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Lapachone AND sirt1

Hui-Ying Liu, Qing-Ran Li, Xue-Fang Cheng, Guang-Ji Wang, Hai-Ping Hao
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death...
August 2016: Chinese Journal of Natural Medicines
Huiying Liu, Qingran Li, Xuefang Cheng, Hong Wang, Guangji Wang, Haiping Hao
UNLABELLED: β-lapachone (β-lap), an NAD(P)H: quinone oxidoreductase 1 (NQO1) targeting antitumor drug candidate in phase II clinical trials, is metabolically eliminated via NQO1 mediated quinone reduction and subsequent UDP-glucuronosyltransferases (UGTs) catalyzed glucuronidation. This study intends to explore the inner link between the cellular glucuronidation and pharmacokinetics of β-lap and its apoptotic effect in human colon cancer cells. HT29 cells S9 fractions exhibited high glucuronidation activity towards β-lap, which can be inhibited by UGT1A9 competitive inhibitor propofol...
2015: PloS One
Moon Hee Jeong, Jin Hwan Kim, Kang-Sik Seo, Tae Hwan Kwak, Woo Jin Park
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease caused by mutations in the mitochondrial genome. This study investigated the efficacy of β-lapachone (β-lap), a natural quinone compound, in rescuing mitochondrial dysfunction in MELAS cybrid cells. β-Lap significantly restored energy production and mitochondrial membrane potential as well as normalized the elevated ROS level in MELAS cybrid cells. Additionally, β-lap reduced lactic acidosis and restored glucose uptake in the MELAS cybrid cells...
November 21, 2014: Biochemical and Biophysical Research Communications
Yong-Hoon Kim, Jung Hwan Hwang, Kyoung-Shim Kim, Jung-Ran Noh, Gil-Tae Gang, Youngwon Seo, Ki-Hoan Nam, Tae Hwan Kwak, Hee Gu Lee, Chul-Ho Lee
BACKGROUND: Endothelial nitric oxide synthase (eNOS) is involved in blood pressure (BP) regulation through the production of nitric oxide. Sirtuin I (SIRT1), an NAD-dependent protein deacetylase, promotes vascular relaxation through deacetylation and activation of eNOS. β-Lapachone (βL) increases the cellular NAD(+)/NADH ratio by activating NAD(P)H: quinone oxidoreductase 1 (NQO1). In this study, we verified whether activation of NQO1 by βL modulates BP through regulation of eNOS acetylation in a hypertensive animal model...
January 2015: American Journal of Hypertension
H-J Kim, G-S Oh, A Shen, S-B Lee, S-K Choe, K-B Kwon, S Lee, K-S Seo, T H Kwak, R Park, H-S So
Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD(+) levels...
2014: Cell Death & Disease
Moon Hee Jeong, Nguyen Khoi Song Tran, Tae Hwan Kwak, Byung Keon Park, Chul Soon Lee, Tae-Sik Park, Young-Hoon Lee, Woo Jin Park, Dong Kwon Yang
Lipotoxic cardiomyopathy is caused by myocardial lipid accumulation and often occurs in patients with diabetes and obesity. This study investigated the effects of β-lapachone (β-lap), a natural compound that activates Sirt1 through elevation of the intracellular NAD+ level, on acyl CoA synthase (ACS) transgenic (Tg) mice, which have lipotoxic cardiomyopathy. Oral administration of β-lap to ACS Tg mice significantly attenuated heart failure and inhibited myocardial accumulation of triacylglycerol. Electron microscopy and measurement of mitochondrial complex II protein and mitochondrial DNA revealed that administration of β-lap restored mitochondrial integrity and biogenesis in ACS Tg hearts...
2014: PloS One
Christopher Y Lu
The clinical utility of cisplatin is limited by nephrotoxicity. Oh et al. report that β-lapachone prevents this nephrotoxicity but not cisplatin's cytotoxicity for cancers. In addition to its potential clinical importance, the beneficial effect of β-lapachone on cisplatin acute kidney injury may illustrate fundamental processes that ordinarily link alterations in nutrient availability and intracellular reactive oxygen species on the one hand, with inflammation and cell death on the other hand.
March 2014: Kidney International
Yong-Hoon Kim, Jung Hwan Hwang, Kyung-Shim Kim, Jung-Ran Noh, Gil-Tae Gang, Won Keun Oh, Kyeong-Hoon Jeong, Tae Hwan Kwak, Hueng-Sik Choi, In-Kyu Lee, Chul-Ho Lee
AIMS: Guanosine 5'-triphosphate cyclohydrolase-1 (GTPCH-1) is a rate-limiting enzyme in de-novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS) coupling. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is crucial for GTPCH-1 preservation, and tumor suppressor kinase liver kinase B1 (LKB1), an upstream kinase of AMPK, is activated by NAD-dependent class III histone deacetylase sirtuin 1 (SIRT1)-mediated deacetylation...
February 2014: Journal of Hypertension
Bae Hyun Shin, Yunki Lim, Hye Jin Oh, Sang Min Park, Sun-Kyung Lee, Joohong Ahnn, Do Han Kim, Woo Keun Song, Tae Hwan Kwak, Woo Jin Park
Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington's disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, β-lapachone (β-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with β-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a pathogenic polyQ stretch fused to green fluorescent protein (HttEx1(97Q)-GFP)...
2013: PloS One
Jung Hwan Hwang, Dong Wook Kim, Eun Jin Jo, Yong Kyung Kim, Young Suk Jo, Ji Hoon Park, Sang Ku Yoo, Myung Kyu Park, Tae Hwan Kwak, Young Lim Kho, Jin Han, Hueng-Sik Choi, Sang-Hee Lee, Jin Man Kim, InKyu Lee, Taeyoon Kyung, Cholsoon Jang, Jongkyeong Chung, Gi Ryang Kweon, Minho Shong
OBJECTIVE: Nicotinamide adenine dinucleotides (NAD+ and NADH) play a crucial role in cellular energy metabolism, and a dysregulated NAD+-to-NADH ratio is implicated in metabolic syndrome. However, it is still unknown whether a modulating intracellular NAD+-to-NADH ratio is beneficial in treating metabolic syndrome. We tried to determine whether pharmacological stimulation of NADH oxidation provides therapeutic effects in rodent models of metabolic syndrome. RESEARCH DESIGN AND METHODS: We used beta-lapachone (betaL), a natural substrate of NADH:quinone oxidoreductase 1 (NQO1), to stimulate NADH oxidation...
April 2009: Diabetes
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