Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several studies have investigated the roles of genetic polymorphisms in rheumatoid arthritis (RA). Some of these studies reported that polymorphisms of poly(ADP-ribose) polymerase 1 gene (PARP-1) are linked to rheumatoid arthritis. Poly(ADP-ribose) polymerase is an enzyme involved in DNA repair, genomic stability, apoptosis, gene transcription, proliferation, and autoimmunity. To determine whether genetic polymorphisms of PARP-1 are related to rheumatoid arthritis in a Korean population, six single nucleotide polymorphisms (SNPs), which were selected based on LDs and minor allele frequency (MAF > 0.05) in our previous study, were genotyped in 1,202 patients with rheumatoid arthritis and 979 unrelated healthy controls. As a result, no significant association between the susceptibility to rheumatoid arthritis and PAPR-1 polymorphisms was found. However, in further analysis depending on the radiological severity of rheumatoid arthritis, one PARP-1 polymorphism, rs1805413 (OR = 0.11; 95% CI = 0.02-0.55; P = 0.007; P (corr) = 0.04), and one haplotype (ht6, OR = 0.11; 95% CI = 0.02-0.55; P = 0.007; P (corr) = 0.04) were significantly associated with the radiological severity risk of RA in a recessive model. In addition, a recessive model revealed a correlation between one RA haplotype (ht4) and anti-CCP antibody negativity (OR 0.24, 95% CI 0.10-0.63, P = 0.003; P (corr) = 0.02). Despite a possible association between PARP-1 and the radiological severity of RA, this study found no statistical association between PARP-1 polymorphisms and the susceptibility to rheumatoid arthritis in a Korean population.
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PMID:Lack of association between poly(ADP-ribose) polymerase (PARP) polymorphisms and rheumatoid arthritis in a Korean population. 2066 26

Hedgehog (Hh) signaling plays an important role in the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). Although gemcitabine (GEM) has been used as a first-line therapy for PDAC, its rapid metabolism and short plasma half-life restrict its use as a single chemotherapy. Combination therapy with more than one drug is a promising approach for treating cancer. Herein, we report the use of methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-dodecanol (mPEG-b-PCC-g-DC) copolymer for conjugating GEM and encapsulating a Hh inhibitor, vismodegib (GDC-0449), into its hydrophobic core for treating PDAC. Our objective was to determine whether the micelle mixtures of these two drugs could show better response in inhibiting Hh signaling pathway and restraining the proliferation and metastasis of pancreatic cancer. The in vivo stability of GEM significantly increased after conjugation, which resulted in its increased antitumor efficacy. Almost 80% of encapsulated GDC-0449 and 19% conjugated GEM were released in vitro at pH 5.5 in 48 h in a sustained manner. The invasion, migration, and colony forming features of MIA PaCa-2 cells were significantly inhibited by micelle mixture carrying GEM and GDC-0449. Remarkable increase in PARP cleavage and Bax proved increased apoptosis by this combination formulation compared to individual micelles. This combination therapy efficiently inhibited tumor growth, increased apoptosis, reduced Hh ligands PTCH-1 and Gli-1, and lowered EMT-activator ZEB-1 when injected to athymic nude mice bearing subcutaneous tumor generated using MIA PaCa-2 cells compared to monotherapy as observed from immunohistochemical analysis. In conclusion, micelle mixtures carrying GEM and GDC-0449 have the potential to treat pancreatic cancer.
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PMID:Micelle Mixtures for Coadministration of Gemcitabine and GDC-0449 To Treat Pancreatic Cancer. 2698 24

The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively1-3. Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic.
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PMID:Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. 3001 82