Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.
- MeSH
- genetická terapie metody MeSH
- katechin * analogy a deriváty farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- NAD * metabolismus MeSH
- neurodegenerativní nemoci farmakoterapie metabolismus genetika MeSH
- neurony * metabolismus účinky léků MeSH
- neuroprotektivní látky * farmakologie MeSH
- nikotinamidnukleotidadenylyltransferasa * metabolismus genetika MeSH
- retina metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Východiska: Bylo provedeno několik studií s cílem zkoumání asociace polymorfizmu NAD(P)H chinin oxidoreduktázy 1 (NQO1) rs1800566 s rizikem karcinomu močového měchýře a prostaty, ale byly předloženy nekonzistentní výsledky. Proto jsme provedli metaanalýzu, abychom poskytli komplexní údaje o asociaci polymorfizmu NQO1 rs1800566 s karcinomem močového měchýře a prostaty. Metody: Příslušné studie byly identifikovány v databázích PubMed, Google Scholar, EMBASE a China National Knowledge Infrastructure před 1. červnem 2019. Výsledky: Bylo vybráno celkem 22 případových kontrolních studií zahrnujících 15 studií karcinomu močového měchýře se 4 413 případy a 4 275 kontrolami a 7 studií karcinomu prostaty s 762 případy a 1 813 kontrolami. Souhrnná data ukázala, že polymorfizmus NQO1 rs1800566 byl významně asociován se zvýšeným rizikem karcinomu močového měchýře (T vs. C: OR 1,300; 95% CI 1,112–1,518; p = 0,001; TT vs. CC: OR 1,415; 95% CI 1,084–1,847; p = 0,011; TC vs. CC: OR 1,389; 95% CI 1,111–1,738; p = 0,004; TT + TC vs. CC: OR 1,428; 95% CI 1,145–1,782; p = 0,002) a karcinomu prostaty (TC vs. CC: OR 1,276; 95% CI 1,047–1,555; p = 0,016; TT + TC vs. CC: OR 1,268; 95% CI 1,050–1,532; p = 0,014). Analýza stratifikovaná podle etnicity odhalila zvýšené riziko karcinomu močového měchýře u Kavkazanů a karcinomu prostaty u Asiatů. Závěr: Tato metaanalýza naznačuje, že polymorfizmus NQO1 rs1800566 byl významně spojen se zvýšeným rizikem karcinomu močového měchýře a prostaty.
Background: Number of studies has been performed to investigate the association of NAD(P)Hquinine oxidoreductase 1 (NQO1) rs1800566 polymorphism with risk of bladder and prostate cancers, but presented inconsistent results. Therefore, we performed a meta-analysis to provide a comprehensive data on the association of NQO1 rs1800566 polymorphism with bladder and prostate cancers. Methods: All eligible studies were identified in PubMed, Google Scholar, EMBASE, and China National Knowledge Infrastructure databases before June 01, 2019. Results: A total of 22 case-control studies includ ing 15 studies with 4,413 cases and 4,275 controls on bladder cancer and 7 studies with 762 cases and 1,813 controls on prostate cancer were selected. Overall, pooled data showed that the NQO1 rs1800566 polymorphism was significantly associated with an increased risk of bladder cancer (T vs. C: OR 1.300; 95% CI 1.112–1.518; P = 0.001; TT vs. CC: OR 1.415; 95% CI 1.084–1.847; P = 0.011; TC vs. CC: OR 1.389; 95% CI 1.111–1.738; P = 0.004; TT + TC vs. CC: OR 1.428; 95% CI 1.145–1.782; P = 0.002) and prostate cancer (TC vs. CC: OR 1.276; 95% CI 1.047–1.555; P = 0.016; TT + TC vs. CC: OR 1.268; 95% CI 1.050–1.532; P = 0.014). The stratified analysis by ethnicity revealed an increased risk of bladder cancer among Caucasians and prostate cancer among Asians. Conclusion: This meta-analysis suggested that the NQO1 rs1800566 polymorphism was significantly associated with increased risk of bladder and prostate cancers.
- Klíčová slova
- gen NQO1,
- MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- nádory močového měchýře * genetika MeSH
- nádory prostaty * genetika MeSH
- polymorfismus genetický MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Nicotinamide adenine dinucleotide (NAD) is a critical component of the cellular metabolism and also serves as an alternative 5' cap on various RNAs. However, the function of the NAD RNA cap is still under investigation. We studied NAD capping of RNAs in HIV-1-infected cells because HIV-1 is responsible for the depletion of the NAD/NADH cellular pool and causing intracellular pellagra. By applying the NAD captureSeq protocol to HIV-1-infected and uninfected cells, we revealed that four snRNAs (e.g., U1) and four snoRNAs lost their NAD cap when infected with HIV-1. Here, we provide evidence that the presence of the NAD cap decreases the stability of the U1/HIV-1 pre-mRNA duplex. Additionally, we demonstrate that reducing the quantity of NAD-capped RNA by overexpressing the NAD RNA decapping enzyme DXO results in an increase in HIV-1 infectivity. This suggests that NAD capping is unfavorable for HIV-1 and plays a role in its infectivity.
- MeSH
- HIV infekce * virologie metabolismus MeSH
- HIV-1 * MeSH
- lidé MeSH
- malá jadérková RNA * metabolismus genetika MeSH
- NAD * metabolismus MeSH
- RNA čepičky metabolismus MeSH
- RNA malá jaderná * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Ingestion of aristolochic acid (AA) is associated with development of urothelial tumors linked with AA nephropathy and is implicated in the development of Balkan endemic nephropathy-associated urothelial tumors. We investigated the efficiency of human NAD(P)H:quinone oxidoreductase (NQO1) to activate aristolochic acid I (AAI) and used in silico docking, using soft-soft (flexible) docking procedure, to study the interactions of AAI with the active site of human NQO1. AAI binds to the active site of NQO1 indicating that the binding orientation allows for direct hydride transfer (i.e., two electron reductions) to the nitro group of AAI. NQO1 activated AAI, generating DNA adduct patterns reproducing those found in urothelial tissues from humans exposed to AA. Because reduced aromatic nitro-compounds are often further activated by sulfotransferases (SULTs) or N,O-acetlytransferases (NATs), their roles in AAI activation were investigated. Our results indicate that phase II reactions do not play a major role in AAI bioactivation; neither native enzymes present in human hepatic or renal cytosols nor human SULT1A1, -1A2, -1A3, -1E, or -2A nor NAT1 or NAT2 further enhanced DNA adduct formation by AAI. Instead under the in vitro conditions used, DNA adducts arise by enzymatic reduction of AAI through the formation of a cyclic hydroxamic acid (N-hydroxyaristolactam I) favored by the carboxy group in peri position to the nitro group without additional conjugation. These results emphasize the major importance of NQO1 in the metabolic activation of AAI and provide the first evidence that initial nitroreduction is the rate limiting step in AAI activation.
- MeSH
- acetyltransferasy metabolismus MeSH
- adukty DNA metabolismus MeSH
- kyseliny aristolochové chemie metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- NAD(P)H dehydrogenasa (chinon) metabolismus MeSH
- sulfotransferasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
