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1.
Acta Crystallogr E Crystallogr Commun ; 71(Pt 12): m240-1, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26870444

ABSTRACT

In the structure of the title compound, [Zn(C8H6NO4)2(C3H10N2)2], the Zn(II) atom is located on a center of symmetry with one independent Zn-O distance of 2.199 (2) Å, and two Zn-N distances of 2.157 (2) and 2.144 (2) Å. The overall coordination geometry around the Zn(II) atom is octa-hedral. Several types of hydrogen-bonding inter-actions are evident. Both intra-molecular [2.959 (3) Å] and inter-molecular [3.118 (3) and 3.124 (3) Šinter-actions occur between the O atoms of the acetate group and the amino N atoms, and weak inter-molecular C-H-O inter-actions involving the nitro groups, leading to an extended chain of the molecules aligned along the ac plane.

3.
J Biol Chem ; 275(28): 21416-21, 2000 Jul 14.
Article in English | MEDLINE | ID: mdl-10748072

ABSTRACT

The mechanisms of UVB-induced apoptosis and the role of p38 mitogen-activated protein kinase (MAPK) were investigated in HaCaT cells. UVB doses that induced apoptosis also produced a sustained activation of p38 MAPK and mitochondrial cytochrome c release, leading to pro-caspase-3 activation. Late into the apoptotic process, UVB also induced a caspase-mediated cleavage of Bid. Caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone substantially blocked the UVB-induced apoptosis without preventing the release of mitochondrial cytochrome c and the p38 MAPK activation. The inhibition of p38 MAPK counteracted both apoptosis and cytochrome c release as well as the DEVD-amino-4-methylcoumarin cleavage activity without affecting the processing of pro-caspase-8. These results indicate that UVB induces multiple and independent apoptotic pathways, which culminate in pro-caspase-3 activation, and that the initial cytochrome c release is independent of caspase activity. Importantly, we show that a sustained p38 MAPK activation contributes to the UVB-induced apoptosis by mediating the release of mitochondrial cytochrome c into the cytosol.


Subject(s)
Apoptosis/physiology , Cytochrome c Group/metabolism , Mitogen-Activated Protein Kinases/metabolism , Ultraviolet Rays , Amino Acid Chloromethyl Ketones/pharmacology , Apoptosis/radiation effects , Caspase Inhibitors , Cell Division/drug effects , Cell Division/radiation effects , Cell Line , Cysteine Proteinase Inhibitors/pharmacology , Humans , Imidazoles/pharmacology , Keratinocytes/cytology , Keratinocytes/physiology , Keratinocytes/radiation effects , Kinetics , Mitogen-Activated Protein Kinases/radiation effects , p38 Mitogen-Activated Protein Kinases
4.
Biochem Biophys Res Commun ; 261(3): 641-5, 1999 Aug 11.
Article in English | MEDLINE | ID: mdl-10441479

ABSTRACT

Wild-type or mutant betaPDGF receptors were introduced into A431 cells that lack endogenous PDGF receptors. PDGF stimulates JNK1 activity in a dose- and time-dependent manner in cells expressing the wild-type receptor. A receptor mutant lacking all the binding sites for SHP-2, GAP, PI3K, and PLC-gamma fails to activate JNK1. Receptor mutants with no binding site for either SHP-2 or GAP can fully activate JNK1 but those which do not bind either PI3K or PLC-gamma are unable to induce JNK1 activation. PDGF-dependent JNK1 activation was reduced upon cell pretreatment with wortmannin or GF109203X and is completely abrogated by chronic PMA stimulation. Altogether, these results indicate that PDGF activates JNK1 through a pathway that involves both PI3K and PLC-gamma and subsequent activation of protein kinase C.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Mitogen-Activated Protein Kinases , Phosphatidylinositol 3-Kinases/metabolism , Platelet-Derived Growth Factor/pharmacology , Receptors, Platelet-Derived Growth Factor/metabolism , Signal Transduction , Type C Phospholipases/metabolism , Androstadienes/pharmacology , Binding Sites , Cell Line , Enzyme Activation , Enzyme Inhibitors/pharmacology , JNK Mitogen-Activated Protein Kinases , Mutation , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase C/antagonists & inhibitors , Receptors, Platelet-Derived Growth Factor/genetics , Tetradecanoylphorbol Acetate/pharmacology , Wortmannin
5.
J Biol Chem ; 274(13): 8788-96, 1999 Mar 26.
Article in English | MEDLINE | ID: mdl-10085120

ABSTRACT

In this study, we elucidate signaling pathways induced by photodynamic therapy (PDT) with hypericin. We show that PDT rapidly activates JNK1 while irreversibly inhibiting ERK2 in several cancer cell lines. In HeLa cells, sustained PDT-induced JNK1 and p38 mitogen-activated protein kinase (MAPK) activations overlap the activation of a DEVD-directed caspase activity, poly(ADP-ribose) polymerase (PARP) cleavage, and the onset of apoptosis. The caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (zDEVD-fmk) protect cells against apoptosis and inhibit DEVD-specific caspase activity and PARP cleavage without affecting JNK1 and p38 MAPK activations. Conversely, stable overexpression of CrmA, the serpin-like inhibitor of caspase-1 and caspase-8, has no effect on PDT-induced PARP cleavage, apoptosis, or JNK1/p38 activations. Cell transfection with the dominant negative inhibitors of the c-Jun N-terminal kinase (JNK) pathway, SEK-AL and TAM-67, or pretreatment with the p38 MAPK inhibitor PD169316 enhances PDT-induced apoptosis. A similar increase in PDT-induced apoptosis was observed by expression of the dual specificity phosphatase MKP-1. The simultaneous inhibition of both stress kinases by pretreating cells with PD169316 after transfection with either TAM-67 or SEK-AL produces a more pronounced sensitizing effect. Cell pretreatment with the p38 inhibitor PD169316 causes faster kinetics of DEVD-caspase activation and PARP cleavage and strongly oversensitizes the cells to apoptosis following PDT. These observations indicate that the JNK1 and p38 MAPK pathways play an important role in cellular resistance against PDT-induced apoptosis with hypericin.


Subject(s)
Apoptosis/drug effects , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Mitogen-Activated Protein Kinases , Perylene/analogs & derivatives , Signal Transduction , Anthracenes , Caspase 3 , Caspases/metabolism , Enzyme Activation , Enzyme Inhibitors/pharmacology , Epidermal Growth Factor/pharmacology , HeLa Cells , Humans , JNK Mitogen-Activated Protein Kinases , Mitogen-Activated Protein Kinase 1 , Oligopeptides/pharmacology , Perylene/pharmacology , Photochemotherapy , Poly(ADP-ribose) Polymerases/metabolism , Radiation-Sensitizing Agents/pharmacology , p38 Mitogen-Activated Protein Kinases
7.
FEBS Lett ; 440(1-2): 19-24, 1998 Nov 27.
Article in English | MEDLINE | ID: mdl-9862416

ABSTRACT

Here we report that photoactivated hypericin can induce either apoptosis or necrosis in HeLa cells. Under apoptotic conditions the cleavage of poly(ADP-ribose) polymerase (PARP) into the 85-kDa product is blocked by the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (z-DEVD-fmk). Both inhibitors protect cells from apoptosis but cannot prevent hypericin-induced necrosis. Conversely, HeLa cells overexpressing the viral cytokine response modifier A (CrmA), which inhibits caspase-1 and -8, still undergo hypericin-induced apoptosis and necrosis. Evidence is provided for the release of mitochondrial cytochrome c in the cytosol and for procaspase-3 activation in the hypericin-induced cell killing.


Subject(s)
Apoptosis , Caspases/metabolism , Cytochrome c Group/metabolism , Enzyme Precursors/metabolism , Necrosis , Perylene/analogs & derivatives , Photosensitizing Agents/pharmacology , Viral Proteins , Amino Acid Chloromethyl Ketones/pharmacology , Anthracenes , Caspase 3 , Caspase Inhibitors , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Size/drug effects , Cell Survival/drug effects , Cysteine Proteinase Inhibitors/genetics , Cysteine Proteinase Inhibitors/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Cytosol/metabolism , DNA Fragmentation/drug effects , Enzyme Activation , HeLa Cells , Humans , Light , Oligopeptides/pharmacology , Perylene/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Serpins/genetics , Serpins/metabolism
8.
J Invest Dermatol ; 108(6): 886-91, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9182816

ABSTRACT

Exposure of mammalian cells to solar ultraviolet (UV) radiation leads to the expression of several genes, and UV has been recognized as a major initiator and promoter of skin cancer. The component of the solar radiation that contributes most to human skin malignancy is UVB (280-320 nm) and, to a lesser extent, UVA (320-400 nm), whereas the high-energy UVC (100-280 nm) is absorbed by the earth's upper atmosphere. Sublethal doses of UVB produce strong induction of c-jun and c-fos transcripts in several cells including human primary keratinocytes. The present report confirms that this is also the case in the HaCaT cell line and shows that similar UVB doses are potent inducers of the JNK/SAPK family of mitogen-activated protein kinases but only weak activators of ERKs. Epidermal growth factor (EGF) caused rapid induction of both JNK- and ERK-signaling pathways, and the downmodulation of the EGF-signaling pathway by EGF pre-treatment inhibited the UVB-induced JNK1 activation. Prior UVB irradiation of the cells decreased the level of the ERK2 activation by a subsequent EGF treatment, but this sensitized the cells and allowed for the super-activation of JNK1 after a rechallenge with either UVB or EGF. The antioxidant N-acetylcysteine impaired the UVB- and EGF-induced activation of JNK1. Our data suggest the presence of shared signaling component(s) in the UVB- and EGF-induced cellular response pathways and imply that oxidative stress plays a significant role in the activation of JNK1 by UVB and EGF.


Subject(s)
Epidermal Growth Factor/pharmacology , JNK Mitogen-Activated Protein Kinases , Keratinocytes/drug effects , Keratinocytes/radiation effects , Mitogen-Activated Protein Kinase Kinases , Mitogen-Activated Protein Kinases/metabolism , Nerve Tissue Proteins/metabolism , Protein Kinases/metabolism , Ultraviolet Rays , Base Sequence , Cell Line , DNA/analysis , DNA/chemistry , DNA/genetics , DNA Primers/analysis , DNA Primers/chemistry , DNA Primers/genetics , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Enzyme Activation/drug effects , Enzyme Activation/radiation effects , Humans , Keratinocytes/chemistry , MAP Kinase Kinase 4 , Mitogen-Activated Protein Kinases/analysis , Mitogen-Activated Protein Kinases/genetics , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/genetics , Precipitin Tests , Protein Kinases/analysis , Protein Kinases/genetics , Proto-Oncogene Proteins c-fos/analysis , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/analysis , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , RNA, Messenger/analysis , RNA, Messenger/genetics , Reactive Oxygen Species , Signal Transduction/physiology
9.
Met Based Drugs ; 1(5-6): 459-66, 1994.
Article in English | MEDLINE | ID: mdl-18476263

ABSTRACT

It has long been established by Khan that the superoxide anion, O(2) (-), generates singlet oxygen, O(2) (1)Delta(g), during dismutation. Auranofin, gold-phosphine thiols, beta-Carotene, and metal-sulfur compounds can rapidly quench singlet O(2). The quenching of the O(2) (1)Delta(g), which exists at 7752 cm(-1) above the ground state triplet, may be due to the direct interaction of the singlet O(2) with gold(I) or may require special ligands such as those containing sulfur coordinated to the metal. Thus we have been examining the excited state behavior of gold(I) species and the mechanisms for luminescence. Luminescence is observed under various conditions, with visible emission ranging from blue to red depending on the ligands coordinated to gold(I). Triplet state emission can be found from mononuclear three coordinate Au(I) species, including species which display this behavior in aqueous solution. A description is given of the luminescent three coordinate TPA (triazaphosphaadamantane) and TPPTS (triphenylphosphine-trisulfonate) complexes, the first examples of water soluble luminescent species of gold(I).

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