Subcellular Compartmentation and Differential Catalytic Properties of the Three Human Nicotinamide Mononucleotide Adenylyltransferase Isoforms

Systematics and health effects of chemically distinct tannins in medicinal plants.

Excessive activation of poly(ADP-ribose) polymerase 1 (PARP1) leads to NAD+ depletion and cell death during ischemia and other conditions that generate extensive DNA damage. When activated by DNA strand breaks, PARP1 uses NAD+ as substrate to form ADP-ribose polymers on specific acceptor proteins. These polymers are in turn rapidly degraded by poly(ADP-ribose) glycohydrolase (PARG), a ubiquitously expressed exo- and endoglycohydrolase. In this study, we examined the role of PARG in the PARP1-mediated cell death pathway. Mouse neuron and astrocyte cultures were exposed to hydrogen peroxide, N-methyl-d-aspartate (NMDA), or the DNA alkylating agent, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Cell death in each condition was markedly reduced by the PARP1 inhibitor benzamide and equally reduced by the PARG inhibitors gallotannin and nobotanin B. The PARP1 inhibitor benzamide and the PARG inhibitor gallotannin both prevented the NAD+ depletion that otherwise results from PARP1 activation by MNNG or H2O2. However, these agents had opposite effects on protein poly(ADP-ribosyl)ation. Immunostaining for poly(ADP-ribose) on Western blots and neuron cultures showed benzamide to decrease and gallotannin to increase poly(ADP-ribose) accumulation during MNNG exposure. These results suggest that PARG inhibitors do not inhibit PARP1 directly, but instead prevent PARP1-mediated cell death by slowing the turnover of poly(ADP-ribose) and thus slowing NAD+ consumption. PARG appears to be a necessary component of the PARP-mediated cell death pathway, and PARG inhibitors may have promise as neuroprotective agents.

https://www.pnas.org/content/pnas/98/21/12227.full.pdf

Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death

Epigenetics is concerned about heritable changes in gene expression without alteration of the coding sequence. Epigenetic modification of chromatin includes methylation of genomic DNA as well as post-translational modification of chromatin-associated proteins, in particular, histones. The spectrum of histone and non-histone modifications ranges from the addition of relatively small groups such as methyl, acetyl and phosphoryl groups to the attachment of larger moieties such as poly(ADP-ribose) and small proteins ubiquitin or small ubiquitin-like modifier (SUMO). The combinatorial nature of DNA methylation and histone modifications constitutes a significant pathway of epigenetic regulation and considerably extends the information potential of the genetic code. Chromatin modification has emerged as a new fundamental mechanism for gene transcriptional activity control associated with many cellular processes like proliferation, growth, and differentiation. Also it is increasingly recognized that epigenetic modifications constitute important regulatory mechanisms for the pathogenesis of malignant transformations. We review here the recent progress in the development of chemical inhibitors/activators that target different chromatin modifying enzymes. Such potent natural or synthetic modulators can be utilized to establish the quantitative contributions of epigenetic modifications in DNA regulated pathways including transcription, replication, recombination and repair, as well as provide leads for developing new cancer therapeutics. © 2008 Wiley Periodicals, Inc. Med Res Rev, 28, No. 5, 645–687, 2008

Chemical regulation of epigenetic modifications: opportunities for new cancer therapy.

Two galloylglucosides, 6-hydroxy-eugenol 4-O-(6'-O-galloyl)-beta-D-4C1-glucopyranoside (4) and 3-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-2-O-(2',6'-di-O-galloyl)-beta-D -4C1-glucopyranoside (7), and two C-glycosidic tannins, vascalaginone (10) and grandininol (14), together with fourteen known metabolites, gallic acid (1), methyl gallate (2), nilocitin (3), 1-O-galloyl-4,6-(S)-hexahydroxydiphenoyl-(alpha/beta)-D-glucopyranose (5), 4,6-(S)-hexahydroxydiphenoyl-(alpha/beta)-D-glucopyranose (6), 3,4,6-valoneoyl-(alpha/beta)-D-glucopyranose (8), pedunculagin (9), casuariin (11), castalagin (12), vascalagin (13), casuarinin (15), grandinin (16), methyl-flavogallonate (17) and ellagic acid (18), were identified from the leaves of Pimenta dioica (Merr.) L. (Myrtaceae) on the basis of their chemical and physicochemical analysis (UV, HRESI-MS, 1D and 2D NMR). It was found that 9 is the most cytotoxic compound against solid tumour cancer cells, the most potent scavenger against the artificial radical DPPH and physiological radicals including ROO*, OH*, and O2-*, and strongly inhibited the NO generation and induced the proliferation of T-lymphocytes and macrophages. On the other hand, 3 was the strongest NO inhibitor and 16 the highest stimulator for the proliferation of T-lymphocytes, while 10 was the most active inducer of macrophage proliferation.

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Yan Jyu Tsai

Papers

Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway.

Novel inhibitors of poly(ADP-ribose) glycohydrolase