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1.
Christine G. Stoehr Elke Nolte Sven Wach Wolf F. Wieland Ferdinand Hofstaedter Arndt Hartmann Robert Stoehr 《International journal of molecular sciences》2012,13(9):10959-10969
NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A “C” to “T” transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in an altered enzyme activity. No NQO1 protein activity was detected in NQO1
609TT genotype, and low to intermediate activity was detected in NQO1
609CT genotype compared with 609CC genotype. Thus, this polymorphism may result in altered cancer predisposition. For prostate cancer, only sparse data are available. We therefore analyzed the distribution of the NQO1 P187S SNP (single nucleotide polymorphism) in prostate cancer patients and a healthy control group. Allelic variants were determined using RFLP analysis. Overall, 232 patients without any malignancy and 119 consecutive prostate cancer patients were investigated. The genotype distribution in our cohorts followed the Hardy–Weinberg equilibrium in cases and controls. The distribution of the NQO1 codon 187 SNP did not differ significantly between prostate cancer patients and the control group (p = 0.242). There was also no association between the allelic variants and stage or Gleason score of the tumors. The NQO1 P187S SNP was not significantly associated with an increased prostate cancer risk in our cohorts. The SNP has also no influence on histopathological characteristics of the tumors. A combined analysis of all available data from published European studies also showed no significant differences in the genotype distribution between controls and prostate cancer patients. Our data suggest a minor role of the NQO1 nucleotide 609 polymorphism in prostate carcinogenesis. 相似文献
2.
Aura Nemeikait-nien Jonas arlauskas Lina Misevi
ien Audron Marozien Violeta Jonuien Mindaugas Lesanavi
ius Narimantas nas 《International journal of molecular sciences》2020,21(22)
Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides. 相似文献
3.
Nobuaki Okumura Takashi Ito Tomomi Degawa Mariko Moriyama Hiroyuki Moriyama 《International journal of molecular sciences》2021,22(23)
Royal jelly (RJ) is secreted by honeybees and has been used as an apitherapy to obtain healthy skin since ancient times. However, the mechanism of the protective effects of RJ against skin aging and skin diseases caused by skin stress and its components have not been clarified. In this study, we attempted to understand the effect of RJ on epidermal function and observed that NAD(P)H quinone dehydrogenase 1 (NQO1) is significantly induced by RJ in keratinocytes. The expression of NQO1 was also increased in the 3D epidermal skin model. NQO1 is involved in antioxidation and detoxification metabolism, and we found that RJ protects against the epidermal stress caused by UVB and menadione through the upregulation of NQO1. We identified 10-hydroxy-2-decenoic acid (10H2DA), a major fatty acid in RJ, as an active compound in this reaction as it induced the expression of NQO1 and protected the skin against oxidative stress. We demonstrated that the protective effect of RJ against epidermal stress is mediated through the upregulation of NQO1 by 10H2DA. 相似文献
4.
Jonas ?arlauskas Lina Misevi?ien? Audron? Marozien? Laimonas Karvelis Jonita Stankevi?iūt? Kastis Krik?topaitis Narimantas ??nas Aleksey Yantsevich Audrius Lauryn?nas ?ilvinas Anusevi?ius 《International journal of molecular sciences》2014,15(12):23307-23331
The enzymatic reactivity of a series of benzo[1,2-c]1,2,5-oxadiazole N-oxides (benzofuroxans; BFXs) towards mammalian single-electron transferring NADPH:cytochrome P-450 reductase (P-450R) and two-electron (hydride) transferring NAD(P)H:quinone oxidoreductase (NQO1) was examined in this work. Since the =N+ (→O)O− moiety of furoxan fragments of BFXs bears some similarity to the aromatic nitro-group, the reactivity of BFXs was compared to that of nitro-aromatic compounds (NACs) whose reduction mechanisms by these and other related flavoenzymes have been extensively investigated. The reduction of BFXs by both P-450R and NQO1 was accompanied by O2 uptake, which was much lower than the NADPH oxidation rate; except for annelated BFXs, whose reduction was followed by the production of peroxide. In order to analyze the possible quantitative structure-activity relationships (QSARs) of the enzymatic reactivity of the compounds, their electron-accepting potency and other reactivity indices were assessed by quantum mechanical methods. In P-450R-catalyzed reactions, both BFXs and NACs showed the same reactivity dependence on their electron-accepting potency which might be consistent with an “outer sphere” electron transfer mechanism. In NQO1-catalyzed two-electron (hydride) transferring reactions, BFXs acted as more efficient substrates than NACs, and the reduction efficacy of BFXs by NQO1 was in general higher than by single-electron transferring P-450R. In NQO1-catalyzed reactions, QSARs obtained showed that the reduction efficacy of BFXs, as well as that of NACs, was determined by their electron-accepting potency and could be influenced by their binding mode in the active center of NQO1 and by their global softness as their electronic characteristic. The reductive conversion of benzofuroxan by both flavoenzymes yielded the same reduction product of benzofuroxan, 2,3-diaminophenazine, with the formation of o-benzoquinone dioxime as a putative primary reductive intermediate, which undergoes a further reduction process. Overall, the data obtained show that by contrast to NACs, the flavoenzyme-catalyzed reduction of BFXs is unlikely to initiate their redox-cycling, which may argue for a minor role of the redox-cycling-type action in the cytotoxicity of BFXs. 相似文献
5.
Xuewen Mu Yun Xu Zheng Wang Dunyun Shi 《Frontiers of Chemical Science and Engineering》2023,17(2):123
The two-electron cytoplasmic reductase NAD(P)H:quinone oxidoreductase 1 is expressed in many tissues. NAD(P)H:quinone oxidoreductase 1 is well-known for being highly expressed in most cancers. Therefore, it could be a target for cancer therapy. Because it is a quinone reductase, many bioimaging probes based on quinone structures target NAD(P)H:quinone oxidoreductase 1 to diagnose tumours. Its expression is higher in tumours than in normal tissues, and using target drugs such as β-lapachone to reduce side effects in normal tissues can help. However, the physicochemical properties of β-lapachone limit its application. The problem can be solved by using nanosystems to deliver β-lapachone. This mini-review summarizes quinone-based fluorescent, near-infrared and two-photon fluorescent probes, as well as nanosystems for delivering the NAD(P)H:quinone oxidoreductase 1-activating drug β-lapachone. This review provides valuable information for the future development of probes and nano-delivery systems that target NAD(P)H:quinone oxidoreductase 1. 相似文献
6.
The 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) enzyme plays a crucial role in female hormonal regulation by catalysing the NADPH-dependent reduction of the less potent estrone E1 into the biologically active estradiol E2. Because 17beta-HSD1 is a key enzyme in E2 biosynthesis, it has emerged as an attractive drug target for inhibitor development. Herein we report the plausible binding modes and a 3D QSAR model of 17beta-HSD1 inhibitors based on a (di)cycloalkenothieno[2,3-d]pyrimidin-4(3H)-one core. Two generated enzyme complexes with potent inhibitors were subjected to molecular dynamics simulation to mimic the dynamic process of inhibitor binding. A set of 17beta-HSD1 inhibitors based on the thieno[2,3-d]pyrimidin-4(3H)-one core were docked into the resulting active site, and a CoMFA model employing the most extensive training set to date was generated. The model was validated with an external test set. Active site residues involved in inhibitor binding and CoMFA fields for steric and electrostatic interactions were identified. The model will be used to guide structural modifications of 17beta-HSD1 inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core in order to improve the biological activity as well as in the design of novel 17beta-HSD1 inhibitors. 相似文献
7.
Basran J; Casarotto MG; Basran A; Roberts GC 《Protein engineering, design & selection : PEDS》1997,10(7):815-826
The effects of six amino acid substitutions in Lactobacillus casei
dihydrofolate reductase, predominantly in the coenzyme binding site, on
catalysis and on the negative cooperativity between NADPH and
tetrahydrofolate binding have been determined. Replacement of Leu62, His64
or Leu54 by alanine has no effect on kcat, and produces only modest changes
in negative cooperativity. Alanine substitution of His77, which interacts
indirectly with the coenzyme adenine ring, leads to a doubling of the
negative cooperativity and a consequent doubling of kcat. Replacement of
Arg43, which interacts with the coenzyme 2'- phosphate, by alanine, or of
Trp21, which interacts with the coenzyme nicotinamide ring, by histidine
leads to a 20-100-fold decrease in negative cooperativity. In both mutants
there is a decrease in kcat; isotope effects show that product release is
largely rate-limiting in R43A, whereas in W21H hydride ion transfer is
rate-limiting. 1H NMR has been used to obtain information on the extent of
the structural changes produced by the substitutions. This varies from very
local effects in H64A to very widespread effects in W21H. These changes are
used as the basis for discussion of the mechanisms of the functional
effects of the various substitutions. It is suggested that residues in
helix C, beta- strand 3 and the beta3-beta4 loop may be involved in the
transmission of effects between the coenzyme and substrate binding sites.
相似文献
8.
Yang CH Jeng KC Yang WH Chen YL Hung CC Lin JW Chen ST Richardson S Martin CR Waring MJ Sheh L 《Chembiochem : a European journal of chemical biology》2006,7(8):1187-1196
The DNA-binding preferences of two oligopeptide amides, (His-Pro-Arg-Lys)(3)NH(2) (HR-12) and (Ser-Pro-Arg-Lys)(3)NH(2) (SP-12), have been examined by quantitative DNase I footprinting studies. Two different DNA fragments were investigated: a pair of 5'-(32)P-labeled duplexes from pBR322 with one or other of the complementary strands labeled and a corresponding pair of 5'-(32)P-labeled duplexes representing fragments of the latent membrane protein (LMP-1) gene from a pathogenic Epstein-Barr virus variant derived from nasopharyngeal carcinoma. The major objective was to examine molecular recognition and cooperative features associated with sequence-selective binding of synthetic peptides to the LMP-1 fragments. At various binding sites on the pBR322 fragments, Hill coefficients (n(H)) ranging from 1.9-2.2 were observed; these results indicate modest positive cooperativity between binding sites for both peptides. By contrast, unusually high values of n(H), ranging from 4.0-9.3, were observed at various binding sites on the LMP-1 fragments. Allosteric models can be constructed to interpret the observed cooperative interactions between different DNA recognition sites in the LMP-1 gene upon binding of the peptide ligands. It is noteworthy that these models feature a novel network of cooperativity interconnecting multiple DNA allosteric sites. The evidence of sequence selectivity and strong cooperativity discovered in this work may prove to be a general feature of peptide interactions with some nucleic acids. 相似文献
9.
Whitehouse CJ Yang W Yorke JA Rowlatt BC Strong AJ Blanford CF Bell SG Bartlam M Wong LL Rao Z 《Chembiochem : a European journal of chemical biology》2010,11(18):2549-2556
The crystal structures of the haem domains of Ala330Pro and Ile401Pro, two single‐site proline variants of CYP102A1 (P450BM3) from Bacillus megaterium, have been solved. In the A330P structure, the active site is constricted by the relocation of the Pro329 side chain into the substrate access channel, providing a basis for the distinctive C? H bond oxidation profiles given by the variant and the enhanced activity with small molecules. I401P, which is exceptionally active towards non‐natural substrates, displays a number of structural similarities to substrate‐bound forms of the wild‐type enzyme, notably an off‐axial water ligand, a drop in the proximal loop, and the positioning of two I‐helix residues, Gly265 and His266, the reorientation of which prevents the formation of several intrahelical hydrogen bonds. Second‐generation I401P variants gave high in vitro oxidation rates with non‐natural substrates as varied as fluorene and propane, towards which the wild‐type enzyme is essentially inactive. The substrate‐free I401P haem domain had a reduction potential slightly more oxidising than the palmitate‐bound wild‐type haem domain, and a first electron transfer rate that was about 10 % faster. The electronic properties of A330P were, by contrast, similar to those of the substrate‐free wild‐type enzyme. 相似文献
10.
L-2-Hydroxyisocaproate dehydrogenase (L-HicDH) is characterized by a broad
substrate specificity and utilizes a wide range of 2-oxo acids branched at
the C4 atom. Modifications have been made to the sequence of the
NAD(H)-dependent L-HicDH from Lactobacillus confusus in order to define and
alter the region of substrate specificity towards various 2- oxocarbonic
acids. All variations were based on a 3D-structure model of the enzyme
using the X-ray coordinates of the functionally related L- lactate
dehydrogenase (L-LDH) from dogfish as a template. This protein displays
only 23% sequence identity to L-HicDH. The active site of L- HicDH was
modelled by homology to the L-LDH based on the conservation of
catalytically essential residues. Substitutions of the active site residues
Gly234, Gly235, Phe236, Leu239 and Thr245 were made in order to identify
their unique participation in substrate recognition and orientation. The
kinetic properties of the L239A, L239M, L236V and T245A enzyme variants
confirmed the structural model of the active site of L-HicDH. The
substrates 2-oxocaproate, 2-oxoisocaproate, phenylpyruvate,
phenylglyoxylate, keto-tert-leucine and pyruvate were fitted into the
active site of the subsequently refined model. In order to design
dehydrogenases with an improved substrate specificity towards keto acids
branched at C3 or C4, amino acid substitutions at positions Leu239, Phe236
and Thr245 were introduced and resulted in mutant enzymes with completely
different substrate specificities. The substitution T245A resulted in a
relative shift of substrate specificity for keto-tert-leucine of more than
17000 compared with the 2-oxocaproate (kcat/KM). For the substrates
branched at C4 a relative shift of up to 500 was obtained for several
enzyme variants. A total of nine mutations were introduced and the kinetic
data for the set of six substrates were determined for each of the
resulting mutant enzymes. These were compared with those of the wild-type
enzyme and rationalized by the active site model of L-HicDH. An analysis of
the enzyme variants provided new insight into the residues involved in
substrate binding and residues of importance for the differences between
LDHs and HicDH. After the protein design project was complete the X-ray
structure of the enzyme was solved in our group. A comparison between the
model and the experimental 3D structure proved the quality of the model.
All the variants were designed, expressed and tested before the 3D
structure became available.
相似文献
11.
Joo V. de Souza Matthew Kondal Piotr Zaborniak Ryland Cairns Agnieszka K. Bronowska 《International journal of molecular sciences》2021,22(4)
Phytosulfokine (PSK) is a phytohormone responsible for cell-to-cell communication in plants, playing a pivotal role in plant development and growth. The binding of PSK to its cognate receptor, PSKR1, is modulated by the formation of a binding site located between a leucine-rich repeat (LRR) domain of PSKR1 and the loop located in the receptor’s island domain (ID). The atomic resolution structure of the extracellular PSKR1 bound to PSK has been reported, however, the intrinsic dynamics of PSK binding and the architecture of the PSKR1 binding site remain to be understood. In this work, we used atomistic molecular dynamics (MD) simulations and free energy calculations to elucidate how the PSKR1 island domain (ID) loop forms and binds PSK. Moreover, we report a novel “druggable” binding site which could be exploited for the targeted modulation of the PSKR1-PSK binding by small molecules. We expect that our results will open new ways to modulate the PSK signalling cascade via small molecules, which can result in new crop control and agricultural applications. 相似文献
12.
Park H; Bradrick TD; Howell EE 《Protein engineering, design & selection : PEDS》1997,10(12):1415-1424
R67 dihydrofolate reductase (DHFR) is a type II DHFR produced by bacteria
as a resistance mechanism to increasing clinical use of the antibacterial
drug trimethoprim. Type II DHFRs are not homologous in either sequence or
structure with chromosomal DHFRs. The crystal structure of R67 DHFR shows a
single active site pore that spans the length of the homotetramer. Related
sites (due to a 222 symmetry element at the center of the pore) are used to
bind ligands, i.e. each half of the pore can accommodate either the
substrate, dihydrofolate (DHF), or the cofactor, NADPH, although DHF and
NADPH are bound differently. To evaluate the role of glutamine 67 (and its
symmetry- related Q167, Q267 and Q367 residues which occur at the center of
the active site pore), a Q67H mutation was constructed. Binary binding of
dihydrofolate (DHF; monitored by isothermal titration calorimetry) displays
two identical sites with a Kd value of 0.04 microM, while binding of NADPH
shows two sites possessing negative cooperativity with Kd values of 0.027
and 0.62 microM. A comparison of ligand binding in Q67H versus wild-type
(wt) R67 DHFR indicates both ligands bind more tightly (80-6000-fold) and
DHF binding in Q67H R67 DHFR no longer displays positive cooperativity as
seen in wt R67 DHFR. Ternary complex binding in the Q67H mutant indicates a
total of two ligands can bind per pore. Substantial substrate and cofactor
inhibition are observed during catalysis, consistent with non-productive
binding of either two DHF or two NADPH molecules in Q67H R67 DHFR. Because
of the symmetry- related binding sites in the active site pore, the
accumulation of potentially positive mutations in R67 DHFR is limited by
the balance between tighter binding of ligands (and thus potentially
increased catalytic efficiency) and inhibition that arises upon tighter
binding of two identical ligands at symmetry-related sites.
相似文献
13.
14.
Engineering protein mechanics: inhibition of concerted motions of the cellular retinol binding protein by site-directed mutagenesis 总被引:2,自引:0,他引:2
van Aalten DM; Jones PC; de Sousa M; Findlay JB 《Protein engineering, design & selection : PEDS》1997,10(1):31-37
Recently we reported on the dynamic properties of the cellular retinol
binding protein, a member of the fatty acid binding protein family. A few
conserved glycines were identified as important for producing the
conformational changes necessary for the uptake and release of retinol.
Here, we describe a multidisciplinary analysis of a genetically engineered
mutation of one of these glycines (Gly67), designed to inhibit an observed
hinge bending motion. The correctly folded mutant protein is unable to bind
retinol. Analysis of the molecular dynamics simulations of the mutant and
wild type protein using the essential dynamics method shows that the
mutation indeed inhibits the hinge bending motions which are important for
retinol binding.
相似文献
15.
Enzymes catalyze a particular reaction in cells, but only a few control the rate of this reaction and the metabolic pathway that follows. One specific mechanism for such enzymatic control of a metabolic pathway involves molecular feedback, whereby a metabolite further down the pathway acts at a unique site on the control enzyme to alter its activity allosterically. This regulation may be positive or negative (or both), depending upon the particular system. Another method of enzymatic control involves the cooperative binding of the substrate, which allows a large change in enzyme activity to emanate from only a small change in substrate concentration. Allosteric regulation and homotropic cooperativity are often known to involve significant conformational changes in the structure of the protein. Escherichia coli aspartate transcarbamoylase (ATCase) is the textbook example of an enzyme that regulates a metabolic pathway, namely, pyrimidine nucleotide biosynthesis, by feedback control and by the cooperative binding of the substrate, L-aspartate. The catalytic and regulatory mechanisms of this enzyme have been extensively studied. A series of X-ray crystal structures of the enzyme in the presence and absence of substrates, products, and analogues have provided details, at the molecular level, of the conformational changes that the enzyme undergoes as it shifts between its low-activity, low-affinity form (T state) to its high-activity, high-affinity form (R state). These structural data provide insights into not only how this enzyme catalyzes the reaction between l-aspartate and carbamoyl phosphate to form N-carbamoyl-L-aspartate and inorganic phosphate, but also how the allosteric effectors modulate this activity. In this Account, we summarize studies on the structure of the enzyme and describe how these structural data provide insights into the catalytic and regulatory mechanisms of the enzyme. The ATCase-catalyzed reaction is regulated by nucleotide binding some 60 ? from the active site, inducing structural alterations that modulate catalytic activity. The delineation of the structure and function in this particular model system will help in understanding the molecular basis of cooperativity and allosteric regulation in other systems as well. 相似文献
16.
Mercklé L de Andrés-Gómez A Dick B Cox RJ Godfrey CR 《Chembiochem : a European journal of chemical biology》2005,6(10):1866-1874
The inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) by fosmidomycin was studied by using a kinetic assay based on the consumption of NADPH and synthetic substrate. Fosmidomycin is a slow tight-binding inhibitor of DXR that shows strong negative cooperativity (absolute value(h) = 0.3) in binding. Cooperativity is displayed during the initial (weak, K0.5 = 10 microM) binding event and does not change as the binding tightens to the equilibrium value of 0.9 nM over a period of seconds to minutes. A series of fosmidomycin fragments was examined, but all showed much weaker inhibition, in the mM range. A series of cyclic fosmidomycin analogues was also synthesised and tested, but these showed high-microM binding at best. None of the synthetic compounds showed time-dependent inhibition. We concluded that the slow tight-binding behaviour, and perhaps also cooperativity, are mediated by significant reorganisation of the active site upon fosmidomycin binding. This makes the rational design of new inhibitors of DXR difficult at best. 相似文献
17.
Songklod Sarapusit Panida Lertkiatmongkol Panida Duangkaew Pornpimol Rongnoparut 《International journal of molecular sciences》2013,14(1):1788-1801
Malaria is one of the most dangerous mosquito-borne diseases in many tropical countries, including Thailand. Studies in a deltamethrin resistant strain of Anopheles minimus mosquito, suggest cytochrome P450 enzymes contribute to the detoxification of pyrethroid insecticides. Purified A. minimus CYPOR enzyme (AnCYPOR), which is the redox partner of cytochrome P450s, loses flavin-adenosine di-nucleotide (FAD) and FLAVIN mono-nucleotide (FMN) cofactors that affect its enzyme activity. Replacement of leucine residues at positions 86 and 219 with phenylalanines in FMN binding domain increases FMN binding, enzyme stability, and cytochrome c reduction activity. Membrane-Bound L86F/L219F-AnCYPOR increases A. minimus P450-mediated pyrethroid metabolism in vitro. In this study, we constructed a comparative model structure of AnCYPOR using a rat CYPOR structure as a template. Overall model structure is similar to rat CYPOR, with some prominent differences. Based on primary sequence and structural analysis of rat and A. minimus CYPOR, C427R, W678A, and W678H mutations were generated together with L86F/L219F resulting in three soluble Δ55 triple mutants. The C427R triple AnCYPOR mutant retained a higher amount of FAD binding and increased cytochrome c reduction activity compared to wild-type and L86F/L219F-Δ55AnCYPOR double mutant. However W678A and W678H mutations did not increase FAD and NAD(P)H bindings. The L86F/L219F double and C427R triple membrane-bound AnCYPOR mutants supported benzyloxyresorufin O-deakylation (BROD) mediated by mosquito CYP6AA3 with a two-to three-fold increase in efficiency over wild-type AnCYPOR. The use of rat CYPOR in place of AnCYPOR most efficiently supported CYP6AA3-mediated BROD compared to all AnCYPORs. 相似文献
18.
Kevin J Lee Griffin Wright Hannah Bryant Leigh Ann Wiggins Valeria L. Dal Zotto Michele Schuler Christopher Malozzi Michael V Cohen Natalie R Gassman 《International journal of molecular sciences》2021,22(14)
Background: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. Methods: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. Results: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). Conclusions: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC. 相似文献
19.
Self‐Immolative Bioluminogenic Quinone Luciferins for NAD(P)H Assays and Reducing Capacity‐Based Cell Viability Assays
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Dr. Wenhui Zhou Dr. Donna Leippe Dr. Sarah Duellman Mary Sobol Dr. Jolanta Vidugiriene Dr. Martha O'Brien Dr. John W. Shultz Joshua J. Kimball Céline DiBernardo Leonard Moothart Dr. Laurent Bernad Dr. James Cali Dr. Dieter H. Klaubert Dr. Poncho Meisenheimer 《Chembiochem : a European journal of chemical biology》2014,15(5):670-675
Highly sensitive self‐cleavable trimethyl lock quinone‐luciferin substrates for diaphorase were designed and synthesized to measure NAD(P)H in biological samples and monitor viable cells via NAD(P)H‐dependent cellular oxidoreductase enzymes and their NAD(P)H cofactors. 相似文献
20.
Enrico Sanjust Dina Cocco Nicoletta Curreli Antonio Rescigno Francesca Sollai Joe Victor Bannister 《应用聚合物科学杂志》2002,85(11):2471-2477
An NAD(P)H oxidase‐like activity was found in semisynthetic flavoadducts, prepared from an aldehyde derivative of riboflavin and commercial poly(vinylalcohol) (PVA), previously grafted with aminopropyl side chains. Both water‐soluble and water‐insoluble beaded preparations were obtained. The products showed a noticeable NAD(P)H oxidase‐like activity, converting the nucleotide substrate to its oxidized counterpart NAD(P)+ at the expense of molecular oxygen, the latter being reduced to hydrogen peroxide. In contrast to some “true” β‐NAD(P)H oxidases, the PVA adducts do not require the presence of additional flavin adenine dinucleotide (FAD) to work; some properties of the flavoadducts were studied that make these flavoadducts good candidates for technological applications. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 2471–2477, 2002 相似文献