Is Required for Oridonin-Enhanced Phagocytosis of Apoptotic Bodies in Human Macrophage-Like U937 Cells

Cited by 31 publications

References 33 publications

Foreign body-type multinucleated giant cell formation requires protein kinase C β, δ, and ζ

Foreign body-type multinucleated giant cell formation requires protein kinase C β, δ, and ζ

Genomic and in vivo evidence of synergy of a herbal extract compared to its most active ingredient: Rabdosia rubescens vs. oridonin

Oridonin induces G2/M cell cycle arrest and apoptosis through MAPK and p53 signaling pathways in HepG2 cells

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