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      Morin, a Flavonoid from Moraceae, Induces Apoptosis by Induction of BAD Protein in Human Leukemic Cells

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          Abstract

          Evidence suggests that phytochemicals can safely modulate cancer cell biology and induce apoptosis. Here, we investigated the anti-cancer activity of morin, a flavone originally isolated from members of the Moraceae family in human leukemic cells, focusing on apoptosis. An anti-cancer effect of morin was screened with several human leukemic cell lines. U937 cells were most sensitive to morin, where it induced caspase-dependent apoptosis in a dose-dependent manner. It also induced loss of MMP ( ΔΨ m ) along with cytochrome c release, down-regulated Bcl-2 protein, and up-regulated BAX proteins. The apoptotic activity of morin was significantly attenuated by Bcl-2 augmentation. In conclusion, morin induced caspase-dependent apoptosis through an intrinsic pathway by upregulating BAD proteins. In addition, Bcl-2 protein expression is also important in morin-induced apoptosis of U937 cells. This study provides evidence that morin might have anticancer properties in human leukemic cells.

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          Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death.

          To extend the mammalian cell death pathway, we screened for further Bcl-2 interacting proteins. Both yeast two-hybrid screening and lambda expression cloning identified a novel interacting protein, Bad, whose homology to Bcl-2 is limited to the BH1 and BH2 domains. Bad selectively dimerized with Bcl-xL as well as Bcl-2, but not with Bax, Bcl-xs, Mcl-1, A1, or itself. Bad binds more strongly to Bcl-xL than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-xL, but not that of Bcl-2. When Bad dimerized with Bcl-xL, Bax was displaced and apoptosis was restored. When approximately half of Bax was heterodimerized, death was inhibited. The susceptibility of a cell to a death signal is determined by these competing dimerizations in which levels of Bad influence the effectiveness of Bcl-2 versus Bcl-xL in repressing death.
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            Distinctive antioxidant and antiinflammatory effects of flavonols.

            The antioxidant and antiinflammatory effects of flavonols have been suggested to be structure-related. Results revealed that selected flavonols, including fisetin (F), kaempferol (K), morin (MO), myricetin (MY), and quercetin (Q), exhibited distinctive free radical scavenging properties against different kinds of free radicals. The H donation (DPPH bleaching) potential was Q > F approximately equals MY > MO > K, indicating that the presence of a 3',4'-catechol moiety in the B ring correlated with high activity. The 4'-OH in the B ring was suggested to be important for reducing xanthing/xanthine oxidase-generated superoxide; while an additional OH moiety on the ortho sites (3' or 5') attenuated the effect as the observed inhibitory potency was K approximately equals MO > Q > F > MY. The relative inhibitory effect for Fenton-mediated hydroxyl radical was K approximately equals MO approximately equals Q > F > MY. This result implies the involvement of 4-keto, 5-OH region in Fe++ chelating and the negative effect of pyrogallol moiety in the B ring. Similar to the inhibitory activity against a N-formyl-methionyl-leucyl-phenylalanine (f-MLP)-stimulated oxidative burst in human polymorphonuclear neutrophils (PMN), our result showed that the structural peculiarity of the di-OH in the B ring obviously rendered F, Q, and MO more potent as ROS inhibitors than MY and K, which have tri- and mono-OH in the B ring, respectively. All of the previous data indicated that the structure prerequisite to reinforce the free radical scavenging activity varies with the type of free radical. We further analyzed the effects of flavonols on nitric oxide (NO) production in endotoxin-stimulated murine macrophages, RAW264.7 cells. Results showed that all flavonols (up to 10 microM) inhibited NO production without exerting detectable cytotoxicity. F, K, and Q dose-dependently repressed iNOS mRNA expression and prostaglandin E2 (PGE2) production, in part through an attenuating NF-kappaB signaling pathway. This result indicates that flavonols, despite structural similarity, have different antioxidant and antiinflammatory effects.
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              Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway.

              The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of two sites, serine-112 (Ser-112) and serine-136 (Ser-136). Phosphorylation at either site results in loss of the ability of BAD to heterodimerize with the survival proteins BCL-XL or BCL-2. Phosphorylated BAD binds to 14-3-3 and is sequestered in the cytoplasm. It has been shown that phosphorylation of BAD at Ser-136 is mediated by the serine/threonine protein kinase Akt-1/PKB which is downstream of phosphatidylinositol 3-kinase (PI3K). The signaling process leading to phophorylation of BAD at Ser-112 has not been identified. In this study, we show that phosphorylation of the two serine residues of BAD is differentially regulated. While Ser-136 phosphorylation is concordant with activation of Akt, Ser-112 phosphorylation does not correlate with Akt activation. Instead, we demonstrate that activated Ras and Raf, which are upstream of mitogen-activated protein kinases (MAPK), stimulate selective phosphorylation of BAD at Ser-112. Furthermore, phosphorylation of Ser-112, but not Ser-136 requires activation of the MAPK pathway as the MEK inhibitor, PD 98059, blocks EGF-, as well as activated Ras- or Raf-mediated phosphorylation of BAD at Ser-112. Therefore, the PI3K-Akt and Ras-MAPK pathways converge at BAD by mediating phosphorylation of distinct serine residues.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                30 December 2014
                January 2015
                : 16
                : 1
                : 645-659
                Affiliations
                [1 ]Department of Molecular Biology, College of Natural Sciences, Dongeui University, Busan 614-714, Korea; E-Mail: parkch@ 123456deu.ac.kr
                [2 ]Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Korea; E-Mails: gose1@ 123456hanmail.net (S.-I.G.); arulbiotechtnau@ 123456gmail.com (A.N.)
                [3 ]Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Korea; E-Mails: alsgh0615@ 123456lycos.co.kr (M.H.H.); hongsh326@ 123456hanmail.net (S.H.H.)
                [4 ]School of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Korea; E-Mail: gonskim@ 123456gnu.ac.kr
                [5 ]Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Korea; E-Mail: immunkim@ 123456jejunu.ac.kr
                [6 ]Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, Korea; E-Mail: kwontk@ 123456dsmc.or.kr
                [7 ]Division of Applied Life Science (BK 21 Program), Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Korea; E-Mail: ryu@ 123456gnu.ac.kr
                [8 ]Department of Chemistry, Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Korea; E-Mail: scshin@ 123456gnu.ac.kr
                [9 ]Anti-Aging Research Center & Blue-Bio Industry RIC, Dongeui University, Busan 614-714, Korea
                Author notes
                [* ]Authors to whom correspondence should be addressed; E-Mails: lwshmo@ 123456hanmail.net or lwshmo@ 123456gnu.ac.kr (W.S.L.); choiyh@ 123456deu.ac.kr (Y.H.C.); Tel.: +82-55-750-8733 (W.S.L.); +82-51-850-7413 (Y.H.C.); Fax: +82-55-758-9122 (W.S.L.); +82-51-853-4036 (Y.H.C.).
                Article
                ijms-16-00645
                10.3390/ijms16010645
                4307266
                25561222
                125f4339-18f5-4e20-acfb-61a68198812f
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 November 2014
                : 11 December 2014
                Categories
                Article

                Molecular biology
                morin,apoptosis,bad,bcl-xl,leukemia
                Molecular biology
                morin, apoptosis, bad, bcl-xl, leukemia

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