Sample records for aaaf 4-nqo dmba-epoxide

  1. Evaluation of ovotoxicity induced by 7, 12-dimethylbenz[a]anthracene and its 3,4-diol metabolite utilizing a rat in vitro ovarian culture system

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Igawa, Yoshiyuki; BioPharma Center, Asubio Pharma Co., Ltd., Gunma; Keating, Aileen F.

    The polycyclic aromatic hydrocarbon 7, 12-dimethylbenz[a]anthracene, (DMBA), targets and destroys all follicle types in rat and mouse ovaries. DMBA requires bioactivation to DMBA-3,4-diol-1,2-epoxide for ovotoxicity via formation of the intermediate, DMBA-3,4-diol (catalyzed by microsomal epoxide hydrolase; mEH). mEH was shown to be involved in DMBA bioactivation for ovotoxicity induction in B6C3F{sub 1} mouse ovaries. The current study compared DMBA and DMBA-3,4-diol mediated ovotoxicity, and investigated mEH involvement in DMBA-3,4-diol bioactivation in Fischer 344 (F344) rat ovary. F344 postnatal day (PND) 4 rat ovaries were cultured in vehicle control or media containing 1) DMBA or DMBA-3,4-diol (12.5 nM - 1 {mu}M;more » 15 days); 2) DMBA (1 {mu}M; 6 h - 15 days); and 3) DMBA (1 {mu}M) or DMBA-3,4-diol (75 nM) {+-} the mEH activity inhibitor cyclohexene oxide (CHO; 2 mM; 4 days). Ovaries were histologically evaluated and mEH mRNA and protein were measured by reverse transcriptase PCR or Western blotting, respectively. Ovotoxicity following 15 days of culture occurred (P < 0.05) at lower concentrations of DMBA-3,4-diol (12.5 nM - primordial; 75 nM - primary) than DMBA (75 nM - primordial; 375 nM - primary). The temporal pattern of mEH expression following DMBA exposure showed mRNA up-regulation (P < 0.05) on day 2, with increased protein (P < 0.05) on day 4, the earliest time of observed follicle loss (P < 0.05). mEH inhibition prevented DMBA-induced, but not DMBA-3,4-diol-induced ovotoxicity. These results demonstrate a conserved response in mice and rats for ovarian mEH involvement in DMBA bioactivation to its ovotoxic, 3,4-diol-1,2-epoxide form.« less

  2. Ovarian expressed microsomal epoxide hydrolase: Role in detoxification of 4-vinylcyclohexene diepoxide and regulation by phosphatidylinositol-3 kinase signaling

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bhattacharya, Poulomi, E-mail: poulomib@iastate.edu; Sen, Nivedita, E-mail: nsen@email.arizona.edu; Hoyer, Patricia B., E-mail: Hoyer@u.arizona.edu

    2012-01-01

    4-vinylcyclohexene diepoxide (VCD) is a metabolite of 4-vinylcyclohexene (VCH) which has the potential to be formed in the ovary through CYP2E1 activity. VCD specifically destroys primordial and small primary follicles in the rodent ovary. Mouse ovaries exposed to VCD demonstrate increased mRNA and protein expression of microsomal epoxide hydrolase (mEH), and an inactive tetrol metabolite (4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane) can be formed in mouse ovarian follicles, potentially through detoxification action of mEH. In contrast, mEH can bioactivate another ovotoxic chemical, 7,12-dimethylbenz[a]anthracene (DMBA) to a more toxic compound, DMBA-3,4-diol-1,2-epoxide. Thus, the present study evaluated a functional role for mEH during detoxification of VCD. Additionally,more » because inhibition of the phosphatidyinositol-3 kinase (PI3K) signaling pathway in a previous study protected primordial follicles from VCD-induced destruction, but accelerated DMBA-induced ovotoxicity, a role for PI3K in ovarian mEH regulation was evaluated. Using a post-natal day (PND) 4 Fischer 344 rat whole ovary culture system inhibition of mEH using cyclohexene oxide during VCD exposure resulted in a greater (P < 0.05) loss of primordial and small primary follicles relative to VCD-treated ovaries. Also, relative to controls, meh mRNA was increased (P < 0.05) on day 4 of VCD (30 μM) exposure, followed by increased (P < 0.05) mEH protein after 6 days. Furthermore, inhibition of PI3K signaling increased mEH mRNA and protein expression. Thus, these results support a functional role for mEH in the rat ovary, and demonstrate the involvement of PI3K signaling in regulation of ovarian xenobiotic metabolism by mEH. -- Highlights: ► Ovarian mEH functions to metabolize VCD to a less toxic compound. ► mEH expression is increased in a temporal pattern in response to VCD exposure. ► PI3K signaling is involved in regulation of ovarian mEH expression.« less

  3. Estrogenic status modulates the effect of soy on hepatic responses to 7,12-dimethylbenz(a)anthracene (DMBA)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Singhal, Rohit; Badger, Thomas M.; Arkansas Children's Nutrition Center, Little Rock, AR-72202

    2009-01-01

    We examined the influence of estradiol (E2) status and soy protein isolate (SPI) intake on the hepatic responses altered by 7,12-dimethylbenz(a)anthracene (DMBA, a polycyclic aromatic hydrocarbon [PAH]). Sprague-Dawley rats were ovariectomized (OVX) at PND50 and infused with E2 or vehicle for 14 d and gavaged with 50 mg/kg DMBA or vehicle 24 h before sacrifice at PND64. Rats were fed an AIN-93G diet made with SPI or casein as sole protein source throughout the study. Basal AhR protein levels were reduced (P < 0.05) by SPI feeding irrespective of the E2 status. However, DMBA increased (P < 0.05) AhR-induced CYP1A1more » gene expression in OVX, SPI-fed rats, but reduced (P < 0.05) CYP1A1 in OVX + E2, SPI-fed rats. Chromatin-immunoprecipitation demonstrated lower (P < 0.05) DMBA-mediated recruitment of estrogen receptor alpha to the CYP1A1 promoter by SPI feeding in the presence of E2, suggesting an estrogen-like action of SPI on DMBA-mediated signaling in the absence of E2. Further, microarray analysis (Rat 230-2.0 Affymetrix-GeneChip{sup TM}) revealed 231 genes common to SPI + DMBA and SPI + E2 + DMBA (normalized to E2) treatments. AhR-activated genes (CYP1A1, CYP1A2, and NQO1) were down-regulated by SPI + E2 + DMBA compared to SPI + DMBA. Unique interactions among SPI, DMBA and E2 altered the expression profile of 316 genes, not observed by either treatment alone. Our data suggest that although E2 status does not effect soy-mediated AhR degradation, it modulates the effects of soy on many genes, including CYP1A1.« less

  4. IL-13 but not IL-4 signaling via IL-4Rα protects mice from papilloma formation during DMBA/TPA two-step skin carcinogenesis

    PubMed Central

    Rothe, Michael; Quarcoo, David; Chashchina, Anna A; Bozrova, Svetlana V; Qin, Zhihai; Nedospasov, Sergei A; Blankenstein, Thomas; Kammertoens, Thomas; Drutskaya, Marina S

    2013-01-01

    Interleukin 4 (IL-4) was shown to be tumor-promoting in full carcinogenesis studies using 3-methylcholanthrene (MCA). Because heretofore the role of IL-4 in DMBA/TPA (9,10-dimethyl-1,2-benz-anthracene/12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis was not studied, we performed such experiments using either IL-4−/− or IL-4Rα−/− mice. We found that IL-4Rα−/− but not IL-4−/− mice have enhanced papilloma formation, suggesting that IL-13 may be involved. Indeed, IL-13−/− mice developed more papillomas after exposure to DMBA/TPA than their heterozygous IL-13-competent littermate controls. However, when tested in a full carcinogenesis experiment, exposure of mice to 25 μg of MCA, both IL-13−/− and IL-13+/− mice led to the same incidence of tumors. While IL-4 enhances MCA carcinogenesis, it does not play a measurable role in our DMBA/TPA carcinogenesis experiments. Conversely, IL-13 does not affect MCA carcinogenesis but protects mice from DMBA/TPA carcinogenesis. One possible explanation is that IL-4 and IL-13, although they share a common IL-4Rα chain, regulate signaling in target cells differently by employing distinct JAK/STAT-mediated signaling pathways downstream of IL-13 or IL-4 receptor complexes, resulting in different inflammatory transcriptional programs. Taken together, our results indicate that the course of DMBA/TPA- and MCA-induced carcinogenesis is affected differently by IL-4 versus IL-13-mediated inflammatory cascades. PMID:24403255

  5. Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans.

    PubMed

    Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

    2012-12-01

    The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. The following were assessed in a cohort of 260 African-Americans and 53 Hispanic-Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic-Americans compared with African-Americans. Multiple regression analysis in the Hispanic-American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African-Americans after adjusting for known genetic and clinical predictors. In our cohort of inner-city Hispanic-Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic-Americans.

  6. Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic–Americans and African–Americans

    PubMed Central

    Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

    2013-01-01

    Aim The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Results Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs. 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. Conclusion In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans. PMID:23215885

  7. Transcriptional Profiling of Saccharomyces cerevisiae Reveals the Impact of Variation of a Single Transcription Factor on Differential Gene Expression in 4NQO, Fermentable, and Nonfermentable Carbon Sources

    PubMed Central

    Rong-Mullins, Xiaoqing; Ayers, Michael C.; Summers, Mahmoud; Gallagher, Jennifer E. G.

    2017-01-01

    Cellular metabolism can change the potency of a chemical’s tumorigenicity. 4-nitroquinoline-1-oxide (4NQO) is a tumorigenic drug widely used on animal models for cancer research. Polymorphisms of the transcription factor Yrr1 confer different levels of resistance to 4NQO in Saccharomyces cerevisiae. To study how different Yrr1 alleles regulate gene expression leading to resistance, transcriptomes of three isogenic S. cerevisiae strains carrying different Yrr1 alleles were profiled via RNA sequencing (RNA-Seq) and chromatin immunoprecipitation coupled with sequencing (ChIP-Seq) in the presence and absence of 4NQO. In response to 4NQO, all alleles of Yrr1 drove the expression of SNQ2 (a multidrug transporter), which was highest in the presence of 4NQO resistance-conferring alleles, and overexpression of SNQ2 alone was sufficient to overcome 4NQO-sensitive growth. Using shape metrics to refine the ChIP-Seq peaks, Yrr1 strongly associated with three loci including SNQ2. In addition to a known Yrr1 target SNG1, Yrr1 also bound upstream of RPL35B; however, overexpression of these genes did not confer 4NQO resistance. RNA-Seq data also implicated nucleotide synthesis pathways including the de novo purine pathway, and the ribonuclease reductase pathways were downregulated in response to 4NQO. Conversion of a 4NQO-sensitive allele to a 4NQO-resistant allele by a single point mutation mimicked the 4NQO-resistant allele in phenotype, and while the 4NQO resistant allele increased the expression of the ADE genes in the de novo purine biosynthetic pathway, the mutant Yrr1 increased expression of ADE genes even in the absence of 4NQO. These same ADE genes were only increased in the wild-type alleles in the presence of 4NQO, indicating that the point mutation activated Yrr1 to upregulate a pathway normally only activated in response to stress. The various Yrr1 alleles also influenced growth on different carbon sources by altering the function of the mitochondria. Hence, the

  8. Geraniol attenuates 4NQO-induced tongue carcinogenesis through downregulating the activation of NF-κB in rats.

    PubMed

    Madankumar, Arumugam; Tamilarasi, Sasivarnam; Premkumar, Thandavamoorthy; Gopikrishnan, Mani; Nagabhishek, Natesh; Devaki, Thiruvengadam

    2017-10-01

    Geraniol, an acyclic monoterpene found in lemon grass and aromatic herb oil, has been shown to exert antitumor and antioxidant activities against various cancer types. The objective of this study was to investigate the potential chemoprotective role of geraniol against 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis in male Wistar rats and furthermore to study anti-inflammatory mechanisms of action through possible NF-κB signaling. 4NQO was administered to rats at the dose of 50 ppm through drinking water to induce tongue cancer in 20 weeks. 4NQO provoked inflammation by upregulating the expressions of the p65 subunit nuclear factor kappa-β (NF-κB) in the nucleus, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Additionally, staining for immature and mature mast cells in cancer niche by toluidine blue staining and alcian blue-safranin staining showed more accumulation. Co-treatment of geraniol 200 mg/kg b.w. showed a significant decrease in the level of p65 NF-κB in the nucleus, and this might be due to the inhibition of NF-κB activation/translocation into nucleus, which was further confirmed by decreased immature and mature mast cell density and the expression of inflammatory downstream mediators such as TNF-α, IL-1β, COX-2, and iNOS. Collectively, our results suggested that geraniol as a potential anti-inflammatory agent having the capability to obstruct 4NQO initiated NF-κB activation and modulated the expression of inflammatory mediators.

  9. Alphatic 3,4-epoxyalcohols. Metabolism by epoxide hydrase and mutagenic activity.

    PubMed

    Ortiz de Montellano, P R; Boparai, A S

    1978-12-18

    Rabbit hepatic microsomal epoxide hydrase catalyzes the rapid hydrolysis of 1,2-epoxy-4-heptanol to 1,2,4-heptanetriol. Both diastereomers of the substrate are hydrolyzed, and both product diastereomers are formed. Similarly both cis- and trans-3,4-epoxy-1-hexanol are hydrolyzed, albeit more slowly, to give 1,3,4-hexanetriol. The trans isomer gives exclusively one diastereomer (erythro) of the triol, while the cis isomer gives the other diastereomer (threo). The product expected if a primary cationic intermediate were to be formed and trapped intramolecularly during the hydrolysis of 1,2-epoxy-4-heptanol, 2-propyl-4-tetrahydrofuranol, was not observed. A comparison of the mutagenic activity in the Ames test of 1-heptane, 1-hepten-4-ol, 1,2-epoxyheptane, and 1,2-epoxy-4-heptanol revealed that only the latter is a detectable mutagen. A vicinal hydroxyl therefore does not interfere significantly with enzymatic epoxide hydrolysis, but it does enhance the bioalkylating potential of even an aliphatic epoxide.

  10. EMODIN DOWNREGULATES CELL PROLIFERATION MARKERS DURING DMBA INDUCED ORAL CARCINOGENESIS IN GOLDEN SYRIAN HAMSTERS.

    PubMed

    Manimaran, Asokan; Buddhan, Rajamanickam; Manoharan, Shanmugam

    2017-01-01

    Cell-cycle disruption is the major characteristic features of neoplastic transformation and the status of cell-cycle regulators can thus be utilized to assess the prognostic significance in patients with cancer. The PCNA, cyclin D1, CDK4, CDK6 and survivin expression in the buccal mucosa was utilized to evaluate the Emodin efficacy on abnormal cell proliferation during 7,12-dimethylbenz(a)anthracene (DMBA) induced oral carcinogenesis in golden Syrian hamsters. Topical application of DMBA, three times a week for 14 weeks, on the hamsters' buccal pouches developed well differentiated squamous cell carcinoma. Cyclin D1 and PCNA over-expression and up-regulation of CDK4, CDK6 and survivin were noticed in the buccal mucosa of hamsters treated with DMBA alone. Emodin administration (50mg/kg b.w) orally to hamsters treated with DMBA down-regulated the expression of cell proliferation markers in the buccal mucosa. The anti-cell proliferative role of Emodin is owing to its modulating efficacy on cell-cycle markers towards the tumor suppression during DMBA induced oral carcinogenesis.

  11. Zyflamend reduces LTB4 formation and prevents oral carcinogenesis in a 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced hamster cheek pouch model.

    PubMed

    Yang, Peiying; Sun, Zheng; Chan, Diana; Cartwright, Carrie A; Vijjeswarapu, Mary; Ding, Jibin; Chen, Xiaoxin; Newman, Robert A

    2008-11-01

    Aberrant arachidonic acid metabolism, especially altered cyclooxygenase and 5-lipoxygenase (LOX) activities, has been associated with chronic inflammation as well as carcinogenesis in human oral cavity tissues. Here, we examined the effect of Zyflamend, a product containing 10 concentrated herbal extracts, on development of 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced inflammation and oral squamous cell carcinoma (SCC). A hamster cheek pouch model was used in which 0.5% DMBA was applied topically onto the left cheek pouch of male Syrian golden hamsters either three times per week for 3 weeks (short term) or 6 weeks (long term). Zyflamend was then applied topically at one of three different doses (25, 50 and 100 microl) onto the left cheek pouch three times for 1 week (short-term study) or chronically for 18 weeks. Zyflamend significantly reduced infiltration of inflammatory cells, incidence of hyperplasia and dysplastic lesions, bromodeoxyuridine-labeling index as well as number of SCC in a concentration-dependent manner. Application of Zyflamend (100 microl) reduced formation of leukotriene B(4) (LTB(4)) by 50% compared with DMBA-treated tissues. The reduction of LTB(4) was concentration dependent. The effect of Zyflamend on inhibition of LTB(4) formation was further confirmed with in vitro cell-based assay. Adding LTB(4) to RBL-1 cells, a rat leukemia cell line expressing high levels of 5-LOX and LTA(4) hydrolase, partially blocked antiproliferative effect of Zyflamend. This study demonstrates that Zyflamend inhibited LTB(4) formation and modulated adverse histopathological changes in the DMBA-induced hamster cheek pouch model. The study suggests that Zyflamend might prevent oral carcinogenesis at the post-initiation stage.

  12. Stereoselective Epoxidation of 4-Deoxypentenosides: A Polarized-πModel

    PubMed Central

    Cheng, Gang; Boulineau, Fabien P.; Liew, Siong-Tern; Shi, Qicun; Wenthold, Paul G.; Wei, Alexander

    2008-01-01

    The high facioselectivity in the epoxidation of 4-deoxypentenosides (4-DPs) by dimethyldioxirane (DMDO) correlates with a stereoelectronic bias in the 4-DPs’ ground-state conformations, as elucidated by polarized-π frontier molecular orbital (PPFMO) analysis. PMID:16986946

  13. NTP Studies of Magnetic Field Promotion (DMBA Initiation) in Female Sprague-Dawley Rats (Whole-body Exposure/Gavage Studies).

    PubMed

    1999-08-01

    Electric and magnetic fields are associated with the production, transmission, and use of electricity; thus, the potential for human exposure is high. These elec-tric and magnetic fields are predominantly of low fre-quency (60 Hz in the United States and 50 Hz in Europe) and generally of low intensity. Because some epidemiology studies and initiation/promotion studies in rats have suggested a potential for increased breast cancer rates with increasing magnetic field exposure, the ability of 50- and 60-Hz magnetic fields to pro-mote mammary gland tumors initiated by the administration of 7,12-dimethylbenz(a)anthracene (DMBA) was examined in female Sprague-Dawley rats in 13- and 26-week whole-body exposure studies. Additional animals were evaluated for changes in pineal gland and serum melatonin concentrations. FIRST 13-WEEK STUDY: Groups of 100 female Sprague-Dawley rats were ad-ministered 20 mg DMBA (four weekly gavage doses of 5 mg in sesame oil) and exposed to 1 G 50-Hz, 5 G 50-Hz, or 1 G 60-Hz magnetic fields for 18.5 hours per day, 7 days per week, for 13 weeks. A group of 100 rats administered 20 mg DMBA served as DMBA controls. A group of 100 vehicle control rats was administered only sesame oil on the same schedule. Additional groups of 10 rats receiving similar treatment were evaluated for pineal gland and serum melatonin concentrations at 4, 8, or 12 weeks. All vehicle control rats survived to the end of the study. Of the animals administered 20 mg DMBA, 6 rats in the DMBA control group, 13 in the DMBA/1 G 50-Hz group, eight in the DMBA/5 G 50-Hz group, and five in the DMBA/1 G 60-Hz group died or were removed from the study prior to the final necropsy. Final mean body weights and body weight gains of the DMBA/1 G 50-Hz and DMBA/1 G 60-Hz groups and the mean body weight gain of the DMBA/5 G 50-Hz group were slightly greater than those of the DMBA control group. Clinical findings including torso masses and ulcers (on the mammary masses) were attributed to

  14. Pro-Oxidant Role of Silibinin in DMBA/TPA Induced Skin Cancer: 1H NMR Metabolomic and Biochemical Study.

    PubMed

    Sati, Jasmine; Mohanty, Biraja Prasad; Garg, Mohan Lal; Koul, Ashwani

    2016-01-01

    Silibinin, a major bioactive flavonolignan in Silybum marianum, has received considerable attention in view of its anticarcinogenic activity. The present study examines its anticancer potential against 7, 12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin cancer. Male LACA mice were randomly segregated into 4 groups: Control, DMBA/TPA, Silibinin and Silibinin+DMBA/TPA. Tumors in DMBA/TPA and Silibinin+DMBA/TPA groups were histologically graded as squamous cell carcinoma. In the Silibinin+DMBA/TPA group, significant reduction in tumor incidence (23%), tumor volume (64.4%), and tumor burden (84.8%) was observed when compared to the DMBA/TPA group. The underlying protective mechanism of Silibinin action was studied at pre-initiation (2 weeks), post-initiation (10 weeks) and promotion (22 weeks) stages of the skin carcinogenesis. The antioxidant nature of Silibinin was evident at the end of 2 weeks of its treatment. However, towards the end of 10 and 22 weeks, elevated lipid peroxidation (LPO) levels indicate the pro-oxidative nature of Silibinin in the cancerous tissue. TUNEL assay revealed enhanced apoptosis in the Silibinin+DMBA/TPA group with respect to the DMBA/TPA group. Therefore, it may be suggested that raised LPO could be responsible for triggering apoptosis in the Silibinin+DMBA/TPA group. 1H Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the metabolic profile of the skin /skin tumors. Dimethylamine (DMA), glycerophosphocholine (GPC), glucose, lactic acid, taurine and guanine were identified as the major contributors for separation between the groups from the Principal Component Analysis (PCA) of the metabolite data. Enhanced DMA levels with no alteration in GPC, glucose and lactate levels reflect altered choline metabolism with no marked Warburg effect in skin tumors. However, elevated guanine levels with potent suppression of taurine and glucose levels in the Silibinin+DMBA/TPA group are

  15. Pro-Oxidant Role of Silibinin in DMBA/TPA Induced Skin Cancer: 1H NMR Metabolomic and Biochemical Study

    PubMed Central

    Sati, Jasmine; Mohanty, Biraja Prasad; Garg, Mohan Lal; Koul, Ashwani

    2016-01-01

    Silibinin, a major bioactive flavonolignan in Silybum marianum, has received considerable attention in view of its anticarcinogenic activity. The present study examines its anticancer potential against 7, 12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin cancer. Male LACA mice were randomly segregated into 4 groups: Control, DMBA/TPA, Silibinin and Silibinin+DMBA/TPA. Tumors in DMBA/TPA and Silibinin+DMBA/TPA groups were histologically graded as squamous cell carcinoma. In the Silibinin+DMBA/TPA group, significant reduction in tumor incidence (23%), tumor volume (64.4%), and tumor burden (84.8%) was observed when compared to the DMBA/TPA group. The underlying protective mechanism of Silibinin action was studied at pre-initiation (2 weeks), post-initiation (10 weeks) and promotion (22 weeks) stages of the skin carcinogenesis. The antioxidant nature of Silibinin was evident at the end of 2 weeks of its treatment. However, towards the end of 10 and 22 weeks, elevated lipid peroxidation (LPO) levels indicate the pro-oxidative nature of Silibinin in the cancerous tissue. TUNEL assay revealed enhanced apoptosis in the Silibinin+DMBA/TPA group with respect to the DMBA/TPA group. Therefore, it may be suggested that raised LPO could be responsible for triggering apoptosis in the Silibinin+DMBA/TPA group. 1H Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the metabolic profile of the skin /skin tumors. Dimethylamine (DMA), glycerophosphocholine (GPC), glucose, lactic acid, taurine and guanine were identified as the major contributors for separation between the groups from the Principal Component Analysis (PCA) of the metabolite data. Enhanced DMA levels with no alteration in GPC, glucose and lactate levels reflect altered choline metabolism with no marked Warburg effect in skin tumors. However, elevated guanine levels with potent suppression of taurine and glucose levels in the Silibinin+DMBA/TPA group are

  16. NQO2 Is a Reactive Oxygen Species Generating Off-Target for Acetaminophen

    PubMed Central

    2014-01-01

    The analgesic and antipyretic compound acetaminophen (paracetamol) is one of the most used drugs worldwide. Acetaminophen overdose is also the most common cause for acute liver toxicity. Here we show that acetaminophen and many structurally related compounds bind quinone reductase 2 (NQO2) in vitro and in live cells, establishing NQO2 as a novel off-target. NQO2 modulates the levels of acetaminophen derived reactive oxygen species, more specifically superoxide anions, in cultured cells. In humans, NQO2 is highly expressed in liver and kidney, the main sites of acetaminophen toxicity. We suggest that NQO2 mediated superoxide production may function as a novel mechanism augmenting acetaminophen toxicity. PMID:25313982

  17. Heterogeneous epoxide carbonylation by cooperative ion-pair catalysis in Co(CO) 4 –-incorporated Cr-MIL-101

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Park, Hoyoung D.; Dinca, Mircea; Roman-Leshkov, Yuriy

    Here, despite the commercial desirability of epoxide carbonylation to β-lactones, the reliance of this process on homogeneous catalysts makes its industrial application challenging. Here we report the preparation and use of a Co(CO) 4 –-incorporated Cr-MIL-101 (Co(CO) 4cCr-MIL-101, Cr-MIL-101 = Cr 3O(BDC) 3F, H2BDC = 1,4-benzenedicarboxylic acid) heterogeneous catalyst for the ring-expansion carbonylation of epoxides, whose activity, selectivity, and substrate scope are on par with those of the reported homogeneous catalysts. We ascribe the observed performance to the unique cooperativity between the postsynthetically introduced Co(CO) 4 – and the site-isolated Lewis acidic Cr(III) centers in the metal–organic framework (MOF). Themore » heterogeneous nature of Co(CO) 4cCr-MIL-101 allows the first demonstration of gas-phase continuous-flow production of β-lactones from epoxides, attesting to the potential applicability of the heterogeneous epoxide carbonylation strategy.« less

  18. Heterogeneous epoxide carbonylation by cooperative ion-pair catalysis in Co(CO) 4 –-incorporated Cr-MIL-101

    DOE PAGES

    Park, Hoyoung D.; Dinca, Mircea; Roman-Leshkov, Yuriy

    2017-03-21

    Here, despite the commercial desirability of epoxide carbonylation to β-lactones, the reliance of this process on homogeneous catalysts makes its industrial application challenging. Here we report the preparation and use of a Co(CO) 4 –-incorporated Cr-MIL-101 (Co(CO) 4cCr-MIL-101, Cr-MIL-101 = Cr 3O(BDC) 3F, H2BDC = 1,4-benzenedicarboxylic acid) heterogeneous catalyst for the ring-expansion carbonylation of epoxides, whose activity, selectivity, and substrate scope are on par with those of the reported homogeneous catalysts. We ascribe the observed performance to the unique cooperativity between the postsynthetically introduced Co(CO) 4 – and the site-isolated Lewis acidic Cr(III) centers in the metal–organic framework (MOF). Themore » heterogeneous nature of Co(CO) 4cCr-MIL-101 allows the first demonstration of gas-phase continuous-flow production of β-lactones from epoxides, attesting to the potential applicability of the heterogeneous epoxide carbonylation strategy.« less

  19. Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation.

    PubMed

    Di Francesco, Andrea; Di Germanio, Clara; Panda, Amaresh C; Huynh, Phu; Peaden, Robert; Navas-Enamorado, Ignacio; Bastian, Paul; Lehrmann, Elin; Diaz-Ruiz, Alberto; Ross, David; Siegel, David; Martindale, Jennifer L; Bernier, Michel; Gorospe, Myriam; Abdelmohsen, Kotb; de Cabo, Rafael

    2016-10-01

    NAD(P)H: quinone oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQO1 target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor α-1-antitrypsin, A1AT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. Biotin pulldown analysis indicated that NQO1 can bind the 3' untranslated region (UTR) and the coding region (CR) of SERPINA1 mRNA. NQO1 did not affect SERPINA1 mRNA levels; instead, it enhanced the translation of SERPINA1 mRNA, as NQO1 silencing decreased the size of polysomes forming on SERPINA1 mRNA and lowered the abundance of A1AT. Luciferase reporter analysis further indicated that NQO1 regulates SERPINA1 mRNA translation through the SERPINA1 3'UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of A1AT and increased activity of neutrophil elastase (NE), one of the main targets of A1AT. We propose that this novel mechanism of action of NQO1 as an RNA-binding protein may help to explain its pleiotropic biological effects. Published by Elsevier Inc.

  20. Inhibition of 4NQO-Induced Oral Carcinogenesis by Dietary Oyster Shell Calcium

    PubMed Central

    Chen, Ying; Jiang, Yi; Liao, Liyan; Zhu, Xiaoxin; Tang, Shengan; Yang, Qing; Sun, Lihua; Li, Yujie; Gao, Shuangrong; Xie, Zhongjian

    2015-01-01

    Oyster has gained much attention recently for its anticancer activity but it is unclear whether calcium, the major antitumor ingredient in oyster shell, is responsible for the anticarcinogenic role of the oyster. To address this issue, C57BL/6 mice were fed with the carcinogen 4-nitroquinoline-1-oxide (4NQO, 50 µg/mL) and normal diet or a diet containing oyster powder, oyster calcium, or calcium depleted oyster powder. The tongue tissue specimens isolated from these mice were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for proliferation and differentiation markers by immunohistochemistry. The results showed that mice on the diet containing oyster calcium significantly reduced rates of tumors in the tongue and proliferation and enhanced differentiation in the oral epithelium compared with the diet containing calcium depleted oyster powder. These results suggest that calcium in oyster plays a critical role in suppressing formation of oral squamous cell carcinoma and proliferation and promoting differentiation of the oral epithelium. PMID:26293805

  1. Comparative DNA binding of 7,12-dimethylbenz[a]anthracene and some of its metabolites in mouse epidermis in vivo as revealed by the 32P-postlabeling technique.

    PubMed

    Schoepe, K B; Friesel, H; Schurdak, M E; Randerath, K; Hecker, E

    1986-04-01

    The binding of some mouse skin metabolites and related derivatives of the tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) was investigated by 32P-postlabeling analysis after its topical administration. DMBA and trans-3,4-dihydro-3,4-dihydroxy-DMBA (DMBA-3,4-dihydrodiol) both led to the formation of four DNA adducts, which showed a very similar pattern of spots on thin-layer chromatograms. With trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthracene (DMBA-8,9-dihydrodiol) one major adduct was obtained which was chromatographically indistinguishable from one of the DMBA adducts. In contrast, 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA) gave rise to two major adducts which were separable from DMBA adducts. 3-hydroxy-7,12-dimethylbenz[a]anthracene (3-OH-DMBA) and 7,12-dimethylbenz[a]anthracene-7,12-epoxide (DMBA-O2) did not lead to detectable amounts of adducts. Quantitative determination of DNA binding showed that an initiating dose (i = 100 nmol) of DMBA yielded approximately 12 adducts/10(7) normal nucleotides. Adduct formation with the same dose of DMBA-3,4-dihydrodiol was 7-8 times higher. At a 4-fold higher dose level, DMBA-8,9-dihydrodiol exhibited a 3- to 6-times weaker binding and 7-OHM-12-MBA a slightly stronger binding than DMBA. Chromatography of the DMBA and DMBA-3,4-dihydrodiol adducts with a solvent containing borate showed a decreased mobility of two out of four adducts in each case. These adducts were also sensitive to oxidation by periodate. The results suggest that two DMBA adducts carried vicinal cis-hydroxyl groups and thus were probably derived from the anti-3,4-dihydrodiol-1,2-oxide(s) of DMBA. The other two adducts were probably derived from the syn-stereoisomer(s). When the DNA-modifying capabilities and initiating activities of the more prominent mouse-skin metabolites are considered in relation to DMBA, DMBA-3,4-dihydrodiol is postulated to be a proximate and DMBA-3,4-dihydrodiol-1,2-oxide(s) to be ultimate

  2. The rabbit liver microsomal biotransformation of 1,1-dialkylethylenes: enantioface selection of epoxidation and enantioselectivity of epoxide hydrolysis.

    PubMed

    Bellucci, G; Chiappe, C; Cordoni, A; Marioni, F

    1994-01-01

    The rabbit liver microsomal biotransformation of alpha-methylstyrene (1a), 2-methyl-1-hexene (1b), 2,4,4-trimethyl-1-pentene (1c), and 1,3,3-trimethyl-1-butene (1d) has been investigated with the aim at establishing the enantioface selection of the cytochrome P-450-promoted epoxidation of the double bond and the enantioselectivity of microsomal epoxide hydrolase(mEH)-catalyzed hydrolysis of the resulting epoxides. GLC on a Chiraldex G-TA (ASTEC) column was used to determine the enantiomeric composition of the products. The epoxides 2 first produced in incubations carried out in the presence of an NADPH regenerating system were not detected, being rapidly hydrolyzed by mEH to diols 3. The enantiomeric composition of the latter showed that no enantioface selection occurred in the epoxidation of 1c and 1d, and a very low (8%) ee of the (R)-epoxide was formed from 1b. Incubation of racemic epoxides 2b-d with the microsomal fraction showed that the mEH-catalyzed hydrolysis of 2c and 2d was practically nonenantioselective, while that of 2b exhibited a selectivity E = 4.9 favoring the hydrolysis of the (S)-enantiomer. A comparison of these results with those previously obtained for linear and branched chain alkyl monosubstituted oxiranes shows that the introduction of the second alkyl substituent suppresses the selectivity of the mEH reaction of the latter and reverses that of the former substrates.

  3. Nrf2-Dependent Induction of NQO1 in Mouse Aortic Endothelial Cells Overexpressing Catalase

    PubMed Central

    Lin, Xinghua; Yang, Hong; Zhou, LiChun; Guo, ZhongMao

    2011-01-01

    Overexpression of catalase has been shown to accelerate benzo(a)pyrene (BaP) detoxification in mouse aortic endothelial cells (MAECs ). NAD(P)H:quinone oxidoreductase1 (NQO1) is an enzyme that catalyzes BaP-quinone detoxification. Aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor-2 (Nrf2) are transcription factors that control NQO1 expression. Here, we investigated the effect of catalase overexpression on NQO1, Nrf2 and AhR expressions. The levels of NQO1 mRNA and protein were comparable in MAECs isolated from wild-type and transgenic mice that overexpress human catalase (hCatTg). BaP treatment increased NQO1 mRNA and protein levels in both groups, with a significantly greater induction in hCatTg MAECs than in wild-type cells. BaP-induced NQO1 promoter activity was dramatically higher in hCatTg MAECs than in wild-type cells. Our data also showed that the basal level of AhR and the BaP-induced level of Nrf2 were significantly higher in hCatTg MAECs than in wild-type cells. Inhibition of specificity protein-1 (Sp1) binding to the AhR promoter region by mithramycin A reversed the enhanced effect of catalase overexpression on AhR expression. Knockdown of AhR by RNA interference diminished BaP-induced expression of Nrf2 and NQO1. Knockdown of Nrf2 significantly decreased NQO1 mRNA and protein levels in cells with or without BaP treatment. NQO1 promoter activity was abrogated by mutation of the Nrf2-binding site in this promoter. In contrast, mutation of the AhR-binding site in NQO1 promoter did not affect the promoter activity. These results suggest that catalase overexpression upregulates BaP-induced NQO1 expression via enhancing the Sp1-AhR-Nrf2 signaling cascade. PMID:21569840

  4. Folic Acid Modulates DMBA/TPA-Induced Changes in Skin of Mice: A Study Relevant to Carcinogenesis.

    PubMed

    Koul, Ashwani; Kaur, Navneet; Chugh, Neha Arora

    2018-01-02

    The present study was aimed at investigating the modulatory effects of folic acid (FA) on early stages of chemically induced skin cancer. For this, a two-stage model of skin tumorigenesis was employed. 7,12-Dimethylbenz(a)anthracene (DMBA, 500 nmol/100 ul of acetone) was applied topically for two weeks (twice weekly), followed by phorbol-12-myristate-13-acetate (TPA, 1.7 nmol/100 ul) twice weekly for six weeks on the depilated skin of mice, and FA was administered orally at a dose of 40 microgram/animal for 10 weeks daily. Balb/c mice were divided into four groups depending upon the treatment they received (control, DMBA/TPA, FA, and FA+DMBA/TPA). DMBA/TPA treatment led to the formation of papillomas in DMBA/TPA and FA+DMBA/TPA groups. Ornithine decarboxylase (ODC), proliferating cell nuclear antigen (PCNA), epidermal thickness, and cell count were evaluated to assess the beneficial effects in the early stages. FA exhibited its ameliorative potential as indicated by decreased epidermal thickness and cell count in FA+DMBA/TPA group when compared to DMBA/TPA group. Concomitantly, FA decreased the expression of ODC and PCNA in skin and activity of serum lactate dehydrogenase, suggesting inhibitory effects on cell proliferation and cell damage. Differential modulation in lipid peroxidation and reduced glutathione was observed in response to DMBA/TPA treatment and its intervention with FA. Although these findings suggest the inhibitory potential of FA during initial stages of murine skin cancer, detailed studies are warranted considering the ambiguous reports available in literature regarding the association of FA and cancer.

  5. Anti-tumor activity of Aloe vera against DMBA/croton oil-induced skin papillomagenesis in Swiss albino mice.

    PubMed

    Saini, M; Goyal, Pradeep Kumar; Chaudhary, Geeta

    2010-01-01

    Human populations are increasingly exposed to various carcinogens such as chemicals, radiation, and viruses in the environment. Chemopreventive drugs of plant origin are a promising strategy for cancer control because they are generally nontoxic or less toxic than synthetic che-mopreventive agents, and can be effective at different stages of carcinogenesis. The present investigation was undertaken to explore the antitumor activity of topical treatment with aloe vera (Aloe vera) gel, oral treatment with aloe vera extract, and topical and oral treatment with both gel and extract in stage-2 skin carcinogenesis in Swiss albino mice induced by 7,12-dim ethylbenz(a)anthracene (DMBA) and promoted croton (Croton tiglium) oil. The animals were randomly divided into 4 groups and treated as follows: Group I, DMBA + croton oil only (controls); Group II, DMBA + croton oil + topical aloe vera gel; Group III, DMBA + croton oil + oral aloe vera extract; Group I V, DMBA + croton oil + topical aloe vera gel + oral aloe vera extract. Results showed that body weight was significantly increased from 78.6% in the control group (Group I) to 92.5%, 87.5%, and 90.0% in Groups II, III, and I V, respectively. A 100% incidence of tumor development was noted in Group I, which was decreased to 50%, 60%, and 40% in Groups II, III, and I V, respectively. Also in Groups II, III, and IV, the cumulative number of papillomas was reduced significantly from 36 to 12, 15, and 11; tumor yield from 3.6 to 1.2, 1.5, and 1.1; and tumor burden from 3.6 to 2.4, 2.50, and 2.75, respectively, after treatment with aloe vera. Conversely, the average latent period increased significantly from 4.9 (Group I) to 5.23, 5.0, and 6.01 weeks in Groups II, III, and I V, respectively. We conclude that aloe vera protects mice against DMBA/croton oil-induced skin papillomagenesis, likely due to the chemopreventive activity of high concentrations of antioxidants such as vitamins A, C, and E; glutathione peroxidase; several

  6. NQO1 gene rs1800566 variant is not associated with risk for multiple sclerosis

    PubMed Central

    2014-01-01

    Background A possible role of oxidative stress in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis has been suggested. The detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1) has been found up-regulated in MS lesions. A previous report described an association between the SNP rs1800566 in the NQO1 gene and the risk for MS in the Greek population. The aim of this study was to replicate a possible influence of the. SNP rs1800566 in the NQO1 gene in the risk for MS in the Spanish Caucasian population. Methods We analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays. Results NQO1 rs1800566 allelic and genotypic frequencies did not differ significantly between MS patients and controls, and were unrelated with age of onset of MS, gender, and clinical type of MS. Conclusions Our results indicate that NQO1 rs1800566 does not have an effect on MS disease risk. PMID:24755231

  7. Sunitinib Improves Some Clinical Aspects and Reverts DMBA-Induced Hyperplasic Lesions in Hamster Buccal Pouch

    PubMed Central

    de Souza, Fernanda Lopes; Oliveira, Mariana; Nunes, Marianne Brochado; Serafim, Lucas Horstmann; Azambuja, Alan Arrieira; Braga, Luisa Maria G. de M.; Saur, Lisiani; de Souza, Maria Antonieta Lopes; Xavier, Léder Leal

    2014-01-01

    Oral squamous cell carcinoma (OSCC) is a public health problem. The hamster buccal pouch model is ideal for analyzing the development of OSCC. This research analysed the effects of sunitinib (tyrosine kinase inhibitor) in precancerous lesions induced by 7,12-dimethylbenz(a)anthracene (DMBA) in this model. Thirty-four male hamsters, divided into six groups: control—C (n = 7), acetone—A (n = 12), carbamide peroxide—CP (n = 5 ), acetone and CP—A+CP (n = 8), 1% DMBA in acetone and CP—DA+CP (n = 6), and 1% DMBA in acetone and CP and 4-week treatment with sunitinib—DA+CP+S (n = 7). The aspects evaluated were anatomopathological features (peribuccal area, paws, nose, and fur), histological sections of the hamster buccal pouches (qualitatively analyzed), epithelium thickness, and the rete ridge density (estimated). Sunitinib was unable to attenuate the decrease in weight gain induced by DMBA; no increase in volume was detected in the pouch and/or ulceration, observed in 43% of the animals in the DA+CP group. DA+CP groups presented a significant increase in rete ridge density compared to the control groups (P < 0.01) which was reverted by sunitinib in the DA+CP+S group. Sunitinib seems to have important benefits in early stage carcinogenesis and may be useful in chemoprevention. PMID:24693453

  8. Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Maayah, Zaid H.; Ghebeh, Hazem; Alhaider, Abdulqader A.

    2015-04-15

    Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted usingmore » 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand

  9. Protective Effect of Piper aduncum Capsule on DMBA-induced Breast Cancer in Rats

    PubMed Central

    Arroyo-Acevedo, J; Chávez-Asmat, RJ; Anampa-Guzmán, A; Donaires, R; Ráez-Gonzáles, José

    2015-01-01

    The possible protective effect of Piper aduncum capsule on DMBA (dimethylbenz[α]anthracene)-induced breast cancer in rats was assessed by monitoring the tumor and lung metastases incidence and recording hematological and biochemical parameters and frequency of micronuclei. Mammary carcinogenesis was induced in 36 female Holtzman rats by providing a single subcutaneous injection of DMBA. Oral administration of P. aduncum capsule lowered adenocarcinoma and lymph node metastases incidence. Pulmonary metastasis was significantly lowered (P < 0.05). Hematological indicators showed that the triglyceride level was significantly lowered (P < 0.01) and high-density lipoprotein (HDL) level was significantly increased (P < 0.01). Also, P. aduncum capsule significantly lowered the C reactive protein (CRP) level (P < 0.01) and malondialdehyde level (P < 0.05). There was a significant decrease in the frequency of DMBA-induced micronucleated polychromatic erythrocyte (P < 0.01). Considering the antitumorigenic, hypolipidemic, anti-inflammatory, antioxidant, and antigenotoxic properties of P. aduncum capsule, we conclude that it has a protective effect on DMBA-induced breast cancer in rats. PMID:26157333

  10. Protective Effect of Piper aduncum Capsule on DMBA-induced Breast Cancer in Rats.

    PubMed

    Arroyo-Acevedo, J; Chávez-Asmat, R J; Anampa-Guzmán, A; Donaires, R; Ráez-Gonzáles, José

    2015-01-01

    The possible protective effect of Piper aduncum capsule on DMBA (dimethylbenz[α]anthracene)-induced breast cancer in rats was assessed by monitoring the tumor and lung metastases incidence and recording hematological and biochemical parameters and frequency of micronuclei. Mammary carcinogenesis was induced in 36 female Holtzman rats by providing a single subcutaneous injection of DMBA. Oral administration of P. aduncum capsule lowered adenocarcinoma and lymph node metastases incidence. Pulmonary metastasis was significantly lowered (P < 0.05). Hematological indicators showed that the triglyceride level was significantly lowered (P < 0.01) and high-density lipoprotein (HDL) level was significantly increased (P < 0.01). Also, P. aduncum capsule significantly lowered the C reactive protein (CRP) level (P < 0.01) and malondialdehyde level (P < 0.05). There was a significant decrease in the frequency of DMBA-induced micronucleated polychromatic erythrocyte (P < 0.01). Considering the antitumorigenic, hypolipidemic, anti-inflammatory, antioxidant, and antigenotoxic properties of P. aduncum capsule, we conclude that it has a protective effect on DMBA-induced breast cancer in rats.

  11. Effects of red mold dioscorea on oral carcinogenesis in DMBA-induced hamster animal model.

    PubMed

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Pan, Tzu-Ming

    2011-06-01

    Monascus-fermented products offer valuable therapeutic benefits and have been extensively used for centuries in East Asia. Dioscorea has been proved to have anti-cancer effect. The aim of this study is to investigate the anti-tumor ability of the ethanol extract of red mold dioscorea (RMDE) on 7,12-dimethyl-1,2-benz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. We induced oral squamous cell carcinoma (OSCC) in the buccal pouch of male Syrian golden hamsters by painting with 0.5% DMBA three times a week for 14 weeks. From 9 to 14 weeks, a dose of 50, 100, and 200 mg RMDE per kg body weight were painting with the hamsters for 6 weeks on days alternate to the DMBA application. The results demonstrated that RMDE decreased nitric oxide (NO), reactive oxygen species (ROS), and prostaglandin E(2) (PGE(2)) overexpression in hamster buccal pouches in the DMBA treatment group and increased p53, serum tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) to significantly stimulate caspase-8 and -3 activities, indicating that RMDE reduced oxidative damage causing by DMBA and induced apoptosis in oral cancer cells. Therefore, RMDE may have therapeutic potentials against OSCC. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. The mechanism of epoxide carbonylation by [Lewis Acid]+[Co(CO)4]- catalysts.

    PubMed

    Church, Tamara L; Getzler, Yutan D Y L; Coates, Geoffrey W

    2006-08-09

    A detailed mechanistic investigation of epoxide carbonylation by the catalyst [(salph)Al(THF)2]+ [Co(CO)4]- (1, salph = N,N'-o-phenylenebis(3,5-di-tert-butylsalicylideneimine), THF = tetrahydrofuran) is reported. When the carbonylation of 1,2-epoxybutane (EB) to beta-valerolactone is performed in 1,2-dimethoxyethane solution, the reaction rate is independent of the epoxide concentration and the carbon monoxide pressure but first order in 1. The rate of lactone formation varies considerably in different solvents and depends primarily on the coordinating ability of the solvent. In mixtures of THF and cis/trans-2,5-dimethyltetrahydrofuran, the reaction is first order in THF. From spectroscopic and kinetic data, the catalyst resting state was assigned to be the neutral (beta-aluminoxy)acylcobalt species (salph)AlOCH(Et)CH2COCo(CO)4 (3a), which was successfully trapped with isocyanates. As the formation of 3a from EB, CO, and 1 is rapid, lactone ring closing is rate-determining. The favorable impact of donating solvents was attributed to the necessity of stabilizing the aluminum cation formed upon generation of the lactone.

  13. Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components

    PubMed Central

    Martínez-Hernández, Angélica; Córdova, Emilio J.; Rosillo-Salazar, Oscar; García-Ortíz, Humberto; Contreras-Cubas, Cecilia; Islas-Andrade, Sergio; Revilla-Monsalve, Cristina; Salas-Labadía, Consuelo; Orozco, Lorena

    2015-01-01

    Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals. PMID:25933176

  14. Association of HMOX1 and NQO1 Polymorphisms with Metabolic Syndrome Components.

    PubMed

    Martínez-Hernández, Angélica; Córdova, Emilio J; Rosillo-Salazar, Oscar; García-Ortíz, Humberto; Contreras-Cubas, Cecilia; Islas-Andrade, Sergio; Revilla-Monsalve, Cristina; Salas-Labadía, Consuelo; Orozco, Lorena

    2015-01-01

    Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals.

  15. Effect of epoxidation level on thermal properties and ionic conductivity of epoxidized natural rubber solid polymer nanocomposite electrolytes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Harun, Fatin; Chan, Chin Han; Winie, Tan

    Effect of epoxide content on the thermal and conductivity properties of epoxidized natural rubber (ENR) solid polymer nanocomposite electrolytes was investigated. Commercial available epoxidized natural rubber having 25 (ENR25) and 50 mole% (ENR50) epoxide, respectively were incorporated with lithium perchlorate (LiClO{sub 4}) salt and titanium dioxide (TiO{sub 2}) nanofiller via solution casting method. The solid polymer nanocomposite electrolytes were characterized by differential scanning calorimetry (DSC) and impedance spectroscopy (IS) for their thermal properties and conductivity, respectively. It was evident that introduction of LiClO{sub 4} causes a greater increase in glass transition temperature (T{sub g}) and ionic conductivity of ENR50 asmore » compared to ENR25. Upon addition of TiO{sub 2} in ENR/LiClO{sub 4} system, a remarkable T{sub g} elevation was observed for both ENRs where ENR50 reveals a more pronounced changes. It is interesting to note that they exhibit different phenomenon in ionic conductivity with TiO{sub 2} loading where ENR25 shows enhancement of conductivity while ENR50 shows declination.« less

  16. Oral carcinogenesis is not achieved in different carcinogen-treated PAI-1 transgenic and wild-type mouse models.

    PubMed

    Avgoustidis, Dimitris; Nisyrios, Themistoklis; Nkenke, Emeka; Lijnen, Roger; Ragos, Vassilis; Perrea, Despina; Donta, Ismini; Vaena, Apostolia; Yapijakis, Christos; Vairaktaris, Eleftherios

    2012-01-01

    In an effort to assess the role of plasminogen activator inhibitor-1 (PAI-1) in oral squamous cancer development and progression, two different carcinogen treatment protocols were conducted. Protocol I included mice from a PAI-1 transgenic (Tg) breed (n=56) and their wild-type (WT) counterparts (n=56), divided into one control group and two main experimental groups, treated with 7,12-dimethylbenz[a]anthracene (DMBA) for 8 and 16 weeks, respectively. Protocol II included the same number and types of animals and groups, which were similarly treated with 4-Nitroquinoline 1-oxide (4-NQO) in drinking water. Two drugs that affect plasma PAI-1 levels, enalapril and pravastatin, were administered to certain subgroups of animals in both protocols. None of the animals developed macroscopically-visible oral cancer lesions. Eleven animals under Protocol I and 52 animals under Protocol II died. Skin lesions were noted only in DMBA-treated animals (n=9). Almost all animals administered with 4-NQO developed alopecia and lost weight, while two of them developed stomach tumours, and one female mouse developed a large ovarian cyst. Transgenic mice may respond differently when used in well-established carcinogen models and oral carcinogenesis is hard to achieve in these rodents.

  17. Decreased adrenal medullary tyrosine hydroxylase mRNA in DMBA (7,12-dimethylbenz(a)anthracene)-induced mammary carcinoma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bunce, O.R.; Badary, O.A.; Abou El-Ela, S.

    1991-03-15

    Adrenal cortical hormones suppress initiation and promotion of DMBA-induced mammary tumorigenesis. The authors found a positive correlation between presence of DMBA-induced adrenal cortical necrosis and mammary tumor incidence. Because they find adrenal medullary as well as cortical lesions in tumor bearing (TB) DMBA-treated rats, they evaluated medullary function by quantitating hybridized cDNA- TH-S{sup 35} with in situ TH-mRNA u sing computer assisted quantitative autoradiographic technique. Virgin female Sprague-Dawley rats were given a 10 mg i.g. dose of DMBA. Three wks later, rats were placed on 20% polyunsaturated (PUFA) fat diets containing omega-6 and omega-3 fatty acids. All were killed 15more » wks post-DMBA. TH-mRNA levels in adrenal medullae of TB animals were decreased compared to non-TB rats. Histopathology indicated a high incidence of medullary necrosis in TB rats, whereas, adrenal necrosis did not occur in non-TB animals. Adrenal necrosis correlated positively with tumor burden, but no correlation was found between incidence of adrenal lesions and type of PUFA in the diet. The authors suggest that DMBA adrenal necrosis may reduce TH-mRNA in the medulla, compromise its catecholamine synthetic capability, and thereby contribute to the overall metabolic stress condition of TB rats.« less

  18. The NQO1 bioactivatable drug, β-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism.

    PubMed

    Silvers, Molly A; Deja, Stanislaw; Singh, Naveen; Egnatchik, Robert A; Sudderth, Jessica; Luo, Xiuquan; Beg, Muhammad S; Burgess, Shawn C; DeBerardinis, Ralph J; Boothman, David A; Merritt, Matthew E

    2017-11-03

    Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide and then peroxide formation, which damages DNA and causes hyperactivation of poly(ADP-ribose) polymerase, resulting in extensive NAD + /ATP depletion. However, the effects of this drug on energy metabolism due to NAD + depletion were never described. The futile redox cycle rapidly consumes O 2 , rendering standard assays of Krebs cycle turnover unusable. In this study, a multimodal analysis, including metabolic imaging using hyperpolarized pyruvate, points to reduced oxidative flux due to NAD + depletion after β-lapachone treatment of NQO1+ human pancreatic cancer cells. NAD + -sensitive pathways, such as glycolysis, flux through lactate dehydrogenase, and the citric acid cycle (as inferred by flux through pyruvate dehydrogenase), were down-regulated by β-lapachone treatment. Changes in flux through these pathways should generate biomarkers useful for in vivo dose responses of β-lapachone treatment in humans, avoiding toxic side effects. Targeting the enzymes in these pathways for therapeutic treatment may have the potential to synergize with β-lapachone treatment, creating unique NQO1-selective combinatorial therapies for specific cancers. These findings warrant future studies of intermediary metabolism in patients treated with β-lapachone. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Effect of 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium on expression of GSTP1 and NQO1 genes and protein transcription factors in BALB/c mouse liver.

    PubMed

    Shintyapina, A B; Safronova, O G; Vavilin, V A; Kandalintseva, N V; Prosenko, A E; Lyakhovich, V V

    2014-08-01

    The study examined dynamics of the effect of novel phenol antioxidant preparation 3-(3'-tertbutyl- 4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on expression of antioxidant protection enzymes genes GSTP1 and NQO1 and on the content of protein transcription factors NF-κB and ATF-2 in mouse liver. Expression of GSTP1 gene decreased significantly on days 4 and 7 after per os administration of TS-13 (100 mg/kg), but increased on post-administration day 14. On days 7 and 14 post-administration, expression of NQO1 gene was significantly increased. On day 7, the hepatic content of the phosphorylated form of ATF-2 and two subunits of nuclear factor NF-κB (p50, p65) decreased significantly.

  20. EMODIN EFFICACY ON THE AKT, MAPK, ERK AND DNMT EXPRESSION PATTERN DURING DMBA-INDUCED ORAL CARCINOMA IN GOLDEN SYRIAN HAMSTERS.

    PubMed

    Manimaran, Asokan; Manoharan, Shanmugam; Neelakandan, Mani

    2016-01-01

    The present study has evaluated the Emodin efficacy on the Akt, MAPK, ERK and DNMT expression pattern during 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinoma in golden Syrian hamsters, in order to explore its antitumor potential. Oral tumors were developed in the buccal pouches of golden Syrian hamsters using the carcinogen, DMBA. While the incidence of tumor formation was 100% in hamsters treated with DMBA alone, the tumor formation was not noticed in DMBA+ Emodin treated hamsters. Also, Emodin reduced the severity of precancerous pathological lesions such as dysplasia, in the hamsters treated with DMBA. Emodin administration corrected the abnormalities in the expression pattern of Akt, MAPK, ERK and DNMT in the buccal mucosa of hamsters treated with DMBA. The present study thus suggests that the tumor preventive potential of Emodin is partly related to its modulating effect on the Akt, MAPK, ERK and DNMT expression pattern, as these molecular markers have a pivotal role in the process of cell proliferation, inflammation, invasion, and apoptosis.

  1. Regio- and enantiofacial selectivity of epoxyeicosatrienoic acid hydration by cytosolic epoxide hydrolase.

    PubMed

    Zeldin, D C; Kobayashi, J; Falck, J R; Winder, B S; Hammock, B D; Snapper, J R; Capdevila, J H

    1993-03-25

    The hydration of cis-epoxyeicosatrienoic acids to the corresponding vic-dihydroxyeicosatrienoic acids by cytosolic epoxide hydrolase demonstrates moderate regioselectivity with rates of hydration highest for the 14,15-epoxide and lower for the 11,12- and 8,9-epoxide (4.5, 1.6, and 1.5 mumol of product/mg of protein/min, respectively). Incubations of the 8,9- and 14,15-epoxides with cytosolic epoxide hydrolase show stereoselective formation of diols (7:3 and 4:1 ratio of antipodes, respectively) and concomitant chiral enrichment of the remaining unmetabolized substrate. In contrast, hydration of the 11,12-epoxide is nonenantioselective. The Km value of the enzyme for the 14(R),15(S)-epoxide is 3 microM. Incubations of the enantiomerically pure 8,9- and 14,15-epoxides with lung or liver cytosol, followed by chiral analysis of the resulting diols demonstrate selective cleavage of the oxirane ring at C9 and C15, respectively. On the other hand, cleavage of the 11,12- oxirane ring was less selective. The stereochemical preference of the cytosolic epoxide hydrolase, together with the known chiral composition of the endogenous arachidonate epoxide pools, suggests a functional role for this enzyme in the metabolism of these important compounds.

  2. Protective and Curative Effects of the Sea Cucumber Holothuria atra Extract against DMBA-Induced Hepatorenal Diseases in Rats

    PubMed Central

    Dakrory, Ahmed I.; Fahmy, Sohair R.; Soliman, Amel M.; Mohamed, Ayman S.; Amer, Sayed A. M.

    2015-01-01

    Oxidative stress is a common mechanism contributing to the initiation and progression of hepatic damage. Hence there is a great demand for the development of agents with potent antioxidant effect. The aim of the present study is to evaluate the efficacy of Holothuria atra extract (HaE) as an antioxidant against 7,12-dimethylbenz[a]anthracene- (DMBA-) induced hepatorenal dysfunction. Experimental animals were divided into two main groups: protective and curative. Each group was then divided into five subgroups pre- or posttreated either with distilled water (DMBA subgroups) or with HaE (200 mg/kg body weight) for seven and fourteen days. Single oral administration of DMBA (15 mg/kg body weight) to Wistar rats resulted in a significant increase in the serum liver enzymes and kidney function's parameters. DMBA increased level of liver malondialdehyde (MDA), decreased levels of reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) in the liver tissue, and induced liver histopathological alterations. Pre- or posttreatment with HaE orally for 14 days significantly reversed the hepatorenal alterations induced following DMBA administration. In conclusion, HaE exhibits good hepatoprotective, curative, and antioxidant potential against DMBA-induced hepatorenal dysfunction in rats that might be due to decreased free radical generation. PMID:25821811

  3. Towards the Synthesis of Dihydrooxepino[4,3-b]pyrrole-Containing Natural Products via Cope Rearrangement of Vinyl Pyrrole Epoxides.

    PubMed

    Cameron, Alex; Fisher, Brendan; Fisk, Nicholas; Hummel, Jessica; White, Jonathan M; Krenske, Elizabeth H; Rizzacasa, Mark A

    2015-12-18

    An approach to the dihydrooxepino[4,3-b]pyrrole core of diketopiperazine natural products which utilizes a vinyl pyrrole epoxide Cope rearrangement was investigated. It was found that an ester substituent on the epoxide was essential for the [3,3]-rearrangement to occur. Density functional calculations with M06-2X provided explanations for the effects of the pyrrole and ester groups on these rearrangements.

  4. Chemoprevention by Quercetin of Oral Squamous Cell Carcinoma by Suppression of the NF-κB Signaling Pathway in DMBA-treated Hamsters.

    PubMed

    Zhang, Wen; Yin, Gang; Dai, Jianguo; Sun, Y U; Hoffman, Robert M; Yang, Zhijian; Fan, Yuan

    2017-08-01

    The aim of this study was to investigate the effects of the flavonoid quercetin on chemoprevention of oral squamous cell carcinoma (OSCC). The study involved molecular signaling pathways in 7,12-dimethylbenz(a) anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. DMBA (0.5%) was painted at the right buccal pouches of hamsters for 14 weeks to induce carcinoma. DMBA-treated hamsters received simultaneous doses of quercetin. Animals without DMBA induction were used as normal controls. The incidence of OSCC and the severity of pre-malignant lesions were determined histologically. Apoptosis in the pouch tissue was determined by TUNEL staining. The mRNA and protein expression of NF-κB p50 and p65, as well as Bcl-2 and Bax genes were analyzed using RT-PCR and Western blotting, respectively. Quercetin, at various doses, significantly reduced OSCC incidence and severity of hyperplasia and dysplasia compared to the DMBA-induction-only group (p<0.01). Apoptosis was induced by quercetin treatment compared to the DMBA-induction-only group (p<0.01). mRNA and protein expression of NF-κB p50, p65 as well as Bcl-2 genes were significantly suppressed by quercetin at high doses compared to DMBA induction only (p<0.05). However, mRNA and protein expression of the Bax gene was increased by quercetin treatment at medium and high doses, compared to the DMBA-induction-only group (p<0.05). Quercetin significantly reduced body-weight loss compared to the DMBA-induction-only group (p<0.05). Quercetin reduced tumor incidence and induced apoptosis through modulation of NF-κB signaling and its target genes Bcl-2 and Bax in the DMBA-induced carcigenesis hamster model, suggesting the potential of quercetin as a candidate for OSCC chemoprevention. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  5. An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis.

    PubMed

    Huang, Xiumei; Dong, Ying; Bey, Erik A; Kilgore, Jessica A; Bair, Joseph S; Li, Long-Shan; Patel, Malina; Parkinson, Elizabeth I; Wang, Yiguang; Williams, Noelle S; Gao, Jinming; Hergenrother, Paul J; Boothman, David A

    2012-06-15

    Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+ /ATP depletion that stimulate Ca2+ -dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1- cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers.

  6. Identification and quantification of 1,3-dimethylbutylamine (DMBA) from Camellia sinensis tea leaves and dietary supplements

    USDA-ARS?s Scientific Manuscript database

    1, 3-Dimethylbutylamine (DMBA), is a CNS stimulant which has recently been identified in multiple dietary supplements and sometimes labeled as a natural constituent of Pouchung tea. DMBA is an homologue of 1,3-dimethylamylamine (DMAA) which the US Food and Drug Administration has attempted to remov...

  7. Preferential glutathione conjugation of a reverse diol epoxide compared to a bay region diol epoxide of phenanthrene in human hepatocytes: relevance to molecular epidemiology studies of glutathione-s-transferase polymorphisms and cancer.

    PubMed

    Hecht, Stephen S; Berg, Jeannette Zinggeler; Hochalter, J Bradley

    2009-03-16

    Bay region diol epoxides are recognized ultimate carcinogens of polycyclic aromatic hydrocarbons (PAH), and in vitro studies have demonstrated that they can be detoxified by conjugation with glutathione, leading to the widely investigated hypothesis that individuals with low activity forms of glutathione-S-transferases are at higher risk of PAH induced cancer, a hypothesis that has found at most weak support in molecular epidemiology studies. A weakness in this hypothesis was that the mercapturic acids resulting from the conjugation of PAH bay region diol epoxides had never been identified in human urine. We recently analyzed smokers' urine for mercapturic acids derived from phenanthrene, the simplest PAH with a bay region. The only phenanthrene diol epoxide-derived mercapturic acid in smokers' urine was produced from the reverse diol epoxide, anti-phenanthrene-3,4-diol-1,2-epoxide (11), not the bay region diol epoxide, anti-phenanthrene-1,2-diol-3,4-epoxide (10), which does not support the hypothesis noted above. In this study, we extended these results by examining the conjugation of phenanthrene metabolites with glutathione in human hepatocytes. We identified the mercapturic acid N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c-1-phenanthryl)-L-cysteine (14a), (0.33-35.9 pmol/mL at 10 microM 8, 24 h incubation, N = 10) in all incubations with phenanthrene-3,4-diol (8) and the corresponding diol epoxide 11, but no mercapturic acids were detected in incubations with phenanthrene-1,2-diol (7), and only trace amounts were observed in incubations with the corresponding bay region diol epoxide 10. Taken together with our previous results, these studies clearly demonstrate that glutathione conjugation of a reverse diol epoxide of phenanthrene is favored over conjugation of a bay region diol epoxide. Since reverse diol epoxides of PAH are generally weakly or nonmutagenic/carcinogenic, these results, if generalizable to other PAH, do not support the widely held

  8. 4D printing smart biomedical scaffolds with novel soybean oil epoxidized acrylate

    PubMed Central

    Miao, Shida; Zhu, Wei; Castro, Nathan J.; Nowicki, Margaret; Zhou, Xuan; Cui, Haitao; Fisher, John P.; Zhang, Lijie Grace

    2016-01-01

    Photocurable, biocompatible liquid resins are highly desired for 3D stereolithography based bioprinting. Here we solidified a novel renewable soybean oil epoxidized acrylate, using a 3D laser printing technique, into smart and highly biocompatible scaffolds capable of supporting growth of multipotent human bone marrow mesenchymal stem cells (hMSCs). Porous scaffolds were readily fabricated by simply adjusting the printer infill density; superficial structures of the polymerized soybean oil epoxidized acrylate were significantly affected by laser frequency and printing speed. Shape memory tests confirmed that the scaffold fixed a temporary shape at −18 °C and fully recovered its original shape at human body temperature (37 °C), which indicated the great potential for 4D printing applications. Cytotoxicity analysis proved that the printed scaffolds had significant higher hMSC adhesion and proliferation than traditional polyethylene glycol diacrylate (PEGDA), and had no statistical difference from poly lactic acid (PLA) and polycaprolactone (PCL). This research is believed to significantly advance the development of biomedical scaffolds with renewable plant oils and advanced 3D fabrication techniques. PMID:27251982

  9. Swelling behaviour in n-pentane and mechanical properties of epoxidized natural rubber with different epoxide content

    NASA Astrophysics Data System (ADS)

    Kinasih, N. A.; Fathurrohman, M. I.; Winarto, D. A.

    2017-07-01

    Epoxidized natural rubber (ENR) with different level of epoxidation (i.e. 10, 20, 30, 40 and 50 mol% indicated as ENR ENR10, ENR20, ENR30, ENR40 and ENR50, respectively) were prepared. They were then vulcanized by using efficient system vulcanization. The effect of epoxide content on curing characteristic, swelling and mechanical properties in N-pentane was investigated. The Attenuated Resonance Fourier Transform Infrared (ATR-FTIR) and H-Nuclear Magnetic Resonance (H-NMR) were used to determine the epoxidation level. Glass transition (Tg) of ENR samples was determined by using Direct Scanning Calorimetry (DSC). The result revealed that the resistance of ENR in N-pentane increased with increasing epoxidation level, which indicated by decreasing equilibrium mol uptake and diffusion coefficient. The compression set of ENR and aging resistance increased with increasing epoxide content, except ENR50 was due to ENR 50 have two Tg value. However, the value of hardness and tensile strength were not effected by epoxidation level.

  10. The oxidation of copper catalysts during ethylene epoxidation.

    PubMed

    Greiner, M T; Jones, T E; Johnson, B E; Rocha, T C R; Wang, Z J; Armbrüster, M; Willinger, M; Knop-Gericke, A; Schlögl, R

    2015-10-14

    The oxidation of copper catalysts during ethylene epoxidation was characterized using in situ photoemission spectroscopy and electron microscopy. Gas chromatography, proton-transfer reaction mass spectrometry and electron-ionization mass spectrometry were used to characterize the catalytic properties of the oxidized copper. We find that copper corrodes during epoxidation in a 1 : 1 mixture of oxygen and ethylene. The catalyst corrosion passes through several stages, beginning with the formation of an O-terminated surface, followed by the formation of Cu2O scale and eventually a CuO scale. The oxidized catalyst exhibits measurable activity for ethylene epoxidation, but with a low selectivity of <3%. Tests on pure Cu2O and CuO powders confirm that the oxides intrinsically exhibit partial-oxidation activity. Cu2O was found to form acetaldehyde and ethylene epoxide in roughly equal amounts (1.0% and 1.2% respectively), while CuO was found to form much less ethyl aldehyde than ethylene epoxide (0.1% and 1.0%, respectively). Metallic copper catalysts were examined in extreme dilute-O2 epoxidation conditions to try and keep the catalyst from oxidizing during the reaction. It was found that in feed of 1 part O2 to 2500 parts C2H4 (PO2 = 1.2 × 10(-4) mbar) the copper surface becomes O-terminated. The O-terminated surface was found to exhibit partial-oxidation selectivity similar to that of Cu2O. With increasing O2 concentration (>8/2500) Cu2O forms and eventually covers the surface.

  11. Di-epoxides of the three isomeric dicyclopenta-fused pyrenes: ultimate mutagenic active agents.

    PubMed

    Otero-Lobato, María José; Kaats-Richters, Veronica E M; Havenith, Remco W A; Jenneskens, Leonardus W; Seinen, Willem

    2004-11-14

    To rationalize the high bacterial mutagenic response recently found for the (di-) cyclopenta-fused pyrene congeners, viz. cyclopenta[cd]-(1), dicyclopenta[cd,mn]-(2), dicyclopenta[cd,fg]-(3) and dicyclopenta[cd,jk]pyrene (4), in the presence of a metabolic activation mixture (S9-mix), their (di-)epoxides at the externally fused unsaturated five-membered rings were previously proposed as the ultimate mutagenic active forms. In this study, cyclopenta[cd]pyrene-3,4-epoxide (5) and the novel dicyclopenta[cd,mn]pyrene-1,2,4,5-di-epoxide (6), dicyclopenta[cd,fg]pyrene-5,6,7,8-di-epoxide (7) and dicyclopenta[cd,jk]pyrene-1,2,6,7-di-epoxide (8) were synthesised from 1 to 4, respectively, and subsequently assayed for bacterial mutagenicity in the standard microsomal/histidine reverse mutation assay (Ames-assay with Salmonella typhimurium strain TA98). The di-epoxides 6-8 are present as a mixture of their cis- and trans-stereo-isomers in a close to 1:1 ratio ((1)H NMR spectroscopy and ab initio IGLO/III//RHF/6-31G** calculations). The direct-acting mutagenic activity and the strong cytotoxicity exerted by 5-8 both in the absence or presence of an exogenous metabolic activation system (+/-S9-mix) demonstrate that the ultimate mutagenic active forms are the proposed (di-)epoxides of 1-4.

  12. Inhibitory effects of Zengshengping fractions on DMBA-induced buccal pouch carcinogenesis in hamsters.

    PubMed

    Guan, Xiao-Bing; Sun, Zheng; Chen, Xiao-Xin; Wu, Hong-Ru; Zhang, Xin-Yan

    2012-01-01

    Zengshengping (ZSP) tablets had inhibitory effects on oral precancerous lesions by reducing the incidence of oral cancer. However, the severe liver toxicity caused by systemic administration of ZSP limits the long-term use of this anti-cancer drug. The purpose of this study was to evaluate the tumor inhibitory effects due to the topical application of extracts from ZSP, a Chinese herbal drug, on 7, 12-dimethlbenz(a)anthracene (DMBA) induced oral tumors in hamsters. The study also investigated the anti-cancer mechanisms of the ZSP extracts on oral carcinogenesis. DMBA (0.5%) was applied topically to the buccal pouches of Syrian golden hamsters (6 - 8 weeks old) three times per week for six weeks in order to induce the development of oral tumors. Different fractions of ZSP were either applied topically to the oral tumor lesions or fed orally at varying dosages to animals with oral tumors for 18 weeks. Tumor volume was measured by histopathological examination. Tumor cell proliferation was evaluated by counting BrdU labeled cells and by Western blotting for mitogen-activated protein kinase (MAPK) protein levels. The protein levels of apoptosis marker Caspase-3 and regulator Bcl-2 protein were also measured by Western blotting. Topical application of DMBA to the left pouch of hamsters induced oral tumor formation. Animals treated with DMBA showed a loss in body weight while animals treated with ZSP maintained normal body weights. Both the ZSP n-butanol fraction and water fraction significantly reduced tumor volume by 32.6% (P < 0.01) and 22.9% (P < 0.01) respectively. Topical application of ZSP also markedly decreased the BrdU-positive cell numbers in oral tumor lesions and reduced the expression level of MAPK. In addition, ZSP promoted tumor cell apoptosis by increasing Caspase-3 expression but decreasing Bcl-2 protein production. The n-butanol and water fractions of ZSP are effective at inhibiting tumor cell proliferation and stimulating apoptosis in oral cancer

  13. Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Jason Z.; Ke, Yuebin; Misra, Hara P.

    Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16–F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone,more » a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16–F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ∼ 80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16–F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells. - Highlights: • Both isolated mitochondria and purified NQO1 are able to generate ROS by beta-Lp. • The differential roles of mitochondria and NQO1 in mediating redox activation of beta-Lp • In cancer cells

  14. Methyltrioxorhenium-catalyzed epoxidation of homoallylic alcohols with hydrogen peroxide.

    PubMed

    Yamazaki, Shigekazu

    2012-11-02

    Homoallylic alcohols were efficiently converted to the corresponding 3,4-epoxy alcohols in excellent yields by methyltrioxorhenium (MTO)-catalyzed epoxidation with aqueous hydrogen peroxide as the terminal oxidant and 3-methylpyrazole (10 mol %) as an additive. The epoxidations of homoallylic alcohols proceeded under organic solvent-free conditions faster than those in dichloromethane.

  15. Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model.

    PubMed

    Lubet, R A; Steele, V E; Eto, I; Juliana, M M; Kelloff, G J; Grubbs, C J

    1997-07-03

    The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%. Anethole trithione, a substituted dithiolthione and an analog of the relatively broad-spectrum chemopreventive oltipraz, was administered in the diet and significantly inhibited mammary cancer multiplicity but not cancer incidence. NAC, an antimucolytic agent, failed to inhibit DMBA-induced mammary tumorigenesis. Surprisingly, treatment with DMBA plus PEITC, a potent inhibitor of cytochrome P450 2E1, actually increased the multiplicity of tumors relative to that observed with DMBA alone.

  16. Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

    PubMed

    Patrick, B A; Jaiswal, A K

    2012-10-04

    Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in the stabilization of p63 against 20S proteasomal degradation resulting in thinning of the epithelium and chemical-induced skin cancer (Oncogene (2011) 30, 1098-1107). Current studies have demonstrated that NQO1 control of CCAAT-enhancer binding protein (C/EBPα) against 20S proteasomal degradation also contributes to the upregulation of p63 expression and protection. Western and immunohistochemistry analysis revealed that disruption of the NQO1 gene in mice and mouse keratinocytes led to degradation of C/EBPα and loss of p63 gene expression. p63 promoter mutagenesis, transfection and chromatin immunoprecipitation assays identified a C/EBPα-binding site between nucleotide position -185 and -174 that bound to C/EBPα and upregulated p63 gene expression. Co-immunoprecipitation and immunoblot analysis demonstrated that 20S proteasomes directly interacted and degraded C/EBPα. NQO1 direct interaction with C/EBPα led to stabilization of C/EBPα against 20S proteasomal degradation. NQO1 protection of C/EBPα required binding of NADH with NQO1. Exposure of skin and keratinocytes to the chemical stress agent benzo(a)pyrene led to induction of NQO1 and stabilization of C/EBPα protein, resulting in an increase in p63 RNA and protein in wild-type but not in NQO1-/- mice. Collectively, the current data combined with previous data suggest that stress induction of NQO1 through both stabilization of C/EBPα and increase in p63 and direct stabilization of p63 controls keratinocyte differentiation, leading to protection against chemical-induced skin carcinogenesis. The studies are significant as 2-4% human individuals are homozygous and 23% are heterozygous for the NQO1P187S mutation and might be susceptible to stress-induced skin diseases.

  17. Epoxidation catalyst and process

    DOEpatents

    Linic, Suljo; Christopher, Phillip

    2010-10-26

    Disclosed herein is a catalytic method of converting alkenes to epoxides. This method generally includes reacting alkenes with oxygen in the presence of a specific silver catalyst under conditions suitable to produce a yield of the epoxides. The specific silver catalyst is a silver nanocrystal having a plurality of surface planes, a substantial portion of which is defined by Miller indices of (100). The reaction is performed by charging a suitable reactor with this silver catalyst and then feeding the reactants to the reactor under conditions to carry out the reaction. The reaction may be performed in batch, or as a continuous process that employs a recycle of any unreacted alkenes. The specific silver catalyst has unexpectedly high selectivity for epoxide products. Consequently, this general method (and its various embodiments) will result in extraordinarily high epoxide yields heretofore unattainable.

  18. Chemomodulatory Potential of Flaxseed Oil Against DMBA/Croton Oil-Induced Skin Carcinogenesis in Mice.

    PubMed

    Sharma, Jyoti; Singh, Ritu; Goyal, P K

    2016-09-01

    The present study was conducted to evaluate the potential of flaxseed oil to prevent chemically induced skin cancer in mice. Cancer was induced on 2-stage skin carcinogenesis model by single topical application of 7,12 dimethylbenz [a]anthracene (DMBA), as, initiator, and two weeks later it was promoted by croton oil treatment thrice a week on the dorsal surface of mice for 16 weeks. Flaxseed oil (FSO; 100µL/animal/d) was orally administered 1 week before and 1 week after DMBA application (Peri-initiation stage). The animals of the FSO-administered group showed a significant reduction in tumor incidence (76.67%), cumulative number of tumors (37), tumor yield (3.7), and tumor burden (4.81) when compared with the carcinogen-treated control animals. Biochemical parameters in skin and liver tissue such as LPO and phase I enzymes were significantly (P < .01) reduced in the FSO-treated experimental group, whereas the phase II enzymes (GST, DT-diaphorase) and antioxidant parameters (GSH, GPx, SOD, catalase, and vitamin C) exhibited a significant (P < .01) elevation when compared with the animals of the carcinogen-treated control group. Histopathological alterations in the carcinogen-treated control animals were also observed in the form of epidermal hyperplasia, keratinized pearl formation, and acanthosis in skin and tumors, whereas these were found to be reduced after FSO administration. The results of the present study demonstrate that the oral administration of FSO has the potential to modulate the levels of LPO, antioxidants, and detoxification enzymes in the DMBA-croton oil-induced skin carcinogenesis in mice. © The Author(s) 2015.

  19. 7,12-Dimethylbenzanthracene induces apoptosis in RL95-2 human endometrial cancer cells: Ligand-selective activation of cytochrome P450 1B1

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Ji Young; Medical Research Science Center, Dong-A University, Busan 602-714; Lee, Seung Gee

    2012-04-15

    7,12-Dimethylbenzanthracene (DMBA), a polycyclic aromatic hydrocarbon, exhibits mutagenic, carcinogenic, immunosuppressive, and apoptogenic properties in various cell types. To achieve these functions effectively, DMBA is modified to its active form by cytochrome P450 1 (CYP1). Exposure to DMBA causes cytotoxicity-mediated apoptosis in bone marrow B cells and ovarian cells. Although uterine endometrium constitutively expresses CYP1A1 and CYP1B1, their apoptotic role after exposure to DMBA remains to be elucidated. Therefore, we chose RL95-2 endometrial cancer cells as a model system for studying DMBA-induced cytotoxicity and cell death and hypothesized that exposure to DMBA causes apoptosis in this cell type following CYP1A1 and/ormore » CYP1B1 activation. We showed that DMBA-induced apoptosis in RL95-2 cells is associated with activation of caspases. In addition, mitochondrial changes, including decrease in mitochondrial potential and release of mitochondrial cytochrome c into the cytosol, support the hypothesis that a mitochondrial pathway is involved in DMBA-induced apoptosis. Exposure to DMBA upregulated the expression of AhR, Arnt, CYP1A1, and CYP1B1 significantly; this may be necessary for the conversion of DMBA to DMBA-3,4-diol-1,2-epoxide (DMBA-DE). Although both CYP1A1 and CYP1B1 were significantly upregulated by DMBA, only CYP1B1 exhibited activity. Moreover, knockdown of CYP1B1 abolished DMBA-induced apoptosis in RL95-2 cells. Our data show that RL95-2 cells are susceptible to apoptosis by exposure to DMBA and that CYP1B1 plays a pivotal role in DMBA-induced apoptosis in this system. -- Highlights: ► Cytotoxicity-mediated apoptogenic action of DMBA in human endometrial cancer cells. ► Mitochondrial pathway in DMBA-induced apoptosis of RL95-2 endometrial cancer cells. ► Requirement of ligand-selective activation of CYP1B1 in DMBA-induced apoptosis.« less

  20. Epoxide Hydrolase Conformational Heterogeneity for the Resolution of Bulky Pharmacologically Relevant Epoxide Substrates.

    PubMed

    Serrano-Hervás, Eila; Casadevall, Guillem; Garcia-Borràs, Marc; Feixas, Ferran; Osuna, Sílvia

    2018-04-06

    The conformational landscape of Bacillus megaterium epoxide hydrolase (BmEH) and how it is altered by mutations that confer the enzyme the ability to accept bulky epoxide substrates has been investigated. Extensive molecular dynamics (MD) simulations coupled to active site volume calculations have unveiled relevant features of the enzyme conformational dynamics and function. Our long-timescale MD simulations identify key conformational states not previously observed by means of X-ray crystallography and short MD simulations that present the loop containing one of the catalytic residues, Asp239, in a wide-open conformation, which is likely involved in the binding of the epoxide substrate. Introduction of mutations M145S and F128A dramatically alters the conformational landscape of the enzyme. These singly mutated variants can accept bulky epoxide substrates due to the disorder induced by mutation in the α-helix containing the catalytic Tyr144 and some parts of the lid domain. These changes impact the enzyme active site, which is substantially wider and more complementary to the bulky pharmacologically relevant epoxide substrates. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Preventive effect of berberine against DMBA-induced breast cancer in female Sprague Dawley rats.

    PubMed

    Karnam, Kalyani Chowdary; Ellutla, Maheswara; Bodduluru, Lakshmi Narendra; Kasala, Eshvendar Reddy; Uppulapu, Shravan Kumar; Kalyankumarraju, Malayamarutham; Lahkar, Mangala

    2017-08-01

    Breast cancer is the prime cause for cancer mortality in women worldwide. The importance of diverse natural and dietary agents to reduce the risk of developing breast cancer is well established. Berberine, a natural isoquinoline alkaloid found in many medicinal plants is widely used in traditional Indian and Chinese medicine. Because of its capability to seize the cell cycle and induce apoptosis of numerous malignant cells, berberine has received considerable attention as a potential anticancer agent. In the present study, breast cancer was induced in Sprague Dawley (SD) rats by intragastric administration of 7, 12-dimethylbenz[a]anthracene (DMBA) at a dose of 80mg/kg of body weight. Treatment of berberine (50mg/kg BW) to breast tumor bearing rats was found to be effective against DMBA induced mammary carcinoma. The increased levels of lipid peroxide (malonaldehyde), pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), enzymatic antioxidants (SOD and CAT), non-enzymatic antioxidants (GSH and vitamin C) and transcription factor NF-κB were decreased significantly by administration of berberine. Furthermore, RT-PCR and western blot analysis showed the down-regulation of NF-κB and PCNA in breast tumors. Histopathological studies validated that berberine is effective against DMBA induced ductal carcinoma & invasive carcinoma. Altogether, these findings demonstrate the preventive role of berberine against DMBA induced mammary carcinoma in SD rats. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Dietary turmeric modulates DMBA-induced p21{sup ras}, MAP kinases and AP-1/NF-{kappa}B pathway to alter cellular responses during hamster buccal pouch carcinogenesis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Garg, Rachana; Ingle, Arvind; Maru, Girish

    2008-11-01

    The chemopreventive efficacy of turmeric has been established in experimental systems. However, its mechanism(s) of action are not fully elucidated in vivo. The present study investigates the mechanism of turmeric-mediated chemoprevention in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis at 2, 4, 6, 10 and 12 weeks. Dietary turmeric (1%) led to decrease in DMBA-induced tumor burden and multiplicity, and enhanced the latency period in parallel, to its modulatory effects on oncogene products and various cellular responses during HBP tumorigenesis. DMBA-induced expression of ras oncogene product, p21 and downstream target, the mitogen-activated protein kinases were significantly decreased by turmeric duringmore » HBP carcinogenesis. Turmeric also diminished the DMBA-induced mRNA expression of proto-oncogenes (c-jun, c-fos) and NF-{kappa}B, leading to decreased protein levels and in further attenuation of DMBA-induced AP-1/NF-{kappa}B DNA-binding in the buccal pouch nuclear extracts. Besides, buccal pouch of hamsters receiving turmeric diet showed significant alterations in DMBA-induced effects: (a) decrease in cell proliferation (diminished PCNA and Bcl2 expression), (b) enhanced apoptosis (increased expression of Bax, caspase-3 and apoptotic index), (c) decrease in inflammation (levels of Cox-2, the downstream target of AP-1/NF-{kappa}B, and PGE2) and (d) aberrant expression of differentiation markers, the cytokeratins (1, 5, 8, and 18). Together, the protective effects of dietary turmeric converge on augmenting apoptosis of the initiated cells and decreasing cell proliferation in DMBA-treated animals, which in turn, is reflected in decreased tumor burden, multiplicity and enhanced latency period. Some of these biomarkers are likely to be helpful in monitoring clinical trials and evaluating drug effect measurements.« less

  3. Catalytic asymmetric epoxidation of alpha,beta-unsaturated amides: efficient synthesis of beta-aryl alpha-hydroxy amides using a one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process.

    PubMed

    Nemoto, Tetsuhiro; Kakei, Hiroyuki; Gnanadesikan, Vijay; Tosaki, Shin-Ya; Ohshima, Takashi; Shibasaki, Masakatsu

    2002-12-11

    The catalytic asymmetric epoxidation of alpha,beta-unsaturated amides using Sm-BINOL-Ph3As=O complex was succeeded. Using 5-10 mol % of the asymmetric catalyst, a variety of amides were epoxidized efficiently, yielding the corresponding alpha,beta-epoxy amides in up to 99% yield and in more than 99% ee. Moreover, the novel one-pot tandem process, one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process, was developed. This method was successfully utilized for the efficient synthesis of beta-aryl alpha-hydroxy amides, including beta-aryllactyl-leucine methyl esters. Interestingly, it was found that beneficial modifications on the Pd catalyst were achieved by the constituents of the first epoxidation, producing a more suitable catalyst for the Pd-catalyzed epoxide opening reaction in terms of chemoselectivity.

  4. Autonomic self-healing in epoxidized natural rubber.

    PubMed

    Rahman, Arifur; Sartore, Luciana; Bignotti, Fabio; Di Landro, Luca

    2013-02-01

    The development of polymers that can repair damage autonomously would be useful to improve the lifetime of polymeric materials. To date, limited attention has been dedicated to developing elastomers with autonomic self-healing ability, which can recover damages without need for an external or internal source of healing agents. This work investigates the self-healing behavior of epoxidized natural rubber (ENR) with two different epoxidation levels (25 and 50 mol % epoxidation) and of the corresponding unfunctionalized rubber, cis-1,4-polyisoprene (PISP). A self-adhesion assisted self-healing behavior was revealed by T-peel tests on slightly vulcanized rubbers. A higher epoxidation level was found to enhance self-healing. Self-healing of rubbers following ballistic damages was also investigated. A pressurized air flow test setup was used to evaluate the self-healing of ballistic damages in rubbers. Microscope (OM, SEM, and TEM) analyses were carried out to provide further evidence of healing in the impact zones. Self-healing of ballistic damages was observed only in ENR with 50 mol % epoxidation and it was found to be influenced significantly by the cross-link density. Finally, self-healing of ballistic damages was also observed in ENR50/PISP blends only when the content of the healing component (i.e., ENR50) was at least 25 wt %. From an analysis of the results, it was concluded that a synergistic effect between interdiffusion and interaction among polar groups leads to self-healing in ENR.

  5. Cynaropicrin attenuates UVB-induced oxidative stress via the AhR-Nrf2-Nqo1 pathway.

    PubMed

    Takei, Kenjiro; Hashimoto-Hachiya, Akiko; Takahara, Masakazu; Tsuji, Gaku; Nakahara, Takeshi; Furue, Masutaka

    2015-04-16

    Due to its antioxidant and anti-inflammatory activities, artichoke (Cynara scolymus) has been used as folk medicine to treat various diseases. Cynaropicrin (Cyn), a sesquiterpene lactone, is the major bioactive phytochemical in the artichoke; however, its pharmacological mechanism remains unknown. Because some phytochemicals exert their antioxidant activity by activating aryl hydrocarbon receptor (AhR), leading to subsequent induction of the antioxidant pathway including nuclear factor E2-related factor 2 (Nrf2) and quinone oxidoreductase 1 (Nqo1), we investigated whether Cyn also activates the AhR-Nrf2-Nqo1 pathway. Cyn indeed induced the activation (nuclear translocation) of AhR, leading to nuclear translocation of Nrf2 and dose-dependent upregulation of Nrf2 and Nqo1 mRNAs in human keratinocytes. The Cyn-induced AhR-Nrf2-Nqo1 activation was AhR- and Nrf2-dependent, as demonstrated by the observation that it was absent in keratinocytes transfected by siRNA against either AhR or Nrf2. In accordance with these findings, Cyn actively inhibited generation of reactive oxygen species from keratinocytes irradiated with ultraviolet B (UVB) in a Nrf2-dependent manner. Cyn also inhibited the production of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor-α from UVB-treated keratinocytes. Our findings demonstrate that Cyn is a potent activator of the AhR-Nrf2-Nqo1 pathway, and could therefore be applied to prevention of UVB-induced photo aging. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. An unexpected epoxidation of benzil derivatives in their reaction with a germene.

    PubMed

    El Kettani, Sakina Ech-Cherif; Lazraq, Mohamed; Ouhsaine, Fatima; Gornitzka, Heinz; Ranaivonjatovo, Henri; Escudié, Jean

    2008-11-07

    The germene Mes(2)Ge=CR(2) (Mes = 2,4,6-trimethylphenyl, CR(2) = fluorenylidene) reacts with various benzil derivatives to lead to germanium-containing bicyclic epoxides by an unexpected new type of epoxidation reaction.

  7. Dual effects of N-acetyl-L-cysteine dependent on NQO1 activity: Suppressive or promotive of 9,10-phenanthrenequinone-induced toxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Toyooka, Tatsushi; Shinmen, Takuya; Aarts, Jac M.M.J.G.

    2012-11-01

    A typical antioxidant, N-acetyl-L-cysteine (NAC) generally protects cells from oxidative damage induced by reactive oxygen species (ROS). 9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, produces ROS in redox cycling following two-electron reduction by NAD(P)H:quinone oxidoreductase 1 (NQO1), which has been considered as a cause of its cyto- and genotoxicity. In this study, we show that NAC unexpectedly augments the toxicity of 9,10-PQ in cells with low NQO1 activity. In four human skin cell lines, the expression and the activity of NQO1 were lower than in human adenocarcinoma cell lines, A549 and MCF7. In the skin cells, the cytotoxicitymore » of 9,10-PQ was significantly enhanced by addition of NAC. The formation of DNA double strand breaks accompanying phosphorylation of histone H2AX, was also remarkably augmented. On the other hand, the cyto- and genotoxicity were suppressed by addition of NAC in the adenocarcinoma cells. Two contrasting experiments: overexpression of NQO1 in CHO-K1 cells which originally expressed low NQO1 levels, and knock‐down of NQO1 in the adenocarcinoma cell line A549 by transfection of RNAi, also showed that NAC suppressed 9,10-PQ-induced toxicity in cell lines expressing high NQO1 activity and enhanced it in cell lines with low NQO1 activity. The results suggested that dual effects of NAC on the cyto- and genotoxicity of 9,10-PQ were dependent on tissue-specific NQO1 activity. -- Highlights: ► NAC augmented the cytotoxicity of 9,10-PQ in skin cell lines. ► 9,10-PQ-induced DSBs accompanying γ-H2AX were also augmented by NAC. ► NAC suppressed the cyto- and genotoxicity of 9,10-PQ in adenocarcinoma cell lines. ► The dual effects of NAC on toxicity of 9,10-PQ were dependent on NQO1 activity.« less

  8. High-Throughput Library Screening Identifies Two Novel NQO1 Inducers in Human Lung Cells

    PubMed Central

    Marquardt, Gaby; Massimi, Aldo B.; Shi, Miao; Han, Weiguo; Spivack, Simon D.

    2012-01-01

    Many phytochemicals possess antioxidant and cancer-preventive properties, some putatively through antioxidant response element–mediated phase II metabolism, entailing mutagen/oxidant quenching. In our recent studies, however, most candidate phytochemical agents were not potent in inducing phase II genes in normal human lung cells. In this study, we applied a messenger RNA (mRNA)–specific gene expression–based high throughput in vitro screening approach to discover new, potent plant-derived phase II inducing chemopreventive agents. Primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBECs) were exposed to 800 individual compounds in the MicroSource Natural Products Library. At a level achievable in humans by diet (1.0 μM), 2,3-dihydroxy-4-methoxy-4′-ethoxybenzophenone (DMEBP), triacetylresveratrol (TRES), ivermectin, sanguinarine sulfate, and daunorubicin induced reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) mRNA and protein expression in NHBE cells. DMEBP and TRES were the most attractive agents as coupling potency and low toxicity for induction of NQO1 (mRNA level, ≥3- to 10.8-fold that of control; protein level, ≥ two- to fourfold that of control). Induction of glutathione S-transferase pi mRNA expression was modest, and none was apparent for glutathione S-transferase pi protein expression. Measurements of reactive oxygen species and glutathione/oxidized glutathione ratio showed an antioxidant effect for DMEBP, but no definite effect was found for TRES in NHBE cells. Exposure of NHBE cells to H2O2 induced nuclear translocation of nuclear factor erythroid 2–related factor 2, but this translocation was not significantly inhibited by TRES and DMEBP. These studies show that potency and low toxicity may align for two potential NQO1-inducing agents, DMEBP and TRES. PMID:22021338

  9. Catalase abrogates β-lapachone-induced PARP1 hyperactivation-directed programmed necrosis in NQO1-positive breast cancers

    PubMed Central

    Bey, Erik A.; Reinicke, Kathryn E.; Srougi, Melissa C.; Varnes, Marie; Anderson, Vernon; Pink, John J.; Li, Long Shan; Patel, Malina; Cao, Lifen; Moore, Zachary; Rommel, Amy; Boatman, Michael; Lewis, Cheryl; Euhus, David M.; Bornmann, William G.; Buchsbaum, Donald J.; Spitz, Douglas R.; Gao, Jinming; Boothman, David A.

    2013-01-01

    Improving patient outcome by personalized therapy involves a thorough understanding of an agent’s mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic (e.g., triple-negative (ER-, PR-, Her2/Neu-)) breast cancers. To define cellular factors that influence the efficacy of β-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where ~120 moles of superoxide were formed per mole of β-lapachone in 5 min. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA single strand break-dependent PARP1 hyperactivation, caused dramatic loss of essential nucleotides (NAD+/ATP) and elicited programmed necrosis in breast cancer cells. While PARP1 hyperactivation and NQO1 expression were major determinants of β-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor, and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase (SOD) enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included AIF translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and GAPDH S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of β-lapachone and other NQO1 bioactivatable drugs. PMID:23883585

  10. Thermodynamics of cooperative binding of FAD to human NQO1: Implications to understanding cofactor-dependent function and stability of the flavoproteome.

    PubMed

    Clavería-Gimeno, Rafael; Velazquez-Campoy, Adrian; Pey, Angel Luis

    2017-12-15

    The stability of human flavoproteins strongly depends on flavin levels, although the structural and energetic basis of this relationship is poorly understood. Here, we report an in-depth analysis on the thermodynamics of FAD binding to one of the most representative examples of such relationship, NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a dimeric enzyme that tightly binds FAD, which triggers large structural changes upon binding. A common cancer-associated polymorphism (P187S) severely compromises FAD binding. We show that FAD binding is described well by a thermodynamic model explicitly incorporating binding cooperativity when applied to different sets of calorimetric analyses and NQO1 variants, thus providing insight on the effects in vitro and in cells of cancer-associated P187S, its suppressor mutation H80R and the role of NQO1 C-terminal domain to modulate binding cooperativity and energetics. Furthermore, we show that FAD binding to NQO1 is very sensitive to physiologically relevant environmental conditions, such as the presence of phosphate buffer and salts. Overall, our results contribute to understanding at the molecular level the link between NQO1 stability and fluctuations of FAD levels intracellularly, and supports the notion that FAD binding energetics and cooperativity are fundamentally linked with the dynamic nature of apo-NQO1 conformational ensemble. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. The effects of metyrapone, chalcone epoxide, benzil, clotrimazole and related compounds on the activity of microsomal epoxide hydrolase in situ, in purified form and in reconstituted systems towards different substrates.

    PubMed

    Seidegård, J; DePierre, J W; Guenthner, T M; Oesch, F

    1986-09-01

    The influence of metyrapone, chalcone epoxide, benzil and clotrimazole on the activity of microsomal epoxide hydrolase towards styrene oxide, benzo[a]pyrene 4,5-oxide, estroxide and androstene oxide was investigated. The studies were performed using liver microsomes from rats, rabbits, mice and humans; epoxide hydrolase purified from rat liver microsomes to apparent homogeneity; and the purified enzyme incorporated into liposomes composed of egg-yolk phosphatidylcholine or total rat liver microsomal lipids. All four effectors were found to activate the hydrolysis of styrene oxide by epoxide hydrolase in situ in rat liver microsomal membranes, in agreement with earlier findings. Epoxide hydrolase activity towards styrene oxide in liver microsomes from mouse, rabbit and man was also increased by all four effectors. The most striking effect was a 680% activation by clotrimazole in rat liver microsomes. However, none of the effectors activated microsomal epoxide hydrolase more than 50% when benzo[a]pyrene 4,5-oxide, estroxide or androstene oxide was used as substrate. Indeed, clotrimazole was found to inhibit microsomal epoxide hydrolase activity towards estroxide 30-50% and towards androstene oxide 60-90%. The effects of these four compounds were found to be virtually identical in the preparations from rats, rabbits, mice and humans. The effects of metyrapone, chalcone epoxide, benzil and clotrimazole on purified epoxide hydrolase were qualitatively the same as those on epoxide hydrolase in intact microsomes, but much smaller in magnitude. These effects were increased in magnitude only slightly by incorporation of the purified enzyme into liposomes made from egg-yolk phosphatidylcholine. However, when incorporation into liposomes composed of total microsomal lipids was performed, the effects seen were essentially of the same magnitude as with intact microsomes. When the extent of activation was plotted against effector concentration, three different patterns were

  12. An NQO1-Initiated and p53-Independent Apoptotic Pathway Determines the Anti-Tumor Effect of Tanshinone IIA against Non-Small Cell Lung Cancer

    PubMed Central

    Wang, Guangji; Liu, Huiying; Wu, Xiaolan; Wang, Qiong; Liu, Miao; Liao, Ke; Wu, Mengqiu; Cheng, Xuefang; Hao, Haiping

    2012-01-01

    NQO1 is an emerging and promising therapeutic target in cancer therapy. This study was to determine whether the anti-tumor effect of tanshinone IIA (TSA) is NQO1 dependent and to elucidate the underlying apoptotic cell death pathways. NQO1+ A549 cells and isogenically matched NQO1 transfected and negative H596 cells were used to test the properties and mechanisms of TSA induced cell death. The in vivo anti-tumor efficacy and the tissue distribution properties of TSA were tested in tumor xenografted nude mice. We observed that TSA induced an excessive generation of ROS, DNA damage, and dramatic apoptotic cell death in NQO1+ A549 cells and H596-NQO1 cells, but not in NQO1− H596 cells. Inhibition or silence of NQO1 as well as the antioxidant NAC markedly reversed TSA induced apoptotic effects. TSA treatment significantly retarded the tumor growth of A549 tumor xenografts, which was significantly antagonized by dicoumarol co-treatment in spite of the increased and prolonged TSA accumulations in tumor tissues. TSA activated a ROS triggered, p53 independent and caspase dependent mitochondria apoptotic cell death pathway that is characterized with increased ratio of Bax to Bcl-xl, mitochondrial membrane potential disruption, cytochrome c release, and subsequent caspase activation and PARP-1 cleavage. The results of these findings suggest that TSA is a highly specific NQO1 target agent and is promising in developing as an effective drug in the therapy of NQO1 positive NSCLC. PMID:22848731

  13. In vivo relevance of two critical levels for NAD(P)H:quinone oxidoreductase (NQO1)-mediated cellular protection against electrophile toxicity found in vitro.

    PubMed

    de Haan, Laura H J; Pot, Gerda K; Aarts, Jac M M J G; Rietjens, Ivonne M C M; Alink, Gerrit M

    2006-08-01

    NAD(P)H:quinone oxidoreductase (NQO1)-mediated detoxification of quinones is suggested to be involved in cancer prevention. In the present study, using transfected CHO cells, it was demonstrated that the relation between NQO1 activity and the resulting protection against the cytotoxicity of menadione shows a steep dose-response curve revealing a 'lower protection threshold' of 0.5mumol DCPIP/min/mg protein and an 'upper protection threshold' at 1mumol DCPIP/min/mg protein. In an additional in vivo experiment it was investigated how both in vitro critical activity levels of NQO1, relate to NQO1 activities in mice and man, either without or upon induction of the enzyme by butylated hydroxyanisol (BHA) or indole-3-carbinol (I(3)C). Data from an experiment with CD1 mice revealed that base-line NQO1 levels in liver, kidney, small intestine, colon and lung are generally below the observed 'lower protection threshold' in vitro, this also holds for most human tissue S-9 samples. To achieve NQO1 levels above this 'lower protection threshold' will require 5-20 fold NQO1 induction. Discussion focuses on the relevance of the in vitro NQO1 activity thresholds for the in vivo situation. We conclude that increased protection against menadione toxicity can probably not be achieved by NQO1 induction but should be achieved by other mechanisms. Whether this conclusion also holds for other electrophiles and the in vivo situation awaits further definition of their NQO1 protection thresholds.

  14. Topical photosan-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premaligant lesions: an in vivo study

    NASA Astrophysics Data System (ADS)

    Hsu, Yih-Chih; Chiang, Chun-Pin; Chen, Jian Wen; Chen, Ying-Ru; Lee, Jeng-Woei

    2010-02-01

    One of the best strategies to prevent the occurrence of oral cancer is to eliminate oral precancers and block their further malignant transformation. Previous studies showed that photosan-mediated photodynamic therapy (photosan-PDT) is very effective for human head and neck cancers. To avoid the systemic photodynamic toxicity of photosan, this study was designed to use a topical photosan-PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. Twelve 10-week-old male Syrian golden hamsters were used in this study. DMBA was applied to the left buccal pouches thrice a week for 8 to 10 weeks and mineral oil was painted on the right buccal pouches thrice a week for 8 to 10 weeks as the normal controls. Six hamsters were euthanized for tissue harvest. Precancerous lesions of moderate to severe dysplasia were consistently induced and proven by histological examination. These induced precancerous lesions in the remaining 6 hamsters were used for testing the efficacy of topical photosan-PDT. Before PDT, fluorescence spectroscopy was used to determine when protoporphyrine IX (PpIX) reached its peak level in the lesional epithelial cells after topical application of photosan-gel. We found that PpIX reached its peak level in precancerous lesions about 13.5 min after topical application of photosan-gel. The precancerous lesions in 4 hamsters were treated with topical photosan-PDT using the 635-nm LED light once or twice a week. Complete regression of the precancerous lesions was found after 2-4 PDT treatments by visual and histological examination. Our findings indicate that topical photosan-PDT is a very effective treatment modality for DMBA-induced hamster buccal pouch precancerous lesions.

  15. Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

    PubMed Central

    Fiorillo, Marco; Sotgia, Federica; Sisci, Diego; Cappello, Anna Rita; Lisanti, Michael P.

    2017-01-01

    Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007). PMID:28411284

  16. 4-Nitroquinoline-1-oxide effects human lung adenocarcinoma A549 cells by regulating the expression of POLD4

    PubMed Central

    HUANG, QIN-MIAO; ZENG, YI-MING; ZHANG, HUA-PING; LV, LIANG-CHAO; YANG, DONG-YONG; LIN, HUI-HUANG

    2016-01-01

    The aim of the present study was to explore the expression of POLD4 in human lung adenocarcinoma A549 cells under 4-nitroquinoline-1-oxide (4NQO) stimulation to investigate the role of POLD4 in smoking-induced lung cancer. The lung cancer A549 cell line was treated with 4NQO, with or without MG132 (an inhibitor of proteasome activity), and subsequently the POLD4 level was determined by western blot analysis. Secondly, the cell sensitivity to 4NQO and Taxol was determined when the POLD4 expression level was downregulated by siRNA. The POLD4 protein levels in the A549 cells decreased following treatment with 4NQO; however, MG132 could reverse this phenotype. Downregulation of the POLD4 expression by siRNA enhanced A549 cell sensitivity to 4NQO, but not to Taxol. In conclusion, 4NQO affects human lung adenocarcinoma A549 cells by regulating the expression of POLD4. PMID:26998273

  17. Epoxidation of Geraniol: An Advanced Organic Experiment that Illustrates Asymmetric Synthesis

    NASA Astrophysics Data System (ADS)

    Bradley, Lynn M.; Springer, Joseph W.; Delate, Gregory M.; Goodman, Andrew

    1997-11-01

    The Sharpless epoxidation reaction is considered one of the most powerful advances in asymmetric organic synthesis (1). It is a classic example of the use of an asymmetric catalyst to provide an enantiomerically enriched mixture of epoxy alcohols. The procedure typically uses titanium(IV) tetraisopropoxide (Ti(OiPr)4) as a catalyst, a peroxide, and dialkyl tartrates to induce asymmetry in the epoxidation reaction of allylic alcohols. The experiment described in this paper illustrates the principle of asymmetric epoxidation and enables students to determine enantiomeric product ratios using chiral shift reagents and NMR spectroscopy.

  18. Stilbene epoxidation and detoxification in a Photorhabdus luminescens-nematode symbiosis

    PubMed Central

    Park, Hyun Bong; Sampathkumar, Parthasarathy; Perez, Corey E.; Lee, Joon Ha; Tran, Jeannie; Bonanno, Jeffrey B.; Hallem, Elissa A.; Almo, Steven C.; Crawford, Jason M.

    2017-01-01

    Members of the gammaproteobacterial Photorhabdus genus share mutualistic relationships with Heterorhabditis nematodes, and the pairs infect a wide swath of insect larvae. Photorhabdus species produce a family of stilbenes, with two major components being 3,5-dihydroxy-4-isopropyl-trans-stilbene (compound 1) and its stilbene epoxide (compound 2). This family of molecules harbors antimicrobial and immunosuppressive activities, and its pathway is responsible for producing a nematode “food signal” involved in nematode development. However, stilbene epoxidation biosynthesis and its biological roles remain unknown. Here, we identified an orphan protein (Plu2236) from Photorhabdus luminescens that catalyzes stilbene epoxidation. Structural, mutational, and biochemical analyses confirmed the enzyme adopts a fold common to FAD-dependent monooxygenases, contains a tightly bound FAD prosthetic group, and is required for the stereoselective epoxidation of compounds 1 and 2. The epoxidase gene was dispensable in a nematode-infective juvenile recovery assay, indicating the oxidized compound is not required for the food signal. The epoxide exhibited reduced cytotoxicity toward its producer, suggesting this may be a natural route for intracellular detoxification. In an insect infection model, we also observed two stilbene-derived metabolites that were dependent on the epoxidase. NMR, computational, and chemical degradation studies established their structures as new stilbene-l-proline conjugates, prolbenes A (compound 3) and B (compound 4). The prolbenes lacked immunosuppressive and antimicrobial activities compared with their stilbene substrates, suggesting a metabolite attenuation mechanism in the animal model. Collectively, our studies provide a structural view for stereoselective stilbene epoxidation and functionalization in an invertebrate animal infection model and provide new insights into stilbene cellular detoxification. PMID:28246174

  19. Tumor initiating activities of various derivatives of benz(a)anthracene and 7, 12-dimethyl-benz(a)anthracene in mouse skin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Slaga, T.J.; Gleason, G.L.; DiGiovanni, J.

    Current information indicates that polycyclic aromatic hydrocarbons (PAH) exert their toxic, mutagenic, and carcinogenic activities after they have been metabolically activated by target cells to reactive epoxides. The results obtained from IN VIVO and IN VITRO binding, mutagenicity, metabolism, and carcinogenicity studies have led to the conclusion that BP-7, 8-diol is a proximate carcinogenic metabolite of BP, and the BP-diol-epoxide is an ultimate carcinogenic metabolite of BP. Recent results concerning the strong carcinogenicity of BP-7..beta.., 8..cap alpha..-diol-9..cap alpha..,10..cap alpha..-epoxide in newborn mice and in mouse skin strongly indicate that it is the ultimate carcinogenic metabolite of BP. Since diol-epoxides maymore » be responsible for the carcinogenicity of PAH other than BP, diols and diol-epoxides as well as other derivatives of PAH were tested for skin tumor-initiation in a two-stage system of tumorigenesis. In addition, since activation of methylated PAH may involve the side-chain methyl group, the skin tumor-initiating activity of various side-chain derivatives of methylated PA were determined. In this report, the skin tumor initiation of various derivatives of a nonmethylated PAH, BA as well as a methylated PAH, DMBA are compared. The data suggest that bay region diol-epoxides may be important in BA and DMBA carcinogenicity in mice which is supportive of the theory proposed by Jerina and co-workers which predicts that diol-epoxides in the bay region are the major determinants of PAH carcinogenicity.« less

  20. Epoxide hydrolases: structure, function, mechanism, and assay.

    PubMed

    Arand, Michael; Cronin, Annette; Adamska, Magdalena; Oesch, Franz

    2005-01-01

    Epoxide hydrolases are a class of enzymes important in the detoxification of genotoxic compounds, as well as in the control of physiological signaling molecules. This chapter gives an overview on the function, structure, and enzymatic mechanism of structurally characterized epoxide hydrolases and describes selected assays for the quantification of epoxide hydrolase activity.

  1. NAD(P)H:quinone oxidoreductase 1 (NQO1) competes with 20S proteasome for binding with C/EBPα leading to its stabilization and protection against radiation-induced myeloproliferative disease.

    PubMed

    Xu, Junkang; Jaiswal, Anil K

    2012-12-07

    NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that protects cells against radiation and chemical-induced oxidative stress. Disruption of NQO1 gene in mice leads to increased susceptibility to myeloproliferative disease. In this report, we demonstrate that NQO1 controls the stability of myeloid differentiation factor C/EBPα against 20S proteasomal degradation during radiation exposure stress. Co-immunoprecipitation studies showed that NQO1, C/EBPα, and 20S all interacted with each other. C/EBPα interaction with 20S led to the degradation of C/EBPα. NQO1 in presence of its cofactor NADH protected C/EBPα against 20S degradation. Deletion and site-directed mutagenesis demonstrated that NQO1 and 20S competed for the same binding region (268)SGAGAGKAKKSV(279) in C/EBPα. Mutagenesis studies also revealed that NQO1Y127/Y129 required for NADH binding is essential for NQO1 stabilization of C/EBPα. Exposure of mice and HL-60 cells to 3 Grays of γ-radiation led to increased NQO1 that stabilized C/EBPα against 20S proteasomal degradation. This mechanism of NQO1 regulation of C/EBPα may provide protection to bone marrow against adverse effects of radiation exposure. The studies have significance for human individuals carrying hetero- or homozygous NQO1P187S mutation and are deficient or lack NQO1 protein.

  2. Succinic anhydrides from epoxides

    DOEpatents

    Coates, Geoffrey W.; Rowley, John M.

    2013-07-09

    Catalysts and methods for the double carbonylation of epoxides are disclosed. Each epoxide molecule reacts with two molecules of carbon monoxide to produce a succinic anhydride. The reaction is facilitated by catalysts combining a Lewis acidic species with a transition metal carbonyl complex. The double carbonylation is achieved in single process by using reaction conditions under which both carbonylation reactions occur without the necessity of isolating or purifying the product of the first carbonylation.

  3. Succinic anhydrides from epoxides

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Coates, Geoffrey W.; Rowley, John M.

    2016-06-28

    Catalysts and methods for the double carbonylation of epoxides are disclosed. Each epoxide molecule reacts with two molecules of carbon monoxide to produce a succinic anhydride. The reaction is facilitated by catalysts combining a Lewis acidic species with a transition metal carbonyl complex. The double carbonylation is achieved in single process by using reaction conditions under which both carbonylation reactions occur without the necessity of isolating or purifying the product of the first carbonylation.

  4. Influence of Ogg1 repair on the genetic stability of ccc2 mutant of Saccharomyces cerevisiae chemically challenged with 4-nitroquinoline-1-oxide (4-NQO).

    PubMed

    da Silva, Claudia R; Almeida, Gabriella S; Caldeira-de-Araújo, Adriano; Leitão, Alvaro C; de Pádula, Marcelo

    2016-01-01

    In Saccharomyces cerevisiae, disruption of genes by deletion allowed elucidation of the molecular mechanisms of a series of human diseases, such as in Wilson disease (WD). WD is a disorder of copper metabolism, due to inherited mutations in human copper-transporting ATPase (ATP7B). An orthologous gene is present in S. cerevisiae, CCC2 gene. Copper is required as a cofactor for a number of enzymes. In excess, however, it is toxic, potentially carcinogenic, leading to many pathological conditions via oxidatively generated DNA damage. Deficiency in ATP7B (human) or Ccc2 (yeast) causes accumulation of intracellular copper, favouring the generation of reactive oxygen species. Thus, it becomes important to study the relative importance of proteins involved in the repair of these lesions, such as Ogg1. Herein, we addressed the influence Ogg1 repair in a ccc2 deficient strain of S. cerevisiae. We constructed ccc2-disrupted strains from S. cerevisiae (ogg1ccc2 and ccc2), which were analysed in terms of viability and spontaneous mutator phenotype. We also investigated the impact of 4-nitroquinoline-1-oxide (4-NQO) on nuclear DNA damage and on the stability of mitochondrial DNA. The results indicated a synergistic effect on spontaneous mutagenesis upon OGG1 and CCC2 double inactivation, placing 8-oxoguanine as a strong lesion-candidate at the origin of spontaneous mutations. The ccc2 mutant was more sensitive to cell killing and to mutagenesis upon 4-NQO challenge than the other studied strains. However, Ogg1 repair of exogenous-induced DNA damage revealed to be toxic and mutagenic to ccc2 deficient cells, which can be due to a detrimental action of Ogg1 on DNA lesions induced in ccc2 cells. Altogether, our results point to a critical and ambivalent role of BER mediated by Ogg1 in the maintenance of genomic stability in eukaryotes deficient in CCC2 gene. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights

  5. 40 CFR 721.2675 - Perfluoroalkyl epoxide (generic name).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Substances § 721.2675 Perfluoroalkyl epoxide (generic name). (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as perfluoroalkyl epoxide (PMN P... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Perfluoroalkyl epoxide (generic name...

  6. 40 CFR 721.2675 - Perfluoroalkyl epoxide (generic name).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Substances § 721.2675 Perfluoroalkyl epoxide (generic name). (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as perfluoroalkyl epoxide (PMN P... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Perfluoroalkyl epoxide (generic name...

  7. 40 CFR 721.2675 - Perfluoroalkyl epoxide (generic name).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Substances § 721.2675 Perfluoroalkyl epoxide (generic name). (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as perfluoroalkyl epoxide (PMN P... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Perfluoroalkyl epoxide (generic name...

  8. 40 CFR 721.2675 - Perfluoroalkyl epoxide (generic name).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Substances § 721.2675 Perfluoroalkyl epoxide (generic name). (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as perfluoroalkyl epoxide (PMN P... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Perfluoroalkyl epoxide (generic name...

  9. 40 CFR 721.2675 - Perfluoroalkyl epoxide (generic name).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Substances § 721.2675 Perfluoroalkyl epoxide (generic name). (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as perfluoroalkyl epoxide (PMN P... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Perfluoroalkyl epoxide (generic name...

  10. Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis

    PubMed Central

    Li, Qing; Karim, Ahmad F.; Ding, Xuedong; Das, Biswajit; Dobrowolski, Curtis; Gibson, Richard M.; Quiñones-Mateu, Miguel E.; Karn, Jonathan; Rojas, Roxana E.

    2016-01-01

    Chemical regulation of macrophage function is one key strategy for developing host-directed adjuvant therapies for tuberculosis (TB). A critical step to develop these therapies is the identification and characterization of specific macrophage molecules and pathways with a high potential to serve as drug targets. Using a barcoded lentivirus-based pooled short-hairpin RNA (shRNA) library combined with next generation sequencing, we identified 205 silenced host genes highly enriched in mycobacteria-resistant macrophages. Twenty-one of these “hits” belonged to the oxidoreductase functional category. NAD(P)H:quinone oxidoreductase 1 (NQO1) was the top oxidoreductase “hit”. NQO1 expression was increased after mycobacterial infection, and NQO1 knockdown increased macrophage differentiation, NF-κB activation, and the secretion of pro-inflammatory cytokines TNF-α and IL-1β in response to infection. This suggests that mycobacteria hijacks NQO1 to down-regulate pro-inflammatory and anti-bacterial functions. The competitive inhibitor of NQO1 dicoumarol synergized with rifampin to promote intracellular killing of mycobacteria. Thus, NQO1 is a new host target in mycobacterial infection that could potentially be exploited to increase antibiotic efficacy in vivo. Our findings also suggest that pooled shRNA libraries could be valuable tools for genome-wide screening in the search for novel druggable host targets for adjunctive TB therapies. PMID:27297123

  11. Enzyme-catalyzed cationic epoxide rearrangements in quinolone alkaloid biosynthesis.

    PubMed

    Zou, Yi; Garcia-Borràs, Marc; Tang, Mancheng C; Hirayama, Yuichiro; Li, Dehai H; Li, Li; Watanabe, Kenji; Houk, K N; Tang, Yi

    2017-03-01

    Epoxides are highly useful synthons and biosynthons for the construction of complex natural products during total synthesis and biosynthesis, respectively. Among enzyme-catalyzed epoxide transformations, a reaction that is notably missing, in regard to the synthetic toolbox, is cationic rearrangement that takes place under strong acid. This is a challenging transformation for enzyme catalysis, as stabilization of the carbocation intermediate upon epoxide cleavage is required. Here, we discovered two Brønsted acid enzymes that can catalyze two unprecedented epoxide transformations in biology. PenF from the penigequinolone pathway catalyzes a cationic epoxide rearrangement under physiological conditions to generate a quaternary carbon center, while AsqO from the aspoquinolone pathway catalyzes a 3-exo-tet cyclization to forge a cyclopropane-tetrahydrofuran ring system. The discovery of these new epoxide-modifying enzymes further highlights the versatility of epoxides in complexity generation during natural product biosynthesis.

  12. Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Hsu, Yih-Chih

    2012-03-01

    In Taiwan, oral cancer has becomes the fastest growth male cancer disease due to the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people. In order to eliminate the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when ALA reached its peak level in the lesional epithelial cells after topical application of ALA gel. We found that ALA reached its peak level in precancerous lesions about 2.5 hrs after topical application of ALA gel. The cancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 150 J/cm2 using LED 635 nm fiber-guided light device. Visual examination demonstrated that adjuvant topical ALA -mediated PDT group has shown better therapeutic results in compared to those of non-adjuvant topical ALA-mediated PDT group for DMBA-induced hamster buccal pouch precancerous lesions.

  13. Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations.

    PubMed

    Brambilla, Marta; Brennan, Méabh B; Csatayová, Kristína; Davies, Stephen G; Fletcher, Ai M; Kennett, Alice M R; Lee, James A; Roberts, Paul M; Russell, Angela J; Thomson, James E

    2017-10-06

    The diastereoselectivities and rates of epoxidation (upon treatment with Cl 3 CCO 2 H then m-CPBA) of a range of cis- and trans-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn 2 ), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it.

  14. Prediction of metabolites of epoxidation reaction in MetaTox.

    PubMed

    Rudik, A V; Dmitriev, A V; Bezhentsev, V M; Lagunin, A A; Filimonov, D A; Poroikov, V V

    2017-10-01

    Biotransformation is a process of the chemical modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicology studies. Epoxides are formed by some oxidation reactions, usually catalysed by cytochromes P450, and represent a large class of three-membered cyclic ethers. Identification of molecules, which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE - site of epoxidation) are important for prediction of epoxide metabolites. Datasets from 355 molecules and 615 reactions were created for training and validation. The prediction of SOE is based on a combination of LMNA (Labelled Multilevel Neighbourhood of Atom) descriptors and Bayesian-like algorithm implemented in PASS software and MetaTox web-service. The average invariant accuracy of prediction (AUC) calculated in leave-one-out and 20-fold cross-validation procedures is 0.9. Prediction of epoxide formation based on the created SAR model is included as the component of MetaTox web-service ( http://www.way2drug.com/mg ).

  15. Zeaxanthin epoxidation - an in vitro approach.

    PubMed

    Kuczyńska, Paulina; Latowski, Dariusz; Niczyporuk, Sylvia; Olchawa-Pajor, Monika; Jahns, Peter; Gruszecki, Wiesław I; Strzałka, Kazimierz

    2012-01-01

    Zeaxanthin epoxidase (ZE) is an enzyme operating in the violaxanthin cycle, which is involved in photoprotective mechanisms. In this work model systems to study zeaxanthin (Zx) epoxidation were developed. Two assay systems are presented in which epoxidation of Zx was observed. In these assays two mutants of Arabidopsis thaliana which have active only one of the two xanthophyll cycle enzymes were used. The npq1 mutant possesses an active ZE and is thus able to convert Zx to violaxanthin (Vx) but the violaxanthin de-epoxidase (VDE) is inactive, so that Vx cannot be converted to Zx. The other mutant, npq2, possesses an active VDE and can convert exogenous Vx to Zx under strong light conditions but reverse reaction is not possible. The first assay containing thylakoids from npq1 and npq2 mutants of A. thaliana gave positive results and high efficiency of epoxidation reaction was observed. The amount of Zx was reduced by 25%. To optimize high efficiency of epoxidation reaction additional factors facilitating both fusion of the two types of thylakoids and incorporation of Zx to their membranes were also studied. The second kind of assay contained npq1 mutant thylakoids of A. thaliana supplemented with exogenous Zx and monogalactosyldiacylglycerol (MGDG). Experiments with different proportions of Zx and MGDG showed that their optimal ratio is 1:60. In such system, due to epoxidation, the amount of Zx was reduced by 38% of its initial level. The in vitro systems of Zx epoxidation described in this paper enable analysis some properties of the ZE without necessity of its isolation.

  16. Elimination of deleterious effects of DMBA-induced skin carcinogenesis in mice by Syzygium cumini seed extract.

    PubMed

    Parmar, Jyoti; Sharma, Priyanka; Verma, Preeti; Sharma, Priyanka; Goyal, Pradeep K

    2011-09-01

    The inhibition of tumor incidence by hydro-alcoholic extract of S.cumini seed was evaluated in mice on two stage process of skin carcinogenesis induced by single application of 7, 12-dimethyl benz(a)anthracene (100 µg/100µl of acetone), and 2 weeks later promoted by repeated application of croton oil (1% acetone/thrice in a week) till the end of the experiment (i.e. 16 weeks). Oral administration of extract at a dose of 250mg/kg b.wt./day at the peri-initiational stage (i.e. 7 days before and 7 days after DMBA application), promotional stage (i.e. from the time of croton oil application) and at both the stages (i.e. 7 days prior to DMBA application & continued till the end of experiment) to the mice, recorded a significant reduction in tumor incidence to 37.5, 50 & 25% respectively in comparison to the carcinogen treated control, where tumor incidence was found as 100%. Tumor yield and Tumor burden were also significantly reduced by SCE. Similarly, the cumulative number of papillomas after 16 weeks was 68 in the control group, which was reduced to 15, 21 & 8 in the animals treated with the SCE continuously at peri-, post- and peri- & post- initiation stage respectively. A significant impairment was noticed in the levels of reduced glutathione, superoxide dismutase, catalase & protein and enhancement in LPO in liver and skin of carcinogen treated control mice as compared with vehicle treated mice. All such parameters were returned to near normal value by administration of SCE to DMBA treated mice. These results suggest a possible chemopreventive property of S.cumini against DMBA induced skin carcinogenesis in mice.

  17. Coenzyme Q(1) as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and Nqo1-null mouse lung.

    PubMed

    Bongard, Robert D; Myers, Charles R; Lindemer, Brian J; Baumgardt, Shelley; Gonzalez, Frank J; Merker, Marilyn P

    2012-05-01

    Previous studies showed that coenzyme Q(1) (CoQ(1)) reduction on passage through the rat pulmonary circulation was catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex I, but that NQO1 genotype was not a factor in CoQ(1) reduction on passage through the mouse lung. The aim of the present study was to evaluate the complex I contribution to CoQ(1) reduction in the isolated perfused wild-type (NQO1(+/+)) and Nqo1-null (NQO1(-)/(-)) mouse lung. CoQ(1) reduction was measured as the steady-state pulmonary venous CoQ(1) hydroquinone (CoQ(1)H(2)) efflux rate during infusion of CoQ(1) into the pulmonary arterial inflow. CoQ(1)H(2) efflux rates during infusion of 50 μM CoQ(1) were not significantly different for NQO1(+/+) and NQO1(-/-) lungs (0.80 ± 0.03 and 0.68 ± 0.07 μmol·min(-1)·g lung dry wt(-1), respectively, P > 0.05). The mitochondrial complex I inhibitor rotenone depressed CoQ(1)H(2) efflux rates for both genotypes (0.19 ± 0.08 and 0.08 ± 0.04 μmol·min(-1)·g lung dry wt(-1) for NQO1(+/+) and NQO1(-/-), respectively, P < 0.05). Exposure of mice to 100% O(2) for 48 h also depressed CoQ(1)H(2) efflux rates in NQO1(+/+) and NQO1(-/-) lungs (0.43 ± 0.03 and 0.11 ± 0.04 μmol·min(-1)·g lung dry wt(-1), respectively, P < 0.05 by ANOVA). The impact of rotenone or hyperoxia on CoQ(1) redox metabolism could not be attributed to effects on lung wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total venous effluent CoQ(1) recoveries, the latter measured by spectrophotometry or mass spectrometry. Complex I activity in mitochondria-enriched lung fractions was depressed in hyperoxia-exposed lungs for both genotypes. This study provides new evidence for the potential utility of CoQ(1) as a nondestructive indicator of the impact of pharmacological or pathological exposures on complex I activity in the intact perfused mouse lung.

  18. The Epoxidation of 2,5-Di-tert-butyl-1,4-benzoquinone: A Consecutive Reaction for the Physical Chemistry Laboratory.

    ERIC Educational Resources Information Center

    Hairfield, E. M.; And Others

    1985-01-01

    Reports a consecutive first-order reaction for which the concentrations of reactant, intermediate, and products can be determined simulataneously. This reaction is the epoxidation of 2,5-di-tert-butyl-1,4-benzoquinone (I) by alkaline hydroperoxidation using tert-butyl hydroperoxide and benzyltrimethylammonium hydroxide (Triton B) catalyst.…

  19. Topical photosan-mediated photodynamic therapy for DMBA-induced hamster buccal pouch early cancer lesions: an in vivo study

    NASA Astrophysics Data System (ADS)

    Hsu, Yih-Chih; Chang, Walter Hong-Shong; Chang, Junn-Liang; Liu, Kuang-Ting; Chiang, Chun-Pin; Liu, Chung-Ji; Chen, Chih-Ping

    2011-03-01

    Oral cancer has becomes the most prominent cancer disease in recent years in Taiwan. The reason is the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people results in oral cancer becomes the fastest growth incident cancer amongst other major cancer diseases. In previous studies showed that photosan, haematoporphyrin derivative (HPD), has demonstrated effective PDT results on human head and neck disease studies. To avoid the systemic phototoxic effect of photosan, this study was designed to use a topical photosan-mediated PDT for treatment of DMBA-induced hamster buccal pouch cancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical photosan-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when photosan reached its peak level in the lesional epithelial cells after topical application of photosan gel. We found that photosan reached its peak level in cancerous lesions about 13.5 min after topical application of photosan gel. The cancerous lesions in hamsters were then treated with topical photosan-mediated PDT (fluence rate: 600 mW/cm2; light exposure dose 200 J/cm2) using the portable Lumacare 635 nm fiber-guided light device. Visual examination demonstrated that topical photosan-mediated PDT was an applicable treatment modality for DMBA-induced hamster buccal pouch cancerous lesions.

  20. Polyisoprenoid epoxides stimulate the biosynthesis of coenzyme Q and inhibit cholesterol synthesis.

    PubMed

    Bentinger, Magnus; Tekle, Michael; Brismar, Kerstin; Chojnacki, Tadeusz; Swiezewska, Ewa; Dallner, Gustav

    2008-05-23

    In our search for compounds that up-regulate the biosynthesis of coenzyme Q (CoQ), we discovered that irradiation of CoQ with ultraviolet light results in the formation of a number of compounds that influence the synthesis of mevalonate pathway lipids by HepG2 cells. Among the compounds that potently stimulated CoQ synthesis while inhibiting cholesterol synthesis, derivatives of CoQ containing 1-4 epoxide moieties in their polyisoprenoid side chains were identified. Subsequently, chemical epoxidation of all-trans-polyprenols of different lengths revealed that the shorter farnesol and geranylgeraniol derivatives were without effect, whereas the longer derivatives of solanesol enhanced CoQ and markedly reduced cholesterol biosynthesis. In contrast, none of the modified trans-trans-poly-cis-polyprenols exerted noticeable effects. Tocotrienol epoxides were especially potent in our system; those with one epoxide moiety in the side-chain generally up-regulated CoQ biosynthesis by 200-300%, whereas those with two such moieties also decreased cholesterol synthesis by 50-90%. Prolonged treatment of HepG2 cells with tocotrienol epoxides for 26 days elevated their content of CoQ by 30%. In addition, the levels of mRNA encoding enzymes involved in CoQ biosynthesis were also elevated by the tocotrienol epoxides. The site of inhibition of cholesterol synthesis was shown to be oxidosqualene cyclase. In conclusion, epoxide derivatives of certain all-trans-polyisoprenoids cause pronounced stimulation of CoQ synthesis and, in some cases, simultaneous reduction of cholesterol biosynthesis by HepG2 cells.

  1. Evaluation of the protective effect of Nigella sativa extract and its primary active component thymoquinone against DMBA-induced breast cancer in female rats

    PubMed Central

    Linjawi, Sabah A. A.; Hassanane, Mahrosa M.; Ahmed, Ekram S.

    2013-01-01

    Introduction The historical use of black cumin seed (Nigella sativa) dates back centuries, being embedded in Arabian culture and having a long history of unsurpassed medicinal value with versatility to treat a wide range of ailments. Thymoquinone (TQ) is now known to be the primary active constituent of black cumin seed oil (BCS oil) responsible for its medicinal effects and also showing promise for treatment of cancer. Material and methods In the current study, we have studied the effects of TQ and BCS oil on tumor markers (MDA, LDH, ALP and AST), histopathological alterations and the regulation of several genes (Brca1, Brca2, Id-1 and P53 mutation) related to breast cancer in female rats induced by 7,12-dimethylbenz[a]anthracene (DMBA) treatment. Rats received a single dose (65 mg/kg b.w.) of DMBA via an intragastric tube to induce breast cancer. Animals that received DMBA were treated orally with 1, 5, 10 mg/kg of TQ or BCS oil via an intragastric tube three times per week for 4 months. Results We found that TQ and then BCS reduced the rate of tumor markers (levels of MDA and LDH as well as ALP and AST activities), inhibited the histopathological alterations and decreased the expression of the Brca1, Brca2, Id-1 and P53 mutations in mammary tissues of female rats induced by DMBA treatment. Conclusions The results suggest that TQ and BCS oil exert a protective effect against breast carcinogens. The antioxidant property of TQ and BCS oil is mediated by their actions and investigating other underlying mechanisms merits further studies. PMID:25861310

  2. Heptachlor epoxide

    Integrated Risk Information System (IRIS)

    Heptachlor epoxide ; CASRN 1024 - 57 - 3 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogen

  3. Sequential enzymatic epoxidation involved in polyether lasalocid biosynthesis.

    PubMed

    Minami, Atsushi; Shimaya, Mayu; Suzuki, Gaku; Migita, Akira; Shinde, Sandip S; Sato, Kyohei; Watanabe, Kenji; Tamura, Tomohiro; Oguri, Hiroki; Oikawa, Hideaki

    2012-05-02

    Enantioselective epoxidation followed by regioselective epoxide opening reaction are the key processes in construction of the polyether skeleton. Recent genetic analysis of ionophore polyether biosynthetic gene clusters suggested that flavin-containing monooxygenases (FMOs) could be involved in the oxidation steps. In vivo and in vitro analyses of Lsd18, an FMO involved in the biosynthesis of polyether lasalocid, using simple olefin or truncated diene of a putative substrate as substrate mimics demonstrated that enantioselective epoxidation affords natural type mono- or bis-epoxide in a stepwise manner. These findings allow us to figure out enzymatic polyether construction in lasalocid biosynthesis. © 2012 American Chemical Society

  4. Regiospecific Epoxidation of Carvone: A Discovery-Oriented Experiment for Understanding the Selectivity and Mechanism of Epoxidation Reactions

    ERIC Educational Resources Information Center

    Mak, Kendrew K. W.; Lai, Y. M.; Siu, Yuk-Hong

    2006-01-01

    This article describes a discovery-oriented experiment for demonstrating the selectivity of two epoxidation reactions. Peroxy acids and alkaline H[subscript 2]O[subscript 2] are two commonly used reagents for alkene epoxidation. The former react preferentially with electron-rich alkenes while the latter works better with alpha,beta-unsaturated…

  5. Maternal handling during pregnancy reduces DMBA-induced mammary tumorigenesis among female offspring.

    PubMed Central

    Hilakivi-Clarke, L.

    1997-01-01

    The present study investigated whether handling of pregnant rats would affect mammary tumorigenesis in their female offspring. Pregnant Sprague-Dawley rats were injected daily with 0.05 ml of vehicle between days 14 and 20 of gestation or were left undisturbed. Handling did not have any effects on pregnancy or early development of the offspring. The female offspring were administered 10 mg of 7,12-dimethylbenz(a)anthracene (DMBA) at the age of 55 days. The rats whose mothers were handled during pregnancy had a significantly reduced mammary tumour incidence when compared with the offspring of non-handled mothers. Thus, on week 18 after DMBA exposure, 15% of the handled offspring had developed mammary tumours, whereas 44% of the non-handled offspring had tumours. No significant differences in the latency to tumour appearance, in the size of the tumours or in their growth rates were noted. Daily handling performed during post-natal days 5 and 20 produced similar data to that obtained for prenatal handling; on week 18 after DMBA exposure, the mammary tumour incidence among the post-natally handled rats was 22% and among the non-handled rats 44%. Possible deviations in hormonal parameters were also studied in adult female rats exposed in utero to handling. The onset of puberty tended to occur later among the handled offspring, but no differences in the uterine wet weights or serum oestradiol levels between the groups were noted. In conclusion, maternal handling reduced the offspring's risk to develop mammary tumours, and this effect was independent of the oestrogenic environment at adulthood. We propose that handling of a pregnant rat reduces mammary tumorigenesis in her offspring by means of changing the morphology of the mammary gland, the pattern of expression of specific genes and/or immune functions. PMID:9231913

  6. Comparsion of light dose on topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Tseng, Meng-Ke; Liu, Chung-Ji; Hsu, Yih-Chih

    2012-03-01

    Oral cancer has becomes the most prominent male cancer disease due to the local betel nut chewing habit combing with smoking and alcohol-drinking lifestyle. In order to minimize the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch cancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 8 to 10 weeks. Precancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA -mediated PDT. We found that ALA reached its peak level in cancerous lesions about 2.5 hrs after topical application of ALA gel. The precancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 75 and 100 J/cm2 using LED 635 nm Wonderlight device. It is suggesting that optimization of the given light dose is critical to the success of PDT results.

  7. Peroxotantalate-Based Ionic Liquid Catalyzed Epoxidation of Allylic Alcohols with Hydrogen Peroxide.

    PubMed

    Ma, Wenbao; Chen, Chen; Kong, Kang; Dong, Qifeng; Li, Kun; Yuan, Mingming; Li, Difan; Hou, Zhenshan

    2017-05-29

    The efficient and environmentally benign epoxidation of allylic alcohols has been attained by using new kinds of monomeric peroxotantalate anion-functionalized ionic liquids (ILs=[P 4,4,4,n ] 3 [Ta(O) 3 (η-O 2 )], P 4,4,4,n =quaternary phosphonium cation, n=4, 8, and 14), which have been developed and their structures determined accordingly. This work revealed the parent anions of the ILs underwent structural transformation in the presence of H 2 O 2 . The formed active species exhibited excellent catalytic activity, with a turnover frequency for [P 4,4,4,4 ] 3 [Ta(O) 3 (η-O 2 )] of up to 285 h -1 , and satisfactory recyclability in the epoxidation of various allylic alcohols under very mild conditions by using only one equivalent of hydrogen peroxide as an oxidant. NMR studies showed the reaction was facilitated through a hydrogen-bonding mechanism, in which the peroxo group (O-O) of the peroxotantalate anion served as the hydrogen-bond acceptor and hydroxyl group in the allylic alcohols served as the hydrogen-bond donor. This work demonstrates that simple monomeric peroxotantalates can catalyze epoxidation of allylic alcohols efficiently. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. The effect of dietary zinc - and polyphenols intake on DMBA-induced mammary tumorigenesis in rats

    PubMed Central

    2012-01-01

    Background The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca) in tumors as compared with normal tissue of the mammary gland. Methods Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene), were treated with zinc ions (Zn) or zinc ions + resveratrol (Zn + resveratrol) or zinc ions + genistein (Zn + genistein) via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry) technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer. Results Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein), DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found - irrespectively of the diet applied - great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue. Conclusions Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of the iron and magnesium

  9. Lycopene, resveratrol, vitamin C and FeSO4 increase damage produced by pro-oxidant carcinogen 4-nitroquinoline-1-oxide in Drosophila melanogaster: Xenobiotic metabolism implications.

    PubMed

    Dueñas-García, I E; Heres-Pulido, M E; Arellano-Llamas, M R; De la Cruz-Núñez, J; Cisneros-Carrillo, V; Palacios-López, C S; Acosta-Anaya, L; Santos-Cruz, L F; Castañeda-Partida, L; Durán-Díaz, A

    2017-05-01

    4-nitroquinoline-1-oxide (4-NQO) is a pro-oxidant carcinogen bioactivated by xenobiotic metabolism (XM). We investigated if antioxidants lycopene [0.45, 0.9, 1.8 μM], resveratrol [11, 43, 172 μM], and vitamin C [5.6 mM] added or not with FeSO 4 [0.06 mM], modulate the genotoxicity of 4-NQO [2 mM] with the Drosophila wing spot test standard (ST) and high bioactivation (HB) crosses, with inducible and high levels of cytochromes P450, respectively. The genotoxicity of 4-NQO was higher when dissolved in an ethanol - acetone mixture. The antioxidants did not protect against 4-NQO in any of both crosses. In the ST cross, resveratrol [11 μM], vitamin C and FeSO 4 resulted in genotoxicity; the three antioxidants and FeSO 4 increased the damage of 4-NQO. In the HB cross, none of the antioxidants, neither FeSO 4 , were genotoxic. Only resveratrol [172 μM] + 4-NQO increased the genotoxic activity in both crosses. We concluded that the effects of the antioxidants, FeSO 4 and the modulation of 4-NQO were the result of the difference of Cyp450s levels, between the ST and HB crosses. We propose that the basal levels of the XM's enzymes in the ST cross interacted with a putative pro-oxidant activity of the compounds added to the pro-oxidant effects of 4-NQO. Copyright © 2017. Published by Elsevier Ltd.

  10. Catalytic performance of Mn 3O 4 and Co 3O 4 nanocrystals prepared by sonochemical method in epoxidation of styrene and cyclooctene

    NASA Astrophysics Data System (ADS)

    Askarinejad, Azadeh; Bagherzadeh, Mojtaba; Morsali, Ali

    2010-09-01

    A simple sonochemical method was developed to synthesis uniform sphere-like Co 3O 4 and Mn 3O 4 nanocrystals. Epoxidation of styrene and cyclooctene by anhydrous tert-butyl hydroperoxide over the prepared Co 3O 4 and Mn 3O 4 nanocatalysts was investigated. The results of conversion activity were compared with bulk Co 3O 4 and Mn 3O 4. Under optimized reaction conditions, the nanocatalysts showed a superior catalytic performance as compared to the bulk catalysts. Powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and BET surface area, were used to characterize and investigate the nanocatalysts.

  11. Enantioselective epoxidation with chiral MN(III)(salen) catalysts: kinetic resolution of aryl-substituted allylic alcohols.

    PubMed

    Adam, W; Humpf, H U; Roschmann, K J; Saha-Möller, C R

    2001-08-24

    A set of aryl-substituted allylic alcohols rac-2 has been epoxidized by chiral Mn(salen*) complexes 1 as the catalyst and iodosyl benzene (PhIO) as the oxygen source. Whereas one enantiomer of the allylic alcohol 2 is preferentially epoxidized to give the threo- or cis-epoxy alcohol 3 (up to 80% ee) as the main product (dr up to >95:5), the other enantiomer of 2 is enriched (up to 53% ee). In the case of 1,1-dimethyl-1,2-dihydronaphthalen-2-ol (2c), the CH oxidation to the enone 4c proceeds enantioselectively and competes with the epoxidation. The absolute configurations of the allylic alcohols 2 and their epoxides 3 have been determined by chemical correlation or CD spectroscopy. The observed diastereo- and enantioselectivities in the epoxidation reactions are rationalized in terms of a beneficial interplay between the hydroxy-directing effect and the attack along the Katsuki trajectory.

  12. Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

    PubMed Central

    2013-01-01

    Summary Enantioselective desymmetrization of meso-aziridines and meso-epoxides with various nucleophiles by organocatalysis has emerged as a cutting-edge approach in recent years. This review summarizes the origin and recent developments of enantioselective desymmetrization of meso-aziridines and meso-epoxides in the presence of organocatalysts. PMID:24062828

  13. RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures

    PubMed Central

    2014-01-01

    Background Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL). Methods Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique. Results Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed. Conclusions Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T). PMID:24571676

  14. RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures.

    PubMed

    Andrade, Francianne Gomes; Furtado-Silva, Juliana Montibeller; Gonçalves, Bruno Alves de Aguiar; Thuler, Luiz Claudio Santos; Barbosa, Thayana Conceição; Emerenciano, Mariana; Siqueira, André; Pombo-de-Oliveira, Maria S

    2014-02-26

    Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL). Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique. Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed. Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T).

  15. Ring opening of epoxides with C-nucleophiles.

    PubMed

    Faiz, Sadia; Zahoor, Ameer Fawad

    2016-11-01

    Ring opening of epoxides has been an area of interest for organic chemists, owing to their reactivity toward nucleophiles. Such reactions yield important products depending on the type of nucleophiles used. This review article covers the synthetic approaches (1991-2015) used for the ring opening of epoxides via carbon nucleophiles.

  16. Topical chlorophyll-pheophytin derivative-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premaligant lesions: an in vivo study

    NASA Astrophysics Data System (ADS)

    Hsu, Yih-Chih; Chiang, Chung-Pin; Chen, Jian Wen; Lee, Jeng-Woei; How, Mon-Hsin

    2010-02-01

    In Taiwan, oral cancer has become a prominent cancer because of its highest annual increase rate among all cancer diseases. Betel quid chewing habit is a major risk factor for oral precancerous and cancerous lesions and there are more than two million people who have this habit in Taiwan. Our previous studies showed that chlorophyll-pheophytin derivative (CPD)-mediated PDT is very effective for killing of SCC-4 cell lines in vitro. In order to decrease the systemic phototoxic effect of CPD, this study was designed to use a topical CPD-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 8 to 10 weeks. Precancerous lesions of moderate to severe dysplasia were induced and proven by histological examination. These induced precancerous lesions were used for testing the efficacy of topical CPD-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when CPD reached its peak level in the lesional epithelial cells after topical application of CPD gel. We found that CPD reached its peak level in precancerous lesions about 1 hour (range, 0 to 30 hours) after topical application of CPD gel. The precancerous lesions in hamsters were then treated with topical CPD-mediated PDT (fluence rate: 200 mW/cm2; light exposure dose 100 J/cm2) using the portable WonderLight LED 635 nm fiber-guided light device once or twice a week. Visual and histological examination demonstrated that topical CPD-mediated PDT was partially effective treatment modality for DMBA-induced hamster buccal pouch precancerous lesions.

  17. Euterpe oleracea extract inhibits tumorigenesis effect of the chemical carcinogen DMBA in breast experimental cancer.

    PubMed

    Alessandra-Perini, Jéssica; Perini, Jamila Alessandra; Rodrigues-Baptista, Karina Cristina; de Moura, Roberto Soares; Junior, Antonio Palumbo; Dos Santos, Thiago Alves; Souza, Pergentino José Cunha; Nasciutti, Luiz Eurico; Machado, Daniel Escorsim

    2018-04-02

    Among the processes involved in the breast tumor microenvironment, angiogenesis and inflammation play a central role, and the main factors of these processes are the vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2) and macrophages. Recently, the extract of Euterpe oleracea (açaí), a fruit that is widely found in the Amazon region, already showed antitumorigenic effects in vitro in human breast cancer cell lines. The present study aimed to investigate the effect of açaí on breast cancer using a chemically DMBA (7,12-dimethylbenzanthracene) experimental model. One day after initiation of treatment with açaí, mammary carcinogenesis was induced in female Wistar rats using a subcutaneous injection of 25 mg/kg of DMBA in the mammary gland. Forty rats were randomized into two groups: treated with 200 mg/kg of either açaí extract or vehicle, via gastric tube for 16 consecutive weeks. After treatment, the tumor was collected for macroscopic, histological and immunohistochemical (VEGF, vascular endothelial growth factor receptor 2 -VEGFR-2, COX-2 and matrix metalloproteinase -MMP-9) analyses; peritoneal fluid was subjected to flow cytometry (F4-80/MAC-2+) and ELISA immunoassay (VEGF, prostaglandin E 2 -PGE 2 and interleukin-10 -IL-10). Heart, liver and kidney samples were collected for histological analysis. After 16 weeks of induction, the mammary carcinoma was confirmed by macroscopic and histological evaluation. Survival analysis indicates that açaí increased the survival (P = .0002, long-rank test) and reduced the deaths number (P = .0036, Chi-square test). Açaí treatment decreased the number of inflammatory cells and macrophage positive cells (Mac-2 + F4-80+), as well as promoting a reduction in immunostaining of VEGF, VEGFR-2 and COX-2. The açaí group also exhibited lower concentrations of PGE 2 , VEGF and IL-10 compared to the control. The histopathological results of the liver and kidneys showed protective effect of a

  18. Development of epoxide compound from kapok oil for enhanced oil recovery

    NASA Astrophysics Data System (ADS)

    Anam, M. K.; Supranto; Murachman, B.; Purwono, S.

    2017-06-01

    Epoxide compound is made by reacting Kapok Oil with acetic acid and hydrogen peroxide with in situ method. The epoxidation reaction was varied at temperatures of 60 °C, 70 °C and 80 °C, while the time of reaction time was varied at 15 minutes, 30 minutes, 60 minutes and 90 minutes. The reaction rate coefficient for the epoxide was obtained as {\\boldsymbol{k}}{\\boldsymbol{=}}{{124}}{\\boldsymbol{,}}{{82}} {{\\exp }} {\\boldsymbol{\\bigg(}}\\frac{{\\boldsymbol-}{{24}}{\\boldsymbol{,}}{{14}}}{{\\boldsymbol{R}}{\\boldsymbol{T}}}{\\boldsymbol{\\bigg)}}. The addition of the epoxide compound 0.5 w/w in the formulation of SLS was able to reduce the IFT value up to 9.95 x 10-2 m N/m. The addition of co-surfactant (1-octanol) was varied between 0.1 and 0.4 of the total mass of the main formulation (SLS + epoxide + water formation). The smallest interfacial tension value is obtained on the addition of co-surfactants as much as 0.2 w/w, with the IFT value is 2.43 x 10-3 m N/m. The effectiveness of the chemicals was tested through micro displacement using artificial porous medium. The experimental results show that some chemicals developed in the laboratory can be used as EOR chemicals. The oil displacement experiments show that as much as 20 to 80 of remaining oil can be recovered by flooding it with the chemicals. The results also show that the oil recovery depends on type of chemicals and chemical concentration.

  19. Inhibitory effect of vitamin D-binding protein-derived macrophage activating factor on DMBA-induced hamster cheek pouch carcinogenesis and its derived carcinoma cell line.

    PubMed

    Toyohara, Yukiyo; Hashitani, Susumu; Kishimoto, Hiromitsu; Noguchi, Kazuma; Yamamoto, Nobuto; Urade, Masahiro

    2011-07-01

    This study investigated the inhibitory effect of vitamin D-binding protein-derived macrophage-activating factor (GcMAF) on carcinogenesis and tumor growth, using a 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis model, as well as the cytocidal effect of activated macrophages against HCPC-1, a cell line established from DMBA-induced cheek pouch carcinoma. DMBA application induced squamous cell carcinoma in all 15 hamsters of the control group at approximately 10 weeks, and all 15 hamsters died of tumor burden within 20 weeks. By contrast, 2 out of the 14 hamsters with GcMAF administration did not develop tumors and the remaining 12 hamsters showed a significant delay of tumor development for approximately 3.5 weeks. The growth of tumors formed was significantly suppressed and none of the hamsters died within the 20 weeks during which they were observed. When GcMAF administration was stopped at the 13th week of the experiment in 4 out of the 14 hamsters in the GcMAF-treated group, tumor growth was promoted, but none of the mice died within the 20-week period. On the other hand, when GcMAF administration was commenced after the 13th week in 5 out of the 15 hamsters in the control group, tumor growth was slightly suppressed and all 15 hamsters died of tumor burden. However, the mean survival time was significantly extended. GcMAF treatment activated peritoneal macrophages in vitro and in vivo, and these activated macrophages exhibited a marked cytocidal effect on HCPC-1 cells. Furthermore, the cytocidal effect of activated macrophages was enhanced by the addition of tumor-bearing hamster serum. These findings indicated that GcMAF possesses an inhibitory effect on tumor development and growth in a DMBA-induced hamster cheek pouch carcinogenesis model.

  20. Inhibitory effect of vitamin D-binding protein-derived macrophage activating factor on DMBA-induced hamster cheek pouch carcinogenesis and its derived carcinoma cell line

    PubMed Central

    TOYOHARA, YUKIYO; HASHITANI, SUSUMU; KISHIMOTO, HIROMITSU; NOGUCHI, KAZUMA; YAMAMOTO, NOBUTO; URADE, MASAHIRO

    2011-01-01

    This study investigated the inhibitory effect of vitamin D-binding protein-derived macrophage-activating factor (GcMAF) on carcinogenesis and tumor growth, using a 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis model, as well as the cytocidal effect of activated macrophages against HCPC-1, a cell line established from DMBA-induced cheek pouch carcinoma. DMBA application induced squamous cell carcinoma in all 15 hamsters of the control group at approximately 10 weeks, and all 15 hamsters died of tumor burden within 20 weeks. By contrast, 2 out of the 14 hamsters with GcMAF administration did not develop tumors and the remaining 12 hamsters showed a significant delay of tumor development for approximately 3.5 weeks. The growth of tumors formed was significantly suppressed and none of the hamsters died within the 20 weeks during which they were observed. When GcMAF administration was stopped at the 13th week of the experiment in 4 out of the 14 hamsters in the GcMAF-treated group, tumor growth was promoted, but none of the mice died within the 20-week period. On the other hand, when GcMAF administration was commenced after the 13th week in 5 out of the 15 hamsters in the control group, tumor growth was slightly suppressed and all 15 hamsters died of tumor burden. However, the mean survival time was significantly extended. GcMAF treatment activated peritoneal macrophages in vitro and in vivo, and these activated macrophages exhibited a marked cytocidal effect on HCPC-1 cells. Furthermore, the cytocidal effect of activated macrophages was enhanced by the addition of tumor-bearing hamster serum. These findings indicated that GcMAF possesses an inhibitory effect on tumor development and growth in a DMBA-induced hamster cheek pouch carcinogenesis model. PMID:22848250

  1. Persistence and changes in bioavailability of dieldrin, DDE and heptachlor epoxide in earthworms over 45 years

    USGS Publications Warehouse

    Beyer, W. Nelson; Gale, Robert W.

    2013-01-01

    The finding of dieldrin (88 ng/g), DDE (52 ng/g), and heptachlor epoxide (19 ng/g) in earthworms from experimental plots after a single moderate application (9 kg/ha) 45 years earlier attests to the remarkable persistence of these compounds in soil and their continued uptake by soil organisms. Half-lives (with 95 % confidence intervals) in earthworms, estimated from exponential decay equations, were as follows: dieldrin 4.9 (4.3-5.7) years, DDE 5.3 (4.7-6.1) years, and heptachlor epoxide 4.3 (3.8-4.9) years. These half-lives were not significantly different from those estimated after 20 years. Concentration factors (dry weight earthworm tissue/dry weight soil) were initially high and decreased mainly during the first 11 years after application. By the end of the study, average concentration factors were 1.5 (dieldrin), 4.0 (DDE), and 1.8 (heptachlor epoxide), respectively.

  2. 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) Decreases Hepatic and Systemic Ratios of Epoxide to Diol Metabolites of Unsaturated Fatty Acids in Male Rats.

    PubMed

    Wu, Xianai; Yang, Jun; Morisseau, Christophe; Robertson, Larry W; Hammock, Bruce; Lehmler, Hans-Joachim

    2016-08-01

    Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3-month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 µg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. for Permissions, please e-mail: journals.permissions@oup.com.

  3. Cu-catalyzed cross-coupling reactions of epoxides with organoboron compounds.

    PubMed

    Lu, Xiao-Yu; Yang, Chu-Ting; Liu, Jing-Hui; Zhang, Zheng-Qi; Lu, Xi; Lou, Xin; Xiao, Bin; Fu, Yao

    2015-02-11

    A copper-catalyzed cross-coupling reaction of epoxides with arylboronates is described. This reaction is not limited to aromatic epoxides, because aliphatic epoxides are also suitable substrates. In addition, N-sulfonyl aziridines can be successfully converted into the products. This reaction provides convenient access to β-phenethyl alcohols, which are valuable synthetic intermediates.

  4. NAD(P)H-dependent quinone oxidoreductase 1 (NQO1) and cytochrome P450 oxidoreductase (CYP450OR) differentially regulate menadione-mediated alterations in redox status, survival and metabolism in pancreatic β-cells.

    PubMed

    Gray, Joshua P; Karandrea, Shpetim; Burgos, Delaine Zayasbazan; Jaiswal, Anil A; Heart, Emma A

    2016-11-16

    NQO1 (NAD(P)H-quinone oxidoreductase 1) reduces quinones and xenobiotics to less-reactive compounds via 2-electron reduction, one feature responsible for the role of NQO1 in antioxidant defense in several tissues. In contrast, NADPH cytochrome P450 oxidoreductase (CYP450OR), catalyzes the 1-electron reduction of quinones and xenobiotics, resulting in enhanced superoxide formation. However, to date, the roles of NQO1 and CYP450OR in pancreatic β-cell metabolism under basal conditions and oxidant challenge have not been characterized. Using NQO1 inhibition, over-expression and knock out, we have demonstrated that, in addition to protection of β-cells from toxic concentrations of the redox cycling quinone menadione, NQO1 also regulates the basal level of reduced-to-oxidized nucleotides, suggesting other role(s) beside that of an antioxidant enzyme. In contrast, over-expression of NADPH cytochrome P450 oxidoreductase (CYP450OR) resulted in enhanced redox cycling activity and decreased cellular viability, consistent with the enhanced generation of superoxide and H 2 O 2 . Basal expression of NQO1 and CYP450OR was comparable in isolated islets and liver. However, NQO1, but not CYP450OR, was strongly induced in β-cells exposed to menadione. NQO1 and CYP450OR exhibited a reciprocal preference for reducing equivalents in β-cells: while CYP450OR preferentially utilized NADPH, NQO1 primarily utilized NADH. Together, these results demonstrate that NQO1 and CYP450OR reciprocally regulate oxidant metabolism in pancreatic β-cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. NAD(P)H-dependent Quinone Oxidoreductase 1 (NQO1) and Cytochrome P450 Oxidoreductase (CYP450OR) differentially regulate menadione-mediated alterations in redox status, survival and metabolism in pancreatic β-cells

    PubMed Central

    Gray, Joshua P.; Karandrea, Shpetim; Burgos, Delaine Zayasbazan; Jaiswal, Anil A; Heart, Emma A.

    2017-01-01

    NQO1 (NAD(P)H-quinone oxidoreductase 1) reduces quinones and xenobiotics to less-reactive compounds via 2-electron reduction, one feature responsible for the role of NQO1 in antioxidant defense in several tissues. In contrast, NADPH cytochrome P450 oxidoreductase (CYP450OR), catalyzes the 1-electron reduction of quinones and xenobiotics, resulting in enhanced superoxide formation. However, to date, the roles of NQO1 and CYP450OR in pancreatic β-cell metabolism under basal conditions and oxidant challenge have not been characterized. Using NQO1 inhibition, over-expression and knock out, we have demonstrated that, in addition to protection of β-cells from toxic concentrations of the redox cycling quinone menadione, NQO1 also regulates the basal level of reduced-to-oxidized nucleotides, suggesting other role(s) beside that of an antioxidant enzyme. In contrast, over-expression of NADPH cytochrome P450 oxidoreductase (CYP450OR) resulted in enhanced redox cycling activity and decreased cellular viability, consistent with the enhanced generation of superoxide and H2O2. Basal expression of NQO1 and CYP450OR was comparable in isolated islets and liver. However, NQO1, but not CYP450OR, was strongly induced in β-cells exposed to menadione. NQO1 and CYP450OR exhibited a reciprocal preference for reducing equivalents in β-cells: while CYP450OR preferentially utilized NADPH, NQO1 primarily utilized NADH. Together, these results demonstrate that NQO1 and CYP450OR reciprocally regulate oxidant metabolism in pancreatic β-cells. PMID:27558805

  6. Versatile Synthesis of Stable, Functional Polypeptides via Reaction with Epoxides.

    PubMed

    Gharakhanian, Eric G; Deming, Timothy J

    2015-06-08

    Methodology was developed for efficient alkylation of methionine residues using epoxides as a general strategy to introduce a wide range of functional groups onto polypeptides. Use of a spacer between epoxide and functional groups further allowed addition of sterically demanding functionalities. Contrary to other methods to alkylate methionine residues, epoxide alkylations allow the reactions to be conducted in wet protic media and give sulfonium products that are stable against dealkylation. These functionalizations are notable since they are chemoselective, utilize stable and readily available epoxides, and allow facile incorporation of an unprecedented range of functional groups onto simple polypeptides using stable linkages.

  7. Epoxidation of cottonseed oil by aqueous hydrogen peroxide catalysed by liquid inorganic acids.

    PubMed

    Dinda, Srikanta; Patwardhan, Anand V; Goud, Vaibhav V; Pradhan, Narayan C

    2008-06-01

    The kinetics of epoxidation of cottonseed oil by peroxyacetic acid generated in situ from hydrogen peroxide and glacial acetic acid in the presence of liquid inorganic acid catalysts were studied. It was possible to obtain up to 78% relative conversion to oxirane with very less oxirane cleavage by in situ technique. The rate constants for sulphuric acid catalysed epoxidation of cottonseed oil were in the range 0.39-5.4 x 10(-6)L mol(-1)s(-1) and the activation energy was found to be 11.7 kcal mol(-1). Some thermodynamic parameters such as enthalpy, entropy, and free energy of activation were determined to be of 11.0 kcal mol(-1), -51.4 cal mol(-1)K(-1) and 28.1 kcal mol(-1), respectively. The order of effectiveness of catalysts was found to be sulphuric acid>phosphoric acid>nitric acid>hydrochloric acid. Acetic acid was found to be superior to formic acid for the in situ cottonseed oil epoxidation.

  8. Menhaden, coconut, and corn oils and mammary tumor incidence in BALB/c virgin female mice treated with DMBA.

    PubMed

    Craig-Schmidt, M; White, M T; Teer, P; Johnson, J; Lane, H W

    1993-01-01

    Omega-3 fatty (n-3) acids are believed to inhibit the rate of occurrence and the growth of mammary tumors in rats treated with 7,12-dimethylbenz[a]anthracene (DMBA). Linoleic acid, on the other hand, has been shown to promote mammary tumorigenesis. This study was undertaken to see whether replacing 18% of the corn oil (high in linoleic acid) in a 20% fat diet with menhaden oil (high in n-3 fatty acids, low in linoleic acid) or coconut oil (low in n-3 fatty acids, low in linoleic acid), while keeping constant the cholesterol, antioxidant, and total fat content, would affect tumor incidence in virgin female BALB/c mice dosed with DMBA. Dietary treatment had no effect on body weight, feed intake, or survival to 44 weeks of age (36 wks after the first of 6 DMBA doses). Mammary tumor incidence was the same in the menhaden oil and coconut oil diet groups but was significantly higher in the 20% corn oil diet group. The protective effect of menhaden oil and coconut oil may be due, at least in part, to the decreased linoleic acid content of these diets relative to the corn oil diet. We conclude that n-3 fatty acids per se do not seem to inhibit tumor formation.

  9. Raman spectroscopic investigation of the chemopreventive response of naringenin and its nanoparticles in DMBA-induced oral carcinogenesis

    NASA Astrophysics Data System (ADS)

    Krishnakumar, N.; Sulfikkarali, N. K.; Manoharan, S.; Venkatachalam, P.

    2013-11-01

    Raman spectroscopy is a vibrational spectroscopic technique that can be used to optically probe the biomolecular changes associated with tumor progression. The aim of the present study is to investigate the biomolecular changes in chemopreventive response of prepared naringenin-loaded nanoparticles (NARNPs) relative to efficacy of free naringenin (NAR) during 7,12-dimethyl benz(a)anthracene (DMBA)-induced oral carcinogenesis by Fourier Transform Raman (FT-Raman) spectroscopy. Oral squamous cell carcinoma (OSCC) was developed in the buccal pouch of golden Syrian hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. Raman spectra differed significantly between the control and tumor tissues, with tumors showing higher percentage signals for nucleic acids, phenylalanine and tryptophan and a lower in the percentage of phospholipids. Moreover, oral administration of free NAR and NARNPs significantly increased phospholipids and decreased the levels of tryptophan, phenylalanine and nucleic acid contents. On a comparative basis, NARNPs was found to have a more potent antitumor effect than free NAR in completely preventing the formation of squamous cell carcinoma and in improving the biochemical status to a normal range in DMBA-induced oral carcinogenesis. The present study further suggest that Raman spectroscopy could be a valuable tool for rapid and sensitive detection of specific biomolecular changes in response to chemopreventive agents.

  10. 40 CFR 721.10210 - Soybean oil, epoxidized, reaction products with diethanolamine.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Soybean oil, epoxidized, reaction... Significant New Uses for Specific Chemical Substances § 721.10210 Soybean oil, epoxidized, reaction products... chemical substance identified as soybean oil, epoxidized, reaction products with diethanolamine (PMN P-09...

  11. Synthesis and physicochemical properties of epoxidized Tmp trioleate by in situ method

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Samidin, Salma; Salimon, Jumat

    2014-09-03

    Tmp trioleate was initially synthesized via esterification of trimetilolprapane and oleic acid (90%) using 1.5% of H{sub 2}SO{sub 4} as a catalyst. The production of Tmp trioleate was observed at 98% (w/w). The iodine value of Tmp trioleate was analyzed for further reaction of epoxidation. Epoxide was important reaction as an intermediate for preparation of chemical modified lubricants from vegetable oils. Finding the best way of epoxidation process will give high quality for further modification of oil instead of reduce the cost and time for the preparation process during reaction of epoxidation. In this study, the epoxidation of unsaturation Tmpmore » trioleate with peroxyformic acid generated in-situ from hydrogen peroxide 30% in H{sub 2}O{sub 2} with formic acid was studied. 95% conversion to oxygen oxirane content (OOC) ring was obtained. The derivatization showed an improvement of the compound's oxidative stability evidenced from pressurized differential scanning calorimetry (PDSC) data which are 177°C to 200°C. Physicochemical properties showed increasing of temperature of flash point from 280°C to 300°C and viscosity index (VI) from 146 to 154. However, the pour point showed increasing temperature which was −58.81°C to −17.32°C. From the data obtained, these derivatives have shown better performance of lubricity properties. Overall, the data indicates that these performances are compatible to the commercial lubricants.« less

  12. Epoxide reduction with hydrazine on graphene: a first principles study.

    PubMed

    Kim, Min Chan; Hwang, Gyeong S; Ruoff, Rodney S

    2009-08-14

    Mechanisms for epoxide reduction with hydrazine on a single-layer graphene sheet are examined using quantum mechanical calculations within the framework of gradient-corrected spin-polarized density-functional theory. We find that the reduction reaction is mainly governed by epoxide ring opening which is initiated by H transfer from hydrazine or its derivatives. In addition, our calculations suggest that the epoxide reduction by hydrazine may predominantly follow a direct Eley-Rideal mechanism rather than a Langmuir-Hinshelwood mechanism. We also discuss the generation of various hydrazine derivatives during the reduction of graphene oxide with hydrazine and their potential contribution to lowering the barrier height of epoxide ring opening.

  13. Enantioselective synthesis of 2,2-disubstituted terminal epoxides via catalytic asymmetric Corey-Chaykovsky epoxidation of ketones.

    PubMed

    Sone, Toshihiko; Yamaguchi, Akitake; Matsunaga, Shigeki; Shibasaki, Masakatsu

    2012-02-07

    Catalytic asymmetric Corey-Chaykovsky epoxidation of various ketones with dimethyloxosulfonium methylide using a heterobimetallic La-Li(3)-BINOL complex (LLB) is described. The reaction proceeded smoothly at room temperature in the presence of achiral phosphine oxide additives, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (97%-91% ee) and yield ( > 99%-88%) from a broad range of methyl ketones with 1-5 mol% catalyst loading. Enantioselectivity was strongly dependent on the steric hindrance, and other ketones, such as ethyl ketones and propyl ketones resulted in slightly lower enantioselectivity (88%-67% ee).

  14. Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives.

    PubMed

    López-Lira, Claudia; Alzate-Morales, Jans H; Paulino, Margot; Mella-Raipán, Jaime; Salas, Cristian O; Tapia, Ricardo A; Soto-Delgado, Jorge

    2018-01-01

    A combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q 2 LOO ) of .75 and .73 as well as conventional correlation coefficients (R 2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r 2 pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity. © 2017 John Wiley & Sons A/S.

  15. Obesity decreases serum selenium levels in DMBA-induced mammary tumor using Obese Zucker Rat Model

    USDA-ARS?s Scientific Manuscript database

    Recently, we reported that obese Zucker rats had increased susceptibility to DMBA-induced mammary tumors compared to lean Zucker rats. Several studies suggest that lower serum selenium may play an important role in increasing the risk of several types of cancers (e.g, colon, breast and prostate canc...

  16. Quercetin attenuates the development of 7, 12-dimethyl benz (a) anthracene (DMBA) and croton oil-induced skin cancer in mice

    PubMed Central

    Ali, Huma; Dixit, Savita

    2015-01-01

    Abstract To evaluate the chemopreventive potential of quercetin in an experimental skin carcinogenesis mouse model. Skin tumor was induced by topical application of 7, 12-dimethyl Benz (a) anthracene (DMBA) and Croton oil in Swiss albino mouse. Quercetin was orally administered at a concentration of 200 mg/kg and 400 mg/kg body weight daily for 16 weeks in mouse to evaluate chemopreventive potential. Skin cancer was assessed by histopathological analysis. We found that quercetin reduced the tumor size and the cumulative number of papillomas. The mean latent period was significantly increased as compared to carcinogen treated controls. Quercetin significantly decreased the serum levels of glutamate oxalate transaminase, glutamate pyruvate transaminase, alkaline phosphatase and bilirubin. It significantly increased the levels of glutathione, superoxide dismutase and catalase. The elevated level of lipid peroxides in the control group was significantly inhibited by quercetin. Futhermore, DNA damage was significantly decreased in quercetin treated mice as compared to DMBA and croton oil treated mice. The results suggest that quercetin exerts chemopreventive effect on DMBA and croton oil induced skin cancer in mice by increasing antioxidant activities. PMID:25859269

  17. Patulin biosynthesis: Epoxidation of toluquinol and gentisyl alcohol by particulate preparations from Penicillium patulum

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Priest, J.W.; Light, R.J.

    1989-11-14

    A crude extract that catalyzes the epoxidation of toluquinol and gentisyl alcohol was isolated from cultures of Penicillium patulum. About 60% of the activity sedimented from crude extract upon centrifugation at 105000g for 2 h, and at 30000g for 30 min after precipitation with 30% ammonium sulfate and resuspension in buffer. The quinone epoxide phyllostine, a product of gentisyl alcohol epoxidation, has previously been shown to be an intermediate in the biosynthesis of patulin and was shown to be further converted to neopatulin by the extract. The epoxide product of toluquinol, desoxyphyllostine (2-methyl-5,6-epoxy-1,4-benzoquinone), has not been reported previously from fungalmore » cultures. Its structure was confirmed by GC-mass spectrometry and proton and {sup 13}C NMR. Its CD spectrum showed the same shape and signs as that of phyllostine, indicating that it too is an enzymatic product with a similar absolute configuration. Whereas chemical epoxidation of toluquinone and gentisly quinone occurs with hydrogen peroxide, the enzymatic epoxidation utilized oxygen and the hydroquinone. The epoxidation was inhibited by 1,10-phenanthroline, EDTA, and {rho}-(chloromercuri)benzenesulfonic acid and by degassing with nitrogen, but no inhibition was observed with KCN, catalase, or CO. The apparent K{sub m}'s were similar for the two substrates with both substrates showing inhibition at 1.0 mM. The rate of desoxyphyllostine formation was more than 10 times that of phyllostine formation at equivalent substrate concentrations. Gentisaldehyde was not a substrate for the enzyme. The epoxidase was induced in late fermentor cultures of P. patulum with the same kinetics as m-hydroxybenzyl alcohol dehydrogenase, another enzyme associated with the induction of patulin biosynthesis.« less

  18. Characterization of an epoxide hydrolase from the Florida red tide dinoflagellate, Karenia brevis.

    PubMed

    Sun, Pengfei; Leeson, Cristian; Zhi, Xiaoduo; Leng, Fenfei; Pierce, Richard H; Henry, Michael S; Rein, Kathleen S

    2016-02-01

    Epoxide hydrolases (EH, EC 3.3.2.3) have been proposed to be key enzymes in the biosynthesis of polyether (PE) ladder compounds such as the brevetoxins which are produced by the dinoflagellate Karenia brevis. These enzymes have the potential to catalyze kinetically disfavored endo-tet cyclization reactions. Data mining of K. brevis transcriptome libraries revealed two classes of epoxide hydrolases: microsomal and leukotriene A4 (LTA4) hydrolases. A microsomal EH was cloned and expressed for characterization. The enzyme is a monomeric protein with molecular weight 44kDa. Kinetic parameters were evaluated using a variety of epoxide substrates to assess substrate selectivity and enantioselectivity, as well as its potential to catalyze the critical endo-tet cyclization of epoxy alcohols. Monitoring of EH activity in high and low toxin producing cultures of K. brevis over a three week period showed consistently higher activity in the high toxin producing culture implicating the involvement of one or more EH in brevetoxin biosynthesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. 3,3′,4,4′,5-Pentachlorobiphenyl (PCB 126) Decreases Hepatic and Systemic Ratios of Epoxide to Diol Metabolites of Unsaturated Fatty Acids in Male Rats

    PubMed Central

    Wu, Xianai; Yang, Jun; Morisseau, Christophe; Robertson, Larry W.; Hammock, Bruce; Lehmler, Hans-Joachim

    2016-01-01

    Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3-month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 µg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention. PMID:27208083

  20. Formation of furan fatty alkyl esters from their bis-epoxide fatty esters

    USDA-ARS?s Scientific Manuscript database

    Epoxidation of vegetable oils and consecutive epoxide ring-opening reaction is a widely investigated path for producing biobased lubricants and polymers. The reaction mechanism and products are considered well-studied and known. In the current study, the reactions of epoxidized alkyl soyate with fou...

  1. Genotoxicity risk assessment of diversely substituted quinolines using the SOS chromotest.

    PubMed

    Duran, Leidy Tatiana Díaz; Rincón, Nathalia Olivar; Galvis, Carlos Eduardo Puerto; Kouznetsov, Vladimir V; Lorenzo, Jorge Luis Fuentes

    2015-03-01

    Quinolines are aromatic nitrogen compounds with wide therapeutic potential to treat parasitic and microbial diseases. In this study, the genotoxicity of quinoline, 4-methylquinoline, 4-nitroquinoline-1-oxide (4-NQO), and diversely functionalized quinoline derivatives and the influence of the substituents (functional groups and/or atoms) on their genotoxicity were tested using the SOS chromotest. Quinoline derivatives that induce genotoxicity by the formation of an enamine epoxide structure did not induce the SOS response in Escherichia coli PQ37 cells, with the exception of 4-methylquinoline that was weakly genotoxic. The chemical nature of the substitution (C-5 to C-8: hydroxyl, nitro, methyl, isopropyl, chlorine, fluorine, and iodine atoms; C-2: phenyl and 3,4-methylenedioxyphenyl rings) of quinoline skeleton did not significantly modify compound genotoxicities; however, C-2 substitution with α-, β-, or γ-pyridinyl groups removed 4-methylquinoline genotoxicity. On the other hand, 4-NQO derivatives whose genotoxic mechanism involves reduction of the C-4 nitro group were strong inducers of the SOS response. Methyl and nitrophenyl substituents at C-2 of 4-NQO core affected the genotoxic potency of this molecule. The relevance of these results is discussed in relation to the potential use of the substituted quinolines. The work showed the sensitivity of SOS chromotest for studying structure-genotoxicity relationships and bioassay-guided quinoline synthesis. © 2013 Wiley Periodicals, Inc.

  2. Sulfuric acid as a catalyst for ring-opening of biobased bis-epoxides

    USDA-ARS?s Scientific Manuscript database

    Vegetable oils can be relatively and easily transformed into bio-based epoxides. Because of this, the acid-catalyzed epoxide ring-opening has been explored for the preparation of bio-based lubricants and polymers. Detailed model studies are carried out only with mono-epoxide made from methyl oleate,...

  3. Conformational dynamics is key to understanding loss-of-function of NQO1 cancer-associated polymorphisms and its correction by pharmacological ligands

    NASA Astrophysics Data System (ADS)

    Encarnación, Medina-Carmona; Palomino-Morales, Rogelio J.; Fuchs, Julian E.; Esperanza, Padín-Gonzalez; Noel, Mesa-Torres; Salido, Eduardo; Timson, David J.; Pey, Angel L.

    2016-02-01

    Protein dynamics is essential to understand protein function and stability, even though is rarely investigated as the origin of loss-of-function due to genetic variations. Here, we use biochemical, biophysical, cell and computational biology tools to study two loss-of-function and cancer-associated polymorphisms (p.R139W and p.P187S) in human NAD(P)H quinone oxidoreductase 1 (NQO1), a FAD-dependent enzyme which activates cancer pro-drugs and stabilizes several oncosuppressors. We show that p.P187S strongly destabilizes the NQO1 dimer in vitro and increases the flexibility of the C-terminal domain, while a combination of FAD and the inhibitor dicoumarol overcome these alterations. Additionally, changes in global stability due to polymorphisms and ligand binding are linked to the dynamics of the dimer interface, whereas the low activity and affinity for FAD in p.P187S is caused by increased fluctuations at the FAD binding site. Importantly, NQO1 steady-state protein levels in cell cultures correlate primarily with the dynamics of the C-terminal domain, supporting a directional preference in NQO1 proteasomal degradation and the use of ligands binding to this domain to stabilize p.P187S in vivo. In conclusion, protein dynamics are fundamental to understanding loss-of-function in p.P187S, and to develop new pharmacological therapies to rescue this function.

  4. Stokes shift spectroscopy for the early diagnosis of epithelial precancers in DMBA treated mouse skin carcinogenesis

    NASA Astrophysics Data System (ADS)

    Jeyasingh, Ebenezar; Singaravelu, Ganesan; Prakasarao, Aruna

    2018-02-01

    In this study, we aim to characterize the tissue transformation in dimethylbenz(a)anthracene (DMBA) treated mouse skin tumor model using stokes shift spectroscopy (SSS) technique for early detection of the neoplastic changes. Stokes shift (SS) spectra measured by scanning both excitation and emission wavelength simultaneously with a fixed wavelength of interval (Δλ=20 nm) in vivo from 33 DMBA treated animals and 6 control animals. The SS spectra of normal (n=6), hyperplasia (n=10), dysplasia (n=10), and WDSCC (n=13) of mice skin shows the distinct peaks around 300, 350, and 386 nm may be attributed to tryptophan, collagen, and NADH respectively. From the observed spectral differences and the ratio variables that resulted in better classification between groups, it is concluded that tryptophan, collagen, and NADH are the key fluorophores that undergo changes during tissue transformation process and hence they can be targeted as tumor markers for early neoplastic changes.

  5. Innate immune response adaptation in mice subjected to administration of DMBA and physical activity

    PubMed Central

    ABDALLA, DOUGLAS R.; ALEIXO, ANDRÉ ADRIANO ROCHA; MURTA, EDDIE F.C.; MICHELIN, MÁRCIA A.

    2014-01-01

    Although there is growing interest in studies that promote the benefits of exercise and the correlation between exercise and fighting cancer, previous studies have not been able to elucidate the underlying mechanisms. The aim of the present study was to investigate cytokine synthesis by peritoneal macrophages in the presence of mammary tumors and the effect of physical activity. Female BALB/c virgin mice (age, eight weeks) were obtained for the present study and divided into four groups: A no tumor/non-trained control group; a no tumor/trained group subjected to swim training; a tumor/non-trained group in which the mice received the carcinogenic drug, DMBA and a tumor/trained group in which the mice were subjected to DMBA and swim training protocols. Following the experimental period, immune cells were collected from the peritoneal fluid, placed in culture medium and stimulated with lipopolysaccharide. The presence of the cluster of differentiation-14 marker and expression of the interleukin (IL)-12 cytokine was assessed by flow cytometry and measured via an enzyme-linked immunosorbent assay. The following cytokines were also identified: Interferon-γ, IL-4, IL-10, IL-12, tumor necrosis factor-α and transforming growth factor-β. Physical activity increased the quantity of IL-12 producing macrophages, whereas the presence of a tumor decreased the quantity of macrophages expressing IL-12. Tumor induction, in the absence of swim training, reduced macrophage-profile 1 (M1) cytokine levels while increasing the presence of macrophage-profile 2 cytokines. Physical activity in mice with tumors resulted in reductions in tumor development and promoted immune system polarization towards an antitumor M1 response pattern profile. PMID:24520305

  6. Innate immune response adaptation in mice subjected to administration of DMBA and physical activity.

    PubMed

    Abdalla, Douglas R; Aleixo, André Adriano Rocha; Murta, Eddie F C; Michelin, Márcia A

    2014-03-01

    Although there is growing interest in studies that promote the benefits of exercise and the correlation between exercise and fighting cancer, previous studies have not been able to elucidate the underlying mechanisms. The aim of the present study was to investigate cytokine synthesis by peritoneal macrophages in the presence of mammary tumors and the effect of physical activity. Female BALB/c virgin mice (age, eight weeks) were obtained for the present study and divided into four groups: A no tumor/non-trained control group; a no tumor/trained group subjected to swim training; a tumor/non-trained group in which the mice received the carcinogenic drug, DMBA and a tumor/trained group in which the mice were subjected to DMBA and swim training protocols. Following the experimental period, immune cells were collected from the peritoneal fluid, placed in culture medium and stimulated with lipopolysaccharide. The presence of the cluster of differentiation-14 marker and expression of the interleukin (IL)-12 cytokine was assessed by flow cytometry and measured via an enzyme-linked immunosorbent assay. The following cytokines were also identified: Interferon-γ, IL-4, IL-10, IL-12, tumor necrosis factor-α and transforming growth factor-β. Physical activity increased the quantity of IL-12 producing macrophages, whereas the presence of a tumor decreased the quantity of macrophages expressing IL-12. Tumor induction, in the absence of swim training, reduced macrophage-profile 1 (M1) cytokine levels while increasing the presence of macrophage-profile 2 cytokines. Physical activity in mice with tumors resulted in reductions in tumor development and promoted immune system polarization towards an antitumor M1 response pattern profile.

  7. Characteristics of Growth Inhibition of Lactobacillus casei by 4-Nitroquinoline-n-Oxide

    PubMed Central

    Bond, T. J.; Young, Kamie Law; Andrus, Teresa Tarbell

    1970-01-01

    The bacteriostatic action of 4-nitroquinoline-n-oxide (4-NQO) for Lactobacillus casei is substantially reversed by d-and l-cysteine, glutathione, and 2,2-dihydroxy-1,4-dithiolbutane (dithioerythritol). The action appears to involve a chemical reaction between carbon atom 4 of 4-NQO and nucleophilic centers, such as -SH groups, located on essential cell constituents. The evidence presented indicates that the protective effect of d- and l-cysteine, glutathione, and dithioerythritol against the action involves reactions between 4-NQO and -SH compounds. PMID:5498599

  8. Dunnione protects against experimental cisplatin-induced nephrotoxicity by modulating NQO1 and NAD+ levels.

    PubMed

    Nazari Soltan Ahmad, Saeed; Rashtchizadeh, Nadereh; Argani, Hassan; Roshangar, Leila; Ghorbani Haghjo, Amir; Sanajou, Davoud; Panah, Fatemeh; Ashrafi Jigheh, Zahra; Dastmalchi, Siavoush; Mesgari-Abbasi, Mehran

    2018-06-04

    Despite being an efficacious anticancer agent, the clinical utility of cisplatin is hindered by its cardinal side effects. This investigation aimed to appraise potential protective impact of dunnione, a natural naphthoquinone pigment with established NQO1 stimulatory effects, on cisplatin nephrotoxicity of rats. Dunnione was administered orally at 10 and 20 mg/kg doses for 4 d and a single injection of cisplatin was delivered at the second day. Renal histopathology, inflammatory/oxidative stress/apoptotic markers, kidney function, and urinary markers of renal injury were assessed. Dunnione repressed cisplatin-induced inflammation in the kidneys as indicated by decreased TNF-α/IL-1β levels, and reduced nuclear phosphorylated NF-κB p65. This agent also obviated cisplatin-invoked oxidative stress as elucidated by decreased MDA/GSH levels and increased SOD/CAT activities. Dunnione, furthermore, improved renal histological deteriorations as well as caspase-3 activities and terminal deoxynucleotidyl transferase (TUNEL) positive cells, the indicators of apoptosis. Moreover, it up-regulated nuclear Nrf2 and cytosolic haeme-oxygenase-1 (HO-1) and NQO1 levels; meanwhile, promoted NAD + /NADH ratios followed by enhancing the activities of Sirt1 and PARP1; and further attenuated nuclear acetylated NF-κB p65. Dunnione additionally declined cisplatin-evoked retrogression in renal function and upraise in urinary markers of glomerular and tubular injury as demonstrated by decreased serum urea and creatinine with simultaneous reductions in urinary excretions of collagen type IV, podocin, cystatin C, and retinol-binding protein (RBP). Altogether, these findings offer dunnione as a potential protective agent against cisplatin-induced nephrotoxicity in rats.

  9. Epoxidation of 1-Octene with hydrogen peroxide aqueous catalyzed by titania supported sulfonated coal

    NASA Astrophysics Data System (ADS)

    Nurhadi, Mukhamad

    2017-02-01

    Titania supported sulfonated coal was created as heterogeneous catalyst for epoxidation of 1-octene with aqueous hydrogen peroxide as oxidant at room temperature. The catalysts were prepared from coal that was sulfonated with H2SO4 (97%) and impregnated 7.2%wt with titanium(IV) isopropoxide (Ti(PrO)4). All catalysts coal (C), CS, Ti(7.2)-CS and Ti(7.2)-CSC were characterized by FTIR. The catalytic performance was tested for epoxidation of 1-octene with H2O2 aqueous as oxidant. It is found that Ti(7.2)-CS possessed the best catalytic performance and it gave the highest 1,2 epoxyoctene 322 µmol.

  10. Ultrasound-assisted chemoenzymatic epoxidation of soybean oil by using lipase as biocatalyst.

    PubMed

    Bhalerao, Machhindra S; Kulkarni, Vaishali M; Patwardhan, Anand V

    2018-01-01

    The present work reports the use of ultrasonic irradiation for enhancing lipase catalyzed epoxidation of soybean oil. Higher degree of unsaturated fatty acids, present in the soybean oil was converted to epoxidized soybean oil by using an immobilized lipase, Candida antarctica (Novozym 435). The effects of various parameters on the relative percentage conversion of the double bond to oxirane oxygen were investigated and the optimum conditions were established. The parameters studied were temperature, hydrogen peroxide to ethylenic unsaturation mole ratio, stirring speed, solvent ratio, catalyst loading, ultrasound frequency, ultrasound input power and duty cycle. The main objective of this work was to intensify chemoenzymatic epoxidation of the soybean oil by using ultrasound, to reduce the time required for epoxidation. Epoxidation of the soybean oil was achieved under mild reaction conditions by indirect ultrasonic irradiations (using ultrasonic bath). The relative percentage conversion to oxirane oxygen of 91.22% was achieved within 5h. The lipase was remarkably stable under optimized reaction conditions, later was recovered and reused six times to produce epoxidized soybean oil (ESO). Copyright © 2017 Elsevier B.V. All rights reserved.

  11. CORRELATION OF CARCINOGENIC POTENCY WITH MOUSE SKIN 32P-POSTLABELING AND LAC Z-MUTATION DATE FOR DMBA AN ITS K-REGION SULPHUR ISOSTERE: COMPARISON WITH ACTIVITIES OBSERVED IN STANDARD GENOTOXICITY ASSAYS

    EPA Science Inventory

    6,11-Dimethylbenzo(b]naphtho[2,3-d]thiophene (S-DMBA) is one of several carcinogenic analogs of the reference mouse skin carcinogen 7,12-dimethylbenz[alanthracene (OMBA)Demonstration of the weak carcinogenicity of S-DMBA by Tilak in 1946 established at that early stage the inadeq...

  12. Vibrational Excitations and Low Energy Electronic Structure of Epoxide-decorated Graphene

    PubMed Central

    Mattson, E.C.; Johns, J.E.; Pande, K.; Bosch, R.A.; Cui, S.; Gajdardziska-Josifovska, M.; Weinert, M.; Chen, J.H.; Hersam, M.C.; Hirschmugl, C.J.

    2014-01-01

    We report infrared studies of adsorbed atomic oxygen (epoxide functional groups) on graphene. Two different systems are used as a platform to explore these interactions, namely, epitaxial graphene/SiC(0001) functionalized with atomic oxygen (graphene epoxide, GE) and chemically reduced graphene oxide (RGO). In the case of the model GE system, IR reflectivity measurements show that epoxide groups distort the graphene π bands around the K-point, imparting a finite effective mass and contributing to a band gap. In the case of RGO, epoxide groups are found to be present following the reduction treatment by a combination of polarized IR reflectance and transmittance measurements. Similar to the GE system, a band gap in the RGO sample is observed as well. PMID:24563725

  13. Vibrational Excitations and Low Energy Electronic Structure of Epoxide-decorated Graphene.

    PubMed

    Mattson, E C; Johns, J E; Pande, K; Bosch, R A; Cui, S; Gajdardziska-Josifovska, M; Weinert, M; Chen, J H; Hersam, M C; Hirschmugl, C J

    2014-01-02

    We report infrared studies of adsorbed atomic oxygen (epoxide functional groups) on graphene. Two different systems are used as a platform to explore these interactions, namely, epitaxial graphene/SiC(0001) functionalized with atomic oxygen (graphene epoxide, GE) and chemically reduced graphene oxide (RGO). In the case of the model GE system, IR reflectivity measurements show that epoxide groups distort the graphene π bands around the K-point, imparting a finite effective mass and contributing to a band gap. In the case of RGO, epoxide groups are found to be present following the reduction treatment by a combination of polarized IR reflectance and transmittance measurements. Similar to the GE system, a band gap in the RGO sample is observed as well.

  14. Production of epoxide hydrolases in batch fermentations of Botryosphaeria rhodina.

    PubMed

    Melzer, Guido; Junne, Stefan; Wohlgemuth, Roland; Hempel, Dietmar C; Götz, Peter

    2008-06-01

    The filamentous fungus Botryosphaeria rhodina (ATCC 9055) was investigated related to its ability for epoxide hydrolase (EH) production. Epoxide hydrolase activity is located at two different sites of the cells. The larger part is present in the cytosol (70%), while the smaller part is associated to membranes (30%). In media optimization experiments, an activity of 3.5 U/gDW for aromatic epoxide hydrolysis of para-nitro-styrene oxide (pNSO) could be obtained. Activity increased by 30% when pNSO was added to the culture during exponential growth. An increase of enzyme activity up to 6 U/gDW was achieved during batch-fermentations in a bioreactor with 2.7 l working volume. Evaluation of fermentations with 30 l working volume revealed a relation of oxygen uptake rate to EH expression. Oxygen limitation resulted in a decreased EH activity. Parameter estimation by the linearization method of Hanes yielded Km values of 2.54 and 1.00 mM for the substrates S-pNSO and R-pNSO, respectively. vmax was 3.4 times higher when using R-pNSO. A protein purification strategy leading to a 47-fold increase in specific activity (940 U/mgProtein) was developed as a first step to investigate molecular and structural characteristics of the EH.

  15. Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides to Form Spiroketals

    PubMed Central

    Wurst, Jacqueline M.; Liu, Guodong; Tan, Derek S.

    2011-01-01

    Mechanistic investigations of a MeOH-induced kinetic epoxide-opening spirocyclization of glycal epoxides have revealed dramatic, specific roles for simple solvents in hydrogen-bonding catalysis of this reaction to form spiroketal products stereoselectively with inversion of configuration at the anomeric carbon. A series of electronically-tuned C1-aryl glycal epoxides was used to study the mechanism of this reaction based on differential reaction rates and inherent preferences for SN2 versus SN1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an SN2 or SN2-like mechanism (ρ = −1.3 vs. ρ = −5.1 for corresponding SN1 reactions of these substrates). Notably, the spirocyclization reaction is second-order dependent on MeOH and the glycal ring oxygen is required for second-order MeOH catalysis. However, acetone cosolvent is a first-order inhibitor of the reaction. A transition state consistent with the experimental data is proposed in which one equivalent of MeOH activates the epoxide electrophile via a hydrogen bond while a second equivalent of MeOH chelates the sidechain nucleophile and glycal ring oxygen. A paradoxical previous observation that decreased MeOH concentration leads to increased competing intermolecular methyl glycoside formation is resolved by the finding that this side reaction is only first-order dependent on MeOH. This study highlights the unusual abilities of simple solvents to act as hydrogen-bonding catalysts and inhibitors in epoxide-opening reactions, providing both stereoselectivity and discrimination between competing reaction manifolds. This spirocyclization reaction provides efficient, stereocontrolled access to spiroketals that are key structural motifs in natural products. PMID:21539313

  16. De-novo NAD+ synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells

    PubMed Central

    Cheng, Xuefang; Li, Qingran; Liu, Fang; Ye, Hui; Zhao, Min; Wang, Hong; Wang, Guangji; Hao, Haiping

    2016-01-01

    Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD+ pool. Particularly, the LAT1-NAD+-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD+ synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress. PMID:27566573

  17. De-novo NAD+ synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells.

    PubMed

    Liu, Huiying; Xing, Rong; Cheng, Xuefang; Li, Qingran; Liu, Fang; Ye, Hui; Zhao, Min; Wang, Hong; Wang, Guangji; Hao, Haiping

    2016-09-20

    Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD+ pool. Particularly, the LAT1-NAD+-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD+ synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress.

  18. Modulation of Nrf2/Keap1 system by Wasabi 6-methylthiohexyl isothiocyanate in ARE-mediated NQO1 expression.

    PubMed

    Korenori, Yoshimi; Tanigawa, Shunsuke; Kumamoto, Takuma; Qin, Si; Daikoku, Yosuke; Miyamori, Koji; Nagai, Masashi; Hou, De-Xing

    2013-05-01

    6-Methylthiohexyl isothiocyanate (6-MTITC), one of the major bioactive ingredients in Japanese Wasabi, has revealed cytoprotective and cancer chemopreventive effects. This study aims to clarify the molecular mechanisms how 6-MTITC modulates nuclear factor E2-related factor 2 (Nrf2)/Kelchlike ECH-associating protein 1 (Keap1) system in antioxidant-responsive element (ARE)-mediated nicotinamide adenine dinucleotide phosphate (NADP): quinone oxidoreductase 1 (NQO1) expression. HepG2 cells were treated with 6-MTITC with varying time and dose. NQO1, Nrf2, and Keap1 proteins were detected by Western blotting. ARE transactivation was detected by electrophilic mobility shift assay and reporter gene assay. Nuclear localization of Nrf2 was determined by immunocytochemistry assay. Ubiquitination of Nrf2 and Keap1 was detected using immunoprecipitation after treatment with MG132. Small interfering RNA was used to knockdown Nrf2 or Keap1. The results revealed that 6-MTITC modulated Nrf2/ARE pathway by stimulating Keap1 modification, and inhibiting Nrf2 ubiquitination and protein turnover. These actions finally increased nuclear Nrf2 accumulation and ARE-binding activity. Moreover, silencing Nrf2 markedly reduced ARE-driven activity induced by 6-MTITC. 6-MTITC modulated ARE-driven NQO1 expression by stabilizing Nrf2 with enhanced Keap1 modification and decreased Nrf2 degradation. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Epoxidation of Short-Chain Alkenes by Resting-Cell Suspensions of Propane-Grown Bacteria

    PubMed Central

    Hou, Ching T.; Patel, Ramesh; Laskin, Allen I.; Barnabe, Nancy; Barist, Irene

    1983-01-01

    Sixteen new cultures of propane-utilizing bacteria were isolated from lake water from Warinanco Park, Linden, N.J. and from lake and soil samples from Bayway Refinery, Linden, N.J. In addition, 19 known cultures obtained from culture collections were also found to be able to grow on propane as the sole carbon and energy source. In addition to their ability to oxidize n-alkanes, resting-cell suspensions of both new cultures and known cultures grown on propane oxidize short-chain alkenes to their corresponding 1,2-epoxides. Among the substrate alkenes, propylene was oxidized at the highest rate. In contrast to the case with methylotrophic bacteria, the product epoxides are further metabolized. Propane and other gaseous n-alkanes inhibit the epoxidation of propylene. The optimum conditions for in vivo epoxidation are described. Results from inhibition studies indicate that a propane monooxygenase system catalyzes both the epoxidation and hydroxylation reactions. Experiments with cell-free extracts show that both hydroxylation and epoxidation activities are located in the soluble fraction obtained after 80,000 × g centrifugation. PMID:16346338

  20. Recent trends in ring opening of epoxides with sulfur nucleophiles.

    PubMed

    Ahmad, Sajjad; Zahoor, Ameer Fawad; Naqvi, Syed Ali Raza; Akash, Muhammad

    2018-02-01

    Thiolysis of epoxides offers an efficient and simple synthetic approach to access [Formula: see text]-hydroxy sulfides which are valuable scaffold in the synthesis of various important molecules in medicinal chemistry. This review article presents a recent compilation of the synthetic approaches developed after 2000 for the thiolysis of epoxides.

  1. Epoxide hydrolase-lasalocid a structure provides mechanistic insight into polyether natural product biosynthesis.

    PubMed

    Wong, Fong T; Hotta, Kinya; Chen, Xi; Fang, Minyi; Watanabe, Kenji; Kim, Chu-Young

    2015-01-14

    Biosynthesis of some polyether natural products involves a kinetically disfavored epoxide-opening cyclic ether formation, a reaction termed anti-Baldwin cyclization. One such example is the biosynthesis of lasalocid A, an ionophore antibiotic polyether. During lasalocid A biosynthesis, an epoxide hydrolase, Lsd19, converts the bisepoxy polyketide intermediate into the tetrahydrofuranyl-tetrahydropyran product. We report the crystal structure of Lsd19 in complex with lasalocid A. The structure unambiguously shows that the C-terminal domain of Lsd19 catalyzes the intriguing anti-Baldwin cyclization. We propose a general mechanism for epoxide selection by ionophore polyether epoxide hydrolases.

  2. CYP1A1, GSTM1, GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

    PubMed Central

    Hamachi, Tadamichi; Tajima, Osamu; Uezono, Kousaku; Tabata, Shinji; Abe, Hiroshi; Ohnaka, Keizo; Kono, Suminori

    2013-01-01

    AIM: To investigate the role of functional genetic polymorphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied were CYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other lifestyle factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1. A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual

  3. Gold(I)-Catalyzed Cascade Cyclization of Allenyl Epoxides

    PubMed Central

    Tarselli, Michael A.; Lucas Zuccarello, J

    2009-01-01

    Cationic gold(I) phosphite catalysts activate allenes for epoxide cascade reactions. The system is tolerant of numerous functional groups (sulfones, esters, ethers, sulfonamides) and proceeds at room temperature in dichloromethane. The cyclization pathway is sensitive to the substitution pattern of the epoxide, and the backbone structure of the A-ring. It is capable of producing medium-ring ethers, fused 6-5 bicyclic, and linked pyran-furan structures. The resulting cycloisomers are reminiscent of structures found in numerous polyether natural products. PMID:19588972

  4. Estrogenic status modulates the effect of soy on hepatic responses to 7,12-dimethylbenz(a)anthracene (DMBA)

    USDA-ARS?s Scientific Manuscript database

    We examined the influence of estradiol (E2) status and soy protein isolate (SPI) intake on the hepatic responses altered by 7,12-dimethylbenz(a)anthracene (DMBA, a polycyclic aromatic hydrocarbon [PAH]). Sprague–Dawley rats were ovariectomized (OVX) at PND50 and infused with E2 or vehicle for 14 d a...

  5. A strategy for position-selective epoxidation of polyprenols.

    PubMed

    Gnanadesikan, Vijay; Corey, E J

    2008-06-25

    An effective strategy has been developed for the efficient site-selective epoxidation of poylolefinic isoprenoid alcohols, based on the use of an internal control element for intramolecular reaction. The approach is illustrated by application to a series of polyisoprenoid alcohols (polyprenols) at substrate concentration of 0.5 mM. With polyprenol substrates having the hydroxyl function at one terminus, the internal epoxidation can be directed at the double bond of the polyprenol, which is either four or five away from the terminal hydroxyprenyl subunit.

  6. Inflammation, oxidative stress, and higher expression levels of Nrf2 and NQO1 proteins in the airways of women chronically exposed to biomass fuel smoke.

    PubMed

    Mondal, Nandan Kumar; Saha, Hirak; Mukherjee, Bidisha; Tyagi, Neetu; Ray, Manas Ranjan

    2018-01-24

    The study was carried out to examine whether chronic exposure to smoke during daily household cooking with biomass fuel (BMF) elicits changes in airway cytology and expressions of Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2]), Keap1 (Kelch-like erythroid-cell-derived protein with CNC homology [ECH]-associated protein 1), and NQO1 (NAD(P)H:quinone oxidoreductase 1) proteins in the airways. For this, 282 BMF-using women (median age 34 year) and 236 age-matched women who cooked with liquefied petroleum gas (LPG) were enrolled. Particulate matter with diameters of < 10 µm (PM 10 ) and < 2.5 µm (PM 2.5 ) were measured in indoor air with real-time laser photometer. Routine hematology, sputum cytology, Nrf2, Keap1, NQO1, and generation of reactive oxygen species (ROS) along with the levels of superoxide dismutase (SOD) and catalase were measured in both groups. PM 10 and PM 2.5 levels were significantly higher in BMF-using households compared to LPG. Compared with LPG users, BMF users had 32% more leukocytes in circulation and their sputa were 1.4-times more cellular with significant increase in absolute number of neutrophils, lymphocytes, eosinophils, and alveolar macrophages, suggesting airway inflammation. ROS generation was 1.5-times higher in blood neutrophils and 34% higher in sputum cells of BMF users while erythrocyte SOD was 31% lower and plasma catalase was relatively unchanged, suggesting oxidative stress. In BMF users, Keap1 expression was reduced, the percentage of AEC with nuclear expression of Nrf2 was two- to three-times more, and NQO1 level in sputum cell lysate was two-times higher than that of LPG users. In conclusion, cooking with BMF was associated with Nrf2 activation and elevated NQO1 protein level in the airways. The changes may be adaptive cellular response to counteract biomass smoke-elicited oxidative stress and inflammation-related tissue injury in the airways.

  7. Mechanism of olefin epoxidation in the presence of a titanium-containing zeolite

    NASA Astrophysics Data System (ADS)

    Danov, S. M.; Krasnov, V. L.; Sulimov, A. V.; Ovcharova, A. V.

    2013-11-01

    The effect of the nature of a solvent on the liquid-phase epoxidation of olefins with an aqueous solution of hydrogen peroxide over a titanium-containing zeolite is studied. Butanol-1, butanol-2, propanol-1, isopropanol, methanol, ethanol, water, acetone, methyl ethyl ketone, isobutanol, and tert-butanol are examined as solvents. A mechanism of olefin epoxidation with hydrogen peroxide in an alcohol medium over a titanium-containing zeolite is proposed. Epoxidation reactions involving hydrogen peroxide and different olefins are studied experimentally.

  8. Anti-Leishmania and cytotoxic activities of perillaldehyde epoxide synthetic positional isomers.

    PubMed

    Keesen, Tatjana Souza Lima; da Silva, Larisse Virgolino; da Câmara Rocha, Juliana; Andrade, Luciana Nalone; Lima, Tamires Cardoso; de Sousa, Damião Pergentino

    2018-03-13

    Leishmaniasis belongs to a complex of zoonotic disease caused by protozoa of the genus Leishmania and is considered a major public health problem. Several essential oil chemical components have inhibitory effect against protozoa, including Leishmania donovani. Thus, the aim of this study was to evaluate for the first time the anti-Leishmania activity of two p-menthane monoterpene isomers (EPER-1: perillaldehyde 1,2-epoxide and EPER-2: perillaldehyde 8,9-epoxide) against L. donovani promastigotes as well as evaluating cytotoxic effect on mononuclear peripheral blood cells. Results of anti-Leishmania assay revealed that EPER-2 (IC 50  = 3.8 μg.mL -1 ) was 16-fold more potent than its isomer EPER-1 (IC 50  = 64.6 μg.mL -1 ). In contrast to PBMC cells, EPER-2 was not cytotoxic (IC 50  > 400 μg.mL -1 ) when compared to positive control. These data suggest that the disposition of epoxide group into the p-menthane skeleton affects the anti-Leishmania activity, being that the presence of the exocyclic epoxide group considerably increased potency. Thus, it was possible to observe that the location of the epoxide group into the p-menthane skeleton resulted in different potencies.

  9. Occurrence of neoxanthin and lutein epoxide cycle in parasitic Cuscuta species.

    PubMed

    Kruk, Jerzy; Szymańska, Renata

    2008-01-01

    In the present study, xanthophyll composition of eight parasitic Cuscuta species under different light conditions was investigated. Neoxanthin was not detected in four of the eight species examined, while in others it occurred at the level of several percent of total xanthophylls. In C. gronovii and C. lupuliformis it was additionally found that the neoxanthin content was considerably stimulated by strong light. In dark-adapted plants, lutein epoxide level amounted to 10-22% of total xanthophylls in only three species, the highest being for C. lupuliformis, while in others it was below 3%, indicating that the lutein epoxide cycle is limited to only certain Cuscuta species. The obtained data also indicate that the presence of the lutein epoxide cycle and of neoxanthin is independent and variable among the Cuscuta species. The xanthophyll cycle carotenoids violaxanthin, antheraxanthin and zeaxanthin were identified in all the examined species and occurred at the level found in other higher plants. The xanthophyll and lutein epoxide cycle pigments showed typical response to high light stress. The obtained results also suggest that the ability of higher plants to synthesize lutein epoxide probably does not depend on the substrate specificity of zeaxanthin epoxidase but on the availability of lutein for the enzyme.

  10. In-Situ Generated Graphene as the Catalytic Site for Visible-Light Mediated Ethylene Epoxidation on AG Nanocatalysts

    NASA Astrophysics Data System (ADS)

    Zhang, Xueqiang Alex; Jain, Prashant

    2017-06-01

    Despite the harsh conditions for chemical conversion, ethylene oxide produced from ethylene epoxidation on Ag-based heterogeneous catalyst constitutes one of the largest volume chemicals in chemical industry. Recently, photocatalytic epoxidation of ethylene over plasmonic Ag nanoparticles enables the chemical conversion under significantly decreased temperature and ambient pressure conditions. Yet a detailed understanding of the photocatalytic process at the reactant/catalyst interface is under debate. Surface enhanced Raman spectroscopy (SERS) is a powerful vibrational spectroscopy technique that enables the localized detection of rare and/or transient chemical species with high sensitivity under in situ and ambient conditions. Using SERS, we are able to monitor at individual sites of an Ag nanocatalyst the visible-light-mediated adsorption and epoxidation of ethylene. From detected intermediates, we find that the primary step in the photoepoxidation is the transient formation of graphene catalyzed by the Ag surface. Density functional theory (DFT) simulations that model the observed SERS spectra suggest that the defective edge sites of the graphene formed on Ag constitute the active site for C2H4 adsorption and epoxidation. Further studies with pre-formed graphene/Ag catalyst composites confirm the indispensable role of graphene in visible-light-mediated ethylene epoxidation. Carbon is often thought to be either an innocent support or a poison for metallic catalysts; however our studies reveal a surprising role for crystalline carbon layers as potential co-catalysts.

  11. Exciton characteristics in graphene epoxide.

    PubMed

    Zhu, Xi; Su, Haibin

    2014-02-25

    Exciton characteristics in graphene epoxide (GE) are investigated by density functional theory with quasi-particle corrections and many-body interactions. The nature of the exciton is influenced by epoxide content and detailed geometric configurations. Two kinds of excitons are identified in GE: Frenkel-like exciton originated from the sp(2) carbon cluster and charge-transfer exciton formed by localized states involving both oxygen and carbon atoms. The unusual blue shift associated with the Frenkel-like exciton leaking is highlighted. One scaling relationship is proposed to address the power-law dependence of Frenkel-like exciton binding strength on its size. The charge-transfer exciton appears in GE samples with the high oxygen coverage. Particularly, the exciton in GE structures exhibits long lifetime by analyzing both radiative and nonradiative decay processes. This study sheds light on the potential applications of GE-based structures with attractive high quantum yield in light emission and optoelectronic technology.

  12. Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome.

    PubMed

    Atiomo, William; Shafiee, Mohamad Nasir; Chapman, Caroline; Metzler, Veronika M; Abouzeid, Jad; Latif, Ayşe; Chadwick, Amy; Kitson, Sarah; Sivalingam, Vanitha N; Stratford, Ian J; Rutland, Catrin S; Persson, Jenny L; Ødum, Niels; Fuentes-Utrilla, Pablo; Jeyapalan, Jennie N; Heery, David M; Crosbie, Emma J; Mongan, Nigel P

    2017-11-01

    Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). To investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC. Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study. We show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P < .0001). The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1. © 2017 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.

  13. Förster resonance energy transfer competitive displacement assay for human soluble epoxide hydrolase

    PubMed Central

    Lee, Kin Sing Stephen; Morisseau, Christophe; Yang, Jun; Wang, Peng; Hwang, Sung Hee; Hammock, Bruce D.

    2013-01-01

    The soluble epoxide hydrolase (sEH), responsible for the hydrolysis of various fatty acid epoxides to their corresponding 1,2-diols, is becoming an attractive pharmaceutical target. These fatty acid epoxides, particularly epoxyeicosatrienoic acids (EETs), play an important role in human homeostatic and inflammation processes. Therefore, inhibition of human sEH, which stabilizes EETs in vivo, brings several beneficial effects to human health. Although there are several catalytic assays available to determine the potency of sEH inhibitors, measuring the in vitro inhibition constant (Ki) for these inhibitors using catalytic assay is laborious. In addition, koff, which has been recently suggested to correlate better with the in vivo potency of inhibitors, has never been measured for sEH inhibitors. To better measure the potency of sEH inhibitors, a reporting ligand, 1-(adamantan-1-yl)-3-(1-(2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetyl) piperidin-4-yl)urea (ACPU), was designed and synthesized. With ACPU, we have developed a Förster resonance energy transfer (FRET)-based competitive displacement assay using intrinsic tryptophan fluorescence from sEH. In addition, the resulting assay allows us to measure the Ki values of very potent compounds to the picomolar level and to obtain relative koff values of the inhibitors. This assay provides additional data to evaluate the potency of sEH inhibitors. PMID:23219719

  14. Epoxidation of Alpha-Methylstyrene and its Lewis Acid Rearrangement to 2-Phenylpropanal

    NASA Astrophysics Data System (ADS)

    Garin, David L.; Gamber, Melissa; Rowe, Bradley J.

    1996-06-01

    This undergraduate organic lab experiment includes procedures for the peracid epoxidation of an olefin and the Lewis acid rearrangement of an epoxide to a carbonyl compound. Product mixtures and transformations can be readily analyzed by several spectroscopic techniques.

  15. Induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) by Glycyrrhiza species used for women's health: differential effects of the Michael acceptors isoliquiritigenin and licochalcone A

    PubMed Central

    Hajirahimkhan, Atieh; Simmler, Charlotte; Dong, Huali; Lantvit, Daniel D.; Li, Guannan; Chen, Shao-Nong; Nikolić, Dejan; Pauli, Guido F.; van Breemen, Richard B.; Dietz, Birgit M.; Bolton, Judy L.

    2016-01-01

    For the alleviation of menopausal symptoms, women frequently turn to botanical dietary supplements, such as licorice and hops. In addition to estrogenic properties, these botanicals could also have chemopreventive effects. We have previously shown that hops and its Michael acceptor xanthohumol (XH) induced the chemoprevention enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), in vitro and in vivo. Licorice species could also induce NQO1, as they contain the Michael acceptors isoliquiritigenin (LigC) found in Glycyrrhiza glabra (GG), G. uralensis (GU), and G. inflata (GI) and licochalcone A (LicA) which is only found in GI. These licorice species and hops induced NQO1 activity in murine hepatoma (Hepa1c1c7) cells; hops >> GI > GG ≅ GU. Similar to the known chemopreventive compounds curcumin (turmeric), sulforaphane (broccoli), and XH, LigC and LicA were active dose-dependently; sulforaphane >> XH > LigC > LicA ≅ curcumin >> LigF. Induction of the antioxidant response element-luciferase in human hepatoma (Hep-G2-ARE-C8) cells suggested involvement of the Keap1-Nrf2 pathway. GG, GU, and LigC also induced NQO1 in non-tumorigenic breast epithelial MCF-10A cells. In female Sprague-Dawley rats treated with GG and GU, LigC and LigF were detected in the liver and mammary gland. GG weakly enhanced NQO1 activity in the mammary tissue but not in the liver. Treatment with LigC alone did not induce NQO1 in vivo most likely due to its conversion to LigF, extensive metabolism, and its low bioavailability in vivo. These data show the chemopreventive potential of licorice species in vitro could be due to LigC and LicA and emphasize the importance of chemical and biological standardization of botanicals used as dietary supplements. Although the in vivo effects in the rat model after four day treatment are minimal, it must be emphasized that menopausal women take these supplements for extended periods of time and long-term beneficial effects are quite possible. PMID:26473469

  16. Physio-pharmacological Investigations About the Anti-inflammatory and Antinociceptive Efficacy of (+)-Limonene Epoxide.

    PubMed

    de Almeida, Antonia Amanda Cardoso; Silva, Renan Oliveira; Nicolau, Lucas Antonio Duarte; de Brito, Tarcísio Vieira; de Sousa, Damião Pergentino; Barbosa, André Luiz Dos Reis; de Freitas, Rivelilson Mendes; Lopes, Luciano da Silva; Medeiros, Jand-Venes Rolim; Ferreira, Paulo Michel Pinheiro

    2017-04-01

    D-limonene epoxidation generates (+)-limonene epoxide, an understudied compound in the pharmacologically point of view. Herein, we investigated the anti-inflammatory and antinociceptive potentialities of (+)-limonene epoxide and suggested a mechanism of action. The anti-inflammatory potential was analyzed using agents to induce paw edema, permeability, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines and cell migration of peritoneal cells were also assessed. Antinociceptive effects were evaluated by writhing test induced by acetic acid, formalin, and hot plate assays and contribution of opioid pathways. Pretreated animals with (+)-limonene epoxide showed reduced carrageenan-induced paw edema in all doses (25, 50, and 75 mg/kg) (P < 0.05). At 75 mg/kg, it suppressed edema provoked by compound 48/80, histamine, prostaglandin E 2 , and serotonin and reduced permeability determined by Evans blue and MPO activity. It also reduced leukocytes, neutrophils, and IL-1β levels in the peritoneal cavity in comparison with carrageenan group (P < 0.05). (+)-Limonene epoxide diminished abdominal contortions induced by acetic acid (78.9%) and paw licking times in both 1 (41.8%) and 2 (51.5%) phases and a pretreatment with naloxone (3 mg/kg) reverted the antinociceptive action in morphine- and (+)-limonene epoxide-treated groups (P < 0.05). Additionally, it enlarged response times to the thermal stimulus after 60 and 90 min. In conclusion, (+)-limonene epoxide inhibited release/activity of inflammatory mediators, vascular permeability, migration of neutrophils and displayed systemic and peripheral analgesic-dependent effects of the opioid system.

  17. Thermochemical Studies of Epoxides and Related Compounds

    PubMed Central

    Morgan, Kathleen M.; Ellis, Jamie A.; Lee, Joseph; Fulton, Ashley; Wilson, Shavonda L.; Dupart, Patrick S.; Dastoori, Rosanna

    2013-01-01

    Gas phase heats of formation for the our butene oxide isomers are reported. They were obtained by measuring the condensed-phase heat of reduction to the corresponding alcohol using reaction calorimetry. Heats of vaporization were determined, and allow gas-phase heats of formation to be obtained. The experimental measurements are compared to calculations obtained using a variety of computational methods. Overall, the G3 and CBS-APNO methods agree quite well with the experimental data. The influence of alkyl substituents on epoxide stability is discussed. Comparisons to alkenes, cyclopropanes, aziridines, thiiranes and phosphiranes are also made. Isodesmic-type reactions were used to determine strain energies of the epoxides and related compounds with various substituents. PMID:23551240

  18. Benzil, a potent activator of microsomal epoxide hydrolase in vitro.

    PubMed

    Seidegård, J; DePierre, J W

    1980-12-01

    Benzil was found to be a very potent activator of microsomal epoxide hydrolase activity (measured with styrene oxide as substrate) in vitro. The activating effect was uncompetitive and benzil causes approximately ninefold increases in both the apparent V and the apparent Km of the enzyme(s). The half-maximal effect on activity was obtained as a 0.3 mM concentration of benzil. The activating effect obtained with benzil was found to be very specific, since a variety of structurally related compounds had little or no effect on microsomal epoxide hydrolase activity. In order to obtain indications for the existence of more than one microsomal epoxide hydrolase the effect of benzil on this activity from rats induced with phenobarbital, 3-methylcholanthrene, 2-acetylaminofluorene, trans-stilbene oxide, and benzil was tested. The differences observed were minor.

  19. Lysophosphatidic acids are new substrates for the phosphatase domain of soluble epoxide hydrolase.

    PubMed

    Oguro, Ami; Imaoka, Susumu

    2012-03-01

    Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that has a C-terminus epoxide hydrolase domain and an N-terminus phosphatase domain. The endogenous substrates of epoxide hydrolase are known to be epoxyeicosatrienoic acids, but the endogenous substrates of the phosphatase activity are not well understood. In this study, to explore the substrates of sEH, we investigated the inhibition of the phosphatase activity of sEH toward 4-methylumbelliferyl phosphate by using lecithin and its hydrolyzed products. Although lecithin itself did not inhibit the phosphatase activity, the hydrolyzed lecithin significantly inhibited it, suggesting that lysophospholipid or fatty acid can inhibit it. Next, we investigated the inhibition of phosphatase activity by lysophosphatidyl choline, palmitoyl lysophosphatidic acid, monopalmitoyl glycerol, and palmitic acid. Palmitoyl lysophosphatidic acid and fatty acid efficiently inhibited phosphatase activity, suggesting that lysophosphatidic acids (LPAs) are substrates for the phosphatase activity of sEH. As expected, palmitoyl, stearoyl, oleoyl, and arachidonoyl LPAs were efficiently dephosphorylated by sEH (Km, 3-7 μM; Vmax, 150-193 nmol/min/mg). These results suggest that LPAs are substrates of sEH, which may regulate physiological functions of cells via their metabolism.

  20. Microdroplets Accelerate Ring Opening of Epoxides

    NASA Astrophysics Data System (ADS)

    Lai, Yin-Hung; Sathyamoorthi, Shyam; Bain, Ryan M.; Zare, Richard N.

    2018-05-01

    The nucleophilic opening of an epoxide is a classic organic reaction that has widespread utility in both academic and industrial applications. We have studied the reaction of limonene oxide with morpholine to form 1-methyl-2-morpholino-4-(prop-1-en-2-yl) cyclohexan-1-ol in bulk solution and in electrosprayed microdroplets with a 1:1 v/ v water/methanol solvent system. We find that even after 90 min at room temperature, there is no product detected by nuclear magnetic resonance spectroscopy in bulk solution whereas in room-temperature microdroplets (2-3 μm in diameter), the yield is already 0.5% in a flight time of 1 ms as observed by mass spectrometry. This constitutes a rate acceleration of 105 in the microdroplet environment, if we assume that as much as 5% of product is formed in bulk after 90 min of reaction time. We examine how the reaction rate depends on droplet size, solvent composition, sheath gas pressure, and applied voltage. These factors profoundly influence the extent of reaction. This dramatic acceleration is not limited to just one system. We have also found that the nucleophilic opening of cis-stilbene oxide by morpholine is similarly accelerated. Such large acceleration factors in reaction rates suggest the use of microdroplets for ring opening of epoxides in other systems, which may have practical significance if such a procedure could be scaled. [Figure not available: see fulltext.

  1. Microbial production of epoxides

    DOEpatents

    Clark, Thomas R.; Roberto, Francisco F.

    2003-06-10

    A method for microbial production of epoxides and other oxygenated products is disclosed. The method uses a biocatalyst of methanotrophic bacteria cultured in a biphasic medium containing a major amount of a non-aqueous polar solvent. Regeneration of reducing equivalents is carried out by using endogenous hydrogenase activity together with supplied hydrogen gas. This method is especially effective with gaseous substrates and cofactors that result in liquid products.

  2. INTERACTION OF BENZO(A)PYRENE DIOL EPOXIDE WITH SVAO MINICHROMOSOMES

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gamper, Howard B.; Yokota, Hisao A.; Bartholomew, James C.

    SV40 minichromosomes were reacted with (+)7{beta},8{alpha}-dihydroxy-9{alpha},10{alpha}-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (BaP diol epoxide). Low levels of modification (< 5 DNA adducts/minichromosome) did not detectably alter the structure of the minichromosomes but high levels (> 200 DNA adducts/minichromosome) led to extensive fragmentation. Relative to naked SV40 DNA BaP diol epoxide induced alkylation and strand scission of minichromosomal DNA was reduced or enhanced by factors of 1.5 and 2.0, respectively. The reduction in covalent binding was attributed to the presence of histones, which competed with DNA for the hydrocarbon and reduced the probability of BaP diol epoxide intercalation by tightening the helix. The enhancement ofmore » strand scission was probably due to the catalytic effect of histones on the rate of S-elimination at apurinic sites, although an altered adduct profile or the presence of a repair endonuclease were not excluded. Staphylococcal nuclease digestion indicated that BaP dial epoxide randomly alkylated the minichromosomal DNA. This is in contrast to studies with cellular chromatin where internucleosomal DNA was preferentially modified. Differences in the minichromosomal protein complement were responsible for this altered susceptibility.« less

  3. Ozonides and epoxides from ozonization of pyrethroids

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ruzo, L.O.; Kimmel, E.C.; Casida, J.E.

    Ozonization of pyrethroids as solutions or thin films yields products proposed to be epoxides from the 2,2-dihalovinyl substituents of deltamethrin and permethrin and transitory ozonides from these compounds and more stable ozonides from the 2-methyl-1-propenyl and 2-chloro-3,3,3-trifluoropropenyl substituents of phenothrin and descyanocyhalothrin, respectively. The unstable epoxydeltamethrin from ozonization is identified by /sup 1/H nuclear magnetic resonance spectroscopy and chemical ionization-mass spectroscopy and by reversion to deltamethrin on treatment of reaction mixtures with triphenylphosphine. Degradation of the ozonides yields the corresponding caronaldehyde in each case and trifluoroacetyl chloride from the chlorotrifluoropropenyl analogues. The ozonolysis mixtures are direct acting but weak bacterialmore » mutagens presumable due to their epoxide and ozonide components.« less

  4. Epoxide-mediated differential packaging of Cif and other virulence factors into outer membrane vesicles.

    PubMed

    Ballok, Alicia E; Filkins, Laura M; Bomberger, Jennifer M; Stanton, Bruce A; O'Toole, George A

    2014-10-01

    Pseudomonas aeruginosa produces outer membrane vesicles (OMVs) that contain a number of secreted bacterial proteins, including phospholipases, alkaline phosphatase, and the CFTR inhibitory factor (Cif). Previously, Cif, an epoxide hydrolase, was shown to be regulated at the transcriptional level by epoxides, which serve as ligands of the repressor, CifR. Here, we tested whether epoxides have an effect on Cif levels in OMVs. We showed that growth of P. aeruginosa in the presence of specific epoxides but not a hydrolysis product increased Cif packaging into OMVs in a CifR-independent fashion. The outer membrane protein, OprF, was also increased under these conditions, but alkaline phosphatase activity was not significantly altered. Additionally, we demonstrated that OMV shape and density were affected by epoxide treatment, with two distinct vesicle fractions present when cells were treated with epibromohydrin (EBH), a model epoxide. Vesicles isolated from the two density fractions exhibited different protein profiles in Western blotting and silver staining. We have shown that a variety of clinically or host-relevant treatments, including antibiotics, also alter the proteins packaged in OMVs. Proteomic analysis of purified OMVs followed by an analysis of transposon mutant OMVs yielded mutants with altered vesicle packaging. Finally, epithelial cell cytotoxicity was reduced in the vesicles formed in the presence of EBH, suggesting that this epoxide alters the function of the OMVs. Our data support a model whereby clinically or host-relevant signals mediate differential packaging of virulence factors in OMVs, which results in functional consequences for host-pathogen interactions. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  5. Asymmetric epoxidation of unsaturated ketones catalyzed by heterobimetallic rare earth-lithium complexes bearing phenoxy-functionalized chiral diphenylprolinolate ligand.

    PubMed

    Qian, Qinqin; Tan, Yufang; Zhao, Bei; Feng, Tao; Shen, Qi; Yao, Yingming

    2014-09-05

    Four novel heterobimetallic complexes [REL2]{[(THF)3Li]2(μ-Cl)} stabilized by chiral phenoxy-functionalized prolinolate (RE = Yb (1), Y (2), Sm (3), Nd (4), H2L = (S)-2,4-di-tert-butyl-6-[[2-(hydroxydiphenylmethyl)pyrrolidin-1-yl]methyl]phenol have been synthesized and characterized. These readily available complexes are highly active in catalyzing the epoxidation of α,β-unsaturated ketones, while the enantioselectivity varies according to the ionic radii of the rare earth center. A series of chalcone derivatives were converted to chiral epoxides in 80 → 99% ee at 0 °C using TBHP as the oxidant in the presence of 10 mol % of 1.

  6. Synthesis of water-soluble multidentate aminoalcohol β-cyclodextrin derivatives via epoxide opening.

    PubMed

    Martina, K; Caporaso, M; Tagliapietra, S; Heropoulos, G; Rosati, O; Cravotto, G

    2011-12-13

    New highly soluble β-aminoalcohol β-cyclodextrin (β-CD) derivatives have been synthesized via nucleophilic epoxide opening reactions with mono-6-amino mono-6-deoxy-permethyl-β-CD and mono-6-amino mono-6-deoxy-β-CD. The binding properties of the β-CD were enhanced by linking aminoalcohol subunits which caused its solubility to improve markedly. The reaction conditions were optimised using microwave irradiation giving moderate-to-good yields with a series of epoxides. A regioselective epoxide opening reaction was observed in the reaction with styrene oxide while the stereoselectivity was strictly dependent on substrate structure. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Methods of producing epoxides from alkenes using a two-component catalyst system

    DOEpatents

    Kung, Mayfair C.; Kung, Harold H.; Jiang, Jian

    2013-07-09

    Methods for the epoxidation of alkenes are provided. The methods include the steps of exposing the alkene to a two-component catalyst system in an aqueous solution in the presence of carbon monoxide and molecular oxygen under conditions in which the alkene is epoxidized. The two-component catalyst system comprises a first catalyst that generates peroxides or peroxy intermediates during oxidation of CO with molecular oxygen and a second catalyst that catalyzes the epoxidation of the alkene using the peroxides or peroxy intermediates. A catalyst system composed of particles of suspended gold and titanium silicalite is one example of a suitable two-component catalyst system.

  8. Functionalization of multi-walled carbon nanotubes by epoxide ring-opening polymerization

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jin Fanlong; Rhee, Kyong Yop; Park, Soo-Jin, E-mail: sjpark@inha.ac.kr

    2011-12-15

    In this study, covalent functionalization of carbon nanotubes (CNTs) was accomplished by surface-initiated epoxide ring-opening polymerization. FT-IR spectra showed that polyether and epoxide group covalently attached to the sidewalls of CNTs. TGA results indicated that the polyether was successfully grown from the CNT surface, with the final products having a polymer weight percentage of ca. 14-74 wt%. The O/C ratio of CNTs increased significantly from 5.1% to 29.8% after surface functionalization of CNTs. SEM and TEM images of functionalized CNTs exhibited that the tubes were enwrapped by polymer chains with thickness of several nanometers, forming core-shell structures with CNTs atmore » the center. - Graphical abstract: Functionalized CNTs were enwrapped by polymer chains with thickness of several nanometers, forming core-shell structures with CNTs at the center. Highlights: Black-Right-Pointing-Pointer CNTs were functionalized by epoxide ring-opening polymerization. Black-Right-Pointing-Pointer Polyether and epoxide group covalently attached to the sidewalls of CNTs. Black-Right-Pointing-Pointer Functionalized CNTs have a polymer weight percentage of ca. 14-74 wt%. Black-Right-Pointing-Pointer Functionalized CNTs were enwrapped by polymer chains with thickness of several nanometers.« less

  9. HMOX1 and NQO1 genes are upregulated in response to contact sensitizers in dendritic cells and THP-1 cell line: role of the Keap1/Nrf2 pathway.

    PubMed

    Ade, Nadège; Leon, Fanny; Pallardy, Marc; Peiffer, Jean-Luc; Kerdine-Romer, Saadia; Tissier, Marie-Hélène; Bonnet, Pierre-Antoine; Fabre, Isabelle; Ourlin, Jean-Claude

    2009-02-01

    Electrophilicity is one of the most common features of skin contact sensitizers and is necessary for protein haptenation. The Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 -signaling pathway is dedicated to the detection of electrophilic stress in cells leading to the upregulation of genes involved in protection or neutralization of chemical reactive species. Signals provided by chemical stress could play an important role in dendritic cell activation and the aim of this work was to test whether contact sensitizers were specific activators of the Keap1/Nrf2 pathway. CD34-derived dendritic cells (CD34-DC) and the THP-1 myeloid cell line were treated by a panel of sensitizers (Ni, 1-chloro 2,4-dinitrobenzene, cinnamaldehyde, 7-hydroxycitronellal, 1,4-dihydroquinone, alpha-methyl-trans-cinnamaldehyde, 2-4-tert-(butylbenzyl)propionaldehyde or Lilial, and 1,4-phenylenediamine), irritants (sodium dodecyl sulfate, benzalkonium chloride), and a nonsensitizer molecule (chlorobenzene). Three well-known Nrf2 activators (tert-butylhydroquinone, lipoic acid, sulforaphane) were also tested. Expression of hmox1 and nqo1 was measured using real-time PCR and cellular accumulation of Nrf2 was assessed by Western blot. Our results showed an increased expression at early time points of hmox1 and nqo1 mRNAs in response to sensitizers but not to irritants. Accumulation of the Nrf2 protein was also observed only with chemical sensitizers. A significant inhibition of the expression of hmox1 and nqo1 mRNAs and CD86 expression was found in 1-chloro 2,4-dinitrobenzene-treated THP-1 cells preincubated with N-acetyl cysteine, a glutathione precursor. Altogether, these data suggested that the Keap1/Nrf2-signaling pathway was activated by electrophilic molecules including sensitizers in dendritic cells and in the THP-1 cell line. Monitoring of this pathway may provide new biomarkers (e.g., Nrf2, hmox1) for the detection of the sensitization potential of chemicals.

  10. Copper-catalyzed cross-coupling reactions of epoxides with gem-diborylmethane: access to γ-hydroxyl boronic esters.

    PubMed

    Ebrahim-Alkhalil, Ahmed; Zhang, Zhen-Qi; Gong, Tian-Jun; Su, Wei; Lu, Xiao-Yu; Xiao, Bin; Fu, Yao

    2016-04-07

    Herein, we describe a novel copper-catalyzed epoxide opening reaction with gem-diborylmethane. Aliphatic, aromatic epoxides as well as aziridines are converted to the corresponding γ-pinacolboronate alcohols or amines in moderate to excellent yields. This new reaction provides beneficial applications for classic epoxide substrates as well as interesting gem-diborylalkane reagents.

  11. Lysophosphatidic acids are new substrates for the phosphatase domain of soluble epoxide hydrolase[S

    PubMed Central

    Oguro, Ami; Imaoka, Susumu

    2012-01-01

    Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that has a C-terminus epoxide hydrolase domain and an N-terminus phosphatase domain. The endogenous substrates of epoxide hydrolase are known to be epoxyeicosatrienoic acids, but the endogenous substrates of the phosphatase activity are not well understood. In this study, to explore the substrates of sEH, we investigated the inhibition of the phosphatase activity of sEH toward 4-methylumbelliferyl phosphate by using lecithin and its hydrolyzed products. Although lecithin itself did not inhibit the phosphatase activity, the hydrolyzed lecithin significantly inhibited it, suggesting that lysophospholipid or fatty acid can inhibit it. Next, we investigated the inhibition of phosphatase activity by lysophosphatidyl choline, palmitoyl lysophosphatidic acid, monopalmitoyl glycerol, and palmitic acid. Palmitoyl lysophosphatidic acid and fatty acid efficiently inhibited phosphatase activity, suggesting that lysophosphatidic acids (LPAs) are substrates for the phosphatase activity of sEH. As expected, palmitoyl, stearoyl, oleoyl, and arachidonoyl LPAs were efficiently dephosphorylated by sEH (Km, 3–7 μM; Vmax, 150–193 nmol/min/mg). These results suggest that LPAs are substrates of sEH, which may regulate physiological functions of cells via their metabolism. PMID:22217705

  12. Derivatization of castor oil based estolide esters: Preparation of epoxides and cyclic carbonates

    USDA-ARS?s Scientific Manuscript database

    Estolides that are based on castor oil and oleic acid are versatile starting points for the production of industrial fluids with new properties. A variety of unsaturated estolides were derivatized by epoxidation with hydrogen peroxide. The epoxidized estolides were further modified using supercritic...

  13. Signature Motifs Identify an Acinetobacter Cif Virulence Factor with Epoxide Hydrolase Activity*

    PubMed Central

    Bahl, Christopher D.; Hvorecny, Kelli L.; Bridges, Andrew A.; Ballok, Alicia E.; Bomberger, Jennifer M.; Cady, Kyle C.; O'Toole, George A.; Madden, Dean R.

    2014-01-01

    Endocytic recycling of the cystic fibrosis transmembrane conductance regulator (CFTR) is blocked by the CFTR inhibitory factor (Cif). Originally discovered in Pseudomonas aeruginosa, Cif is a secreted epoxide hydrolase that is transcriptionally regulated by CifR, an epoxide-sensitive repressor. In this report, we investigate a homologous protein found in strains of the emerging nosocomial pathogens Acinetobacter nosocomialis and Acinetobacter baumannii (“aCif”). Like Cif, aCif is an epoxide hydrolase that carries an N-terminal secretion signal and can be purified from culture supernatants. When applied directly to polarized airway epithelial cells, mature aCif triggers a reduction in CFTR abundance at the apical membrane. Biochemical and crystallographic studies reveal a dimeric assembly with a stereochemically conserved active site, confirming our motif-based identification of candidate Cif-like pathogenic EH sequences. Furthermore, cif expression is transcriptionally repressed by a CifR homolog (“aCifR”) and is induced in the presence of epoxides. Overall, this Acinetobacter protein recapitulates the essential attributes of the Pseudomonas Cif system and thus may facilitate airway colonization in nosocomial lung infections. PMID:24474692

  14. Direct Epoxidation of Propylene over Stabilized Cu + Surface Sites on Ti Modified Cu 2O

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yang, X.; Kattel, S.; Xiong, K.

    2015-07-17

    Direct propylene epoxidation by O 2 is a challenging reaction because of the strong tendency for complete combustion. Results from the current study demonstrate the feasibility to tune the epoxidation selectivity by generating highly dispersed and stabilized Cu + active sites in a TiCuO x mixed oxide. The TiCuO x surface anchors the key surface intermediate, oxametallacycle, leading to higher selectivity for epoxidation of propylene.

  15. Effects of thalidomide on DMBA-induced oral carcinogenesis in hamster with respect to angiogenesis.

    PubMed

    Yang, Y; Ge, J-P; Zhou, Z-T

    2009-05-01

    Thalidomide has been shown to have anti-angiogenic effects in pre-clinical models as well as a significant antitumor effect in hematologic tumors. However, the effects of thalidomide on oral pre-malignant lesions and oral carcinogenesis remain unexplored. The authors aimed to investigate the chemopreventive effect of thalidomide on 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters with respect to angiogenesis. Seventy male Syrian golden hamsters were randomly divided into five groups, with two of 20 and three of 10. DMBA solution (0.5% in acetone) was applied topically to the left cheek pouch of male Syrian golden hamsters in group A and B, while animals in group C were painted with acetone, three times a week for 6 weeks. For the next 18 weeks, animals in group B and D received thalidomide daily (40 mg/kg body weight/day) by gavage, animals in group A and C received same volume of saline. Animals in group E received no treatment and served as blank control. At the end of the experiment, animals were killed and tissue samples were collected for examinations. Thalidomide significantly decreased the squamous cell carcinoma (SCC) incidence from 57.9 to 11.8%; angiogenesis was inhibited in dysplasia and SCC. The gene expression of vascular endothelium growth factor and tumor necrosis factor (TNF)-alpha was downregulated. Thalidomide has inhibitory effect against the malignant transformation of oral pre-cancerous lesion and angiogenesis during oral carcinogenesis. Such inhibition is related to its modulation of TNF-alpha.

  16. Teaching Green Chemistry with Epoxidized Soybean Oil

    ERIC Educational Resources Information Center

    Barcena, Homar; Tuachi, Abraham; Zhang, Yuanzhuo

    2017-01-01

    The synthesis of epoxidized soybean oil (ESO) provides students a vantage point on the application of green chemistry principles in a series of experiments. Qualitative tests review the reactions of alkenes, whereas spectroscopic analyses provide insight in monitoring functional group transformations.

  17. 40 CFR 721.2685 - Polyisobutene epoxide (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ....2685 Section 721.2685 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.2685 Polyisobutene epoxide (generic). (a) Chemical substances and significant new uses...

  18. Enantioselective Ring Opening of Epoxides with 4-Methoxyphenol Catalyzed by Gallium Heterobimetallic Complexes: An Efficient Method for the Synthesis of Optically Active 1,2-Diol Monoethers.

    PubMed

    Iida, Takehiko; Yamamoto, Noriyoshi; Matsunaga, Shigeki; Woo, Hee-Gweon; Shibasaki, Masakatsu

    1998-09-04

    Useful chiral building blocks such as 1,2-diols can be obtained by the enantioselective ring opening of achiral epoxides with oxygen nucleophiles. The ring opening is carried out effectively (up to 94 % ee) with 4-methoxyphenol and catalytic amounts of gallium complexes. The novel complex GaSO 1 displays a particularly high catalytic activity. © 1998 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

  19. Silica-supported, single-site titanium catalysts for olefin epoxidation. A molecular precursor strategy for control of catalyst structure.

    PubMed

    Jarupatrakorn, Jonggol; Don Tilley, T

    2002-07-17

    A molecular precursor approach involving simple grafting procedures was used to produce site-isolated titanium-supported epoxidation catalysts of high activity and selectivity. The tris(tert-butoxy)siloxy titanium complexes Ti[OSi(O(t)Bu)(3)](4) (TiSi4), ((i)PrO)Ti[OSi(O(t)Bu)(3)](3) (TiSi3), and ((t)BuO)(3)TiOSi(O(t)Bu)(3) (TiSi) react with the hydroxyl groups of amorphous Aerosil, mesoporous MCM-41, and SBA-15 via loss of HO(t)Bu and/or HOSi(O(t)Bu)(3) and introduction of titanium species onto the silica surface. Powder X-ray diffraction, nitrogen adsorption/desorption, infrared, and diffuse reflectance ultraviolet spectroscopies were used to investigate the structures and chemical natures of the surface-bound titanium species. The titanium species exist mainly in isolated, tetrahedral coordination environments. Increasing the number of siloxide ligands in the molecular precursor decreases the amount of titanium that can be introduced this way, but also enhances the catalytic activity and selectivity for the epoxidation of cyclohexene with cumene hydroperoxide as oxidant. In addition, the high surface area mesoporous silicas (MCM-41 and SBA-15) are more effective than amorphous silica as supports for these catalysts. Supporting TiSi3 on the SBA-15 affords highly active cyclohexene epoxidation catalysts (0.25-1.77 wt % Ti loading) that provide turnover frequencies (TOFs) of 500-1500 h(-1) after 1 h (TOFs are reduced by about half after calcination). These results demonstrate that oxygen-rich siloxide complexes of titanium are useful as precursors to supported epoxidation catalysts.

  20. Ring-opening Polymerization of Epoxidized Soybean Oil

    USDA-ARS?s Scientific Manuscript database

    Ring opening polymerization of epoxidized soybean oil (ESO) initiated by boron trifluoride diethyl etherate, (BF3•OEt2), in methylene chloride was conducted in an effort to develop useful biodegradable polymers. The resulting polymers (PESO) were characterized using Infrared (IR), differential scan...

  1. Oxidations of alkenes and lignin model compounds in aqueous dispersions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhu, Weiming.

    1991-01-01

    The objective was to develop methods to oxidize water-immiscible alkenes and lignin model compounds with polymer colloid supported transition metal catalysts. The oxidations of organic compounds were carried out in aqueous phase with several water-soluble oxidants and dioxygen. Cationic polymer latexes were prepared by the emulsion copolymerization of vinylbenzyl chloride, divinylbenzene, and vinyl octadecyl ether, or styrene, or n-decyl methacrylate, and the subsequent quaternization of copolymers with trimethylamine. The latex particles were 44 nm to 71 nm in diameter. The latex bound Mn porphyrin catalysts were formed with MnTSPP [TSPP = meso-tetrakis(2,6-dichloro-3-sulfonatophenyl)porphyrin], which catalyzed the oxidation of cyclohexene, cycloocetene, allylbenzene,more » and 1-octene by sodium hypochlorite (NaOCl) and potassium peroxymonosulfate (KHSO[sub 5]). The latex bound porphyrin catalysts showed higher activity than MnTSPP in solution. Oxidations of 3,4-dimethoxybenzyl alcohol (DMBA), 4-hydroxy-3-methoxytoluene (HMT), and 3,4-dimethoxytoluene (DMT) were performed with either dioxygen or hydrogen peroxide and CoPcTS (PcTS = tetrasulfonatophthalocyanine), FePcTS, CuPcTS, NiPcTS, FeTCPP [TCPP = meso-tetrakis(4-carboxyphenyl)porphyrin], and MnTSPP. CoPcTS catalyzed the autoxidation of DMBA and HMT at 70-85[degrees]C and pH [ge] 8. All catalysts were active for the oxidation of DMBA, HMT, and DMT with H[sub 2]O[sub 2]. Aqueous solutions of KHSO[sub 5] oxidized water-immiscible alkenes at room temperature in the absence of organic solvent. The acidic pH [le] 1.7 solutions of commercial 2KHSO[sub 5][center dot]K[sub 2]SO[sub 4] in water produced diols from all reactive alkenes except cyclooctene. Adjustment of initial pH to [ge]6.7 with NaHCO[sub 3] enabled selective epoxidations.« less

  2. Heteropolytungstate nanoparticles: Microemulsion-mediated preparation and investigation of their catalytic activity in the epoxidation of olefins

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Masteri-Farahani, M., E-mail: mfarahany@yahoo.com; Ghorbani, M.

    2016-04-15

    Highlights: • Keggin type Q{sub 3}PW{sub 12}O{sub 40} nanoparticles were synthesized by using microemulsion system. • The nanoparticles have uniform size of about 25 nm and spherical morphologies. • The prepared nanoparticles act as reusable catalyst in the epoxidation of olefins with H{sub 2}O{sub 2}. - Abstract: Keggin type Q{sub 3}PW{sub 12}O{sub 40} nanoparticles (Q = cetyltrimethylammonium cation) were synthesized in water-in-oil (w/o) microemulsion consisted of water/cetyltrimethylammonium bromide/n-butanol/isooctane. Reaction of Na{sub 2}WO{sub 4}, Na{sub 2}HPO{sub 4} and hydrochloric acid within water containing nanoreactors of reverse micelles resulted in the preparation of Q{sub 3}PW{sub 12}O{sub 40} nanoparticles. The resultant nanoparticles weremore » analyzed by physicochemical methods such as FT-IR spectroscopy, X-ray diffraction, energy-dispersive X-ray analysis, thermogravimetric analyses (TGA-DTA), scanning and transmission electron microscopy and atomic force microscopy which show nearly uniform spherical nanoparticles with size of about 15 nm. Finally, catalytic activity of the Q{sub 3}PW{sub 12}O{sub 40} nanoparticles was examined in the epoxidation of olefins with H{sub 2}O{sub 2}. The prepared nanoparticles acted as recoverable and reusable catalyst in the epoxidation of olefins with H{sub 2}O{sub 2}.« less

  3. Alkene epoxidation employing metal nitro complexes

    DOEpatents

    Andrews, M.A.; Cheng, C.W.; Kelley, K.P.

    1982-07-15

    Process for converting alkenes to form epoxides utilizes transition metal nitro complexes of the formula: M(RCN)/sub 2/XNO/sub 2/ wherein M is palladium or platinum, R is an alkyl or aryl group containing up to 12 carbon atoms, and X is a monoanionic, monodentate ligand such as chlorine, optionally in the presence of molecular oxygen.

  4. Impact of Obesity on Ovotoxicity Induced by 7,12-dimethylbenz[a]anthracene in Mice1

    PubMed Central

    Nteeba, Jackson; Ganesan, Shanthi; Keating, Aileen F.

    2014-01-01

    ABSTRACT Insulin, elevated during obesity, regulates xenobiotic biotransformation enzymes, potentially through phosphatidylinositol 3-kinase (PI3K) signaling, in extraovarian tissues. PI3K regulates oocyte viability, follicular activation, and ovarian chemical biotransformation. 7,12-Dimethylbenz[a]anthracene (DMBA), a carcinogen and ovotoxicant, destroys all stages of follicles, leading to premature ovarian failure. Obesity has been reported to promote DMBA-induced tumors, but it remains unknown whether obesity affects ovarian xenobiotic metabolism. Therefore, we investigated ovarian expression of xenobiotic metabolism genes—microsomal epoxide hydrolase (Ephx1), glutathione S-transferase (GST) class Pi (Gstp1) and class mu 1 (Gstm1), and PI3K-signaling members (protein kinase B [AKT] alpha [Akt1], beta [Akt2], and the forkhead transcription factor subfamily 3 [Foxo3])—in lean and obese female mice after DMBA exposure (1 mg/kg; intraperitoneal injection for 14 days). Relative to lean, obese mice had decreased (P < 0.05) healthy primordial and primary follicle numbers but increased (P < 0.05) secondary and preovulatory follicles numbers. Obesity increased (P < 0.05) Akt1, Akt2, Gstm1, and Ephx1 mRNA and pAKTSer473/Thr308, GSTM1, GSTP1, and EPHX1 protein levels. DMBA decreased (P < 0.05) ovarian weight in lean and obese mice, however, obese DMBA-treated females had a greater reduction (P < 0.05) in ovarian weight. In both lean and obese mice, DMBA decreased (P < 0.05) all stages of healthy follicle numbers, increased Gstp1 and Ephx1 mRNA as well as GSTM1, GSTP1, and EPHX1 protein levels, and decreased Akt1 and Akt2 mRNA as well as pAKTSer473 or pAKTThr308, FOXO3, and pFOXO3Ser253 protein expression. There was an additive effect between obesity and DMBA exposure for increased Gstm1 and Ephx1 mRNA as well as GSTM1 and EPHX1 protein expression. PMID:24501177

  5. Simple Epoxide Formation for the Organic Laboratory Using Oxone

    ERIC Educational Resources Information Center

    Broshears, Williams C.; Esteb, John J.; Richter, Jeremy; Wilson, Anne M.

    2004-01-01

    Epoxide chemistry is widely used in organic synthesis and regularly discussed in organic chemistry textbooks. An experiment to generate dimethyldioxirane in situ from acetone using Oxone is explained.

  6. Assignment of the relative and absolute stereochemistry of two novel epoxides using NMR and DFT-GIAO calculations

    NASA Astrophysics Data System (ADS)

    Moraes, F. C.; Alvarenga, E. S.; Demuner, A. J.; Viana, V. M.

    2018-07-01

    Considering the potential biological application of isobenzofuranones, especially as agrochemical defensives, two novel epoxides, (1aR,2R,2aR,5S,5aS,6S,6aS)-5-(hydroxymethyl)hexahydro-2,6-methanooxireno[2,3-f]isobenzofuran-3(1aH)-one (9), and (1aS,2S,2aR,5S,5aS,6R,6aR)-5-(hydroxymethyl)hexahydro-2,6-methanooxireno[2,3-f]isobenzofuran-3(1aH)-one (10), were synthesized from the readily available D-mannitol in six steps. The multiplicities of the hydrogens located at the bridge of the bicycle are distinct for epoxides 9 and 10 due to W coupling, and this feature was employed to confirm the assignment of these nuclei. Besides analyses of the 2D NMR spectra, the assignments of the nuclei at the epoxide ring were also inferred from information obtained by theoretical calculations. The calculated 1H and 13C NMR chemical shifts for eight candidate structures were compared with the experimental chemical shifts of 9 and 10 by measuring the mean absolute errors (MAE) and by the DP4 statistical analysis. The structures and relative configurations of 9, and 10 were determined via NMR spectroscopy assisted with theoretical calculations. As consequence of the enantioselective syntheses starting from a natural polyol, the absolute configurations of the epoxides 9 and 10 were also defined.

  7. Polymerization of epoxidized triglycerides with fluorosulfonic acid

    USDA-ARS?s Scientific Manuscript database

    The use of triglycerides as agri-based renewable raw materials for the development of new products is highly desirable in view of uncertain future petroleum prices. A new method of polymerizing epoxidized soybean oil has been devised with the use of fluorosulfonic acid. Depending on the reaction con...

  8. 21 CFR 172.723 - Epoxidized soybean oil.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Epoxidized soybean oil. 172.723 Section 172.723 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN...

  9. 21 CFR 172.723 - Epoxidized soybean oil.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Epoxidized soybean oil. 172.723 Section 172.723 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN...

  10. Allenes in Asymmetric Catalysis. Asymmetric Ring-Opening of Meso-Epoxides Catalyzed by Allene-Containing Phosphine Oxides

    PubMed Central

    Pu, Xiaotao; Qi, Xiangbing; Ready, Joseph M.

    2009-01-01

    Unsymmetrically substituted allenes (1,2 dienes) are inherently chiral and can be prepared in optically pure form. Nonetheless, to date the allene framework has not been incorporated into ligands for asymmetric catalysis. Since allenes project functionality differently than either tetrahedral carbon or chiral biaryls, they may create complementary chiral environments. This study demonstrates that optically active C2 symmetric allene-containing bisphosphine oxides can catalyze the addition of SiCl4 to meso epoxides with high enantioselectivity. The epoxide-opening likely involves generation of a Lewis acidic, cationic (bisphosphine oxide)SiCl3 complex. The fact that high asymmetric induction is observed suggests that allenes may represent a new platform for the development of ligands and catalysts for asymmetric synthesis. PMID:19722613

  11. In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols.

    PubMed

    Cossar, Peter J; Baker, Jennifer R; Cain, Nicholas; McCluskey, Adam

    2018-04-01

    The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of analogues of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol 1 , a potential antibiotic lead. The in situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidation abrogates this limitation and afforded facile access to structurally diverse β-amino alcohols. Analogues of 1 were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in situ generation of DMDO, with olefin epoxidation in typically good yields and a flow-mediated ring opening aminolysis to form an expanded library of β-amino alcohols 1 and 10a - 18g , resulting in modest ( 11a , 21%) to excellent ( 12g , 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols 4a - 4m (22%-89%) and a Bi(OTf) 3 catalysed microwave ring opening with amines afforded a select range of β-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach.

  12. First-principles chemical kinetic modeling of methyl trans-3-hexenoate epoxidation by HO 2

    DOE PAGES

    Cagnina, S.; Nicolle, Andre; de Bruin, T.; ...

    2017-02-16

    The design of innovative combustion processes relies on a comprehensive understanding of biodiesel oxidation kinetics. The present study aims at unraveling the reaction mechanism involved in the epoxidation of a realistic biodiesel surrogate, methyl trans-3-hexenoate, by hydroperoxy radicals using a bottom-up theoretical kinetics methodology. The obtained rate constants are in good agreement with experimental data for alkene epoxidation by HO 2. The impact of temperature and pressure on epoxidation pathways involving H-bonded and non-H-bonded conformers was assessed. As a result, the obtained rate constant was finally implemented into a state-of-the-art detailed combustion mechanism, resulting in fairly good agreement with enginemore » experiments.« less

  13. Reaction Mechanism for Direct Propylene Epoxidation by Alumina-Supported Silver Aggregates. The Role of the Particle / Support Interface

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cheng, Lei; Yin, Chunrong; Mehmood, Faisal

    2013-11-21

    Sub-nanometer Ag aggregates on alumina supports have been found to be active toward direct propylene epoxidation to propylene oxide by molecular oxygen at low temperatures, with a negligible amount of carbon dioxide formation (Science 328, p. 224, 2010). In this work, we computationally and experimentally investigate the origin of the high reactivity of the sub-nanometer Ag aggregates. Computationally, we study O 2 dissociation and propylene epoxidation on unsupported Ag 19 and Ag 20 clusters, as well as alumina-supported Ag 19. The O 2 dissociation and propylene epoxidation apparent barriers at the interface between the Ag aggregate and the alumina supportmore » are calculated to be 0.2 and 0.2~0.4 eV, respectively. These barriers are somewhat lower than those on sites away from the interface. The mechanism at the interface is similar to what was previously found for the silver trimer on alumina and can account for the high activity observed for the direct oxidation of propylene on the Ag aggregates. The barriers for oxygen dissociation on these model systems both at the interface and on the surfaces are small compared to crystalline surfaces, indicating that availability of oxygen will not be a rate limiting step for the aggregates, as in the case of the crystalline surfaces. Experimentally, we investigate Ultrananocrystalline Diamond (UNCD)-supported silver aggregates under reactive conditions of propylene partial oxidation. The UNCD-supported Ag clusters are found to be not measurably active toward propylene oxidation, in contrast to the alumina supported Ag clusters. This suggests that the lack of metal-oxide interfacial sites of the Ag-UNCD catalyst, limits the epoxidation catalytic activity. This combined computational and experimental study shows the importance of the metal-oxide interface as well as the non-crystalline nature of the alumina-supported sub-nanometer Ag aggregate catalysts for propylene epoxidation.« less

  14. Concurrent Cooperativity and Substrate Inhibition in the Epoxidation of Carbamazepine by Cytochrome P450 3A4 Active Site Mutants Inspired by Molecular Dynamics Simulations

    PubMed Central

    2015-01-01

    Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, and A370L, in which the productive binding orientation was expected to be stabilized, thus leading to increased turnover of CBZ to the 10,11-epoxide product. In addition, we generated CYP3A4 mutant S119A as a control construct with putative destabilization of the productive binding pose. Evaluation of the kinetics profiles of CBZ epoxidation demonstrate that CYP3A4-containing bacterial membranes (bactosomes) as well as purified CYP3A4 (wild-type and mutants I369L/F) exhibit substrate inhibition in reconstituted systems. In contrast, mutants S119A and A370V/L exhibit S-shaped profiles that are indicative of homotropic cooperativity. MD simulations with two to four CBZ molecules provide evidence that the substrate-binding pocket of CYP3A4 can accommodate more than one molecule of CBZ. Analysis of the kinetics profiles of CBZ metabolism with a model that combines the formalism of the Hill equation with an allowance for substrate inhibition demonstrates that the mechanism of interactions of CBZ with CYP3A4 involves multiple substrate-binding events (most likely three). Despite the retention of the multisite binding mechanism in the mutants, functional manifestations reveal an exquisite sensitivity to even minor structural changes in the binding pocket that are introduced by conservative substitutions such as I369F, I369L, and A370V. PMID:25545162

  15. Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations.

    PubMed

    Müller, Christian S; Knehans, Tim; Davydov, Dmitri R; Bounds, Patricia L; von Mandach, Ursula; Halpert, James R; Caflisch, Amedeo; Koppenol, Willem H

    2015-01-27

    Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, and A370L, in which the productive binding orientation was expected to be stabilized, thus leading to increased turnover of CBZ to the 10,11-epoxide product. In addition, we generated CYP3A4 mutant S119A as a control construct with putative destabilization of the productive binding pose. Evaluation of the kinetics profiles of CBZ epoxidation demonstrate that CYP3A4-containing bacterial membranes (bactosomes) as well as purified CYP3A4 (wild-type and mutants I369L/F) exhibit substrate inhibition in reconstituted systems. In contrast, mutants S119A and A370V/L exhibit S-shaped profiles that are indicative of homotropic cooperativity. MD simulations with two to four CBZ molecules provide evidence that the substrate-binding pocket of CYP3A4 can accommodate more than one molecule of CBZ. Analysis of the kinetics profiles of CBZ metabolism with a model that combines the formalism of the Hill equation with an allowance for substrate inhibition demonstrates that the mechanism of interactions of CBZ with CYP3A4 involves multiple substrate-binding events (most likely three). Despite the retention of the multisite binding mechanism in the mutants, functional manifestations reveal an exquisite sensitivity to even minor structural changes in the binding pocket that are introduced by conservative substitutions such as I369F, I369L, and A370V.

  16. Monolithic Nickel (II) Oxide Aerogels Using an Organic Epoxide: The Importance of the Counter Ion

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gash, A E; Satcher, J H; Simpson, R L

    2004-01-13

    The synthesis and characterization of nickel (II) oxide aerogel materials prepared using the epoxide addition method is described. The addition of the organic epoxide propylene oxide to an ethanolic solution of NiCl{sub 2} 6H{sub 2}O resulted in the formation of an opaque light green monolithic gel and subsequent drying with supercritical CO{sub 2} gave a monolithic aerogel material of the same color. This material has been characterized using powder X-ray diffraction, electron microscopy, elemental analysis, and nitrogen adsorption/desorption analysis. The results indicate that the nickel (II) oxide aerogel has very low bulk density (98 kg/m{sup 3} ({approx}98 %porous)), high surfacemore » area (413 m{sup 2}/g), and has a particulate-type aerogel microstructure made up of very fine spherical particles with an open porous network. By comparison, a precipitate of Ni{sub 3}(NO{sub 3}){sub 2}(OH){sub 4} is obtained when the same preparation is attempted with the common Ni(NO{sub 3}){sub 2} 6H{sub 2}O salt as the precursor. The implications of the difference of reactivity of the two different precursors are discussed in the context of the mechanism of gel formation via the epoxide addition method. The synthesis of nickel (II) oxide aerogel, using the epoxide addition method, is especially unique in our experience. It is our first example of the successful preparation of a metal oxide aerogel using a metal divalent metal ion and may have implications for the application of this method to the preparation of aerogels or nanoparticles of other divalent metal oxides. To our knowledge this is the first report of a monolithic pure nickel (II) oxide aerogel materials.« less

  17. Na@SiO2-Mediated Addition of Organohalides to Carbonyl Compounds for the Formation of Alcohols and Epoxides

    NASA Astrophysics Data System (ADS)

    Kapoor, Mohit; Hwu, Jih Ru

    2016-11-01

    Alcohols and epoxides were generated by the addition of organohalides to carbonyl compounds in the presence of sodium metal impregnated with silica gel (Na@SiO2) in THF at 25 °C through a radical pathway. Under the same conditions, Schiff bases were also successfully converted to the corresponding amines. Furthermore, the reaction of aldehydes with α-haloesters or 4-(chloromethyl)-coumarin with the aid of Na@SiO2 generated trans epoxides. An unprecedented mechanism is proposed for their formation. The advantages associated with these new reactions include: (1) products are obtained in good-to-excellent yields, (2) reactions are completed at room temperatures in a short period of time (<2.0 h), (3) it is unnecessary to perform the reactions under anhydrous conditions, and (4) the entire process requires only simple manipulations.

  18. Cholesterol-5,6-epoxides: chemistry, biochemistry, metabolic fate and cancer.

    PubMed

    Poirot, Marc; Silvente-Poirot, Sandrine

    2013-03-01

    In the nineteen sixties it was proposed that cholesterol might be involved in the etiology of cancers and cholesterol oxidation products were suspected of being causative agents. Researchers had focused their attention on cholesterol-5,6-epoxides (5,6-ECs) based on several lines of evidence: 1) 5,6-ECs contained an oxirane group that was supposed to confer alkylating properties such as those observed for aliphatic and aromatic epoxides. 2) cholesterol-5,6-epoxide hydrolase (ChEH) was induced in pre-neoplastic lesions of skin from rats exposed to ultraviolet irradiations and ChEH was proposed to be involved in detoxification processes like other epoxide hydrolases. However, 5,6-ECs failed to induce carcinogenicity in rodents which ruled out a potent carcinogenic potential for 5,6-ECs. Meanwhile, clinical studies revealed an anomalous increase in the concentrations of 5,6β-EC in the nipple fluids of patients with pre-neoplastic breast lesions and in the blood of patients with endometrious cancers, suggesting that 5,6-ECs metabolism could be linked with cancer. Paradoxically, ChEH has been recently shown to be totally inhibited by therapeutic concentrations of tamoxifen (Tam), which is one of the main drugs used in the hormonotherapy and the chemoprevention of breast cancers. These data would suggest that the accumulation of 5,6-ECs could represent a risk factor, but we found that 5,6-ECs were involved in the induction of breast cancer cell differentiation and death induced by Tam suggesting a positive role of 5,6-ECs. These observations meant that the biochemistry and the metabolism of 5,6-ECs needed to be extensively studied. We will review the current knowledge and the future direction of 5,6-ECs chemistry, biochemistry, metabolism, and relationship with cancer. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  19. Arabidopsis thaliana EPOXIDE HYDROLASE1 (AtEH1) is a cytosolic epoxide hydrolase involved in the synthesis of poly-hydroxylated cutin monomers.

    PubMed

    Pineau, Emmanuelle; Xu, Lin; Renault, Hugues; Trolet, Adrien; Navrot, Nicolas; Ullmann, Pascaline; Légeret, Bertrand; Verdier, Gaëtan; Beisson, Fred; Pinot, Franck

    2017-07-01

    Epoxide hydrolases (EHs) are present in all living organisms. They have been extensively characterized in mammals; however, their biological functions in plants have not been demonstrated. Based on in silico analysis, we identified AtEH1 (At3g05600), a putative Arabidopsis thaliana epoxide hydrolase possibly involved in cutin monomer synthesis. We expressed AtEH1 in yeast and studied its localization in vivo. We also analyzed the composition of cutin from A. thaliana lines in which this gene was knocked out. Incubation of recombinant AtEH1 with epoxy fatty acids confirmed its capacity to hydrolyze epoxides of C18 fatty acids into vicinal diols. Transfection of Nicotiana benthamiana leaves with constructs expressing AtEH1 fused to enhanced green fluorescent protein (EGFP) indicated that AtEH1 is localized in the cytosol. Analysis of cutin monomers in loss-of-function Ateh1-1 and Ateh1-2 mutants showed an accumulation of 18-hydroxy-9,10-epoxyoctadecenoic acid and a concomitant decrease in corresponding vicinal diols in leaf and seed cutin. Compared with wild-type seeds, Ateh1 seeds showed delayed germination under osmotic stress conditions and increased seed coat permeability to tetrazolium red. This work reports a physiological role for a plant EH and identifies AtEH1 as a new member of the complex machinery involved in cutin synthesis. © 2017 CNRS New Phytologist © 2017 New Phytologist Trust.

  20. COMPARATIVE STUDIES OF THE EFFECT OF POLYCYCLIC AROMATIC HYDROCARBON GEOMETRY ON THE HYDROLYSIS OF DIOL EPOXIDES

    EPA Science Inventory

    Comparative studies of the effect of polycyclic aromatic hydrocarbon geometry on the hydrolysis of diol epoxides

    The interaction of the diol epoxides (DEs) of both planar and non-planar PAHs with water have been examined using quantum mechanical and molecular dynamics. Th...

  1. Asymmetric Epoxidation: A Twinned Laboratory and Molecular Modeling Experiment for Upper-Level Organic Chemistry Students

    ERIC Educational Resources Information Center

    Hii, King Kuok; Rzepa, Henry S.; Smith, Edward H.

    2015-01-01

    The coupling of a student experiment involving the preparation and use of a catalyst for the asymmetric epoxidation of an alkene with computational simulations of various properties of the resulting epoxide is set out in the form of a software toolbox from which students select appropriate components. At the core of these are the computational…

  2. In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols

    PubMed Central

    Cossar, Peter J.; Baker, Jennifer R.; Cain, Nicholas

    2018-01-01

    The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of analogues of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol 1, a potential antibiotic lead. The in situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidation abrogates this limitation and afforded facile access to structurally diverse β-amino alcohols. Analogues of 1 were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in situ generation of DMDO, with olefin epoxidation in typically good yields and a flow-mediated ring opening aminolysis to form an expanded library of β-amino alcohols 1 and 10a–18g, resulting in modest (11a, 21%) to excellent (12g, 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols 4a–4m (22%–89%) and a Bi(OTf)3 catalysed microwave ring opening with amines afforded a select range of β-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach. PMID:29765627

  3. Cancer-promoting effect of capsaicin on DMBA/TPA-induced skin tumorigenesis by modulating inflammation, Erk and p38 in mice.

    PubMed

    Liu, Zhaoguo; Zhu, Pingting; Tao, Yu; Shen, Cunsi; Wang, Siliang; Zhao, Lingang; Wu, Hongyan; Fan, Fangtian; Lin, Chao; Chen, Chen; Zhu, Zhijie; Wei, Zhonghong; Sun, Lihua; Liu, Yuping; Wang, Aiyun; Lu, Yin

    2015-07-01

    Epidemiologic and animal studies revealed that capsaicin (8-methyl-N-vanillyl-6-noneamide) can act as a carcinogen or cocarcinogen. However, the influence of consumption of capsaicin-containing foods or vegetables on skin cancer patients remains largely unknown. In the present study, we demonstrated that capsaicin has a cocarcinogenic effect on 9, 10-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis. Our results showed that topical application of capsaicin on the dorsal skin of DMBA-initiated and TPA-promoted mice could significantly accelerate tumor formation and growth and induce more and larger skin tumors than the model group (DMBA + TPA). Moreover, capsaicin could promote TPA-induced skin hyperplasia and tumor proliferation. Mechanistic study found that inflammation-related factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were highly elevated by pretreatment with capsaicin, suggesting an inflammation-dependent mechanism. Furthermore, mice that were administered capsaicin exhibited significant up-regulation of phosphorylation of nuclear factor kappaB (NF-κB), Erk and p38 but had no effect on JNK. Thus, our results indicated that inflammation, Erk and P38 collectively played a crucial role in cancer-promoting effect of capsaicin on carcinogen-induced skin cancer in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Epoxidation of alkenes and oxidation of alcohols with hydrogen peroxide catalyzed by a manganese(V) nitrido complex.

    PubMed

    Kwong, Hoi-Ki; Lo, Po-Kam; Lau, Kai-Chung; Lau, Tai-Chu

    2011-04-14

    The manganese(V) nitrido complex (PPh(4))(2)[Mn(N)(CN)(4)] is an active catalyst for alkene epoxidation and alcohol oxidation using H(2)O(2) as an oxidant. The catalytic oxidation is greatly enhanced by the addition of just one equivalent of acetic acid. The oxidation of ethene by this system has been studied computationally by the DFT method.

  5. Epoxidized natural rubber toughened aqueous resole type liquefied EFB resin: Physical and chemical characterization

    NASA Astrophysics Data System (ADS)

    Amran, Umar Adli; Zakaria, Sarani; Chia, Chin Hua

    2013-11-01

    A preliminary study on the reaction between aqueous resole type resinified liquefied palm oil empty fruit bunches fibres (RLEFB) with epoxidized natural rubber (ENR). Liquefaction of empty fruit bunches (EFB) is carried out at different ratio of phenol to EFB (P:EFB). Resole type phenolic resin is prepared using sodium hydroxide (NaOH) as the catalyst with the ratio of liquefied EFB (LEFB) to formaldehyde (LEFB:F) of 1:1.8. 50% epoxidation of epoxidized natural rubber (ENR-50) is used to react with resole resin by mixing with ENR with aqueous resole resin. The cured resin is characterized with FT-IR and SEM. Aqueous system have been found to be unsuitable medium in the reaction between resin and ENR. This system produced a highly porous product when RLEFB/ENR resin is cured.

  6. Kinetics and mechanism of styrene epoxidation by chlorite: role of chlorine dioxide.

    PubMed

    Leigh, Jessica K; Rajput, Jonathan; Richardson, David E

    2014-07-07

    An investigation of the kinetics and mechanism for epoxidation of styrene and para-substituted styrenes by chlorite at 25 °C in the pH range of 5-6 is described. The proposed mechanism in water and water/acetonitrile includes seven oxidation states of chlorine (-I, 0, I, II, III, IV, and V) to account for the observed kinetics and product distributions. The model provides an unusually detailed quantitative mechanism for the complex reactions that occur in mixtures of chlorine species and organic substrates, particularly when the strong oxidant chlorite is employed. Kinetic control of the reaction is achieved by the addition of chlorine dioxide to the reaction mixture, thereby eliminating a substantial induction period observed when chlorite is used alone. The epoxidation agent is identified as chlorine dioxide, which is continually formed by the reaction of chlorite with hypochlorous acid that results from ClO produced by the epoxidation reaction. The overall stoichiometry is the result of two competing chain reactions in which the reactive intermediate ClO reacts with either chlorine dioxide or chlorite ion to produce hypochlorous acid and chlorate or chloride, respectively. At high chlorite ion concentrations, HOCl is rapidly eliminated by reaction with chlorite, minimizing side reactions between HOCl and Cl2 with the starting material. Epoxide selectivity (>90% under optimal conditions) is accurately predicted by the kinetic model. The model rate constant for direct reaction of styrene with ClO2(aq) to produce epoxide is (1.16 ± 0.07) × 10(-2) M(-1) s(-1) for 60:40 water/acetonitrile with 0.20 M acetate buffer. Rate constants for para substituted styrenes (R = -SO3(-), -OMe, -Me, -Cl, -H, and -NO2) with ClO2 were determined. The results support the radical addition/elimination mechanism originally proposed by Kolar and Lindgren to account for the formation of styrene oxide in the reaction of styrene with chlorine dioxide.

  7. Capsanthone 3,6-epoxide, a new carotenoid from the fruits of the red paprika Capsicum annuum L.

    PubMed

    Maoka, T; Fujiwara, Y; Hashimoto, K; Akimoto, N

    2001-08-01

    The structure of a new carotenoid, isolated from the fruits of the red tomato-shaped paprika Capsicum annuum L., was elucidated to be (3S,5R,6S,5'R)-3,6-epoxy-5,6-dihydro-5-hydroxy-beta,kappa-carotene-3',6'-dione by spectroscopic analyses, including fast atom bombardment collision-induced dissociation-mass spectrometry/mass spectrometry (FAB CID-MS/MS) and was designated capsanthone 3,6-epoxide. Capsanthone 3,6-epoxide is assumed to be an oxidative metabolite of capsanthin 3,6-epoxide in paprika.

  8. Oxidation catalysis of Nb(salan) complexes: asymmetric epoxidation of allylic alcohols using aqueous hydrogen peroxide as an oxidant.

    PubMed

    Egami, Hiromichi; Oguma, Takuya; Katsuki, Tsutomu

    2010-04-28

    Several optically active Nb(salan) complexes were synthesized, and their oxidation catalysis was examined. A dimeric mu-oxo Nb(salan) complex that was prepared from Nb(OiPr)(5) and a salan ligand was found to catalyze the asymmetric epoxidation of allylic alcohols using a urea-hydrogen peroxide adduct as an oxidant with good enantioselectivity. However, subsequent studies of the time course of this epoxidation and of the relationship between the ee of the ligand and the ee of the product indicated that the mu-oxo dimer dissociates into a monomeric species prior to epoxidation. Moreover, monomeric Nb(salan) complexes prepared in situ from Nb(OiPr)(5) and salan ligands followed by water treatment were found to catalyze the epoxidation of allylic alcohols better using aqueous hydrogen peroxide in CHCl(3)/brine or toluene/brine solution with high enantioselectivity ranging from 83 to 95% ee, except for the reaction of cinnamyl alcohol that showed a moderate ee of 74%. This is the first example of the highly enantioselective epoxidation of allylic alcohols using aqueous hydrogen peroxide as an oxidant.

  9. In Vivo Suppression of Heat Shock Protein (HSP)27 and HSP70 Accelerates DMBA-Induced Skin Carcinogenesis by Inducing Antigenic Unresponsiveness to the Initiating Carcinogenic Chemical.

    PubMed

    Yusuf, Nabiha; Nasti, Tahseen H; Ahmad, Israr; Chowdhury, Sanim; Mohiuddin, Hasan; Xu, Hui; Athar, Mohammad; Timares, Laura; Elmets, Craig A

    2015-05-15

    Heat shock proteins (HSPs) are constitutively expressed in murine skin. HSP27 is present in the epidermis, and HSP70 can be found in both the epidermis and dermis. The purpose of this study was to investigate the role of these proteins in cutaneous chemical carcinogenesis and to determine whether their effects on cell-mediated immune function were a contributing factor. In vivo inhibition of HSP27 and HSP70 produced a reduction in the T cell-mediated immune response to 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene in C3H/HeN mice and resulted in a state of Ag-specific tolerance. When mice were pretreated with anti-HSP27 and anti-HSP70 Abs in vivo prior to subjecting them to a standard two-stage DMBA/12-O-tetradecanoylphorbol-13-acetate cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (p < 0.05) in anti-HSP27- and HSP70-pretreated animals compared with mice pretreated with control Ab. Similar results were obtained when the data were evaluated as the cumulative number of tumors per group. Mice pretreated with HSP27 and HSP70 Abs developed more H-ras mutations and fewer DMBA-specific cytotoxic T lymphocytes. These findings indicate that in mice HSP27 and HSP70 play a key role in the induction of cell-mediated immunity to carcinogenic polyaromatic hydrocarbons. Bolstering the immune response to carcinogenic polyaromatic hydrocarbons may be an effective method for prevention of the tumors that they produce. Copyright © 2015 by The American Association of Immunologists, Inc.

  10. Direct valorisation of waste cocoa butter triglycerides via catalytic epoxidation, ring-opening and polymerisation.

    PubMed

    Plaza, Dorota D; Strobel, Vinzent; Heer, Parminder Kaur Ks; Sellars, Andrew B; Hoong, Seng-Soi; Clark, Andrew J; Lapkin, Alexei A

    2017-09-01

    Development of circular economy requires significant advances in the technologies for valorisation of waste, as waste becomes new feedstock. Food waste is a particularly important feedstock, containing large variation of complex chemical functionality. Although most food waste sources are complex mixtures, waste from food processing, no longer suitable for the human food chain, may also represent relatively clean materials. One such material requiring valorisation is cocoa butter. Epoxidation of a triglyceride from a food waste source, processing waste cocoa butter, into the corresponding triglyceride epoxide was carried out using a modified Ishii-Venturello catalyst in batch and continuous flow reactors. The batch reactor achieved higher yields due to the significant decomposition of hydrogen peroxide in the laminar flow tubular reactor. Integral and differential models describing the reaction and the phase transfer kinetics were developed for the epoxidation of cocoa butter and the model parameters were estimated. Ring-opening of the epoxidised cocoa butter was undertaken to provide polyols of varying molecular weight (M w = 2000-84 000 Da), hydroxyl value (27-60 mg KOH g -1 ) and acid value (1-173 mg KOH g -1 ), using either aqueous ortho-phosphoric acid (H 3 PO 4 ) or boron trifluoride diethyl etherate (BF 3 · OEt 2 )-mediated oligomerisation in bulk, using hexane or tetrahydrofuran (THF) as solvents. The thermal and tensile properties of the polyurethanes obtained from the reaction of these polyols with 4,4'-methylene diphenyl diisocyanate (MDI) are described. The paper presents a complete valorisation scheme for a food manufacturing industry waste stream, starting from the initial chemical transformation, developing a process model for the design of a scaled-up process, and leading to synthesis of the final product, in this case a polymer. This work describes aspects of optimisation of the conversion route, focusing on clean synthesis and also demonstrates

  11. Gold nanoparticle-catalyzed environmentally benign deoxygenation of epoxides to alkenes.

    PubMed

    Noujima, Akifumi; Mitsudome, Takato; Mizugaki, Tomoo; Jitsukawa, Koichiro; Kaneda, Kiyotomi

    2011-09-28

    We have developed a highly efficient and green catalytic deoxygenation of epoxides to alkenes using gold nanoparticles (NPs) supported on hydrotalcite [HT: Mg(6)Al(2)CO(3)(OH)(16)] (Au/HT) with alcohols, CO/H(2)O or H(2) as the reducing reagent. Various epoxides were selectively converted to the corresponding alkenes. Among the novel metal NPs on HT, Au/HT was found to exhibit outstanding catalytic activity for the deoxygenation reaction. Moreover, Au/HT can be separated from the reaction mixture and reused with retention of its catalytic activity and selectivity. The high catalytic performance of Au/HT was attributed to the selective formation of Au-hydride species by the cooperative effect between Au NPs and HT.

  12. Selective and metal-free epoxidation of terminal alkenes by heterogeneous polydioxirane in mild conditions

    NASA Astrophysics Data System (ADS)

    Kazemnejadi, M.; Shakeri, A.; Nikookar, M.; Shademani, R.; Mohammadi, M.

    2018-05-01

    Polydioxirane (PDOX) was prepared by the treatment of polysalicylaldehyde with Oxone and was found as a selective, highly efficient and heterogeneous reagent for epoxidation of alkenes which can be successfully isolated. This work also introduced a simpler, safer and milder way for epoxidation of alkenes with dioxirane groups than before. PDOX can be simply recovered from the reaction mixture by plain filtration and reused for eight runs without significant reactivity loss.

  13. Epoxide metabolism in the liver of mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate)), a peroxisome proliferator.

    PubMed

    Moody, D E; Loury, D N; Hammock, B D

    1985-05-01

    An increase in cytosolic epoxide hydrolase (cEH) activity occurs in the livers of mice treated with peroxisome proliferating-hypolipidemic-nongenotoxic carcinogens. As increases in activity of epoxide metabolizing enzymes may reflect the carcinogenic mechanism, a detailed comparison of the response of cEH, microsomal epoxide hydrolase (mEH), and cytosolic glutathione S-transferase (cGST) activities using the geometrical isomers trans- and cis-stilbene oxide as substrates has been performed in livers from mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate]. The maximal increase of cEH activity occurred at lower dietary doses of clofibrate (0.5%) and within a shorter time (5 days) than mEH and cGST (2%, 14 days) activity. After 14 days at 0.5% clofibrate, cEH, mEH, and cGST activities were 250, 175, and 165% and 290, 220, and 75% of control values in male and female mice, respectively. Withdrawal of clofibrate from the diet resulted in a reversion of activities to control values within 7 days. Clofibrate treatment shifted the apparent subcellular compartmentation of all three enzymatic activities with an increase in the ratio of soluble to particulate activity. In particular, the relative specific activity of all three enzymes decreased in the light mitochondrial (peroxisomal) cell fraction, and an increase of a mEH-like activity (benzo[a]pyrene-4,5-oxide and cis-stilbene oxide hydrolysis) in the cytosol occurred. Both the increase of cEH activity and the appearance of mEH-like activity in the cytosol are novel responses of epoxide metabolizing enzymes, which may be related to the novel cellular responses that follow clofibrate treatment, peroxisome proliferation, hypolipidemia, and nongenotoxic carcinogenesis.

  14. Interaction of water, alkyl hydroperoxide, and allylic alcohol with a single-site homogeneous Ti-Si epoxidation catalyst: A spectroscopic and computational study.

    PubMed

    Urakawa, Atsushi; Bürgi, Thomas; Skrabal, Peter; Bangerter, Felix; Baiker, Alfons

    2005-02-17

    Tetrakis(trimethylsiloxy)titanium (TTMST, Ti(OSiMe3)4) possesses an isolated Ti center and is a highly active homogeneous catalyst in epoxidation of various olefins. The structure of TTMST resembles that of the active sites in some heterogeneous Ti-Si epoxidation catalysts, especially silylated titania-silica mixed oxides. Water cleaves the Ti-O-Si bond and deactivates the catalyst. An alkyl hydroperoxide, TBHP (tert-butyl hydroperoxide), does not cleave the Ti-O-Si bond, but interacts via weak hydrogen-bonding as supported by NMR, DOSY, IR, and computational studies. ATR-IR spectroscopy combined with computational investigations shows that more than one, that is, up to four, TBHP can undergo hydrogen-bonding with TTMST, leading to the activation of the O-O bond of TBHP. The greater the number of TBHP molecules that form hydrogen bonds to TTMST, the more electrophilic the O-O bond becomes, and the more active the complex is for epoxidation. An allylic alcohol, 2-cyclohexen-1-ol, does not interact strongly with TTMST, but the interaction is prominent when it interacts with the TTMST-TBHP complex. On the basis of the experimental and theoretical findings, a hydrogen-bond-assisted epoxidation mechanism of TTMST is suggested.

  15. ULTRASOUND-ASSISTED ORGANIC SYNTHESIS: ALCOHOL OXIDATION AND OLEFIN EPOXIDATION

    EPA Science Inventory

    Ultrasound-assisted Organic Synthesis: Alcohol Oxidation and Olefin Epoxidation

    Unnikrishnan R Pillai, Endalkachew Sahle-Demessie , Vasudevan Namboodiri, Quiming Zhao, Juluis Enriquez
    U.S. EPA , 26 W. Martin Luther King Dr. , Cincinnati, OH 45268
    Phone: 513-569-773...

  16. Dietary lipids differentially modulate the initiation of experimental breast carcinogenesis through their influence on hepatic xenobiotic metabolism and DNA damage in the mammary gland.

    PubMed

    Manzanares, Miguel Ángel; de Miguel, Cristina; Ruiz de Villa, M Carme; Santella, Regina M; Escrich, Eduard; Solanas, Montserrat

    2017-05-01

    Breast cancer is the most common malignancy among women worldwide. In addition to reproductive factors, environmental factors such as nutrition and xenobiotic exposure have a role in the etiology of this malignancy. A stimulating and a potentially protective effect on experimental breast cancer has been previously described for high corn oil and high extra-virgin olive oil diets, respectively. This work investigates the effect of these lipids on the metabolism of 7,12-dimethylbenz(a)anthracene (DMBA), a polycyclic aromatic hydrocarbon that can initiate carcinogenesis and its consequences in an experimental rat breast cancer model. The PUFA n-6-enriched diet increased expression of Phase I enzymes prior to DMBA administration and raised the activity of CYP1s in the hours immediately after induction, while reducing the activity of Phase II enzymes, mainly NQO1. The levels of reactive metabolites measured in plasma by GC-MS and DMBA-DNA adducts in the mammary gland of the animals fed the high corn oil diet were also higher than in the other groups. On the other hand, the high extra-virgin olive oil diet and the control low-fat diet exhibited better coordinated Phase I and Phase II activity, with a lower production of reactive metabolites and less DNA damage in the mammary gland. The concordance between these effects and the different efficacy of the carcinogenesis process due to the dietary treatment suggest that lipids may differently modify mammary gland susceptibility or resistance to cancer initiation over the exposure to environmental carcinogens. Dietary lipids influence the initiation of DMBA-induced mammary cancer through the modulation of liver xenobiotic metabolism, formation of reactive metabolites and subsequent DNA damage in the target tissue. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Mutagenic, cytotoxic, and teratogenic effects of 2-acetylaminofluorene and reactive metabolites in vitro.

    PubMed

    Faustman-Watts, E M; Yang, H Y; Namkung, M J; Greenaway, J C; Fantel, A G; Juchau, M R

    1984-01-01

    The embryotoxic, mutagenic, and cytotoxic properties of 2-acetylaminofluorene (AAF) and two of its reactive metabolites, N-acetoxy-2-acetylaminofluorene (AAAF) and 2-nitrosofluorene (NF) were assessed in vitro. A combined embryo culture/biotransformation system was used to determine the ability of these compounds to produce embryonic malformations, growth retardation, and/or embryolethality. Salmonella typhimurium auxotrophs (his-) were utilized to measure the mutagenic and cytotoxic potentials of these compounds. The parent compound, AAF, did not produce embryonic malformations or mutagenicity in the absence of an added cytochrome P-450-dependent monooxygenase system. Both metabolites produced each of the measured toxic effects without supplementation of a bioactivation system. However, the three chemicals each elicited a different spectrum of malformations. Bioactivated AAF produced neural tube abnormalities, whereas embryos treated with AAAF primarily exhibited prosencephalic malformations, and NF produced abnormalities of axial rotation or flexure. NF was approximately ten times more potent than AAAF as a direct-acting mutagen but only slightly more active in producing embryonic malformations in vitro. The results indicated that differential effects on the various measured parameters could be produced by these chemicals. The results indicated further that neither NF nor AAAF appeared to be individually responsible for the neural tube abnormalities generated by biotransformed AAF.

  18. Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?

    PubMed

    Hagvall, Lina; Niklasson, Ida B; Luthman, Kristina; Karlberg, Ann-Therese

    2018-06-01

    Cinnamyl alcohol is considered to be a prohapten and prehapten with cinnamal as the main metabolite. However, many individuals who are allergic to cinnamyl alcohol do not react to cinnamal. Sensitizing epoxides of cinnamyl alcohol and cinnamal have been identified as metabolites and autoxidation products of cinnamyl alcohol. To investigate the clinical relevance of contact allergy to epoxycinnamyl alcohol and epoxycinnamal. Irritative effects of the epoxides were investigated in 12 dermatitis patients. Epoxycinnamyl alcohol and epoxycinnamal were patch tested in 393 and 390 consecutive patients, respectively. In parallel, cinnamyl alcohol and cinnamal were patch tested in 607 and 616 patients, respectively. Both epoxides were irritants, but no more positive reactions were detected than when testing was performed with cinnamyl alcohol and cinnamal. Late allergic reactions to epoxycinnamyl alcohol were observed. In general, patients with late reactions showed doubtful or positive reactions to cinnamal and fragrance mix I at regular patch testing. The investigated epoxides are not important haptens in contact allergy to cinnamon fragrance. The high frequency of fragrance allergy among patients included in the irritancy study showed the difficulty of suspecting fragrance allergy on the basis of history; patch testing broadly with fragrance compounds is therefore important. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Mechanism of epoxide hydrolysis in microsolvated nucleotide bases adenine, guanine and cytosine: a DFT study.

    PubMed

    Vijayalakshmi, Kunduchi P; Mohan, Neetha; Ajitha, Manjaly J; Suresh, Cherumuttathu H

    2011-07-21

    Six water molecules have been used for microsolvation to outline a hydrogen bonded network around complexes of ethylene epoxide with nucleotide bases adenine (EAw), guanine (EGw) and cytosine (ECw). These models have been developed with the MPWB1K-PCM/6-311++G(3df,2p)//MPWB1K/6-31+G(d,p) level of DFT method and calculated S(N)2 type ring opening of the epoxide due to amino group of the nucleotide bases, viz. the N6 position of adenine, N2 position of guanine and N4 position of cytosine. Activation energy (E(act)) for the ring opening was found to be 28.06, 28.64, and 28.37 kcal mol(-1) respectively for EAw, EGw and ECw. If water molecules were not used, the reactions occurred at considerably high value of E(act), viz. 53.51 kcal mol(-1) for EA, 55.76 kcal mol(-1) for EG and 56.93 kcal mol(-1) for EC. The ring opening led to accumulation of negative charge on the developing alkoxide moiety and the water molecules around the charge localized regions showed strong hydrogen bond interactions to provide stability to the intermediate systems EAw-1, EGw-1 and ECw-1. This led to an easy migration of a proton from an activated water molecule to the alkoxide moiety to generate a hydroxide. Almost simultaneously, a proton transfer chain reaction occurred through the hydrogen bonded network of water molecules and resulted in the rupture of one of the N-H bonds of the quaternized amino group. The highest value of E(act) for the proton transfer step of the reaction was 2.17 kcal mol(-1) for EAw, 2.93 kcal mol(-1) for EGw and 0.02 kcal mol(-1) for ECw. Further, the overall reaction was exothermic by 17.99, 22.49 and 13.18 kcal mol(-1) for EAw, EGw and ECw, respectively, suggesting that the reaction is irreversible. Based on geometric features of the epoxide-nucleotide base complexes and the energetics, the highest reactivity is assigned for adenine followed by cytosine and guanine. Epoxide-mediated damage of DNA is reported in the literature and the present results suggest that

  20. Catalytic Efficiency of Titanium Dioxide (TiO2) and Zeolite ZSM-5 Catalysts in the in-situ Epoxidation of Palm Olein

    NASA Astrophysics Data System (ADS)

    Yunus, M. Z. Mohd; Jamaludin, S. K.; Abd. Karim, S. F.; Gani, A. Abd; Sauki, A.

    2018-05-01

    Titanium dioxide and zeolite ZSM-5 are the commonly used heterogeneous catalysts in many chemical reactions. They have several advantages such as low cost and environmental friendly. In this study, titanium dioxide and zeolite ZSM-5 act as catalyst in the in-situ epoxidation of palm olein. Epoxidation of palm olein was carried out by using in-situ generated performic acid to produce epoxidized palm olein in a semi-batch reactor at different temperatures (45°C and 60°C) and agitation speed of 400 rpm. The effects of both catalysts are studied to compare their efficiency in catalyzing the in-situ epoxidation. Epoxidized palm olein was analyzed by using percent of relative conversion to oxirane (RCO%) and fourier transform infrared spectroscopy (FTIR). Surface area of the catalysts used were then characterized by using BET. The results indicated that titanium dioxide is a better catalyst in the in-situ epoxidation of palm olein since it provides higher RCO% compared to Zeolite ZSM-5 at 45°C.

  1. Mechanistic Basis for High Reactivity of (salen)Co–OTs in the Hydrolytic Kinetic Resolution of Terminal Epoxides

    PubMed Central

    Nielsen, Lars P. C.; Zuend, Stephan J.; Ford, David D.; Jacobsen, Eric N.

    2012-01-01

    The (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides is a bimetallic process with a rate controlled by partitioning between a nucleophilic (salen)Co–OH catalyst and a Lewis acidic (salen)Co–X catalyst. The commonly used (salen)Co–OAc and (salen)Co–Cl precatalysts undergo complete and irreversible counterion addition to epoxide during the course of the epoxide hydrolysis reaction, resulting in quantitative formation of weakly Lewis acidic (salen)Co–OH, and severely diminished reaction rates in the late stages of HKR reactions. In contrast, (salen)Co–OTs maintains high reactivity over the entire course of HKR reactions. We describe here an investigation of catalyst partitioning with different (salen)Co–X precatalysts, and demonstrate that counterion addition to epoxide is reversible in the case of the (salen)Co–OTs. This reversible counterion addition results in stable partitioning between nucleophilic and Lewis acidic catalyst species, allowing highly efficient catalysis throughout the course of the HKR reaction. PMID:22292515

  2. Mechanistic basis for high reactivity of (salen)Co-OTs in the hydrolytic kinetic resolution of terminal epoxides.

    PubMed

    Nielsen, Lars P C; Zuend, Stephan J; Ford, David D; Jacobsen, Eric N

    2012-03-02

    The (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides is a bimetallic process with a rate controlled by partitioning between a nucleophilic (salen)Co-OH catalyst and a Lewis acidic (salen)Co-X catalyst. The commonly used (salen)Co-OAc and (salen)Co-Cl precatalysts undergo complete and irreversible counterion addition to epoxide during the course of the epoxide hydrolysis reaction, resulting in quantitative formation of weakly Lewis acidic (salen)Co-OH and severely diminished reaction rates in the late stages of HKR reactions. In contrast, (salen)Co-OTs maintains high reactivity over the entire course of HKR reactions. We describe here an investigation of catalyst partitioning with different (salen)Co-X precatalysts and demonstrate that counterion addition to epoxide is reversible in the case of the (salen)Co-OTs. This reversible counterion addition results in stable partitioning between nucleophilic and Lewis acidic catalyst species, allowing highly efficient catalysis throughout the course of the HKR reaction.

  3. A Bimetallic Aluminium(Salphen) Complex for the Synthesis of Cyclic Carbonates from Epoxides and Carbon Dioxide.

    PubMed

    Wu, Xiao; North, Michael

    2017-01-10

    A bimetallic aluminium(salphen) complex is reported as a sustainable, efficient and inexpensive catalyst for the synthesis of cyclic carbonates from epoxides and carbon dioxide. In the presence of this complex and tetrabutylammonium bromide, terminal and internal epoxides reacted at 50 °C and 10 bar carbon dioxide pressure to afford their corresponding cyclic carbonates in yields of 50-94 % and 30-71 % for terminal and internal cyclic carbonates, respectively. Mechanistic studies using deuterated epoxides and an analogous monometallic aluminium(salphen) chloride complex support a mechanism for catalysis by the bimetallic complex, which involves intramolecular cooperative catalysis between the two aluminium centres. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Comparable Molecular Alterations in 4-Nitroquinoline 1-Oxide-induced Oral and Esophageal Cancer in Mice and in Human Esophageal Cancer, Associated with Poor Prognosis of Patients

    PubMed Central

    YANG, ZHENGDUO; GUAN, BAOXIANG; MEN, TAOYAN; FUJIMOTO, JUNYA; XU, XIAOCHUN

    2013-01-01

    Background The murine model of 4-nitroquinoline 1-oxide (4-NQO)-induced oral and esophageal cancer is frequently used to assess the effects of different cancer prevention/therapy agents in vivo, but the molecular mechanisms in those 4-NQO-induced carcinogenesis are unknown. This study investigated aberrant expression of cell growth-critical genes in 4-NQO-induced oral and esophageal cancer tissues in mice compared to human disease for association with survival of patients. Materials and Methods C57LB6/129Sv mice were given 4-NQO in their drinking water to induce oral and esophageal cancer. Quantitative-reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were used to detect gene expression in the cancer tissues from mice and in 4-NQO-treated human esophageal cancer cell lines and esophageal cancer tissues. Methylation-specific PCR and DNA sequencing were performed to assess methylation of Rarb2 promoter in murine tissues. Kaplan-Meier analysis was performed to associate gene expression in esophageal cancer tissues with survival data for patients with esophageal cancer. Results 4-NQO dose-dependently induced pre-malignant and malignant lesions in oral cavity and esophagus in mice that pathologically and morphologically mimicked human oral and esophageal cancer. Molecularly, 4-NQO inhibited Rarβ2 but induced expression of phosphorylated extracellular-signal-regulated kinase 1 and 2 (p-ERK1/2) and Cox2 proteins and Rarβ2 gene promoter methylation in murine tumors. In vitro treatment with 4-NQO altered expression of RARβ2, p-ERK1/2, and COX2 in human esophageal cancer cells. In tissues from 90 patients with esophageal cancer, expression of p-ERK1/2 and COX2 was up-regulated, and p-ERK1/2 expression was associated with advanced clinical tumor stage and consumption of hot beverages, while COX2 expression was associated with tumor de-differentiation in esophageal cancer. Furthermore, expression of p-ERK1/2 was associated

  5. Anti-inflammatory Effects of Omega-3 Polyunsaturated Fatty Acids and Soluble Epoxide Hydrolase Inhibitors in Angiotensin-II Dependent Hypertension

    PubMed Central

    Ulu, Arzu; Harris, Todd R; Morisseau, Christophe; Miyabe, Christina; Inoue, Hiromi; Schuster, Gertrud; Dong, Hua; Iosif, Ana-Maria; Liu, Jun-Yan; Weiss, Robert H; Chiamvimonvat, Nipavan; Imig, John D; Hammock, Bruce D

    2013-01-01

    The mechanisms underlying the anti-inflammatory and anti-hypertensive effects of long chain ω-3 polyunsaturated fatty acids (PUFAs) are still unclear. The epoxides of an ω-6 fatty acid, arachidonic acid (epoxyeicosatrienoic acids; EETs) also exhibit anti-hypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may lower blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for three weeks in a murine model of angiotensin-II dependent hypertension. Also, since EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of a sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II increased blood pressure, further increased renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (i.e. prostaglandins and MCP-1), down-regulated an epithelial sodium channel and up-regulated Angiotensin converting enzyme-2 message (ACE-2) and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the ω-3 PUFAs contribute to lowering SBP and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by up-regulation of ACE-2 in angiotensin-II dependent hypertension. PMID:23676336

  6. 40 CFR 63.1427 - Process vent requirements for processes using extended cookout as an epoxide emission reduction...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... reactor liquid at the beginning of the time period, weight percent. k = Reaction rate constant, 1/hr. t = Time, hours. Note: This equation assumes a first order reaction with respect to epoxide concentration... measuring the concentration of the unreacted epoxide, or by using process knowledge, reaction kinetics, and...

  7. Species differences in the hydrolysis of 2-cyanoethylene oxide, the epoxide metabolite of acrylonitrile.

    PubMed

    Kedderis, G L; Batra, R

    1993-04-01

    The carcinogenic effects of acrylonitrile in rats are believed to be mediated by its DNA-reactive epoxide metabolite, 2-cyanoethylene oxide (CEO). Previous studies have shown that conjugation with glutathione is the major detoxication pathway for both acrylonitrile and CEO. This study investigated the role of epoxide hydrolase in the hydrolysis of CEO by HPLC analysis of the products from [2,3-14C]CEO. CEO is a relatively stable epoxide with a half-life of 99 min at 37 degrees C in sodium phosphate buffer (0.1 M), pH 7.3. Incubation with hepatic microsomes or cytosols from male F-344 rats or B6C3F1 mice did not enhance the rate of hydrolysis of CEO (0.69 nmol/min). Human hepatic microsomes significantly increased the rate of hydrolysis of CEO, whereas human hepatic cytosols did not. Human hepatic microsomal hydrolysis activity was heat-sensitive and potently inhibited by 1,1,1-trichloropropene oxide (IC50 of 23 microM), indicating that epoxide hydrolase was the catalyst. The hydrolysis of CEO catalyzed by hepatic microsomes from six individuals exhibited normal saturation kinetics with KM ranging from 0.6 to 3.2 mM and Vmax from 8.3 to 18.8 nmol hydrolysis products/min/mg protein. Pretreatment of rodents with phenobarbital or acetone induced hepatic microsomal hydrolysis activity toward CEO, whereas treatment with beta-naphthoflavone, dexamethasone or acrylonitrile itself was without effect. These data show that humans possess an additional detoxication pathway for CEO that is not active in rodents (but is inducible). The presence of an active epoxide hydrolase hydrolysis activity toward CEO in humans should be considered in assessments of cancer risk from acrylonitrile exposure.

  8. Modeling of Toxicity-Relevant Electrophilic Reactivity for Guanine with Epoxides: Estimating the Hard and Soft Acids and Bases (HSAB) Parameter as a Predictor.

    PubMed

    Zhang, Jing; Wang, Chenchen; Ji, Li; Liu, Weiping

    2016-05-16

    According to the electrophilic theory in toxicology, many chemical carcinogens in the environment and/or their active metabolites are electrophiles that exert their effects by forming covalent bonds with nucleophilic DNA centers. The theory of hard and soft acids and bases (HSAB), which states that a toxic electrophile reacts preferentially with a biological macromolecule that has a similar hardness or softness, clarifies the underlying chemistry involved in this critical event. Epoxides are hard electrophiles that are produced endogenously by the enzymatic oxidation of parent chemicals (e.g., alkenes and PAHs). Epoxide ring opening proceeds through a SN2-type mechanism with hard nucleophile DNA sites as the major facilitators of toxic effects. Thus, the quantitative prediction of chemical reactivity would enable a predictive assessment of the molecular potential to exert electrophile-mediated toxicity. In this study, we calculated the activation energies for reactions between epoxides and the guanine N7 site for a diverse set of epoxides, including aliphatic epoxides, substituted styrene oxides, and PAH epoxides, using a state-of-the-art density functional theory (DFT) method. It is worth noting that these activation energies for diverse epoxides can be further predicted by quantum chemically calculated nucleophilic indices from HSAB theory, which is a less computationally demanding method than the exacting procedure for locating the transition state. More importantly, the good qualitative/quantitative correlations between the chemical reactivity of epoxides and their bioactivity suggest that the developed model based on HSAB theory may aid in the predictive hazard evaluation of epoxides, enabling the early identification of mutagenicity/carcinogenicity-relevant SN2 reactivity.

  9. Effect of dietary glutamine on tumor glutathione levels and apoptosis-related proteins in DMBA-induced breast cancer of rats.

    PubMed

    Todorova, Valentina K; Harms, Stacy A; Kaufmann, Yihong; Luo, Shaoke; Luo, Kevin Q; Babb, Kirk; Klimberg, V Suzanne

    2004-12-01

    Glutamine (GLN) is a non-essential amino acid that is present in nearly every biochemical pathway and is the major intraorgan nitrogen carrier. GLN via glutamate, is one of the precursors for the synthesis of glutathione (GSH), the major endogenous antioxidant in mammalian cells, which protects them from oxidative injury and cell death. Cancer cells have higher GSH levels than the surrounding normal cells, which attributes to a higher rate of cell proliferation and resistance to chemotherapy. Therefore, selective tumor depletion of GSH presents a promising strategy in cancer treatment. Experimental studies have associated decreased GSH levels with inhibition of proliferation and stimulation of apoptosis. Previous results of our laboratory have provided evidence that dietary GLN diminished tumor development in implantable as well as 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer and elevated GSH in the host tissues. In this study we examined the effects of GLN on GSH levels in DMBA-induced mammary tumors and correlated the results with protein and mRNA expression of apoptosis-related proteins Bcl-2, Bax and caspase-3 in tumor cells. The results have shown that GLN supplementation caused a significant decrease in the tumor GSH levels and the ratio GSH/oxidized GSH (GSSG), accompanied by up-regulation of Bax and caspase-3, and down-regulation of Bcl-2. These findings suggest that dietary GLN supplementation suppresses mammary carcinogenesis by activation of apoptosis in tumor cells and this probably is a result of GSH down-regulation.

  10. Integrated process and dual-function catalyst for olefin epoxidation

    DOEpatents

    Zhou, Bing; Rueter, Michael

    2003-01-01

    The invention discloses a dual-functional catalyst composition and an integrated process for production of olefin epoxides including propylene oxide by catalytic reaction of hydrogen peroxide from hydrogen and oxygen with olefin feeds such as propylene. The epoxides and hydrogen peroxide are preferably produced simultaneously in situ. The dual-functional catalyst comprises noble metal crystallites with dimensions on the nanometer scale (on the order of <1 nm to 10 nm), specially dispersed on titanium silicalite substrate particles. The dual functional catalyst catalyzes both the direct reaction of hydrogen and oxygen to generate hydrogen peroxide intermediate on the noble metal catalyst surface and the reaction of the hydrogen peroxide intermediate with the propylene feed to generate propylene oxide product. Combining both these functions in a single catalyst provides a very efficient integrated process operable below the flammability limits of hydrogen and highly selective for the production of hydrogen peroxide to produce olefin oxides such as propylene oxide without formation of undesired co-products.

  11. Infectivity and reconstitution of TMV RNA modified with N-acetoxy-2-acetylaminofluorene or benzol [a] pyrene 7,8-dihydrodiol 9,10 oxide.

    PubMed Central

    Singer, B; Pulkrabek, P; Weinstein, I B; Grunberger, D

    1980-01-01

    TMV RNA was modified by two bulky carcinogens, N-acetoxy-2-acetylamino-fluorene (AAAF) and (+/-)-7beta, 8alpha- dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene (BPDE), and the effects of such substituents on biological and physical properties was studied. For both types of modification, the loss of infectivity was directly proportional to the number of chemical modifications indicating that all modifications are lethal. Neither AAAF nor BPDE produced measurable mutations. Reconstitution of modified RNA with TMV protein was partially inhibited, but such inhibition occurred to similar extents with either carcinogen and a varying levels of modification. The data suggest that both types of substitution of TMV RNA generally permit the TMV coat protein to aggregate normally around the RNA, but that AAAF and BPDE may induce some conformational change in the initiation region that inhibits the initiation step. PMID:6776494

  12. The Role of Dietary Extra Virgin Olive Oil and Corn Oil on the Alteration of Epigenetic Patterns in the Rat DMBA-Induced Breast Cancer Model.

    PubMed

    Rodríguez-Miguel, Cristina; Moral, Raquel; Escrich, Raquel; Vela, Elena; Solanas, Montserrat; Escrich, Eduard

    2015-01-01

    Disruption of epigenetic patterns is a major change occurring in all types of cancers. Such alterations are characterized by global DNA hypomethylation, gene-promoter hypermethylation and aberrant histone modifications, and may be modified by environment. Nutritional factors, and especially dietary lipids, have a role in the etiology of breast cancer. Thus, we aimed to analyze the influence of different high fat diets on DNA methylation and histone modifications in the rat dimethylbenz(a)anthracene (DMBA)-induced breast cancer model. Female Sprague-Dawley rats were fed a low-fat, a high corn-oil or a high extra-virgin olive oil (EVOO) diet from weaning or from induction with DMBA. In mammary glands and tumors we analyzed global and gene specific (RASSF1A, TIMP3) DNA methylation by LUMA and bisulfite pyrosequencing assays, respectively. We also determined gene expression and enzymatic activity of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) and evaluated changes in histone modifications (H3K4me2, H3K27me3, H4K20me3 and H4K16ac) by western-blot. Our results showed variations along time in the global DNA methylation of the mammary gland displaying decreases at puberty and with aging. The olive oil-enriched diet, on the one hand, increased the levels of global DNA methylation in mammary gland and tumor, and on the other, changed histone modifications patterns. The corn oil-enriched diet increased DNA methyltransferase activity in both tissues, resulting in an increase in the promoter methylation of the tumor suppressor genes RASSF1A and TIMP3. These results suggest a differential effect of the high fat diets on epigenetic patterns with a relevant role in the neoplastic transformation, which could be one of the mechanisms of their differential promoter effect, clearly stimulating for the high corn-oil diet and with a weaker influence for the high EVOO diet, on breast cancer progression.

  13. 40 CFR 63.1427 - Process vent requirements for processes using extended cookout as an epoxide emission reduction...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... obtaining the liquid sample, along with the test method used to determine the epoxide concentration. This... pressures, the owner or operator shall determine the time when the pressure has fallen to half its total pressure by using Equation 13: ER08MY00.008 Where: Phalf1 = Half the total pressure of the epoxide for...

  14. Transition-metal-free catalysts for the sustainable epoxidation of alkenes: from discovery to optimisation by means of high throughput experimentation.

    PubMed

    Lueangchaichaweng, Warunee; Geukens, Inge; Peeters, Annelies; Jarry, Benjamin; Launay, Franck; Bonardet, Jean-Luc; Jacobs, Pierre A; Pescarmona, Paolo P

    2012-02-01

    Transition-metal-free oxides were studied as heterogeneous catalysts for the sustainable epoxidation of alkenes with aqueous H₂O₂ by means of high throughput experimentation (HTE) techniques. A full-factorial HTE approach was applied in the various stages of the development of the catalysts: the synthesis of the materials, their screening as heterogeneous catalysts in liquid-phase epoxidation and the optimisation of the reaction conditions. Initially, the chemical composition of transition-metal-free oxides was screened, leading to the discovery of gallium oxide as a novel, active and selective epoxidation catalyst. On the basis of these results, the research line was continued with the study of structured porous aluminosilicates, gallosilicates and silica-gallia composites. In general, the gallium-based materials showed the best catalytic performances. This family of materials represents a promising class of heterogeneous catalysts for the sustainable epoxidation of alkenes and offers a valid alternative to the transition-metal heterogeneous catalysts commonly used in epoxidation. High throughput experimentation played an important role in promoting the development of these catalytic systems.

  15. Secondary Organic Aerosol Formation from 2-Methyl-3-Buten-2-ol Photooxidation: Evidence of Acid-Catalyzed Reactive Uptake of Epoxides

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Haofei; Zhang, Zhenfa; Cui, Tianqu

    2014-04-08

    Secondary organic aerosol (SOA) formation from 2-methyl-3-buten-2-ol (MBO) photooxidation has recently been observed in both field and laboratory studies. Similar to isoprene, MBO-derived SOA increases with elevated aerosol acidity in the absence of nitric oxide; therefore, an epoxide intermediate, (3,3-dimethyloxiran-2-yl)methanol (MBO epoxide) was synthesized and tentatively proposed here to explain this enhancement. In the present study, the potential of the synthetic MBO epoxide to form SOA via reactive uptake was systematically examined. SOA was observed only in the presence of acidic aerosols. Major SOA constituents, 2,3-dihydroxyisopentanol (DHIP) and MBO-derived organosulfate isomers, were chemically characterized in both laboratory-generated SOA and inmore » ambient fine aerosols collected from the BEACHON-RoMBAS field campaign during summer 2011, where MBO emissions are substantial. Our results support epoxides as potential products of MBO photooxidation leading to formation of atmospheric SOA and suggest that reactive uptake of epoxides may generally explain acid enhancement of SOA observed from other biogenic hydrocarbons.« less

  16. Changes in antioxidant capacity and colour associated with the formation of β-carotene epoxides and oxidative cleavage derivatives.

    PubMed

    Gurak, Poliana D; Mercadante, Adriana Z; González-Miret, M L; Heredia, Francisco J; Meléndez-Martínez, Antonio J

    2014-03-15

    In this study HPLC-DAD-MS/MS was applied for the identification of compounds derived from (all-E)-β-carotene following epoxidation and oxidative cleavage. The consequences on the CIELAB colour parameters and antioxidant capacity (AC) were also evaluated. Five apocarotenoids, three secocarotenoids, seven Z isomers and two epoxides were detected as a result of the oxidative cleavage. Four epoxides and three Z isomers were detected as a consequence of the epoxidation reaction. Some compounds were detected for the first time as a result of oxidation reactions. Both treatments led to a marked decrease in b(∗) and Cab(∗) values, indicating that these colour parameters can be used for the rapid assessment of β-carotene oxidation. The oxidative cleavage of β-carotene resulted in increased capacity to both scavenge ABTS(+) and quench singlet oxygen. These results suggest that the study of the AC of these oxidative derivatives and their possible usefulness as food ingredients deserves further attention. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pecic, Stevan; Pakhomova, Svetlana; Newcomer, Marcia E.

    2013-09-27

    A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure–activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.

  18. Practical synthesis of Shi's diester fructose derivative for catalytic asymmetric epoxidation of alkenes.

    PubMed

    Nieto, N; Molas, P; Benet-Buchholz, J; Vidal-Ferran, A

    2005-11-25

    [reaction: see text] A practical synthesis of Shi's diester 3 for catalytic asymmetric epoxidations has been developed. The catalyst has been prepared in multigram quantities from D-fructose in four steps with a 66% overall yield. Efficiency, cost, and selectivity aspects of the reagents involved for its preparation have been taken care of during its preparation. The workup procedures have been simplified to the bare minimum, rendering a very practical preparation method. The well-known high efficiency of this catalyst 3 in the epoxidation of alpha,beta-unsaturated carbonyl compounds has also proved to be high in unfunctionalized alkenes.

  19. Optical properties and indentation hardness of thin-film acrylated epoxidized oil

    NASA Astrophysics Data System (ADS)

    Rahman, Mohammad Syuhaimi Ab.; Shaktur, Khaled Mohamed; Mohammad, Rahmah; Zalikha, Wan Aimi; Nawi, Norwimie; Mohd, Ahmad Faiza

    2012-02-01

    Epoxy acrylate has been widely used as optical resin for applications such as cladding, the core of a waveguide, and other photonic devices. In this study, sustainable resin from edible oil was used as an alternative to epoxy acrylate. Structural features and the transmission of planar thin-film resin from an ultraviolet-visible spectroscopy (UV-VIS) spectrometer were investigated upon UV exposure. It was found that high transmission still persists for all samples with and without an UV absorber for exposed and unexposed samples. The film was found to absorb strongly below 400 nm. A change in the cut-off wavelength was observed upon exposure. Thin-film hardness and its dynamic indentation in the load-unload mode with different test forces were evaluated. Vickers hardness and the elastic modulus were determined for unacrylated epoxidized soybean oil (ESO) and acrylated epoxidized soybean oil (AESO). It was found that the AESO has a higher Vickers hardness and elastic modulus than those of unacrylated thin film. The Vickers hardness and elastic modulus were found to increase as the applied test force increased. The refractive index, thickness, and modes present were characterized from a spin-coated planar thin film. The refractive index in the transverse electric mode (TE) and transverse magnetic mode (TM) were determined and compared for unacrylated and acrylated epoxidized oil.

  20. 40 CFR 63.1427 - Process vent requirements for processes using extended cookout as an epoxide emission reduction...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... epoxides, and that are using ECO as a control technique to reduce epoxide emissions in order to comply with... provisions of this section. The owner or operator that is using ECO in order to comply with the emission... used to further reduce the HAP emissions from a process vent already controlled by ECO, then the owner...

  1. Chemopreventive effect of fermented brown rice and rice bran on 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats.

    PubMed

    Long, Nguyen Khanh; Makita, Hiroki; Yamashita, Tomomi; Toida, Makoto; Kato, Keizo; Hatakeyama, Daijiro; Shibata, Toshiyuki

    2007-04-01

    The preventive effects of the dietary administration of brown rice and rice bran fermented with Aspergillus oryzae (FBRA) on oral carcinogenesis induced by 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats. At 7 weeks of age, the animals were given 20 ppm 4-NQO in their drinking water for 8 weeks to induce tongue neoplasms. Groups of rats were fed diets containing 5 or 10% FBRA during the initiation or postinitiation phases of the 4-NQO-induced oral carcinogenesis. The other groups consisted of rats fed 10% FBRA or untreated rats. At the termination of the study (week 32), the incidences, multiplicities of tongue lesions (pre-neoplasms and neoplasms) and the cell proliferation activity estimated by the 5-bromodeoxyuridine (BrdU)-labeling index were compared among the groups. Feeding of 5% FBRA during the initiation phase significantly decreased the incidence (68.2 vs 36.8%; p<0.05) and multiplicity (1.05+/-0.84 vs 0.37+/-0.50; p<0.005) of the tongue carcinoma. When feeding of 10% FBRA occurred after the 4-NQO exposure, the multiplicity of tongue carcinoma was also reduced (1.05+/-0.84 vs 0.52+/-0.60; p<0.05). In addition, the dietary administration of FBRA at both doses significantly decreased the BrdU-labeling index in the oral squamous epithelium (p<0.05). Although a dose-dependent response was not observed, FBRA is effective in suppressing the development of 4-NQO-induced oral carcinogenesis by its concurrent exposure to the carcinogen. The inhibitory effect could be related to the suppression of the hyperproliferation of cells in the tongue epithelium and the radical scavenging activity of FBRA.

  2. An efficient hybrid, nanostructured, epoxidation catalyst: titanium silsesquioxane-polystyrene copolymer supported on SBA-15.

    PubMed

    Zhang, Lei; Abbenhuis, Hendrikus C L; Gerritsen, Gijsbert; Bhriain, Nollaig Ní; Magusin, Pieter C M M; Mezari, Brahim; Han, Wei; van Santen, Rutger A; Yang, Qihua; Li, Can

    2007-01-01

    A novel interfacial hybrid epoxidation catalyst was designed with a new immobilization method for homogeneous catalysts by coating an inorganic support with an organic polymer film containing active sites. The titanium silsesquioxane (TiPOSS) complex, which contains a single-site titanium active center, was immobilized successfully by in-situ copolymerization on a mesoporous SBA-15-supported polystyrene polymer. The resulting hybrid materials exhibit attractive textural properties (highly ordered mesostructure, large specific surface area (>380 m2 g-1) and pore volume (>or==0.46 cm3 g-1)), and high activity in the epoxidation of alkenes. In the epoxidation of cyclooctene with tert-butyl hydrogen peroxide (TBHP), the hybrid catalysts have rate constants comparable with that of their homogeneous counterpart, and can be recycled at least seven times. They can also catalyze the epoxidation of cyclooctene with aqueous H2O2 as the oxidant. In two-phase reaction media, the catalysts show much higher activity than their homogeneous counterpart due to the hydrophobic environment around the active centers. They behave as interfacial catalysts due to their multifunctionality, that is, the hydrophobicity of polystyrene and the polyhedral oligomeric silsesquioxanes (POSS), and the hydrophilicity of the silica and the mesoporous structure. Combination of the immobilization of homogeneous catalysts on two conventional supports, inorganic solid and organic polymer, is demonstrated to achieve novel heterogeneous catalytic ensembles with the merits of attractive textural properties, tunable surface properties, and optimized environments around the active sites.

  3. Layered transition metal carboxylates: efficient reusable heterogeneous catalyst for epoxidation of olefins.

    PubMed

    Sen, Rupam; Bhunia, Susmita; Mal, Dasarath; Koner, Subratanath; Miyashita, Yoshitaro; Okamoto, Ken-Ichi

    2009-12-01

    Layered metal carboxylates [M(malonato)(H(2)O)(2)](n) (M = Ni(II) and Mn(II)) that have a claylike structure have been synthesized hydrothermally and characterized. The interlayer separation in these layered carboxylates is comparable to that of the intercalation distance of the naturally occurring clay materials or layered double hydroxides (LDHs). In this study, we have demonstrated that, instead of intercalating the metal complex into layers of the clay or LDH, layered transition metal carboxylates, [M(malonato)(H(2)O)(2)](n), as such can be used as a recyclable heterogeneous catalyst in olefin epoxidation reaction. Metal carboxylates [M(malonato)(H(2)O)(2)](n) exhibit excellent catalytic performance in olefin epoxidation reaction.

  4. β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

    PubMed

    Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

    2015-11-02

    β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency

  5. A structural study of epoxidized natural rubber (ENR-50) and its cyclic dithiocarbonate derivative using NMR spectroscopy techniques.

    PubMed

    Hamzah, Rosniza; Bakar, Mohamad Abu; Khairuddean, Melati; Mohammed, Issam Ahmed; Adnan, Rohana

    2012-09-12

    A structural study of epoxidized natural rubber (ENR-50) and its cyclic dithiocarbonate derivative was carried out using NMR spectroscopy techniques. The overlapping (1)H-NMR signals of ENR-50 at δ 1.56, 1.68-1.70, 2.06, 2.15-2.17 ppm were successfully assigned. In this work, the <(13)C-NMR chemical shift assignments of ENR-50 were consistent to the previously reported work. A cyclic dithiocarbonate derivative of ENR-50 was synthesized from the reaction of purified ENR-50 with carbon disulfide (CS(2)), in the presence of 4-dimethylaminopyridine (DMAP) as catalyst at reflux temperature. The cyclic dithiocarbonate formation involved the epoxide ring opening of the ENR-50. This was followed by insertion of the C-S moiety of CS(2) at the oxygen attached to the quaternary carbon and methine carbon of epoxidized isoprene unit, respectively. The bands due to the C=S and C-O were clearly observed in the FTIR spectrum while the (1)H-NMR spectrum of the derivative revealed the peak attributed to the methylene protons had split. The (13)C-NMR spectrum of the derivative further indicates two new carbon peaks arising from the >C=S and quaternary carbon of cyclic dithiocarbonate. All other (1)H- and (13)C-NMR chemical shifts of the derivative remain unchanged with respect to the ENR-50.

  6. In Silico Prediction of Cytochrome P450-Mediated Biotransformations of Xenobiotics: A Case Study of Epoxidation.

    PubMed

    Zhang, Jing; Ji, Li; Liu, Weiping

    2015-08-17

    Predicting the biotransformation of xenobiotics is important in toxicology; however, as more compounds are synthesized than can be investigated experimentally, powerful computational methods are urgently needed to prescreen potentially useful candidates. Cytochrome P450 enzymes (P450s) are the major enzymes involved in xenobiotic metabolism, and many substances are bioactivated by P450s to form active compounds. An example is the conversion of olefinic substrates to epoxides, which are intermediates in the metabolic activation of many known or suspected carcinogens. We have calculated the activation energies for epoxidation by the active species of P450 enzymes (an iron-oxo porphyrin cation radical oxidant, compound I) for a diverse set of 36 olefinic substrates with state-of-the-art density functional theory (DFT) methods. Activation energies can be estimated by the computationally less demanding method of calculating the ionization potentials of the substrates, which provides a useful and simple predictive model based on the reaction mechanism; however, the preclassification of these diverse substrates into weakly polar and strongly polar groups is a prerequisite for the construction of specific predictive models with good predictability for P450 epoxidation. This approach has been supported by both internal and external validations. Furthermore, the relation between the activation energies for the regioselective epoxidation and hydroxylation reactions of P450s and experimental data has been investigated. The results show that the computational method used in this work, single-point energy calculations with the B3LYP functional including zero-point energy and solvation and dispersion corrections based on B3LYP-optimized geometries, performs well in reproducing the experimental trends of the epoxidation and hydroxylation reactions.

  7. Ladder Polyether Synthesis via Epoxide-Opening Cascades Directed by a Disappearing Trimethylsilyl Group

    PubMed Central

    Heffron, Timothy P.; Simpson, Graham L.; Merino, Estibaliz; Jamison, Timothy F.

    2010-01-01

    Epoxide-opening cascades offer the potential to construct complex polyether natural products expeditiously and in a manner that emulates the biogenesis proposed for these compounds. Herein we provide a full account of our development of a strategy that addresses several important challenges of such cascades. The centerpiece of the method is a trimethylsilyl (SiMe3) group that serves several purposes and leaves no trace of itself by the time the cascade has come to an end. The main function of the SiMe3 group is to dictate the regioselectivity of epoxide opening. This strategy is the only general method of effecting endo-selective cascades under basic conditions. PMID:20302314

  8. CD34 Expression by Hair Follicle Stem Cells Is Required for Skin Tumor Development in Mice

    PubMed Central

    Trempus, Carol S.; Morris, Rebecca J.; Ehinger, Matthew; Elmore, Amy; Bortner, Carl D.; Ito, Mayumi; Cotsarelis, George; Nijhof, Joanne G.W.; Peckham, John; Flagler, Norris; Kissling, Grace; Humble, Margaret M.; King, Leon C.; Adams, Linda D.; Desai, Dhimant; Amin, Shantu; Tennant, Raymond W.

    2007-01-01

    The cell surface marker CD34 marks mouse hair follicle bulge cells, which have attributes of stem cells, including quiescence and multipotency. Using a CD34 knockout (KO) mouse, we tested the hypothesis that CD34 may participate in tumor development in mice because hair follicle stem cells are thought to be a major target of carcinogens in the two-stage model of mouse skin carcinogenesis. Following initiation with 200 nmol 7,12-dimethylbenz(a)anthracene (DMBA), mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Under these conditions, CD34KO mice failed to develop papillomas. Increasing the initiating dose of DMBA to 400 nmol resulted in tumor development in the CD34KO mice, albeit with an increased latency and lower tumor yield compared with the wild-type (WT) strain. DNA adduct analysis of keratinocytes from DMBA-initiated CD34KO mice revealed that DMBA was metabolically activated into carcinogenic diol epoxides at both 200 and 400 nmol. Chronic exposure to TPA revealed that CD34KO skin developed and sustained epidermal hyperplasia. However, CD34KO hair follicles typically remained in telogen rather than transitioning into anagen growth, confirmed by retention of bromodeoxyuridine-labeled bulge stem cells within the hair follicle. Unique localization of the hair follicle progenitor cell marker MTS24 was found in interfollicular basal cells in TPA-treated WT mice, whereas staining remained restricted to the hair follicles of CD34KO mice, suggesting that progenitor cells migrate into epidermis differently between strains. These data show that CD34 is required for TPA-induced hair follicle stem cell activation and tumor formation in mice. PMID:17483328

  9. Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

    NASA Astrophysics Data System (ADS)

    Medina-Carmona, Encarnación; Neira, Jose L.; Salido, Eduardo; Fuchs, Julian E.; Palomino-Morales, Rogelio; Timson, David J.; Pey, Angel L.

    2017-03-01

    Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention.

  10. A new efficient iron catalyst for olefin epoxidation with hydrogen peroxide.

    PubMed

    Mikhalyova, Elena A; Makhlynets, Olga V; Palluccio, Taryn D; Filatov, Alexander S; Rybak-Akimova, Elena V

    2012-01-18

    A new aminopyridine ligand derived from bipiperidine (the product of full reduction of bipyridine, bipy) coordinates to iron(II) in a cis-α fashion, yielding a new selective catalyst for olefin epoxidation with H(2)O(2) under limiting substrate conditions.

  11. Effect of exercise and caloric restriction on DMBA induced mammary tumorigenesis and plasma lipids in rats fed high fat diets

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Magrane, D.

    1991-03-15

    Female Sprague-Dawley rats were given a single 10 mg dose of 7, 12-Dimethylbenz(a)anthracene (DMBA) and grouped as follows: (1) low fat-sedentary (LF-SED), (2) low fat-exercised (LF-EX), (3) high fat-sedentary (HF-SED), (4) high fat-exercised (HF-EX), (5) high fat-caloric restricted (HF-RES). Diets were isocaloric and contained 3.9% (LF) and 19.4% (HF) of corn oil. Group 5 was fed a 25% caloric restricted diet but with 24.6% fat content to equalize fat intake to HF-SED. After 12 weeks of diet or treadmill exercise, tumor data and plasma lipid profiles were determined. Results show that rats on HF-EX had more total tumors, % ofmore » tumors and tumors per tumor bearing rat than rats on HF-SED. The effect of exercise was also evident in LF-EX rats, when compared to LF-SED. Average tumor size and tumor volumes were not affected. The HF-RES group showed reduced tumor profiles compared to HF-SED. HDL, LDL, triglycerides and total cholesterol were unaffected by HF or LF diets or exercise. These data suggest that tumorigenesis is increased by moderate and constant exercise.« less

  12. Ring-Opening Copolymerization of Epoxides and Cyclic Anhydrides with Discrete Metal Complexes: Structure-Property Relationships.

    PubMed

    Longo, Julie M; Sanford, Maria J; Coates, Geoffrey W

    2016-12-28

    Polyesters synthesized through the alternating copolymerization of epoxides and cyclic anhydrides compose a growing class of polymers that exhibit an impressive array of chemical and physical properties. Because they are synthesized through the chain-growth polymerization of two variable monomers, their syntheses can be controlled by discrete metal complexes, and the resulting materials vary widely in their functionality and physical properties. This polymer-focused review gives a perspective on the current state of the field of epoxide/anhydride copolymerization mediated by discrete catalysts and the relationships between the structures and properties of these polyesters.

  13. A Polyoxovanadate-Resorcin[4]arene-Based Porous Metal-Organic Framework as an Efficient Multifunctional Catalyst for the Cycloaddition of CO2 with Epoxides and the Selective Oxidation of Sulfides.

    PubMed

    Lu, Bing-Bing; Yang, Jin; Liu, Ying-Ying; Ma, Jian-Fang

    2017-10-02

    In this work, we report a new polyoxovanadate-resorcin[4]arene-based metal-organic framework (PMOF), [Co 2 L 0.5 V 4 O 12 ]·3DMF·5H 2 O (1), assembled with a newly functionalized wheel-like resorcin[4]arene ligand (L). 1 features an elegant porous motif and represents a rare example of PMOFs composed of both a resorcin[4]arene ligand and polyoxovanadate. Remarkably, 1 shows open V sites in the channel, which makes 1 an efficient heterogeneous Lewis acid catalyst for the cycloaddition of carbon dioxide to epoxides with high conversion and selectivity. Strikingly, 1 also exhibits high catalytic activity for the heterogeneous oxidative desulfurization of sulfides. Particularly, the heterogeneous catalyst 1 can be easily separated and reused with good catalytic activity.

  14. Zirconium(IV)-Catalyzed Ring Opening of on-DNA Epoxides in Water.

    PubMed

    Fan, Lijun; Davie, Christopher P

    2017-05-04

    DNA-encoded library technology (ELT) has spurred wide interest in the pharmaceutical industry as a powerful tool for hit and lead generation. In recent years a number of "DNA-compatible" chemical modifications have been published and used to synthesize vastly diverse screening libraries. Herein we report a newly developed, zirconium tetrakis(dodecyl sulfate) [Zr(DS) 4 ] catalyzed ring-opening of on-DNA epoxides in water with amines, including anilines. Subsequent cyclization of the resulting on-DNA β-amino alcohols leads to a variety of biologically interesting, nonaromatic heterocycles. Under these conditions, a library of 137 million on-DNA β-amino alcohols and their cyclization products was assembled. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Propylene epoxidation over biogenic Au/TS-1 catalysts by Cinnamomum camphora extract in the presence of H2 and O2

    NASA Astrophysics Data System (ADS)

    Du, Mingming; Huang, Jiale; Sun, Daohua; Li, Qingbiao

    2016-03-01

    The Au/TS-1 catalysts with different Au nanoparticles (NPs) sizes ranging from 3.1 to 8.4 nm but the same Au loading of 0.5 wt% were prepared by Cinnamomum camphora (CC) extract, and were used for propylene epoxidation. The results showed that the interaction between Au and TS-1 support surface is important for propylene epoxidation and much smaller Au NPs (<3 nm) are the dominant active sites. After reaction of 100 h, there is no decreasing in both the activity and the PO selectivity for the Au/TS-1 catalysts, and only 1.8 wt% of the carbonaceous deposits on the surface of the catalyst after reaction, suggesting that the desorption of the product from the modified catalysts surface by residual biomolecules is much easier.

  16. Hybrid networks based on epoxidized camelina oil

    PubMed Central

    Balanuca, Brindusa; Stan, Raluca; Lungu, Adriana; Vasile, Eugeniu; Iovu, Horia

    2017-01-01

    Abstract Lately, renewable resources received great attention in the macromolecular compounds area, regarding the design of the monomers and polymers with different applications. In this study the capacity of several modified vegetable oil-based monomers to build competitive hybrid networks was investigate, taking into account thermal and mechanical behavior of the designed materials. In order to synthesize such competitive nanocomposites, the selected renewable raw material, camelina oil, was employed due to the non-toxicity and biodegradability behavior. General properties of epoxidized camelina oil-based materials were improved by loading of different types of organic-inorganic hybrid compounds – polyhedral oligomeric silsesquioxane (POSS) bearing one (POSS1Ep) or eight (POSS8Ep) epoxy rings on the cages. In order to identify the chemical changes occurring after the thermal curing reactions, FT-IR spectrometry was employed. The new synthesized nanocomposites based on epoxidized camelina oil (ECO) were characterized by dynamic mechanical analyze and thermogravimetric analyze. The morphology of the ECO-based materials was investigate by scanning electron microscopy and supplementary information regarding the presence of the POSS compounds were establish by energy dispersive X-ray analysis and X-ray photoelectron spectroscopy. The smooth materials without any separation phase indicates a well dispersion of the Si–O–Si cages within the organic matrix and the incorporation of this hybrid compounds into the ECO network demonstrates to be a well strategy to improve the thermal and mechanical properties, simultaneously. PMID:29491775

  17. Efficient epoxidation of a terminal alkene containing allylic hydrogen atoms: trans-methylstyrene on Cu{111}.

    PubMed

    Cropley, Rachael L; Williams, Federico J; Urquhart, Andrew J; Vaughan, Owain P H; Tikhov, Mintcho S; Lambert, Richard M

    2005-04-27

    The selective oxidation of trans-methylstyrene, a phenyl-substituted propene that contains labile allylic hydrogen atoms, has been studied on Cu{111}. Mass spectrometry and synchrotron fast XPS were used to detect, respectively, desorbing gaseous products and the evolution of surface species as a function of temperature and time. Efficient partial oxidation occurs yielding principally the epoxide, and the behavior of the system is sensitive to the order in which reactants are adsorbed. The latter is understandable in terms of differences in the spatial distribution of oxygen adatoms; isolated adatoms lead to epoxidation, while islands of "oxidic" oxygen do not. NEXAFS data taken over a range of coverages and in the presence and absence of coadsorbed oxygen indicate that the adsorbed alkene lies essentially flat with the allylic hydrogen atoms close to the surface. The photoemission results and comparison with the corresponding behavior of styrene on Cu{111} strongly suggest that allylic hydrogen abstraction is indeed a critical factor that limits epoxidation selectivity. An overall mechanism consistent with the structural and reactive properties is proposed.

  18. Diastereoselective Synthesis of a Strawberry Flavoring Agent by Epoxidation of Ethyl trans-b-Methylcinnamate

    NASA Astrophysics Data System (ADS)

    Pageau, Gayle J.; Mabaera, Rodwell; Kosuda, Kathryn M.; Sebelius, Tamara A.; Ghaffari, Ali H.; Kearns, Kenneth A.; McIntyre, Jean P.; Beachy, Tina M.; Thamattoor, Dasan M.

    2002-01-01

    The diastereoselective synthesis of ethyl (E)-3-methyl-3-phenylglycidate, a strawberry flavoring agent, is carried out by epoxidizing ethyl trans-b-methylcinnamate with m-chloroperbenzoic acid. This epoxidation is appropriate for the introductory organic laboratory and augments the small number of such experiments currently available for undergraduate education. In the course of performing this exercise, students are exposed to many important facets of organic chemistry such as synthesis, reaction mechanism, stereochemistry, chromatography, quantitative analysis, spectroscopy, and computational chemistry. The 1H NMR spectrum of this compound is especially interesting and presents instructive examples of diastereotopic protons and shielding effects of the aromatic ring current.

  19. The Molecular Structure of Epoxide Hydrolase B From And Its Complex With Urea-Based Inhibitor

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Biswal, B.K.; Morisseau, C.; Garen, G.

    2009-05-11

    Mycobacterium tuberculosis (Mtb), the intracellular pathogen that infects macrophages primarily, is the causative agent of the infectious disease tuberculosis in humans. The Mtb genome encodes at least six epoxide hydrolases (EHs A to F). EHs convert epoxides to trans-dihydrodiols and have roles in drug metabolism as well as in the processing of signaling molecules. Herein, we report the crystal structures of unbound Mtb EHB and Mtb EHB bound to a potent, low-nanomolar (IC(50) approximately 19 nM) urea-based inhibitor at 2.1 and 2.4 A resolution, respectively. The enzyme is a homodimer; each monomer adopts the classical alpha/beta hydrolase fold that composesmore » the catalytic domain; there is a cap domain that regulates access to the active site. The catalytic triad, comprising Asp104, His333 and Asp302, protrudes from the catalytic domain into the substrate binding cavity between the two domains. The urea portion of the inhibitor is bound in the catalytic cavity, mimicking, in part, the substrate binding; the two urea nitrogen atoms donate hydrogen bonds to the nucleophilic carboxylate of Asp104, and the carbonyl oxygen of the urea moiety receives hydrogen bonds from the phenolic oxygen atoms of Tyr164 and Tyr272. The phenolic oxygen groups of these two residues provide electrophilic assistance during the epoxide hydrolytic cleavage. Upon inhibitor binding, the binding-site residues undergo subtle structural rearrangement. In particular, the side chain of Ile137 exhibits a rotation of around 120 degrees about its C(alpha)-C(beta) bond in order to accommodate the inhibitor. These findings have not only shed light on the enzyme mechanism but also have opened a path for the development of potent inhibitors with good pharmacokinetic profiles against all Mtb EHs of the alpha/beta type.« less

  20. Iron-catalyzed olefin epoxidation in the presence of acetic acid: insights into the nature of the metal-based oxidant.

    PubMed

    Mas-Ballesté, Rubén; Que, Lawrence

    2007-12-26

    The iron complexes [(BPMEN)Fe(OTf)2] (1) and [(TPA)Fe(OTf)2] (2) [BPMEN = N,N'-bis-(2-pyridylmethyl)-N,N'-dimethyl-1,2-ethylenediamine; TPA = tris-(2-pyridylmethyl)amine] catalyze the oxidation of olefins by H2O2 to yield epoxides and cis-diols. The addition of acetic acid inhibits olefin cis-dihydroxylation and enhances epoxidation for both 1 and 2. Reactions carried out at 0 degrees C with 0.5 mol % catalyst and a 1:1.5 olefin/H2O2 ratio in a 1:2 CH3CN/CH3COOH solvent mixture result in nearly quantitative conversions of cyclooctene to epoxide within 1 min. The nature of the active species formed in the presence of acetic acid has been probed at low temperature. For 2, in the absence of substrate, [(TPA)FeIII(OOH)(CH3COOH)]2+ and [(TPA)FeIVO(NCCH3)]2+ intermediates can be observed. However, neither is the active epoxidizing species. In fact, [(TPA)FeIVO(NCCH3)]2+ is shown to form in competition with substrate oxidation. Consequently, it is proposed that epoxidation is mediated by [(TPA)FeV(O)(OOCCH3)]2+, generated from O-O bond heterolysis of the [(TPA)FeIII(OOH)(CH3COOH)]2+ intermediate, which is promoted by the protonation of the terminal oxygen atom of the hydroperoxide by the coordinated carboxylic acid.

  1. Crystal Structure and Catalytic Behavior in Olefin Epoxidation of a One-Dimensional Tungsten Oxide/Bipyridine Hybrid.

    PubMed

    Amarante, Tatiana R; Antunes, Margarida M; Valente, Anabela A; Paz, Filipe A Almeida; Pillinger, Martyn; Gonçalves, Isabel S

    2015-10-19

    The tungsten oxide/2,2'-bipyridine hybrid material [WO3(2,2'-bpy)]·nH2O (n = 1-2) (1) has been prepared in near quantitative yield by the reaction of H2WO4, 2,2'-bpy, and H2O in the mole ratio of ca. 1:2:700 at 160 °C for 98 h in a rotating Teflon-lined digestion bomb. The solid-state structure of 1 was solved and refined through Rietveld analysis of high-resolution synchrotron X-ray diffraction data collected for the microcrystalline powder. The material, crystallizing in the orthorhombic space group Iba2, is composed of a one-dimensional organic-inorganic hybrid polymer, ∞(1)[WO3(2,2'-bpy)], topologically identical to that found in the previously reported anhydrous phases [MO3(2,2'-bpy)] (M = Mo, W). While in the latter the N,N'-chelated 2,2'-bpy ligands of adjacent corner-shared {MO4N2} octahedra are positioned on the same side of the 1D chain, in 1 the 2,2'-bpy ligands alternate above and below the chain. The catalytic behavior of compound 1 for the epoxidation of cis-cyclooctene was compared with that for several other tungsten- or molybdenum-based (pre)catalysts, including the hybrid polymer [MoO3(2,2'-bpy)]. While the latter exhibits superior performance when tert-butyl hydroperoxide (TBHP) is used as the oxidant, compound 1 is superior when aqueous hydrogen peroxide is used, allowing near-quantitative conversion of the olefin to the epoxide. With H2O2, compounds 1 and [MoO3(2,2'-bpy)] act as sources of soluble active species, namely, the oxodiperoxo complex [MO(O2)2(2,2'-bpy)], which is formed in situ. Compounds 1 and [WO(O2)2(2,2'-bpy)] (2) were further tested in the epoxidation of cyclododecene, trans-2-octene, 1-octene, (R)-limonene, and styrene. The structure of 2 was determined by single-crystal X-ray diffraction and found to be isotypical with the molybdenum analogue.

  2. Covalent Heterogenization of a Discrete Mn(II) Bis-Phen Complex by a Metal-Template/Metal-Exchange Method: An Epoxidation Catalyst with Enhanced Reactivity

    PubMed Central

    Terry, Tracy J.; Stack, T. Daniel P.

    2009-01-01

    Considerable attention has been devoted to the immobilization of discrete epoxidation catalysts onto solid supports due to the possible benefits of site isolation such as increased catalyst stability, catalyst recycling, and product separation. A synthetic metal-template/metal-exchange method to imprint a covalently attached bis-1,10-phenanthroline coordination environment onto high-surface area, mesoporous SBA-15 silica is reported herein along with the epoxidation reactivity once reloaded with manganese. Comparisons of this imprinted material with material synthesized by random grafting of the ligand show that the template method creates more reproducible, solution-like bis-1,10-phenanthroline coordination at a variety of ligand loadings. Olefin epoxidation with peracetic acid shows the imprinted manganese catalysts have improved product selectivity for epoxides, greater substrate scope, more efficient use of oxidant, and higher reactivity than their homogeneous or grafted analogues independent of ligand loading. The randomly grafted manganese catalysts, however, show reactivity that varies with ligand loading while the homogeneous analogue degrades trisubstituted olefins and produces trans-epoxide products from cis-olefins. Efficient recycling behavior of the templated catalysts is also possible. PMID:18351763

  3. Suppression on the mutagenicity of 4-nitroquinoline-N-oxide by the methanol extracts of soybean koji prepared with various filamentous fungi.

    PubMed

    Lin, Chia-Hung; Chou, Cheng-Chun

    2006-07-01

    In this study, solid fermentation of soybean with various GRAS filamentous fungi including Aspergillus sojae BCRC 30103, Aspergillus oryzae BCRC 30222, Aspergillus awamori, Actinomucor taiwanesis and Rhizopus sp. was performed to prepare various soybean kojis. Toxicity, mutagenicity and suppression on the mutagenesis induced by a direct mutagen, 4-nitroquinoline-N-oxide (4-NQO) on Salmonella typhimurium TA 100, by the various methanol extracts of the prepared soybean koji and unfermented soybean were determined and compared. Results revealed that methanol extracts of unfermented soybean and kojis show no toxicity and mutagenic activity within the dose levels examined on test organism. On the other hand, antimutagenic activity against 4-NQO was observed with the extract of unfermented soybean. Furthermore, fermentation, regardless of the starter organism employed, resulted in an enhanced antimutagenic effect on the mutagenesis of 4-NQO by the extracts of the soybean koji. Across the dose range (0.625-5.0 mg/plate) tested, a dose-dependent antimutagenic activity was observed. Antimutagenic activities of the koji extracts varied with starter organism, with A. awamori-prepared koji extract exhibiting the highest rate of suppression on the mutagenicity of 4-NQO. Further study with A. awamori also revealed that fermentation temperature affected the antimutagenic activity of the prepared koji extract. In general, the extract of the A. awamori-soybean koji prepared at 30 degrees C showed a higher antimutagenic activity than those prepared at 25 or 35 degrees C.

  4. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer.

    PubMed

    Moi, Line L Haugan; Flågeng, Marianne Hauglid; Gjerde, Jennifer; Madsen, Andre; Røst, Therese Halvorsen; Gudbrandsen, Oddrun Anita; Lien, Ernst A; Mellgren, Gunnar

    2012-06-15

    Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). The expression of SRCs

  5. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer

    PubMed Central

    2012-01-01

    Background Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Methods Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Results Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0

  6. A Computational Study of Acid Catalyzed Aerosol Reactions of Atmospherically Relevant Epoxides

    EPA Science Inventory

    Epoxides are important intermediates of atmospheric isoprene oxidation. Their subsequent reactions in the particle phase lead to the production of organic compounds detected in ambient aerosols. We apply density functional theory to determine the important kinetic factors that ...

  7. Dynamics of Nrf2 and Keap1 in ARE-mediated NQO1 expression by wasabi 6-(methylsulfinyl)hexyl isothiocyanate.

    PubMed

    Hou, De-Xing; Korenori, Yoshimi; Tanigawa, Shunsuke; Yamada-Kato, Tomoe; Nagai, Masashi; He, Xi; He, Jianhua

    2011-11-23

    6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a bioactive ingredient present in wasabi, a popular pungent spice in Japan. Previous studies have revealed the cytoprotective and cancer chemopreventive effects of 6-MSITC. This study aims to clarify the molecular mechanisms by investigating the action of 6-MSITC on the Nrf2/Keap1 system. 6-MSITC up-regulated the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) by increasing the Nrf2 level. Treatment with 6-MSITC extended the half-life (t(1/2)) of Nrf2 protein from 11.5 to 35.2 min, approximately three times longer. Moreover, 6-MSITC suppressed the ubiquitination of Nrf2 but not Keap1. Alternatively, a modified Keap1 was observed in 6-MSITC-treated cells accompanying reduction of normal Keap1 protein. The results from cellular fractionation and immunocytochemistry assay revealed that Nrf2 was primarily accumulated in nucleus. EMSA and the reporter gene assay further demonstrated that 6-MSITC augmented Nrf2-ARE binding and transcription activity. Silencing Nrf2 using Nrf2 siRNA markedly reduced the Nrf2 level and ARE-driven activity under both baseline and 6-MSITC-induced conditions. Our data revealed that 6-MSITC enhanced Nrf2/ARE-driven NQO1 expression by stabilizing Nrf2 that was accomplished by modifying Keap1 with consequent inhibition of the ubiquitination and proteasomal turnover of Nrf2. The findings provide an insight into the mechanisms underlying 6-MSITC in cytoprotection and cancer chemoprevention.

  8. Induction of hepatic aryl hydrocarbon hydroxylase and epoxide hydrase in Wistar rats pretreated with oral methadone hydrochloride.

    PubMed

    Bellward, G D; Gontovnick, L S; Otten, M

    1977-01-01

    Methadone-HCl added to the drinking water of adult female Wistar rats for 4 weeks produced an increase in the aryl hydrocarbon hydroxylase activity of the hepatic microsomal fraction to 222% of control levels. No change was seen in epoxide hydrase activity. In contrast, when male rats were treated similarly, there was an increase in epoxide hydrase activity to 212% of controls with no change in aryl hydrocarbon hydroxylase activity. No such changes were observed when the subcutaneous route of administration or chronic, low-dose, intraperitoneal injections were used. There were no differences in hepatic cytochrome P-450 or protein concentrations in treated animals as compared to their respective control groups. Control studies were carried out with quinine sulfate in the drinking water to decrease water intake to the level of the methadone-treated group. No elevation in either enzyme activity occurred in this control group. Similarly, paired-feeding studies showed the elevation of enzyme activity to be due to the methadone, not food deprivation. The effects of concurrent therapy of methadone with phenobarbital sodium or 3-methylcholanthrene were compared.

  9. An NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles for tumor targeted drug delivery in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Gayam, Srivardhan Reddy; Venkatesan, Parthiban; Sung, Yi-Ming; Sung, Shuo-Yuan; Hu, Shang-Hsiu; Hsu, Hsin-Yun; Wu, Shu-Pao

    2016-06-01

    The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this smart biocompatible carrier system showed obvious uptake and consequent release of the drug in tumor cells, could selectively induce the tumor cell death and enhance the capability of inhibition of tumor growth in vivo. The controlled drug delivery system demonstrated its use as a potential theranostic material.The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this

  10. Formation of a Cyclopropyl Epoxide via a Leukotriene A Synthase-related Pathway in an Anaerobic Reaction of Soybean Lipoxygenase-1 with 15S-Hydroperoxyeicosatetraenoic Acid

    PubMed Central

    Zheng, Yuxiang; Brash, Alan R.

    2010-01-01

    The further conversion of an arachidonic acid hydroperoxide to a leukotriene A (LTA) type epoxide by specific lipoxygenase (LOX) enzymes constitutes a key step in inflammatory mediator biosynthesis. Whereas mammalian 5-LOX transforms its primary product (5S-hydroperoxyeicosatetraenoic acid; 5S-HPETE) almost exclusively to LTA4, the model enzyme, soybean LOX-1, normally produces no detectable leukotrienes and instead further oxygenates its primary product 15S-HPETE to 5,15- and 8,15-dihydroperoxides. Mammalian 15-LOX-1 displays both types of activity. We reasoned that availability of molecular oxygen within the LOX active site favors oxygenation, whereas lack of O2 promotes LTA epoxide synthesis. To test this, we reacted 15S-HPETE with soybean LOX-1 under anaerobic conditions and identified the products by high pressure liquid chromatography, UV, mass spectrometry, and NMR. Among the products, we identified a pair of 8,15-dihydroxy diastereomers with all-trans-conjugated trienes that incorporated 18O from H218O at C-8, indicative of the formation of 14,15-LTA4. A pair of 5,15-dihydroxy diastereomers containing two trans,trans-conjugated dienes (6E,8E,11E,13E) and that incorporated 18O from H218O at C-5 was deduced to arise from hydrolysis of a novel epoxide containing a cyclopropyl ring, 14,15-epoxy-[9,10,11-cyclopropyl]-eicosa-5Z,7E,13E-trienoic acid. Also identified was the δ-lactone of the 5,15-diol, a derivative that exhibited no 18O incorporation due to its formation by intramolecular reaction of the carboxyl anion with the proposed epoxide intermediate. Our results support a model in which access to molecular oxygen within the active site directs the outcome from competing pathways in the secondary reactions of lipoxygenases. PMID:20194505

  11. Attenuation of Cisplatin-Induced Renal Injury by Inhibition of Soluble Epoxide Hydrolase Involves Nuclear Factor κB Signaling

    PubMed Central

    Liu, Yingmei; Webb, Heather K.; Fukushima, Hisayo; Micheli, Janine; Markova, Svetlana; Olson, Jean L.

    2012-01-01

    Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(−/−) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(−/−) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy. PMID:22414856

  12. Epoxidation with Possibilities: Discovering Stereochemistry in Organic Chemistry via Coupling Constants

    ERIC Educational Resources Information Center

    Treadwell, Edward M.; Yan, Zhiqing; Xiao, Xiao

    2017-01-01

    A one-day laboratory epoxidation experiment, requiring no purification, is described, wherein the students are given an "unknown" stereoisomer of 3-hexen-1-ol, and use [superscript 1]H NMR coupling constants to determine the stereochemistry of their product. From this they work backward to determine the stereochemistry of their starting…

  13. E&V Guidebook, Version 1.1

    DTIC Science & Technology

    1989-08-15

    checklist 14.1] Chapter 3, Language-related issues, extracts from the Ada language reference manua! [,_D 1982] those features exp!icitly a!owcd to vay...welcome. Please send comments electronically (preferred) to szymansk~aja;po.sei.cmu.edu, or by regular mail to Mr. Raymond Szymanski , AFWAL/AAAF, Wright...of Tool Features for the Ada Programming Support Environment (APSE) 4-3 4.3 E&V Report: DoD APSE Analysis 4-4 4.4 Classification Schema/E&V Taxonomy

  14. Photodynamic therapy using a novel irradiation source, LED lamp, is similarly effective to photodynamic therapy using diode laser or metal-halide lamp on DMBA- and TPA-induced mouse skin papillomas.

    PubMed

    Takahashi, Hidetoshi; Nakajima, Susumu; Ogasawara, Koji; Asano, Ryuji; Nakae, Yoshinori; Sakata, Isao; Iizuka, Hajime

    2014-08-01

    Photodynamic therapy (PDT) is useful for superficial skin tumors such as actinic keratosis and Bowen disease. Although PDT is non-surgical and easily-performed treatment modality, irradiation apparatus is large and expensive. Using 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-ο-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin papilloma model, we compared the efficacy of TONS501- and ALA-PDT with a LED lamp, a diode laser lamp or a metal-halide lamp on the skin tumor regression. TONS501-PDT using 660 nm LED lamp showed anti-tumor effect at 1 day following the irradiation and the maximal anti-tumor effect was observed at 3 days following the irradiation. There was no significant difference in the anti-tumor effects among TONS501-PDT using LED, TONS501-PDT using diode laser, and 5-aminolevulinic acid hydrochloride (ALA)-PDT using metal-halide lamp. Potent anti-tumor effect on DMBA- and TPA-induced mouse skin papilloma was observed by TONS501-PDT using 660 nm LED, which might be more useful for clinical applications. © 2014 Japanese Dermatological Association.

  15. 40 CFR 63.1431 - Process vent annual epoxides emission factor plan requirements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., recovery, or recapture device, along with the expected percent efficiency. (iii) Annual emissions after the... section, kg/yr. R = Expected control efficiency of the combustion, recovery, or recapture device, percent....1426(c) to determine the epoxide control efficiency of the combustion, recovery, or recapture device...

  16. 40 CFR 63.1431 - Process vent annual epoxides emission factor plan requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., recovery, or recapture device, along with the expected percent efficiency. (iii) Annual emissions after the... section, kg/yr. R = Expected control efficiency of the combustion, recovery, or recapture device, percent....1426(c) to determine the epoxide control efficiency of the combustion, recovery, or recapture device...

  17. Formation of furan fatty alkyl esters from their bis-epoxide fatty esters

    USDA-ARS?s Scientific Manuscript database

    Reactions of epoxidized alkyl soyate with four different alcohols: ethanol, isopropyl alcohol, 2-ethylhexanol, and benzyl alcohol were investigated in the presence of Bronsted acid catalyst. Products not reported in prior studies of similar reactions were found. These were furan fatty acid alkyl est...

  18. Formation of furan fatty alkyl esters from their bis-epoxide fatty esters

    USDA-ARS?s Scientific Manuscript database

    Reactions of epoxidized alkyl soyate with four different alcohols: ethanol, isopropyl alcohol, 2-ethylhexanol, benzyl alcohol, in the presence of Bronsted acid catalyst, were investigated. Products that were not reported in prior studies of similar reactions were found. These were furan fatty acid a...

  19. Ethylene Epoxidation with Nitrous Oxide over Fe-BTC Metal-Organic Frameworks: A DFT Study.

    PubMed

    Maihom, Thana; Choomwattana, Saowapak; Wannakao, Sippakorn; Probst, Michael; Limtrakul, Jumras

    2016-11-04

    The epoxidation of ethylene with N 2 O over the metal-organic framework Fe-BTC (BTC=1,3,5-benzentricarboxylate) is investigated by means of density functional calculations. Two reaction paths for the production of ethylene oxide or acetaldehyde are systematically considered in order to assess the efficiency of Fe-BTC for the selective formation of ethylene oxide. The reaction starts with the decomposition of N 2 O to form an active surface oxygen atom on the Fe site of Fe-BTC, which subsequently reacts with an ethylene molecule to form an ethyleneoxy intermediate. This intermediate can then be selectively transformed either by 1,2-hydride shift into the undesired product acetaldehyde or into the desired product ethylene oxide by way of ring closure of the intermediate. The production of ethylene oxide requires an activation energy of 5.1 kcal mol -1 , which is only about one-third of the activation energy of acetaldehyde formation (14.3 kcal mol -1 ). The predicted reaction rate constants for the formation of ethylene oxide in the relevant temperature range are approximately 2-4 orders of magnitude higher than those for acetaldehyde. Altogether, the results suggest that Fe-BTC is a good candidate catalyst for the epoxidation of ethylene by molecular N 2 O. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Effect of Binding on Enantioselectivity of Epoxide Hydrolase.

    PubMed

    Zaugg, Julian; Gumulya, Yosephine; Bodén, Mikael; Mark, Alan E; Malde, Alpeshkumar K

    2018-03-26

    Molecular dynamics simulations and free energy calculations have been used to investigate the effect of ligand binding on the enantioselectivity of an epoxide hydrolase (EH) from Aspergillus niger. Despite sharing a common mechanism, a wide range of alternative mechanisms have been proposed to explain the origin of enantiomeric selectivity in EHs. By comparing the interactions of ( R)- and ( S)-glycidyl phenyl ether (GPE) with both the wild type (WT, E = 3) and a mutant showing enhanced enantioselectivity to GPE (LW202, E = 193), we have examined whether enantioselectivity is due to differences in the binding pose, the affinity for the ( R)- or ( S)- enantiomers, or a kinetic effect. The two enantiomers were easily accommodated within the binding pockets of the WT enzyme and LW202. Free energy calculations suggested that neither enzyme had a preference for a given enantiomer. The two substrates sampled a wide variety of conformations in the simulations with the sterically hindered and unhindered carbon atoms of the GPE epoxide ring both coming in close proximity to the nucleophilic aspartic acid residue. This suggests that alternative pathways could lead to the formation of a ( S)- and ( R)-diol product. Together, the calculations suggest that the enantioselectivity is due to kinetic rather than thermodynamic effects and that the assumption that one substrate results in one product when interpreting the available experimental data and deriving E-values may be inappropriate in the case of EHs.

  1. Biobased composites from thermoplastic polyurethane elastomer and cross-linked acrylated-epoxidized soybean oil

    USDA-ARS?s Scientific Manuscript database

    Soybean oil is an important sustainable material. Crosslinked acrylated epoxidized soybean oil (AESO) is brittle without flexibility and the incorporation of thermoplastic polyurethane improves its toughness for industrial applications. The hydrophilic functional groups from both oil and polyurethan...

  2. Nordihydroguaiaretic acid ameliorates cisplatin induced nephrotoxicity and potentiates its anti-tumor activity in DMBA induced breast cancer in female Sprague-Dawley rats.

    PubMed

    Mundhe, Nitin Arunrao; Kumar, Parveen; Ahmed, Sahabuddin; Jamdade, Vinayak; Mundhe, Sanjay; Lahkar, Mangala

    2015-09-01

    Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. The hydrolysis of epoxides catalyzed by inorganic ammonium salts in water: kinetic evidence for hydrogen bond catalysis.

    PubMed

    Nozière, B; Fache, F; Maxut, A; Fenet, B; Baudouin, A; Fine, L; Ferronato, C

    2018-01-17

    Naturally-occurring inorganic ammonium ions have been recently reported as efficient catalysts for some organic reactions in water, which contributes to the understanding of the chemistry in some natural environments (soils, seawater, atmospheric aerosols, …) and biological systems, and is also potentially interesting for green chemistry as many of their salts are cheap and non-toxic. In this work, the effect of NH 4 + ions on the hydrolysis of small epoxides in water was studied kinetically. The presence of NH 4 + increased the hydrolysis rate by a factor of 6 to 25 compared to pure water and these catalytic effects were shown not to result from other ions, counter-ions or from acid or base catalysis, general or specific. The small amounts of amino alcohols produced in the reactions were identified as the actual catalysts by obtaining a strong acceleration of the reactions when adding these compounds directly to the epoxides in water. Replacing the amino alcohols by other strong hydrogen-bond donors, such as trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) gave the same results, demonstrating that the kinetics of these reactions was driven by hydrogen-bond catalysis. Because of the presence of many hydrogen-bond donors in natural environments (for instance amines and hydroxy-containing compounds), hydrogen-bond catalysis is likely to contribute to many reaction rates in these environments.

  4. Catalysts for CO2/epoxide ring-opening copolymerization

    PubMed Central

    Trott, G.; Saini, P. K.; Williams, C. K.

    2016-01-01

    This article summarizes and reviews recent progress in the development of catalysts for the ring-opening copolymerization of carbon dioxide and epoxides. The copolymerization is an interesting method to add value to carbon dioxide, including from waste sources, and to reduce pollution associated with commodity polymer manufacture. The selection of the catalyst is of critical importance to control the composition, properties and applications of the resultant polymers. This review highlights and exemplifies some key recent findings and hypotheses, in particular using examples drawn from our own research. PMID:26755758

  5. Protective role for ovarian glutathione S-transferase isoform pi during 7,12-dimethylbenz[a]anthracene-induced ovotoxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bhattacharya, Poulomi, E-mail: poulomib@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    2012-04-15

    7,12-Dimethylbenz[a]anthracene (DMBA) destroys ovarian follicles at all developmental stages. This study investigated a role for the glutathione S-transferase (Gst) isoforms alpha (a), mu (m) and pi (p) and the transcription factors, Ahr and Nrf2, during DMBA-induced ovotoxicity, and their regulation by phosphatidylinositol-3 kinase (PI3K) signaling. Negative regulation of JNK by GSTP during DMBA exposure was also studied. Post-natal day (PND) 4 Fischer 344 rat ovaries were exposed to vehicle control (1% DMSO) ± DMBA (1 μM) or vehicle control (1% DMSO) ± LY294002 (PI3K inhibitor; 20 μM) for 1, 2, 4, or 6 days. Total RNA or protein was isolated,more » followed by RT-PCR or Western blotting to determine mRNA or protein level, respectively. Immunoprecipitation using an anti-GSTP antibody was performed to determine interaction between GSTP and JNK, followed by Western blotting to determine JNK and p-c-Jun protein level. DMBA had no impact on Gsta, Gstm or Nrf2 mRNA level, but increased Gstp mRNA and protein after 2 days. Ahr mRNA and protein increased after 2 and 4 days of DMBA exposure, respectively and DMBA increased NRF2 protein level after 4 days. JNK bound to GSTP was increased during DMBA exposure, with a concomitant decrease in unbound JNK and p-c-Jun. Ahr and Gstp mRNA were decreased (2 days) and increased (4 days) by PI3K inhibition, while Gstm mRNA increased (P < 0.05) after both time points, and there was no effect on Nrf2 mRNA. PI3K inhibition increased AHR, NRF2 and GSTP protein level. These findings support involvement of ovarian GSTP during DMBA exposure, and indicate a regulatory role for the PI3K signaling pathway on ovarian xenobiotic metabolism gene expression. -- Highlights: ► Ovarian GSTP is activated in response to DMBA exposure. ► AhR and Nrf2 transcription factors are up-regulated by DMBA. ► PI3K signaling regulates Ahr, Nrf2 and Gstp expression. ► GSTP negatively regulates ovarian JNK in response to DMBA exposure.« less

  6. Rapid, high performance method for the determination of vitamin K(1), menaquinone-4 and vitamin K(1) 2,3-epoxide in human serum and plasma using liquid chromatography-hybrid quadrupole linear ion trap mass spectrometry.

    PubMed

    Gentili, Alessandra; Cafolla, Arturo; Gasperi, Tecla; Bellante, Simona; Caretti, Fulvia; Curini, Roberta; Fernández, Virginia Pérez

    2014-04-18

    Unlike the other fat-soluble vitamins, vitamin K circulates in the human bloodstream at very low levels because of a low intake in the diet. Mammals have developed an efficient recycling system, known as vitamin K-epoxide cycle, which involve quinone, hydroquinone and epoxide forms of the vitamin. Phylloquinone (K(1)) is the main homologue, while menaquinone-4 (MK-4) is both a member of the vitamin K(2) family and metabolite of K(1) in extra-hepatic tissues. Notwithstanding the recent advances, many aspects of the complex vitamin K physiology still remain to be investigated. Therefore, there is a critical need to develop more reliable analytical methods for determining the vitamin K and its metabolites in biological fluids and tissues. Nevertheless, relatively low concentrations, unavailability of some authentic standards and occurrence of interfering lipids make this a challenging task. The method proposed in the present paper can directly and accurately estimate K(1), K(1) 2,3-epoxide (K(1)O), and MK-4 in human serum and plasma at concentrations in the ng/L-μg/L range, using labelled internal standards and a quadrupole linear ion trap instrument operated in multiple reaction monitoring (MRM) mode. High sensitivity was achieved by removing signal "endogenous suppressors" and making the composition of the non-aqueous mobile phase suitable to support the positive atmospheric pressure chemical ionization of the analytes. An excellent selectivity resulted from the combination of some factors: the MRM acquisition, the adoption of an identification point system, an extraction optimized to remove most of the lipids and a tandem-C18 column-system necessary to separate isobaric interferences from analytes. The method was validated according to the Food and Drug Administration (FDA) guidelines and its accuracy was assessed by analysing 9 samples from the Vitamin K External Quality Assessment Scheme (KEQAS). Its feasibility in evaluating vitamin K status in human serum was

  7. Microsomal epoxide hydrolase of rat liver. Purification and characterization of enzyme fractions with different chromatographic characteristics.

    PubMed Central

    Bulleid, N J; Graham, A B; Craft, J A

    1986-01-01

    Microsomal epoxide hydrolase was purified from rat liver, and different fractions of the purified enzyme, which varied in their contents of phospholipid, were obtained by ion-exchange chromatography. One fraction (A), which did not bind to CM-cellulose, had a high phospholipid content, and a second fraction (B), which was eluted from CM-cellulose at high ionic strength, had a low phospholipid content. Removal of most of the phospholipid from fraction A altered its chromatographic behaviour. When the delipidated material was re-applied to CM-cellulose, most of the enzyme bound to the cation-exchanger. The specific activities of all the fractions described (with styrene epoxide [(1,2-epoxyethyl)benzene] as substrate) were altered by adding the non-ionic detergent Lubrol PX or phospholipid. Lubrol PX inhibited enzyme activity, and phospholipid reversed this inhibition. The various enzyme fractions isolated appeared to be different forms of the same protein, as judged by their minimum Mr values and immunochemical properties. These results indicate that different fractions of epoxide hydrolase isolated by ion-exchange chromatography probably are not different isoenzyme forms. Images Fig. 2. Fig. 3. PMID:3082328

  8. Exploring the origins of selectivity in soluble epoxide hydrolase from Bacillus megaterium† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7ob01847a

    PubMed Central

    Serrano-Hervás, Eila

    2017-01-01

    Epoxide hydrolase (EH) enzymes catalyze the hydration of racemic epoxides to yield their corresponding vicinal diols. These enzymes present different enantio- and regioselectivity depending upon either the substrate structure or the substitution pattern of the epoxide ring. In this study, we computationally investigate the Bacillus megaterium epoxide hydrolase (BmEH)-mediated hydrolysis of racemic styrene oxide (rac-SO) and its para-nitro styrene oxide (rac-p-NSO) derivative using density functional theory (DFT) and an active site cluster model consisting of 195 and 197 atoms, respectively. Full reaction mechanisms for epoxide ring opening were evaluated considering the attack at both oxirane carbons and considering two possible orientations of the substrate at the BmEH active site. Our results indicate that for both SO and p-NSO substrates the BmEH enantio- and regioselectivity is opposite to the inherent (R)-BmEH selectivity, the attack at the benzylic position (C1) of the (S)-enantiomer being the most favoured chemical outcome. PMID:29026902

  9. cis-Stilbene and (1 alpha,2 beta,3 alpha)-(2-ethenyl-3-methoxycyclopropyl)benzene as mechanistic probes in the Mn(III)(salen)-catalyzed epoxidation: influence of the oxygen source and the counterion on the diastereoselectivity of the competitive concerted and radical-type oxygen transfer.

    PubMed

    Adam, Waldemar; Roschmann, Konrad J; Saha-Möller, Chantu R; Seebach, Dieter

    2002-05-08

    cis-Stilbene (1) has been epoxidized by a set of diverse oxygen donors [OxD], catalyzed by the Mn(III)(salen)X complexes 3 (X = Cl, PF(6)), to afford a mixture of cis- and trans-epoxides 2. The cis/trans ratios range from 29:71 (extensive isomerization) to 92:8, which depends both on the oxygen source [OxD] and on the counterion X of the catalyst. When (1 alpha,2 beta,3 alpha)-(2-ethenyl-3-methoxycyclopropyl)-benzene (4) is used as substrate, a mechanistic probe which differentiates between radical and cationic intermediates, no cationic ring-opening products are found in this epoxidation reaction; thus, isomerized epoxide product arises from intermediary radicals. The dependence of the diastereoselectivity on the oxygen source is rationalized in terms of a bifurcation step in the catalytic cycle, in which concerted Lewis-acid-activated oxygen transfer competes with stepwise epoxidation by the established Mn(V)(oxo) species. The experimental counterion effect is attributed to the computationally assessed ligand-dependent reaction profiles and stereoselectivities of the singlet, triplet, and quintet spin states available to the manganese species.

  10. Tungsten-catalyzed asymmetric epoxidation of allylic and homoallylic alcohols with hydrogen peroxide.

    PubMed

    Wang, Chuan; Yamamoto, Hisashi

    2014-01-29

    A simple, efficient, and environmentally friendly asymmetric epoxidation of primary, secondary, tertiary allylic, and homoallylic alcohols has been accomplished. This process was promoted by a tungsten-bishydroxamic acid complex at room temperature with the use of aqueous 30% H2O2 as oxidant, yielding the products in 84-98% ee.

  11. NQO1 and CYP450 reductase decrease the systemic exposure of rifampicin-quinone and mediate its redox cycle in rats.

    PubMed

    Shi, Fuguo; Li, Xiaobing; Pan, Hong; Ding, Li

    2017-01-05

    Rifampicin (RIF) is used in regimens for infections caused by Mycobacteria accompanied by serious adverse reactions. Rifampicin-quinone (RIF-Q) is a major autoxidation product of RIF. It is not clear whether RIF-Q plays a role in RIF induced adverse reactions. Investigation of the systemic exposure of RIF-Q is helpful to better understand the role of RIF-Q in RIF induced adverse reactions. In this study, a simple and reproducible high performance liquid chromatography-mass spectrometry (LC-MS) method involving a procedure to prevent the RIF from oxidation for simultaneous quantification of RIF and RIF-Q in rat plasma has been developed and validated, and applied to elucidate the systemic exposure of RIF-Q in rats. The pharmacokinetics data showed that the systemic exposure of RIF-Q was very low (0.67% of RIF, AUC 0-24 ) in rats after oral administration of RIF. However, RIF-Q may undergo the redox cycle in vivo by the evidence that the majority of RIF-Q was reduced to RIF after an oral dose of RIF-Q. Pretreatment with the NAD(P)H: quinone oxidoreductase 1 (NQO1) specific inhibitor dicoumarol and/or cytochrome P450 reductase (CPR) inhibitor diphenyleneiodonium suppressed the redox cycle and significantly increased the systemic exposure of RIF-Q. The inhibitors also attenuated the redox cycle induced reactive oxygen species formation and cytotoxicity in RIF-Q-treated HepG2 cells. These results indicate that NQO1 and CPR play an important role in redox cycle of RIF-Q and may thus contribute to RIF-induced adverse reactions. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Fucoxanthin enhances HO-1 and NQO1 expression in murine hepatic BNL CL.2 cells through activation of the Nrf2/ARE system partially by its pro-oxidant activity.

    PubMed

    Liu, Cheng-Ling; Chiu, Yu-Ting; Hu, Miao-Lin

    2011-10-26

    To determine whether fucoxanthin, a major carotenoid in brown sea algae, may activate cellular antioxidant enzymes via up-regulation of the Nrf2/antioxidant-response element (ARE) pathway, we incubated mouse hepatic BNL CL.2 cells with fucoxanthin (0.5-20 μM) for 0-24 h. We found that fucoxanthin (≥5 μM) significantly increased cellular reactive oxygen species (ROS) at 6 h of incubation, whereas preincubation with α-d-tocopherol (30 μM) significantly attenuated the increase of ROS, indicating the pro-oxidant nature of fucoxanthin. Fucoxanthin significantly increased the phosphorylation of ERK and p38 and markedly increased nuclear Nrf2 protein accumulation after incubation for 12 h. Moreover, fucoxanthin significantly enhanced binding activities of nuclear Nrf2 with ARE and increased mRNA and protein expression of HO-1 and NQO1 after incubation for 12 h. siRNA inhibition of Nrf2 led to markedly decreased HO-1 and NQO1 protein expression. Thus, fucoxanthin may exert its antioxidant activity, at least partly, through its pro-oxidant actions.

  13. Induction of rat liver microsomal epoxide hydrolase by thiazole and pyrazine: hydrolysis of 2-cyanoethylene oxide.

    PubMed

    Kim, S G; Kedderis, G L; Batra, R; Novak, R F

    1993-08-01

    Liver microsomal epoxide hydrolase (mEH) is active in the detoxification of epoxide-containing carcinogens. The effects of thiazole and pyrazine, constituents of tobacco and tobacco smoke as well as of a variety of foods, on the expression and regulation of mEH were examined in rats (200 mg/kg body wt/day, i.p., 1-3 days). Immunoblot analyses using rabbit anti-rat mEH antibody revealed a significant increase in mEH levels in hepatic microsomes isolated from either thiazole- or pyrazine-treated animals. Another protein (approximately 43 kd) cross-reacting with polyclonal mEH antibody was found to be increased concomitantly following pyrazine treatment. Northern and slot blot analyses showed substantial increases in mEH mRNA following either thiazole or pyrazine treatment. The level of mEH mRNA increased 17-fold at 24 h following thiazole treatment, relative to control. Approximately 20- and 16-fold increases in mEH mRNA were also observed at 48 and 72 h respectively following treatment with pyrazine. The level of polymerase chain reaction (PCR)-amplified mEH DNA derived from poly(A)+ RNA was clearly elevated following either thiazole or pyrazine treatment relative to that from untreated animals. Both sense and antisense strands of PCR-amplified mEH DNA were cloned into an M13mp19 phage vector in order to examine the nucleotide sequences of PCR-amplified mEH DNA derived from the poly(A)+ RNA isolated from thiazole- or pyrazine-treated animals. Sequence analyses revealed that the sequence of PCR-amplified DNA from the induced mRNA was identical to that published for mEH cDNA. Epoxide hydrolase activity toward the hydrolysis of 2-cyanoethylene oxide (CEO), the epoxide metabolite of the rat carcinogen acrylonitrile, was not significant in hepatic microsomes from untreated rats, but was substantially induced by treatment with thiazole or pyrazine. Microsomal hydrolysis activity was heat-sensitive and potently inhibited by 1,1,1-trichloropropene-2,3-oxide, indicating that

  14. Lipase catalyzed epoxidation of fatty acid methyl esters derived from unsaturated vegetable oils in absence of carboxylic acid.

    PubMed

    Sustaita-Rodríguez, Alejandro; Ramos-Sánchez, Víctor H; Camacho-Dávila, Alejandro A; Zaragoza-Galán, Gerardo; Espinoza-Hicks, José C; Chávez-Flores, David

    2018-04-11

    Nowadays the industrial chemistry reactions rely on green technologies. Enzymes as lipases are increasing its use in diverse chemical processes. Epoxidized fatty acid methyl esters obtained from transesterification of vegetable oils have recently found applications as polymer plasticizer, agrochemical, cosmetics, pharmaceuticals and food additives. In this research article, grapeseed, avocado and olive oils naturally containing high percents of mono and poly unsaturations were used as starting materials for the production of unsaturated fatty acid methyl esters. The effect of lauric acid as an active oxygen carrier was studied on epoxidation reactions where unsaturated fatty acid methyl esters were converted to epoxy fatty acid methyl esters using immobilized Candida antarctica Lipase type B as catalyst and hydrogen peroxide as oxygen donor at mild temperature and pressure conditions. After this study it was confirmed by 1 H NMR, 13 C NMR and GC-MS that the addition of lauric acid to the enzymatic reaction is unnecessary to transform the alkenes in to epoxides. It was found that quantitative conversions were possible in despite of a carboxylic acid absence.

  15. Synthesis of epoxidized cardanol and its antioxidative properties for vegetable oils and biodiesel

    USDA-ARS?s Scientific Manuscript database

    A novel antioxidant epoxidized cardanol (ECD), derived from cardanol, was synthesized and characterized by FT-IR, 1H-NMR and 13C-NMR. Oxidative stability of ECD used in vegetable oils and biodiesel was evaluated by pressurized differential scanning calorimetry (PDSC) and the Rancimat method, respect...

  16. Tannic acid mitigates the DMBA/croton oil-induced skin cancer progression in mice.

    PubMed

    Majed, Ferial; Rashid, Summya; Khan, Abdul Quaiyoom; Nafees, Sana; Ali, Nemat; Ali, Rashid; Khan, Rehan; Hasan, Syed Kazim; Mehdi, Syed Jafar; Sultana, Sarwat

    2015-01-01

    Skin cancer is the most common malignancy in the world and also one of the major causes of death worldwide. The toxic environmental pollutant 7,12-dimethylbenz[a]anthracene (DMBA) is a skin-specific carcinogen. Tannic acid (TA) is reported to be effective against various types of chemical-induced toxicities and carcinogenesis as well. In the present study, we have evaluated the therapeutic potential of tannic acid in DMBA + croton oil-induced skin cancer in Swiss albino mice. Protective effect of TA against skin cancer was evaluated in terms of antioxidant enzymes activities, lipid peroxidation, histopathological changes and expression of inflammation and early tumour markers. DMBA + croton oil causes depletion of antioxidant enzymes (p < 0.001) and elevation of early inflammatory and tumour promotional events. TA prevents the DMBA + croton oil-induced toxicity through a protective mechanism that involves the reduction of oxidative stress as well as COX-2, i-NOS, PCNA protein expression and level of proinflammatory cytokine such as IL-6 release at a very significant level (p < 0.001). It could be concluded from our results that TA attenuates DMBA + croton oil-induced tumour promotional potential possibly by inhibiting oxidative and inflammatory responses and acts as antioxidant, anti-inflammatory and antiproliferative agent.

  17. Artificial sunlight and ultraviolet light induced photo-epoxidation of propylene over V-Ti/MCM-41 photocatalyst

    PubMed Central

    Nguyen, Van-Huy; Bai, Hsunling

    2014-01-01

    Summary The light irradiation parameters, including the wavelength spectrum and intensity of light source, can significantly influence a photocatalytic reaction. This study examines the propylene photo-epoxidation over V-Ti/MCM-41 photocatalyst by using artificial sunlight (Xe lamp with/without an Air Mass 1.5 Global Filter at 1.6/18.5 mW·cm−2) and ultraviolet light (Mercury Arc lamp with different filters in the range of 0.1–0.8 mW·cm−2). This is the first report of using artificial sunlight to drive the photo-epoxidation of propylene. Over V-Ti/MCM-41 photocatalyst, the propylene oxide (PO) formation rate is 193.0 and 112.1 µmol·gcat −1·h−1 with a PO selectivity of 35.0 and 53.7% under UV light and artificial sunlight, respectively. A normalized light utilization (NLU) index is defined and found to correlate well with the rate of both PO formation and C3H6 consumption in log–log scale. The light utilization with a mercury arc lamp is better than with a xenon lamp. The selectivity to PO remains practically unchanged with respect to NLU, suggesting that the photo-epoxidation occurs through the same mechanism under the conditions tested in this study. PMID:24991493

  18. Near-infrared spectroscopic studies of the hydrogen bonding between thioacetamide and N, N-disubstituted benzamide derivatives in CCl 4

    NASA Astrophysics Data System (ADS)

    Choi, Young Sang; Kim, Jeongkwon; Park, Jeunghee; Yu, Jeong-A.; Yoon, Chang-Ju

    1996-11-01

    The hydrogen bonding interactions between thioacetamide (TA) and several N, N-disubstituted benzamides ( N, N-dimethylbenzamide (DMBA), N-methoxy- N-methylbenzamide (MMBA), N, N-diethyl- m-toluamide (DEMT), and N, N-diethyl-2,5-difluorobenzamide (DEDF)) have been studied using near-infrared absorption spectroscopy. Thermodynamic parameters for the interactions between TA and benzamides were determined by analyzing the νN-Has + amide II combination band of TA. The - ΔH0 values, indicating the intrinsic strength of hydrogen bonding, are -17.4, -21.6, -21.9 and -20.8 kJ mol -1 for DMBA, MMBA, DEMT and DEDF, respectively. The results show that the inductive and resonance effects of substituents appear to influence the formation of hydrogen bonds.

  19. Immortalization of normal human fibroblasts by treatment with 4-nitroquinoline 1-oxide.

    PubMed

    Bai, L; Mihara, K; Kondo, Y; Honma, M; Namba, M

    1993-02-01

    Normal human fibroblasts (the OUMS-24 strain), derived from a 6-week-old human embryo, were transformed (into the OUMS-24F line) and immortalized by repeated treatments (59 times) with 4-nitroquinoline 1-oxide (4NQO). Treatment began during primary culture and ended at the 51st population doubling level (PDL). At the 57th PDL (146 days after the last treatment), morphologically altered, epithelial-type cells appeared, began to grow and became immortal (now past the 100th PDL). However, the control fibroblasts, which were not treated with 4NQO, senesced at the 62nd PDL. The finding that extensive, repeated treatments with 4NQO are required for the immortalization of normal human cells, indicates that multiple mutational events are involved in the immortalization of human cells in general. In other words, immortalization itself seems to be a multi-step process. Karyotypic analysis showed that many cells were hypodiploid before immortalization, but that afterwards chromosomes were distributed broadly in the diploid to tetraploid regions. The immortalized cells showed amplification and enhanced expression of c-myc. Two-dimensional electrophoretic analysis showed that the number of disappearing cellular proteins was greater than the number of the newly appearing ones after the cells became immortalized. Since the immortalized cells showed neither anchorage-independent growth nor tumorigenicity, they are useful for studying factors that can contribute to multi-step carcinogenesis in human cells. In addition, genetically matched normal (OUMS-24) and immortalized (OUMS-24F) cells will be useful for analyzing the genes related to cellular mortality and immortalization.

  20. Theoretical study of photoinduced epoxidation of olefins catalyzed by ruthenium porphyrin.

    PubMed

    Ishikawa, Atsushi; Sakaki, Shigeyoshi

    2011-05-12

    Epoxidation of olefin by [Ru(TMP)(CO)(O)](-) (TMP = tetramesitylporphine), which is a key step of the photocatalyzed epoxidation of olefin by [Ru(TMP)(CO)], is studied mainly with the density functional theory (DFT) method, where [Ru(Por)(CO)] is employed as a model complex (Por = unsubstituted porphyrin). The CASSCF method was also used to investigate the electronic structure of important species in the catalytic cycle. In all of the ruthenium porphyrin species involved in the catalytic cycle, the weight of the main configuration of the CASSCF wave function is larger than 85%, suggesting that the static correlation is not very large. Also, unrestricted-DFT-calculated natural orbitals are essentially the same as CASSCF-calculated ones, here. On the basis of these results, we employed the DFT method in this work. Present computational results show characteristic features of this reaction, as follows: (i) The epoxidation reaction occurs via carboradical-type transition state. Neither carbocation-type nor concerted oxene-insertion-type character is observed in the transition state. (ii) Electron and spin populations transfer from the olefin moiety to the porphyrin ring in the step of the C-O bond formation. (iii) Electron and spin populations of the olefin and porphyrin moieties considerably change around the transition state. (iv) The atomic and spin populations of Ru change little in the reaction, indicating that the Ru center keeps the +II oxidation state in the whole catalytic cycle. (v) The stability of the olefin adduct [Ru(Por)(CO)(O)(olefin)](-) considerably depends on the kind of olefin, such as ethylene, n-hexene, and styrene. In particular, styrene forms a stable olefin adduct. And, (vi) interestingly, the difference in the activation barrier among these olefins is small in the quantitative level (within 5 kcal/mol), indicating that this catalyst can be applied to various substrates. This is because the stabilities and electronic structures of both the

  1. Lipid Sulfates and Sulfonates Are Allosteric Competitive Inhibitors of the N-Terminal Phosphatase Activity of the Mammalian Soluble Epoxide Hydrolase†

    PubMed Central

    Tran, Katherine L.; Aronov, Pavel A.; Tanaka, Hiromasa; Newman, John W.; Hammock, Bruce D.; Morisseau, Christophe

    2006-01-01

    The EPXH2 gene encodes for the soluble epoxide hydrolase (sEH), a homodimeric enzyme with each monomer containing two domains with distinct activities. The C-terminal domain, containing the epoxide hydrolase activity (Cterm-EH), is involved in the metabolism of arachidonic acid epoxides, endogenous chemical mediators that play important roles in blood pressure regulation, cell growth, and inflammation. We recently demonstrated that the N-terminal domain contains a Mg2+-dependent lipid phosphate phosphatase activity (Nterm-phos). However, the biological role of this activity is unknown. The inability of known phosphatase inhibitors to inhibit the Nterm-phos constitutes a significant barrier to the elucidation of its function. We describe herein sulfate, sulfonate, and phosphonate lipids as novel potent inhibitors of Nterm-phos. These compounds are allosteric competitive inhibitors with KI in the hundred nanomolar range. These inhibitors may provide a valuable tool to investigate the biological role of the Nterm-phos. We found that polyisoprenyl phosphates are substrates of Nterm-phos, suggesting a possible role in sterol synthesis or inflammation. Furthermore, some of these compounds inhibit the C-terminal sEH activity through a noncompetitive inhibition mechanism involving a new binding site on the C-terminal domain. This novel site may play a role in the natural in vivo regulation of epoxide hydrolysis by sEH. PMID:16142916

  2. Synthesis of an Epoxide Carbonylation Catalyst: Exploration of Contemporary Chemistry for Advanced Undergraduates

    ERIC Educational Resources Information Center

    Getzler, Yutan D. Y. L.; Schmidt, Joseph A. R.; Coates, Geoffrey W.

    2005-01-01

    A class of highly active, well-defined compounds for the catalytic carbonylation of epoxides and aziridines to beta-lactones and beta-lactams are introduced. The synthesis of one of the catalysts involves a simple imine condensation to form the ligand followed by air-sensitive metalation and salt metathesis steps.

  3. Acute 7,12-dimethylbenz[a]anthracene exposure causes differential concentration-dependent follicle depletion and gene expression in neonatal rat ovaries

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Madden, Jill A.; Hoyer, Patricia B.; Devine, Patrick J.

    2014-05-01

    Chronic exposure to the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA), generated during combustion of organic matter including cigarette smoke, depletes all ovarian follicle types in the mouse and rat, and in vitro models mimic this effect. To investigate the mechanisms involved in follicular depletion during acute DMBA exposure, two concentrations of DMBA at which follicle depletion has (75 nM) and has not (12.5 nM) been observed were investigated. Postnatal day four F344 rat ovaries were maintained in culture for four days before a single exposure to vehicle control (1% DMSO; CT) or DMBA (12 nM; low-concentration or 75 nM; high-concentration). Aftermore » four or eight additional days of culture, DMBA-induced follicle depletion was evaluated via follicle enumeration. Relative to control, DMBA did not affect follicle numbers after 4 days of exposure, but induced large primary follicle loss at both concentrations after 8 days; while, the low-concentration DMBA also caused secondary follicle depletion. Neither concentration affected primordial or small primary follicle number. RNA was isolated and quantitative RT-PCR performed prior to follicle loss to measure mRNA levels of genes involved in xenobiotic metabolism (Cyp2e1, Gstmu, Gstpi, Ephx1), autophagy (Atg7, Becn1), oxidative stress response (Sod1, Sod2) and the phosphatidylinositol 3-kinase (PI3K) pathway (Kitlg, cKit, Akt1) 1, 2 and 4 days after exposure. With the exception of Atg7 and cKit, DMBA increased (P < 0.05) expression of all genes investigated. Also, BECN1 and pAKT{sup Thr308} protein levels were increased while cKIT was decreased by DMBA exposure. Taken together, these results suggest an increase in DMBA bioactivation, add to the mechanistic understanding of DMBA-induced ovotoxicity and raise concern regarding female low concentration DMBA exposures. - Highlights: • Acute DMBA exposures induce large primary and/or secondary follicle loss. • Acute DMBA exposure did not

  4. Impact of 7,12-dimethylbenz[a]anthracene exposure on connexin gap junction proteins in cultured rat ovaries

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    2014-01-15

    7,12-Dimethylbenz[a]anthracene (DMBA) destroys ovarian follicles in a concentration-dependent manner. The impact of DMBA on connexin (CX) proteins that mediate communication between follicular cell types along with pro-apoptotic factors p53 and Bax were investigated. Postnatal day (PND) 4 Fisher 344 rat ovaries were cultured for 4 days in vehicle medium (1% DMSO) followed by a single exposure to vehicle control (1% DMSO) or DMBA (12.5 nM or 75 nM) and cultured for 4 or 8 days. RT-PCR was performed to quantify Cx37, Cx43, p53 and Bax mRNA level. Western blotting and immunofluorescence staining were performed to determine CX37 or CX43 levelmore » and/or localization. Cx37 mRNA and protein increased (P < 0.05) at 4 days of 12.5 nM DMBA exposure. Relative to vehicle control-treated ovaries, mRNA encoding Cx43 decreased (P < 0.05) but CX43 protein increased (P < 0.05) at 4 days by both DMBA exposures. mRNA expression of pro-apoptotic p53 was decreased (P < 0.05) but no changes in Bax expression were observed after 4 days of DMBA exposures. In contrast, after 8 days, DMBA decreased Cx37 and Cx43 mRNA and protein but increased both p53 and Bax mRNA levels. CX43 protein was located between granulosa cells, while CX37 was located at the oocyte cell surface of all follicle stages. These findings support that DMBA exposure impacts ovarian Cx37 and Cx43 mRNA and protein prior to both observed changes in pro-apoptotic p53 and Bax and follicle loss. It is possible that such interference in follicular cell communication is detrimental to follicle viability, and may play a role in DMBA-induced follicular atresia. - Highlights: • DMBA increases Cx37 and Cx43 expression prior to follicle loss. • During follicle loss both Cx37 and Cx43 expressions are reduced. • CX43 protein is absent in follicle remnants lacking an oocyte.« less

  5. Rotational Spectrum and Large Amplitude Motions of 3,4-, 2,5- and 3,5-DIMETHYL-BENZALDEHYDE

    NASA Astrophysics Data System (ADS)

    Kleiner, I.; Tudorie, M.; Jahn, M.; Grabow, J.-U.; Goubet, M.

    2012-06-01

    The microwave spectra of the 3,4-, 2,5- and 3,5-Dimethyl-Benzaldehyde (DMBA) molecules have been recorded for the first time in the 2-26.5 GHz frequency range, using the COBRA-FTMW spectrometer in Hannover, with an instrumental uncertainty of 0.5 kHz for unblended lines. The experimental assignments and fits are supplemented by ab initio quantum chemical calculations,conformational energy landscape, and dipole moment components. The analysis of the spectra for the three isomers are in progress. The latest results, including spectroscopic constants and large amplitude motion parameters, will be presented. This investigation follows the study of the spectra of the 4-Methyl-Benzaldehyde molecule. The DMBA isomers belong to a similar series of molecules formally obtained by adding a second methyl group at the aromatic ring. These molecules serve as prototype systems for the development of the theoretical model of asymmetric top molecules having Cs symmetry while containing two inequivalent methyl tops (C3v), exhibiting different barrier heights and coupling terms to methyl internal rotation. Thus, the DMBA isomers represent benchmark species for testing the two-top internal rotors BELGI program written recently. Supported by the ANR-08-BLAN-0054 contract (France), the Deutsche Forschungsgemeinschaft, and the Land Niedersachsen (Germany). H. Saal, W. Caminati, I. Kleiner, A. R. Hight-Walker, J. T. Hougen, J.-U. Grabow, to be published. M. Tudorie, I. Kleiner, J. T. Hougen, S. Melandri, L. W. Sutikdja, W. Stahl, J. Mol. Spectrosc., 269 (2011), 211-225

  6. Lactobacillus salivarius REN inhibits rat oral cancer induced by 4-nitroquioline 1-oxide.

    PubMed

    Zhang, Ming; Wang, Fang; Jiang, Lu; Liu, Ruihai; Zhang, Lian; Lei, Xingen; Li, Jiyou; Jiang, Jingli; Guo, Huiyuan; Fang, Bing; Zhao, Liang; Ren, Fazheng

    2013-07-01

    Despite significant advances in cancer therapy, cancer-related mobility and mortality are still rising. Alternative strategies such as cancer prevention thus become essential. Probiotics represent an emerging option for cancer prevention, but studies are limited to colon cancers. The efficiency of probiotics in the prevention of other cancers and the correlative mechanism remains to be explored. A novel probiotics Lactobacillus salivarius REN (L. salivarius REN) was isolated from centenarians at Bama of China, which showed highly potent antigenotoxicity in an initial assay. 4-nitroquioline 1-oxide (4NQO)-induced oral cancer model was introduced to study the anticancer activity of L. salivarius REN in vivo. The results indicated that oral administration of probiotic L. salivarius REN or its secretions could effectively suppress 4NQO-induced oral carcinogenesis in the initial and postinitial stage, and the inhibition was in a dose-dependent manner. A significant decrease of neoplasm incidence (65%-0%) was detected in rats fed with the high dose of L. salivarius REN [5 × 10(10) CFU/kg body weight (bw)/d]. In vivo evidences indicated that the probiotics inhibited 4NQO-induced oral cancer by protecting DNA against oxidative damage and downregulating COX-2 expression. L. salivarius REN treatment significantly decreased the expression of proliferating cell nuclear antigen (PCNA) and induced apoptosis in a dose-dependent manner. Our findings suggest that probiotics may act as potential agents for oral cancer prevention. This is the first report showing the inhibitory effect of the probiotics on oral carcinogenesis. ©2013 AACR.

  7. A novel immunocompetent murine model for Candida albicans-promoted oral epithelial dysplasia

    PubMed Central

    DWIVEDI, P. P.; MALLYA, S.; DONGARI-BAGTZOGLOU, A.

    2009-01-01

    Candida albicans is a common opportunistic pathogen found in the oral mucosa. Clinical observations indicate a significant positive association between oral Candida carriage or infection and oral epithelial dysplasia/neoplasia. The aim of this study was to test whether C. albicans is able to promote epithelial dysplasia or carcinoma in a mouse model of infection where a carcinogen (4 Nitroquinoline 1-oxide [4NQO]) was used as initiator of neoplasia. Mice were divided into four groups: group 1 received 4NQO alone; group 2 received 4NQO followed by C. albicans (ATCC 90234); group 3 received vehicle dimethyl sulfoxide (DMSO) followed by C. albicans and group 4 was untreated. Although 4NQO treated mice did not develop oral lesions, mice exposed to both 4NQO and C. albicans developed oral dysplastic lesions 19 weeks after exposure to 4NQO. Mice challenged with C. albicans only developed hyperplastic lesions. The expression of Ki-67 and p16, two cell-cycle associated proteins that are frequently deregulated in oral dysplasia/neoplasia, was also tested in these lesions. Ki-67 and p16 expression increased from normal to hyperplastic to dysplastic mucosa and was highest in the group exposed to both 4NQO and C. albicans. In conclusion, we showed that C. albicans plays a role in the promotion of oral dysplasia in a mouse model of infection when 4NQO was used as initiator of oral neoplasia. PMID:18608888

  8. Asymmetric and symmetric triazenido cyclopalladated complexes: Synthesis, structural analysis and DFT calculations

    NASA Astrophysics Data System (ADS)

    Härter Vaniel, Ana Paula; Mauro, Antonio Eduardo; de Godoy Netto, Adelino Vieira; de Almeida, Eduardo Tonon; Piquini, Paulo Cesar; Zambiazi, Priscilla; Back, Davi Fernando; Hörner, Manfredo

    2015-03-01

    The reaction of [Pd{dmba}(μ-N3)]2 (dmba = N,N-dimethylbenzylamine) with 1-(2-fluorophenyl)-3-(4-nitrophenyl)triazenido (L1) or 1,3-bis(4-nitrophenyl)triazenido (L2) anions, in methanol, and subsequent treatment with pyridine (py) allows the preparation of the corresponding cyclopalladated compounds [Pd(dmba)(L1)(py)] (1) and [Pd(dmba)(L2)(py)]ṡpy (2). The acentric mononuclear entities of (1) and (2) are connected by weak intermolecular non-classical Csbnd H⋯C hydrogen bonds, which results in 2-D arrangements by translation, along the [1 0 0] and [0 0 1] crystallographic directions, respectively.

  9. Carbon nitride supported Fe2 cluster catalysts with superior performance for alkene epoxidation.

    PubMed

    Tian, Shubo; Fu, Qiang; Chen, Wenxing; Feng, Quanchen; Chen, Zheng; Zhang, Jian; Cheong, Weng-Chon; Yu, Rong; Gu, Lin; Dong, Juncai; Luo, Jun; Chen, Chen; Peng, Qing; Draxl, Claudia; Wang, Dingsheng; Li, Yadong

    2018-06-15

    Sub-nano metal clusters often exhibit unique and unexpected properties, which make them particularly attractive as catalysts. Herein, we report a "precursor-preselected" wet-chemistry strategy to synthesize highly dispersed Fe 2 clusters that are supported on mesoporous carbon nitride (mpg-C 3 N 4 ). The obtained Fe 2 /mpg-C 3 N 4 sample exhibits superior catalytic performance for the epoxidation of trans-stilbene to trans-stilbene oxide, showing outstanding selectivity of 93% at high conversion of 91%. Molecular oxygen is the only oxidant and no aldehyde is used as co-reagent. Under the same condition, by contrast, iron porphyrin, single-atom Fe, and small Fe nanoparticles (ca. 3 nm) are nearly reactively inert. First-principles calculations reveal that the unique reactivity of the Fe 2 clusters originates from the formation of active oxygen species. The general applicability of the synthesis approach is further demonstrated by producing other diatomic clusters like Pd 2 and Ir 2 , which lays the foundation for discovering diatomic cluster catalysts.

  10. Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats.

    PubMed

    Iyer, Abishek; Kauter, Kathleen; Alam, Md Ashraful; Hwang, Sung Hee; Morisseau, Christophe; Hammock, Bruce D; Brown, Lindsay

    2012-01-01

    The signs of metabolic syndrome following chronic excessive macronutrient intake include body weight gain, excess visceral adipose deposition, hyperglycaemia, glucose and insulin intolerances, hypertension, dyslipidaemia, endothelial damage, cardiovascular hypertrophy, inflammation, ventricular contractile dysfunction, fibrosis, and fatty liver disease. Recent studies show increased activity of soluble epoxide hydrolase (sEH) during obesity and metabolic dysfunction. We have tested whether sEH inhibition has therapeutic potential in a rat model of diet-induced metabolic syndrome. In these high-carbohydrate, high-fat-fed rats, chronic oral treatment with trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a potent sEH inhibitor, alleviated the signs of metabolic syndrome in vivo including glucose, insulin, and lipid abnormalities, changes in pancreatic structure, increased systolic blood pressure, cardiovascular structural and functional abnormalities, and structural and functional changes in the liver. The present study describes the pharmacological responses to this selective sEH inhibitor in rats with the signs of diet-induced metabolic syndrome.

  11. The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype

    PubMed Central

    Dalli, Jesmond; Zhu, Min; Vlasenko, Nikita A.; Deng, Bin; Haeggström, Jesper Z.; Petasis, Nicos A.; Serhan, Charles N.

    2013-01-01

    Maresins are produced by macrophages from docosahexaenoic acid (DHA) and exert potent proresolving and tissue homeostatic actions. Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid) is the first identified maresin. Here, we investigate formation, stereochemistry, and precursor role of 13,14-epoxy-docosahexaenoic acid, an intermediate in MaR1 biosynthesis. The 14-lipoxygenation of DHA by human macrophage 12-lipoxygenase (hm12-LOX) gave 14-hydro(peroxy)-docosahexaenoic acid (14-HpDHA), as well as several dihydroxy-docosahexaenoic acids, implicating an epoxide intermediate formation by this enzyme. Using a stereo-controlled synthesis, enantiomerically pure 13S,14S-epoxy-docosa-4Z,7Z,9E,11E,16Z,19Z-hexaenoic acid (13S,14S-epoxy-DHA) was prepared, and its stereochemistry was confirmed by NMR spectroscopy. When this 13S,14S-epoxide was incubated with human macrophages, it was converted to MaR1. The synthetic 13S,14S-epoxide inhibited leukotriene B4 (LTB4) formation by human leukotriene A4 hydrolase (LTA4H) ∼40% (P<0.05) to a similar extent as LTA4 (∼50%, P<0.05) but was not converted to MaR1 by this enzyme. 13S,14S-epoxy-DHA also reduced (∼60%; P<0.05) arachidonic acid conversion by hm12-LOX and promoted conversion of M1 macrophages to M2 phenotype, which produced more MaR1 from the epoxide than M1. Together, these findings establish the biosynthesis of the 13S,14S-epoxide, its absolute stereochemistry, its precursor role in MaR1 biosynthesis, and its own intrinsic bioactivity. Given its actions and role in MaR1 biosynthesis, this epoxide is now termed 13,14-epoxy-maresin (13,14-eMaR) and exhibits new mechanisms in resolution of inflammation in its ability to inhibit proinflammatory mediator production by LTA4 hydrolase and to block arachidonate conversion by human 12-LOX rather than merely terminating phagocyte involvement.—Dalli, J., Zhu, M., Vlasenko, N. A., Deng, B., Haeggström, J. Z., Petasis, N. A., Serhan, C. N. The novel 13S

  12. ULTRASOUND-ASSISTED EPOXIDATION OF OLEFINS AND A,B-UNSATURATED KETONES OVER HYDROTALCITES USING HYDROGEN PEROXIDE

    EPA Science Inventory

    An efficient ultrasound-assisted epoxidation of olefins and a,B-unsaturated ketones over hydrotacite catalysts in the presence of hydrogen peroxide and acetonitrile is described. This general and selective protocol is relatively fast and is applicable to a wide variety of substra...

  13. Exploiting epoxidized natural rubber latex (ENRL) as a starting raw material for latex-based products

    NASA Astrophysics Data System (ADS)

    Siti Nor Qamarina, M.; Fatimah Rubaizah, M. R.; Nurul Suhaira, A.; Norhanifah, M. Y.

    2017-12-01

    Epoxidized natural rubber latex (ENRL) is a chemically modified natural rubber latex produced from epoxidation process that involves usage of organic peracids. Conversion of the ENRL into dry rubber products has been known to exhibit many beneficial properties, however limited published works were found on diversifiying the ENRL latex-based products applications. In this preliminary work, different source of raw materials and neutralization systems were investigated. The objective was to explore possibilities in producing distinctive ENRL. Findings have demonstrated that different source of raw materials and neutralization systems influenced the typical ENRL specifications, stability behavior and particle size distribution. Morphological observations performed on these ENRL systems appeared to agree with the ENRL characteristics achieved. Since experimenting these two main factors resulted in encouraging ENRL findings, detailed work shall be further scrutinized to search for an optimum condition in producing marketable ENRL specifically for latex-based products applications.

  14. A Lewis acid β-diiminato-zinc-complex as all-rounder for co- and terpolymerisation of various epoxides with carbon dioxide.

    PubMed

    Reiter, M; Vagin, S; Kronast, A; Jandl, C; Rieger, B

    2017-03-01

    A β-diiminato-zinc-N(SiMe 3 ) 2 complex ( 1 ) was synthesised and fully characterised, including an X-ray diffraction study. The activity of catalyst 1 towards the coupling reaction of CO 2 and various epoxides, including propylene oxide (PO), cyclohexene oxide (CHO), styrene oxide (SO), limonene oxide (LO), octene oxide (OO) and epichlorohydrin (ECH), was investigated. Terpolymerisation of CO 2 , PO and LO, as well as CO 2 , CHO and PO, was successfully realised, resulting in polymers with adjustable glass transition temperatures and transparencies. Reaction conditions such as temperature, pressure and catalyst concentration were varied to find the optimal reaction values, especially regarding LO/CO 2 . In situ IR experiments hinted that at 60 °C and a critical LO concentration, polymerisation and depolymerisation are in an equilibrium (ceiling effect). Pressurising catalyst 1 with carbon dioxide resulted in a dimeric catalyst ( 2 ) with a OSiMe 3 group as a new initiator. Homopolymerisation of different epoxides was carried out in order to explain the reactivity concerning copolymerisation reaction of CO 2 and epoxides.

  15. The coupling of carbon dioxide and epoxides by phenanthroline derivatives containing different Cu(II) complexes as catalyst

    NASA Astrophysics Data System (ADS)

    Kilic, Ahmet; Palali, Ahmet Arif; Durgun, Mustafa; Tasci, Zeynep; Ulusoy, Mahmut

    2013-09-01

    A series of the mononuclear Cu(II) metal complexes containing the ligand Bdppz [(9a,13a-dihydro-4,5,9,14-tetraaza-benzo[b]triphenylene-11-yl)-phenyl-methanone] (L1) and Aqphen [(12,17-dihydronaphthol[2,3-h]dipyrido[3,2-a:2‧,3‧-c]-phenazine-12,17-dione)] (L2) were synthesized and used as catalyst for the coupling of carbon dioxide (CO2) and liquid epoxide which served as both reactant and solvent. Dimethylamino pyridine (DMAP) was used as co-catalyst. The yields of epoxides to corresponding cyclic carbonates were determined by comparing the ratio of product to substrate in the 1H NMR spectrum of an aliquot of the reaction mixture. The mononuclear Cu(II) complexes of these ligands were synthesized by treating an ethanol solvent of the appropriate ligand with a different molar amount of CuCl2·2H2O. The Cu(II) complexes were characterized by FT-IR, UV-Vis, elemental analysis, melting point analysis, mass spectra, molar conductivity measurements and magnetic susceptibility techniques. The reaction of the Bdppz and Aqphen ligands in a 1:1, 1:2 or 1:3 mole ratio with CuCl2·2H2O afforded ionic Cu(II) complexes in the presence of Et3N.

  16. 7,8-Dihydroxycoumarin exerts antitumor potential on DMBA-induced mammary carcinogenesis by inhibiting ERα, PR, EGFR, and IGF1R: involvement of MAPK1/2-JNK1/2-Akt pathway.

    PubMed

    Kumar, Abhishek; Sunita, Priyashree; Jha, Shivesh; Pattanayak, Shakti P

    2018-05-01

    Breast cancer (BC) is a persistent and impulsive metabolic disorder with the highest prevalence in women, worldwide. 7,12-Dimethylbenz(a)anthracene (DMBA) is a potent polyaromatic hydrocarbon (PAH)-based carcinogen producing mammary carcinomas in rats resembling the human hormone-dependent BC. 7,8-Dihydroxycoumarin (78DC) is a coumarin derivative that possesses diversified and favorable pharmacology profile to be considered in anticancer research against various malignancies. The present study was intended to investigate the antiproliferative and chemotherapeutic potentials of 78DC (20, 40, and 80 mg/kg BW) against DMBA (20 mg in olive oil)-induced mammary carcinoma Sprague-Dawley rats. We established the in silico approach for evaluation of the effect of 78DC on hormonal (estrogen receptor-α (ERα), progesterone receptor (PR)), growth factor receptors (EGFR and IGFR), 17β-hydroxysteroid dehydrogenase type 1 (17β-HD1), and aromatase. Effect of 78DC on estrogen synthesis, tumor growth, proliferation markers (Ki-67 and PCNA), cytokines (IL-10, IL-1β, IL-12), chemokine (MCP-1), and cellular expressions of ERα, PR, EGFR, IGF1R, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase was evaluated in mammary carcinoma bearing SD rats. DMBA induces large tumor burden and histological alterations in mammary gland with a subsequent increase in ERα, PR, EGFR, IGF1R, Ki-67, proliferating cell nuclear antigen (PCNA ), cytokines, and chemokine expressions. This was also correlated with the changes in rapid cell differentiation and proliferation. In contrast, 78DC treatment to the cancer-bearing animals abbreviated these changes and revealed to possess antitumorigenic and antiproliferative potentials. Further, a significant decrease in expressions of ERα, PR, EGFR, IGFR, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase signifies a reduction in estrogen sensitivity and secondary signaling pathways that may contribute to the prevention of tumor growth. The current

  17. Soluble epoxide hydrolase inhibitory activity of components from Leonurus japonicus.

    PubMed

    Leem, Hyun Hee; Lee, Ga Young; Lee, Ji Sun; Lee, Hanna; Kim, Jang Hoon; Kim, Young Ho

    2017-10-01

    One new compound, 10-methoxy-leonurine (1), and four known compounds (2-5) were purified by silica gel, C-18, and Sephadex LH-20 column chromatography from Leonurus japonicus. Their structures were elucidated using one-dimensional (1D)/two-dimensional (2D)-nuclear magnetic resonance (NMR), high-resolution (HR)-electrospray ionization (ESI) mass spectrometry (MS). The compounds were evaluated to determine their inhibition of the catalysis of soluble epoxide hydrolase (sEH). According to the results from in vitro analyses, compounds 1 and 2, which contain guanidine and flavonoid (3), were determined to be potential inhibitors of this enzyme. All compounds were revealed to be non-competitive inhibitors according to Lineweaver-Burk plots. Furthermore, in silico molecular docking indicated that compounds 1-3 are bound to sEH in a similar fashion and have stable binding energies, as calculated by AutoDock 4.2. Molecular dynamics determined the root-mean-square deviation (RMSD), total energy, RMS fluctuation (RMSF), hydrogen bonds, and distance of the complex according to time. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Natural Optical Activity of Chiral Epoxides: the Influence of Structure and Environment on the Intrinsic Chiroptical Response

    NASA Astrophysics Data System (ADS)

    Lemler, Paul M.; Craft, Clayton L.; Vaccaro, Patrick

    2017-06-01

    Chiral epoxides built upon nominally rigid frameworks that incorporate aryl substituents have been shown to provide versatile backbones for asymmetric syntheses designed to generate novel pharmaceutical and catalytic agents. The ubiquity of these species has motivated the present studies of their intrinsic (solvent-free) circular birefringence (CB), the measurement of which serves as a benchmark for quantum-chemical predictions of non-resonant chiroptical behavior and as a beachhead for understanding the often-pronounced mediation of such properties by environmental perturbations (e.g., solvation). The optical rotatory dispersion (or wavelength-resolved CB) of (R)-styrene oxide (R-SO) and (S,S)-phenylpropylene oxide (S-PPO) have been interrogated under ambient solvated and isolated conditions, where the latter efforts exploited the ultrasensitive techniques of cavity ring-down polarimetry. Both of the targeted systems display marked solvation effects as evinced by changes the magnitude and (in the case of R-SO) the sign of the extracted specific optical rotation, with the anomalously large response evoked from S-PPO distinguishing it from other members of the epoxide family. Linear-response calculations of dispersive optical activity have been performed at both density-functional and coupled-cluster levels of theory to unravel the structural and electronic origins of experimental findings, thereby suggesting the possible involvement of hindered torsional motion along dihedral coordinates adjoining phenyl and epoxide moieties.

  19. Efficient alkene epoxidation catalyzed by molybdenyl acetylacetonate supported on aminated UiO-66 metal-organic framework

    NASA Astrophysics Data System (ADS)

    Kardanpour, Reihaneh; Tangestaninejad, Shahram; Mirkhani, Valiollah; Moghadam, Majid; Mohammadpoor-Baltork, Iraj; Zadehahmadi, Farnaz

    2015-03-01

    Metal-organic frameworks (MOFs) containing Mo Schiff base complexes were prepared by post-synthesis method and applied as efficient catalysts in the epoxidation of alkenes with tert-BuOOH. In this manner, UiO-66-NH2 (UiO=University of Oslo) MOF was reacted with salicylaldehyde and thiophene-2-carbaldehyde to produce bidentate Schiff bases. Then, the Schiff base ligands were used for immobilization of molybdenyl acetylacetonate. These new catalysts were characterized by FT-IR, UV-vis spectroscopic techniques, X-ray diffraction (XRD), BET, inductively coupled plasma atomic emission spectroscopy (ICP-AES) and field emission scanning electron microscopy (FE-SEM). These catalytic systems showed excellent activity in the epoxidation of alkenes such as cyclic and linear ones with tert-butyl hydroperoxide (TBHP) in 1,2-dichloroethane, and reused several times without any appreciable loss of their activity.

  20. Genotoxicity studies of organically grown broccoli (Brassica oleracea var. italica) and its interactions with urethane, methyl methanesulfonate and 4-nitroquinoline-1-oxide genotoxicity in the wing spot test of Drosophila melanogaster.

    PubMed

    Heres-Pulido, María Eugenia; Dueñas-García, Irma; Castañeda-Partida, Laura; Santos-Cruz, Luis Felipe; Vega-Contreras, Viridiana; Rebollar-Vega, Rosa; Gómez-Luna, Juan Carlos; Durán-Díaz, Angel

    2010-01-01

    Broccoli (Brassica oleracea var. italica) has been defined as a cancer preventive food. Nevertheless, broccoli contains potentially genotoxic compounds as well. We performed the wing spot test of Drosophila melanogaster in treatments with organically grown broccoli (OGB) and co-treatments with the promutagen urethane (URE), the direct alkylating agent methyl methanesulfonate (MMS) and the carcinogen 4-nitroquinoline-1-oxide (4-NQO) in the standard (ST) and high bioactivation (HB) crosses with inducible and high levels of cytochrome P450s (CYPs), respectively. Larvae of both crosses were chronically fed with OGB or fresh market broccoli (FMB) as a non-organically grown control, added with solvents or mutagens solutions. In both crosses, the OGB added with Tween-ethanol yielded the expected reduction in the genotoxicity spontaneous rate. OGB co-treatments did not affect the URE effect, MMS showed synergy and 4-NQO damage was modulated in both crosses. In contrast, FMB controls produced damage increase; co-treatments modulated URE genotoxicity, diminished MMS damage, and did not change the 4-NQO damage. The high dietary consumption of both types of broccoli and its protective effects in D. melanogaster are discussed. Copyright 2009 Elsevier Ltd. All rights reserved.

  1. Thermal behavior of epoxidized cardanol diethyl phosphate as novel renewable plasticizer for poly(vinyl chloride)

    USDA-ARS?s Scientific Manuscript database

    A novel plasticizer, epoxidized cardanol diethyl phosphate (ECEP), based on cardanol was synthesized. Chemical structure of ECEP was characterized by fourier transform infrared (FTIR), 1H-nuclear magnetic resonance(1H NMR) and 13C-nuclear magnetic resonance(13C NMR) spectroscopy. Effects of ECEP sub...

  2. Quantitation of enantiomers of r-7,t-8,9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]-pyrene in human urine: evidence supporting metabolic activation of benzo[a]pyrene via the bay region diol epoxide.

    PubMed

    Hecht, Stephen S; Hochalter, Jon Bradley

    2014-09-01

    Benzo[a]pyrene (BaP), a potent polycyclic aromatic hydrocarbon carcinogen, is widely distributed in the human environment. All humans are exposed to BaP through the diet and contact with the general environment; cigarette smokers have higher exposure. An important pathway of BaP metabolism proceeds through formation of diol epoxides including the 'bay region diol epoxide' 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [BaP-(7R,8S)-diol-(9S,10R)-epoxide] and the 'reverse diol epoxide' 9S,10R-dihydroxy-7R,8S-epoxy-7,8,9,10-tetrahydrobenzo [a]pyrene [BaP-(9S,10R)-diol-(7R,8S)-epoxide]. The bay region diol epoxide is considered a major ultimate carcinogen of BaP based on studies in cell culture and laboratory animals, but the available data in humans are less convincing. The bay region diol epoxide and the reverse diol epoxide react with H2O to produce enantiomeric BaP-tetraols that are excreted in the urine. We used chiral stationary-phase high-performance liquid chromatography and gas chromatography-negative ion chemical ionisation-tandem mass spectrometry to quantify these enantiomeric BaP-tetraols in the urine of 25 smokers and 25 non-smokers. The results demonstrated that the BaP-tetraol enantiomer representing the carcinogenic bay region diol epoxide pathway accounted for 68±6% (range 56-81%) of total BaP-tetraol in smokers and 64±6% (range 46-78%) in non-smokers. Levels of the major BaP-tetraol enantiomer decreased by 75% in smokers who quit smoking. These data provide convincing evidence in support of the bay region diol epoxide mechanism of BaP carcinogenesis in humans. © The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Catalytic epoxidation activity of keplerate polyoxomolybdate nanoball toward aqueous suspension of olefins under mild aerobic conditions.

    PubMed

    Rezaeifard, Abdolreza; Haddad, Reza; Jafarpour, Maasoumeh; Hakimi, Mohammad

    2013-07-10

    Catalytic efficiency of a sphere-shaped nanosized polyoxomolybdate {Mo132} in the aerobic epoxidation of olefins in water at ambient temperature and pressure in the absence of reducing agent is exploited which resulted good-to-high yields and desired selectivity.

  4. Detection and characterization of human serum antibodies to polycyclic aromatic hydrocarbon diol-epoxide DNA adducts.

    PubMed Central

    Newman, M J; Light, B A; Weston, A; Tollurud, D; Clark, J L; Mann, D L; Blackmon, J P; Harris, C C

    1988-01-01

    The presence of serum antibodies to the diol-epoxide DNA adducts of representative polycyclic aromatic hydrocarbons (PAH), chrysene, benz[a]anthracene and benzo[a]pyrene, was determined by ELISA using serum samples obtained from normal healthy individuals. Antibodies that reacted against PAH adducted-DNA, but not against PAH-adducted protein, were found in the serum of approximately 40% of the test individuals. Specificity analysis of the antibodies demonstrated that serological cross-reactions between the benzo[a]pyrene and the chrysene diol-epoxide adducts were present. Similar cross-reactivity between the benz[a]anthracene and the chrysene adducts was observed. Sera containing antibodies that were apparently specific for each of the three PAH-DNA adducts were also identified. The presence of antibodies to PAH-DNA adducts indicates both past exposure to these carcinogenic PAH and their metabolic activation to the DNA damaging metabolites. These antibodies may prove to be useful in both retrospective and prospective epidemiological studies of various diseases associated with PAH exposure. PMID:3392204

  5. Direct characterization of cotton fabrics treated with di-epoxide by nuclear magnetic resonance.

    PubMed

    Xiao, Min; Chéry, Joronia; Keresztes, Ivan; Zax, David B; Frey, Margaret W

    2017-10-15

    A non-acid-based, di-functional epoxide, neopentyl glycol diglycidyl ether (NPGDGE), was used to modify cotton fabrics. Direct characterization of the modified cotton was conducted by Nuclear Magnetic Resonance (NMR) without grinding the fabric into a fine powder. NaOH and MgBr 2 were compared in catalyzing the reaction between the epoxide groups of NPGDGE and the hydroxyl groups of cellulose. Possible reaction routes were discussed. Scanning electron microscopy (SEM) images showed that while the MgBr 2 -catalyzed reaction resulted in self-polymerization of NPGDGE, the NaOH-catalyzed reaction did not. Fourier transform infrared spectroscopy (FTIR) showed that at high NaOH concentration cellulose restructures from allomorph I to II. NMR studies verified the incorporation of NPGDGE into cotton fabrics with a clear NMR signal, and confirmed that at higher NaOH concentration the efficiency of grafting of NPGDGE was increased. This demonstrates that use of solid state NMR directly on woven fabric samples can simultaneously characterize chemical modification and crystalline polymorph of cotton. No loss of tensile strength was observed for cotton fabrics modified with NPGDGE. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Fibroblasts from patients with hereditary cutaneous malignant melanoma are abnormally sensitive to the mutagenic effect of simulated sunlight and 4-nitroquinoline 1-oxide

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Howell, J.N.; Greene, M.H.; Corner, R.C.

    Because of a possible etiologic link between mutations and carcinogenesis, the authors compared fibroblasts derived from skin biopsies of several patients with hereditary cutaneous malignant melanoma and the dysplastic nevus syndrome for sensitivity to the mutagenic and/or cytotoxic effect of broad-spectrum simulated sunlight and of a UV mimetic carcinogen, 4-nitroquinoline 1-oxide (4NQO). The genetic marker was resistant to 6-thioguanine; loss of colony-forming ability was the assay for cytotoxicity. All five strains tested were more sensitive than normal to the killing effect of 4NQO (slopes of survival curves were 2- to 3-fold steeper), but only one strain was hypersensitive to killingmore » by Sun Lamp radiation. Two strains were tested for mutagenicity. The response of each to the mutagenic action of these agents corresponded to its response to cell killing. Both strains were hypermutable after exposure to 4NQO, but only one showed a higher than normal frequency of mutants induced by simulated sunlight. The finding that nonmalignant fibroblasts from patients with a hereditary variant of malignant fibroblasts from patients with a hereditary variant of malignant melanoma are abnormally susceptible to carcinogen-induced mutations suggests that hypersensitivity to mutagens contributes to risk of melanoma in patients. It also supports the somatic cell mutation hypothesis for the origin of cancer. 46 references, 3 figures.« less

  7. 40 CFR 721.10145 - Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Modified reaction products of alkyl... Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino compound... identified generically as modified reaction products of alkyl alcohol, halogenated alkane, substituted...

  8. 40 CFR 721.10145 - Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Modified reaction products of alkyl... Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino compound... identified generically as modified reaction products of alkyl alcohol, halogenated alkane, substituted...

  9. Determinants of reactivity and selectivity in soluble epoxide hydrolase from quantum mechanics/molecular mechanics modeling.

    PubMed

    Lonsdale, Richard; Hoyle, Simon; Grey, Daniel T; Ridder, Lars; Mulholland, Adrian J

    2012-02-28

    Soluble epoxide hydrolase (sEH) is an enzyme involved in drug metabolism that catalyzes the hydrolysis of epoxides to form their corresponding diols. sEH has a broad substrate range and shows high regio- and enantioselectivity for nucleophilic ring opening by Asp333. Epoxide hydrolases therefore have potential synthetic applications. We have used combined quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations (at the AM1/CHARMM22 level) and high-level ab initio (SCS-MP2) QM/MM calculations to analyze the reactions, and determinants of selectivity, for two substrates: trans-stilbene oxide (t-SO) and trans-diphenylpropene oxide (t-DPPO). The calculated free energy barriers from the QM/MM (AM1/CHARMM22) umbrella sampling MD simulations show a lower barrier for phenyl attack in t-DPPO, compared with that for benzylic attack, in agreement with experiment. Activation barriers in agreement with experimental rate constants are obtained only with the highest level of QM theory (SCS-MP2) used. Our results show that the selectivity of the ring-opening reaction is influenced by several factors, including proximity to the nucleophile, electronic stabilization of the transition state, and hydrogen bonding to two active site tyrosine residues. The protonation state of His523 during nucleophilic attack has also been investigated, and our results show that the protonated form is most consistent with experimental findings. The work presented here illustrates how determinants of selectivity can be identified from QM/MM simulations. These insights may also provide useful information for the design of novel catalysts for use in the synthesis of enantiopure compounds.

  10. Cooperation of NAD(P)H:quinone oxidoreductase 1 and UDP-glucuronosyltransferases reduces menadione cytotoxicity in HEK293 cells.

    PubMed

    Nishiyama, Takahito; Izawa, Tadashi; Usami, Mami; Ohnuma, Tomokazu; Ogura, Kenichiro; Hiratsuka, Akira

    2010-04-09

    Previous studies have shown that NAD(P)H:quinone oxidoreductase 1 (NQO1) plays an important role in the detoxification of menadione (2-methyl-1,4-naphthoquinone, also known as vitamin K3). However, menadiol (2-methyl-1,4-naphthalenediol) formed from menadione by NQO1-mediated reduction continues to be an unstable substance, which undergoes the reformation of menadione with concomitant formation of reactive oxygen species (ROS). Hence, we focused on the roles of phase II enzymes, with particular attention to UDP-glucuronosyltransferases (UGTs), in the detoxification process of menadione. In this study, we established an HEK293 cell line stably expressing NQO1 (HEK293/NQO1) and HEK293/NQO1 cell lines with doxycycline (DOX)-regulated expression of UGT1A6 (HEK293/NQO1/UGT1A6) and UGT1A10 (HEK293/NQO1/UGT1A10), and evaluated the role of NQO1 and UGTs against menadione-induced cytotoxicity. Our results differed from those of previous studies. HEK293/NQO1 was the most sensitive cell line to menadione cytotoxicity among cell lines established in this study. These phenomena were also observed in HEK293/NQO1/UGT1A6 and HEK293/NQO1/UGT1A10 cells in which the expression of UGT was suppressed by DOX treatment. On the contrary, HEK293/NQO1/UGT1A6 and HEK293/NQO1/UGT1A10 cells without DOX treatment were resistant to menadione-induced cytotoxicity. These results demonstrated that NQO1 is not a detoxification enzyme for menadione and that UGT-mediated glucuronidation of menadiol is the most important detoxification process. Copyright 2009 Elsevier Inc. All rights reserved.

  11. In-vivo characterization of endogenous porphyrin fluorescence from DMBA-treated Swiss Albino mice skin carcinogenesis for measuring tissue transformation

    NASA Astrophysics Data System (ADS)

    Ganesan, Singaravelu; Ebenezar, Jeyasingh; Hemamalini, Srinivasan; Aruna, Prakasa R.

    2002-05-01

    Steady state fluorescence spectroscopic characterization of endogenous porphyrin emission from DMBA treated skin carcinogenesis in Swiss albino mice was carried out. The emission of endogenous porphyrin from normal and abnormal skin tissues was studied both in the presence and absence of exogenous ALA to compare the resultant porphyrin emission characterictics. The mice skin is excited at 405nm and emission spectra are scanned from 430 to 700nm. The average fluorescence emission spectra of mice skin at normal and various tissues transformation conditions were found to be different. Two peaks around 460nm and 636nm were observed and they may be attributed to NADH, Elastin and collagen combination and endogenous porphyrin emission. The intensity at 636nm increases as the stage of the cancer increases. Although exogenous ALA enhances the PPIX level in tumor, the synthesis of PPIX was also found in normal surrounding skin, in fact, with higher concentration than that of tumor tissues.

  12. Epoxide pathways improve model predictions of isoprene markers and reveal key role of acidity in aerosol formation

    EPA Science Inventory

    Isoprene significantly contributes to organic aerosol in the southeastern United States where biogenic hydrocarbons mix with anthropogenic emissions. In this work, the Community Multiscale Air Quality model is updated to predict isoprene aerosol from epoxides produced under both ...

  13. Kinetic and Mechanistic Study of the pH-Dependent Activation (Epoxidation) of Prodrug Treosulfan Including the Reaction Inhibition in a Borate Buffer.

    PubMed

    Romański, Michał; Ratajczak, Whitney; Główka, Franciszek

    2017-07-01

    A prodrug treosulfan (T) undergoes a pH-dependent activation to epoxide derivatives. The process seems to involve an intramolecular Williamson reaction (IWR) but clear kinetic evidence is lacking. Moreover, a cis-diol system present in the T structure is expected to promote complexation with boric acid. As a result, the prodrug epoxidation would be inhibited; however, this phenomenon has not been investigated. In this article, the effect of pH on the kinetics of T conversion to its monoepoxide was studied from a mechanistic point of view. Also, the influence of boric acid on the reaction kinetics was examined. The rate constants observed for the activation of T (k obs ) in acetate, phosphate, and carbonate buffers satisfied the equation logk obs  = -7.48 + 0.96 pH. The reaction was inhibited in the excess of boric acid over T, and the k obs decreased with increasing borate buffer concentration. The experimental results were consistent with the inhibition model that included the formation of a tetrahedral, anionic T-boric acid monoester. To conclude, in nonborate buffers, the T activation to (2S,3S)-1,2-epoxybutane-3,4-diol 4-methanesulfonate follows IWR mechanism. A borate buffer changes the reaction kinetics and complicates kinetic analysis. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  14. FAD C(4a)-hydroxide stabilized in a naturally fused styrene monooxygenase

    PubMed Central

    Schlömann, Michael; van Berkel, Willem J.H.; Gassner, George T.

    2013-01-01

    StyA2B represents a new class of styrene monooxygenases that integrates flavin-reductase and styrene-epoxidase activities into a single polypeptide. This naturally-occurring fusion protein offers new avenues for studying and engineering biotechnologically relevant enantioselective biochemical epoxidation reactions. Stopped-flow kinetic studies of StyA2B reported here identify reaction intermediates similar to those reported for the separate reductase and epoxidase components of related two-component systems. Our studies identify substrate epoxidation and elimination of water from the FAD C(4a)-hydroxide as rate-limiting steps in the styrene epoxidation reaction. Efforts directed at accelerating these reaction steps are expected to greatly increase catalytic efficiency and the value of StyA2B as biocatalyst. PMID:24157359

  15. Soluble epoxide hydrolase activity and pharmacologic inhibition in horses with chronic severe laminitis.

    PubMed

    Guedes, A; Galuppo, L; Hood, D; Hwang, S H; Morisseau, C; Hammock, B D

    2017-05-01

    The roles of soluble epoxide hydrolase and lipid mediators in inflammatory and neuropathic pain could be relevant in laminitis pain management. To determine soluble epoxide hydrolase (sEH) activity in the digital laminae, sEH inhibitor potency in vitro, and efficacy of a sEH inhibitor as an adjunct analgesic therapy in chronic laminitic horses. In vitro experiments and clinical case series. sEH activity was measured in digital laminae from euthanised healthy and laminitic horses (n = 5-6/group). Potency of 7 synthetic sEH inhibitors was determined in vitro using equine liver cytosol. One of them (t-TUCB; 0.1 mg/kg bwt i.v. every 24 h) was selected based on potency and stability, and used as adjunct therapy in 10 horses with severe chronic laminitis (Obel grades 2, one horse; 3-4, nine horses). Daily assessments of forelimb lifts, pain scores, physiologic and laboratory examinations were performed before (baseline) and during t-TUCB treatment. Data are presented as mean ± s.d. and 95% confidence intervals (CI). sEH activity in the digital laminae from laminitic horses (0.9±0.6 nmol/min/mg; 95% CI 0.16-1.55 nmol/min/mg) was significantly greater (P = 0.01) than in healthy horses (0.17±0.09 nmol/min/mg; CI 0.07-0.26 nmol/min/mg). t-TUCB as an adjunct analgesic up to 10 days (4.3±3 days) in laminitic horses was associated with significant reduction in forelimb lifts (36±22%; 95% CI 9-64%) and in pain scores (18±23%; 95% CI 2-35%) compared with baseline (P = 0.04). One horse developed gas colic and another corneal vascularisation in a blind eye during treatment. No other significant changes were observed. Absence of control group and evaluator blinding in case series. sEH activity is significantly higher in the digital laminae of actively laminitic compared with healthy horses, and use of a potent inhibitor of equine sEH as adjunct analgesic therapy appears to decrease signs of pathologic pain in laminitic horses. © 2016 EVJ Ltd.

  16. EXPRESSION AND CHARACTERIZATION OF THE RECOMBINANT JUVENILE HORMONE EPOXIDE HYDROLASE (JHEH) FROM MANDUCA SEXTA. (R825433)

    EPA Science Inventory

    The cDNA of the microsomal Juvenile Hormone Epoxide Hydrolase (JHEH) from Manduca sexta was expressed in vitro in the baculovirus system. In insect cell culture, the recombinant enzyme (Ms-JHEH) was produced at a high level (100 fold over background EH catalytic activit...

  17. Stable and solubilized active Au atom clusters for selective epoxidation of cis-cyclooctene with molecular oxygen

    DOE PAGES

    Qian, Linping; Wang, Zhen; Beletskiy, Evgeny V.; ...

    2017-03-28

    Here, the ability of Au catalysts to effect the challenging task of utilizing molecular oxygen for the selective epoxidation of cyclooctene is fascinating. Although supported nanometre-size Au particles are poorly active, here we show that solubilized atomic Au clusters, present in ng ml –1 concentrations and stabilized by ligands derived from the oxidized hydrocarbon products, are active. They can be formed from various Au sources. They generate initiators and propagators to trigger the onset of the auto-oxidation reaction with an apparent turnover frequency of 440 s –1, and continue to generate additional initiators throughout the auto-oxidation cycle without direct participationmore » in the cycle. Spectroscopic characterization suggests that 7–8 atom clusters are effective catalytically. Extension of work based on these understandings leads to the demonstration that these Au clusters are also effective in selective oxidation of cyclohexene, and that solubilized Pt clusters are also capable of generating initiators for cyclooctene epoxidation.« less

  18. Stable and solubilized active Au atom clusters for selective epoxidation of cis-cyclooctene with molecular oxygen

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Qian, Linping; Wang, Zhen; Beletskiy, Evgeny V.

    Here, the ability of Au catalysts to effect the challenging task of utilizing molecular oxygen for the selective epoxidation of cyclooctene is fascinating. Although supported nanometre-size Au particles are poorly active, here we show that solubilized atomic Au clusters, present in ng ml –1 concentrations and stabilized by ligands derived from the oxidized hydrocarbon products, are active. They can be formed from various Au sources. They generate initiators and propagators to trigger the onset of the auto-oxidation reaction with an apparent turnover frequency of 440 s –1, and continue to generate additional initiators throughout the auto-oxidation cycle without direct participationmore » in the cycle. Spectroscopic characterization suggests that 7–8 atom clusters are effective catalytically. Extension of work based on these understandings leads to the demonstration that these Au clusters are also effective in selective oxidation of cyclohexene, and that solubilized Pt clusters are also capable of generating initiators for cyclooctene epoxidation.« less

  19. Electronic Structure Calculations of Ammonia Adsorption on Graphene and Graphene Oxide with Epoxide and Hydroxyl Groups

    NASA Astrophysics Data System (ADS)

    Nancy Anna Anasthasiya, A.; Khaneja, Mamta; Jeyaprakash, B. G.

    2017-10-01

    Ammonia adsorption on graphene (G) and graphene oxide (GO) was investigated through density functional theory calculations. In the GO system, the obtained binding energy, band gap, charge transfer and electronic structure revealed that the epoxide (GO-O) and hydroxyl groups (GO-OH) in GO enhance the NH3 adsorption, which leads to the chemisorption of NH3 on GO. The dissociation of NH3 to NH2 and formation of OH was also observed when the O and H atoms were separated at 0.985 Å, 1.019 Å, 1.035 Å, and 1.044 Å for various GO systems. The maximum charge transfer value was found to be 0.054 |e| with the binding energy of 1.143 eV for GO with a single epoxide (GO-1O) group. The charge transfer from NH3 to G or GO and the bond formation in this study agree with the reported experimental results.

  20. Chemopreventive activity of systemically administered curcumin on oral cancer in the 4-nitroquinoline 1-oxide model.

    PubMed

    Gonçalves, Vinícius de Paiva; Ortega, Adriana Alicia C; Guimarães, Morgana R; Curylofo, Fabiana Almeida; Rossa Junior, Carlos; Ribeiro, Daniel Araki; Spolidorio, Luis C

    2015-05-01

    Curcumin has therapeutic potential in preventing several types of cancer, including colon, liver, prostate, and breast. The goal of this study was to evaluate the chemopreventive activity of systemically administered curcumin on oral carcinogenesis induced by 4-nitroquinolone-1-oxide (4-NQO). A total of 50 male albino rats, Rattus norvegicus, (Holtzman), were divided into five groups (n = 10 per group). Four of these groups were exposed to 50 ppm 4-NQO in their drinking water ad libitum for 8 or 12 weeks, two groups were treated with curcumin by oral gavage at 30 or 100 mg/kg per day, and one group was treated with corn oil (vehicle) only. The negative control group was euthanized at baseline. Tongues of all animals were removed after euthanasia and used in the subsequent analysis because the tongue is the primary site of carcinogenesis in this model. Descriptive histological analysis and immunohistochemistry for PCNA, Bcl-2, SOCS1 e-3, and STAT3 were performed to assess the oncogenic process. The gene expression of Vimentin, E-cadherin, N-cadherin, or TWIST1 was assessed using RT-qPCR as a representative of epithelial-mesenchymal transition (EMT) events. The administration of curcumin at 100 mg/kg during the 12 weeks markedly decreased the expression of PCNA, Bcl-2, SOCS1 e -3, and STAT3. Curcumin also minimized the cellular atypia under microscopic analysis and diminished the expression of the genes associated with EMT. These findings demonstrate that the systemic administration of curcumin has chemopreventive activity during oral carcinogenesis induced by 4-NQO. © 2014 Wiley Periodicals, Inc.

  1. Enhanced metal loading in SBA-15-type catalysts facilitated by salt addition. Synthesis, characterization and catalytic epoxide alcoholysis activity of molybdenum incorporated porous silica

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Budhi, Sridhar; Peeraphatdit, Chorthip; Pylypenko, Svitlana

    2014-02-07

    We report a novel method to increase the metal loading in SBA-15 silica matrix via direct synthesis. It was demonstrated through the synthesis and characterization of a series of molybdenum containing SBA-15 mesoporous silica catalysts prepared with and without diammonium hydrogen phosphate (DHP) as an additive. Catalysts prepared with DHP show a 2–3 times increase in incorporation of molybdenum in the silica matrix and pore size enlargement. The synthesized catalysts were characterized using nitrogen sorption, X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and inductively coupled plasma–optical emission spectroscopy (ICP–OES). Themore » catalytic activity of catalysts prepared with DHP for alcoholysis of epoxides was superior than the catalyst prepared without DHP. Alcoholysis of epoxides was demonstrated for a range of alcohols and epoxides under ambient conditions in as little as 30 min with high selectivity.« less

  2. Lithium Diisopropylamide-Mediated Reactions of Imines, Unsaturated Esters, Epoxides, and Aryl Carbamates: Influence of Hexamethylphosphoramide and Ethereal Cosolvents on Reaction Mechanisms

    PubMed Central

    Ma, Yun

    2010-01-01

    Several reactions mediated by lithium diisopropylamide (LDA) with added hex-amethylphosphoramide (HMPA) are described. The N-isopropylimine of cyclohex-anone lithiates via an ensemble of monomer-based pathways. Conjugate addition of LDA/HMPA to an unsaturated ester proceeds via di- and tetra-HMPA-solvated dimers. Deprotonation of norbornene epoxide by LDA/HMPA proceeds via an intermediate metalated epoxide as a mixed dimer with LDA. Ortholithiation of an aryl carbamate proceeds via a mono-HMPA-solvated monomer-based pathway. Dependencies on THF and other ethereal cosolvents suggest that secondary-shell solvation effects are important in some instances. The origins of the inordinate mechanistic complexity are discussed. PMID:17985891

  3. Effect of mangrove black tea extract from Ceriops decandra (Griff.) on hematology and biochemical changes in dimethyl benz[a]anthracene-induced hamster buccal pouch carcinogenesis.

    PubMed

    Sithranga Boopathy, N; Kathiresan, K; Jeon, Y J

    2011-09-01

    Effect of the black tea extracted from a mangrove plant species, Ceriops decandra (Griff.) was studied on dimethyl benz[a]anthracene (DMBA)-induced changes in blood hematology and plasma non-enzymatic antioxidants in male hamsters. Hamsters were painted with 0.5% solution of DMBA in liquid paraffin on the right buccal pouch three times in a week up to 14 weeks. Each application treated with 0.4mg of DMBA. The mangrove black tea extract (MBTE) was administrated orally with 5mgkg(-1) twice a day and then with DMBA on alternate days. Results showed that the DMBA caused a significant (P<0.05) decline in the levels of reduced glutathione (GSH), vitamin-C, -E, red blood cells, hemoglobin, mean corpuscular volume and hematocrit; and increase in the levels of WBC, platelets, lymphocytes and neutrophils. The MBTE prevented the DMBA-induced adverse changes significantly in blood and biochemical parameters of the male hamsters. This work concluded that the black tea extracted from the coastal mangrove species C. decandra prevented the DMBA-induced buccal pouch carcinogenesis in hamsters. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Circadian time-dependent chemopreventive potential of withaferin-A in 7,12-dimethylbenz[a]anthracene-induced oral carcinogenesis.

    PubMed

    Manoharan, Shanmugam; Panjamurthy, Kuppusamy; Balakrishnan, Subramanian; Vasudevan, Kalaiarasan; Vellaichamy, Lakshmanan

    2009-01-01

    Circadian time-dependent treatment with chemotherapeutic drugs (chronotherapy) optimizes the therapeutic index by maximizing treatment efficacy and minimizing toxicity. The circadian time-dependent chemopreventive and anti-lipid peroxidative efficacy of withaferin-A in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis was investigated in the present study. We induced oral squamous cell carcinoma in the buccal pouches of golden Syrian hamsters during the day (4:00, 8:00, 12:00, 16:00, 20:00 and 24:00) by application of DMBA three times per week for 14 weeks. The circadian time-dependent tumor incidence, volume and burden were observed in hamsters treated with either DMBA alone or DMBA + withaferin-A. The circadian pattern of lipid peroxidation by-products, as measured by the formation of thiobarbituric acid reactive substances (TBARS) and enzymatic antioxidants [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], was also analyzed in the buccal mucosa of DMBA-treated hamsters. We found the highest incidence of tumor formation at 24.00 h in hamsters treated with DMBA alone as compared to other experimental groups. Circadian dysregulation of lipid peroxidation and antioxidant status was observed in DMBA-treated animals as compared to control animals. Oral (po) administration of withaferin-A (20 mg/kg) completely prevented the formation of tumors between 8.00 h and 12.00 h and synchronized the status of lipid peroxidation and antioxidants in the buccal mucosa of hamsters treated with DMBA alone. Also, oral administration of withaferin-A to DMBA-treated animals significantly reduced the formation of tumors and synchronized the status of lipid peroxidation and antioxidants in the rest of the time intervals. Our study thus suggests that withaferin-A has significant chemopreventive and anti-lipid peroxidative potential in DMBA-induced oral carcinogenesis, probably by interfering with DMBA-induced abnormal cell

  5. Radiation-Induced Carcinogenesis: Mechanistically Based Differences between Gamma-Rays and Neutrons, and Interactions with DMBA

    PubMed Central

    Shuryak, Igor; Brenner, David J.; Ullrich, Robert L.

    2011-01-01

    Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis. PMID:22194850

  6. Olefin Epoxidation by Methyltrioxorhenium: A Density Functional Study on Energetics and Mechanisms.

    PubMed

    Gisdakis, Philip; Antonczak, Serge; Köstlmeier, Sibylle; Herrmann, Wolfgang A; Rösch, Notker

    1998-09-04

    A spiro attack on a peroxo group is calculated to be the preferred reaction pathway for olefin epoxidation with the catalytic system CH 3 ReO 3 /H 2 O 2 (see picture). This finding is supported by density functional calculations on more than ten transition states for the most probable mechanisms. Hydration has significant effects on various reaction species: it stabilizes the intermediates and destabilizes, with one exception, the transition states. © 1998 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.

  7. Further characterization of benzo[a]pyrene diol-epoxide (BPDE)-induced comet assay effects.

    PubMed

    Bausinger, Julia; Schütz, Petra; Piberger, Ann Liza; Speit, Günter

    2016-03-01

    The present study aims to further characterize benzo[a]pyrene diol-epoxide (BPDE)-induced comet assay effects. Therefore, we measured DNA effects by the comet assay and adduct levels by high-performance liquid chromatography (HPLC) in human lymphocytes and A549 cells exposed to (±)-anti-benzo[a]pyrene-7,8-diol 9,10-epoxide [(±)-anti-BPDE] or (+)-anti-benzo[a]pyrene-7,8-diol 9,10-epoxide [(+)-anti-BPDE]. Both, the racemic form and (+)-anti-BPDE, which is the most relevant metabolite with regard to mutagenicity and carcinogenicity, induced DNA migration in cultured lymphocytes in the same range of concentrations to a similar extent in the alkaline comet assay after exposure for 2h. Nevertheless, (+)-anti-BPDE induced significantly enhanced DNA migration after 16 and 18h post-cultivation which was not seen in response to (±)-anti-BPDE. Combination of the comet assay with the Fpg (formamidopyrimidine-DNA glycosylase) protein did not enhance BPDE-induced effects and thus indicated the absence of Fpg-sensitive sites (oxidized purines, N7-guanine adducts, AP-sites). The aphidicolin (APC)-modified comet assay suggested significant excision repair activity of cultured lymphocytes during the first 18h of culture after a 2 h-exposure to BPDE. In contrast to these repair-related effects measured by the comet assay, HPLC analysis of stable adducts did not reveal any significant removal of (+)-anti-BPDE-induced adducts from lymphocytes during the first 22h of culture. On the other hand, HPLC measurements indicated that A549 cells repaired about 70% of (+)-anti-BPDE-induced DNA-adducts within 22h of release. However, various experiments with the APC-modified comet assay did not indicate significant repair activity during this period in A549 cells. The conflicting results obtained with the comet assay and the HPLC-based adduct analysis question the real cause for BPDE-induced DNA migration in the comet assay and the reliability of the APC-modified comet assay for the

  8. Chemo-Enzymatic Synthesis of Chiral Epoxides Ethyl and Methyl (S)-3-(Oxiran-2-yl)propanoates from Renewable Levoglucosenone: An Access to Enantiopure (S)-Dairy Lactone.

    PubMed

    Peru, Aurélien A M; Flourat, Amandine L; Gunawan, Christian; Raverty, Warwick; Jevric, Martyn; Greatrex, Ben W; Allais, Florent

    2016-07-29

    Chiral epoxides-such as ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((S)-1a/1b)-are valuable precursors in many chemical syntheses. Until recently, these compounds were synthesized from glutamic acid in four steps (deamination, reduction, tosylation and epoxide formation) in low to moderate overall yield (20%-50%). Moreover, this procedure requires some harmful reagents such as sodium nitrite ((eco)toxic) and borane (carcinogen). Herein, starting from levoglucosenone (LGO), a biobased chiral compound obtained through the flash pyrolysis of acidified cellulose, we propose a safer and more sustainable chemo-enzymatic synthetic pathway involving lipase-mediated Baeyer-Villiger oxidation, palladium-catalyzed hydrogenation, tosylation and treatment with sodium ethoxide/methoxide as key steps. This route afforded ethyl and methyl (S)-3-(oxiran-2-yl)propanoates in 57% overall yield, respectively. To demonstrate the potentiality of this new synthetic pathway from LGO, the synthesis of high value-added (S)-dairy lactone was undertaken from these epoxides and provided the target in 37% overall yield from LGO.

  9. ABT-510 is an effective chemopreventive agent in the mouse 4-nitroquinoline 1-oxide model of oral carcinogenesis.

    PubMed

    Hasina, Rifat; Martin, Leslie E; Kasza, Kristen; Jones, Colleen L; Jalil, Asif; Lingen, Mark W

    2009-04-01

    Despite numerous advances, the 5-year survival rate for head and neck squamous cell cancer (HNSCC) has remained largely unchanged. This poor outcome is due to several variables, including the development of multiple primary tumors. Therefore, it is essential to supplement early detection with preventive strategies. Using the 4-nitroquinoline 1-oxide (4-NQO) mouse model, we sought to define an appropriate dose and duration of administration that would predict the histologic timeline of HNSCC progression. Additionally, we sought to determine the timing of the onset of the angiogenic phenotype. Finally, using ABT-510 as a proof-of-principle drug, we tested the hypothesis that inhibitors of angiogenesis can slow/delay the development of HNSCC. We determined that 8 weeks of 100 microg/mL 4-NQO in the drinking water was the optimal dosage and duration to cause a sufficient incidence of hyperkeratoses, dysplasias, and HNSCC over a period of 32 weeks with minimal morbidity and mortality. Increased microvessel density and vascular endothelial growth factor expression in hyperkeratotic lesions provided evidence that the initiation of the angiogenic phenotype occurred before the development of dysplasia. Importantly, ABT-510 significantly decreased the overall incidence of HNSCC from 37.3% to 20.3% (P = 0.021) as well as the combined incidence of dysplasia and HNSCC from 82.7% to 50.6% (P < 0.001). These findings suggest that our refinement of the 4-NQO model allows for the investigation of the histologic, molecular, and biological alterations that occur during the premalignant phase of HNSCC. In addition, these data support the hypothesis that inhibitors of angiogenesis may be promising chemopreventive agents.

  10. ELONGATED UPPERMOST INTERNODE Encodes a Cytochrome P450 Monooxygenase That Epoxidizes Gibberellins in a Novel Deactivation Reaction in RiceW⃞

    PubMed Central

    Zhu, Yongyou; Nomura, Takahito; Xu, Yonghan; Zhang, Yingying; Peng, Yu; Mao, Bizeng; Hanada, Atsushi; Zhou, Haicheng; Wang, Renxiao; Li, Peijin; Zhu, Xudong; Mander, Lewis N.; Kamiya, Yuji; Yamaguchi, Shinjiro; He, Zuhua

    2006-01-01

    The recessive tall rice (Oryza sativa) mutant elongated uppermost internode (eui) is morphologically normal until its final internode elongates drastically at the heading stage. The stage-specific developmental effect of the eui mutation has been used in the breeding of hybrid rice to improve the performance of heading in male sterile cultivars. We found that the eui mutant accumulated exceptionally large amounts of biologically active gibberellins (GAs) in the uppermost internode. Map-based cloning revealed that the Eui gene encodes a previously uncharacterized cytochrome P450 monooxygenase, CYP714D1. Using heterologous expression in yeast, we found that EUI catalyzed 16α,17-epoxidation of non-13-hydroxylated GAs. Consistent with the tall and dwarfed phenotypes of the eui mutant and Eui-overexpressing transgenic plants, respectively, 16α,17-epoxidation reduced the biological activity of GA4 in rice, demonstrating that EUI functions as a GA-deactivating enzyme. Expression of Eui appeared tightly regulated during plant development, in agreement with the stage-specific eui phenotypes. These results indicate the existence of an unrecognized pathway for GA deactivation by EUI during the growth of wild-type internodes. The identification of Eui as a GA catabolism gene provides additional evidence that the GA metabolism pathway is a useful target for increasing the agronomic value of crops. PMID:16399803

  11. Assessment of epoxidized soy bean oil (ESBO) migrating into foods: comparison with ESBO-like epoxy fatty acids in our normal diet.

    PubMed

    Fankhauser-Noti, Anja; Fiselier, Katell; Biedermann-Brem, Sandra; Grob, Koni

    2006-08-01

    Epoxidized soy bean oil (ESBO) was found to be toxic for rats, but the toxic constituent is unknown. It became an issue as the migration from the gaskets in the lids for jars into oily foods regularly far exceeds the European legal limit (overall migration limit and specific migration limit derived from the tolerable daily intake (TDI)). In the context of risk management it was of interest to determine the epoxidized fatty acids of ESBO in those foods of our normal diet which are expected to contain the highest concentrations, i.e., oxidized edible oils (including degraded frying oils), fried foods, bakery ware and roasted meat. The contribution of epoxy oleic acid from ESBO to our diet turned out to be negligible. If this acid were the toxic component in ESBO, the toxicological assessment would primarily be a warning regarding oxidized fats and oils. The contribution of diepoxy linoleic acid from ESBO might be similar to the exposure from oxidized fats and oils of our diet, whereas the intake of triepoxy linolenic acid from ESBO exceeds that from normal food by around two orders of magnitude. Hence use of an epoxidized edible oil virtually free of linolenic acid would be inconspicuous in our diet.

  12. Expanding the Catalytic Triad in Epoxide Hydrolases and Related Enzymes.

    PubMed

    Amrein, Beat A; Bauer, Paul; Duarte, Fernanda; Janfalk Carlsson, Åsa; Naworyta, Agata; Mowbray, Sherry L; Widersten, Mikael; Kamerlin, Shina C L

    2015-10-02

    Potato epoxide hydrolase 1 exhibits rich enantio- and regioselectivity in the hydrolysis of a broad range of substrates. The enzyme can be engineered to increase the yield of optically pure products as a result of changes in both enantio- and regioselectivity. It is thus highly attractive in biocatalysis, particularly for the generation of enantiopure fine chemicals and pharmaceuticals. The present work aims to establish the principles underlying the activity and selectivity of the enzyme through a combined computational, structural, and kinetic study using the substrate trans -stilbene oxide as a model system. Extensive empirical valence bond simulations have been performed on the wild-type enzyme together with several experimentally characterized mutants. We are able to computationally reproduce the differences between the activities of different stereoisomers of the substrate and the effects of mutations of several active-site residues. In addition, our results indicate the involvement of a previously neglected residue, H104, which is electrostatically linked to the general base H300. We find that this residue, which is highly conserved in epoxide hydrolases and related hydrolytic enzymes, needs to be in its protonated form in order to provide charge balance in an otherwise negatively charged active site. Our data show that unless the active-site charge balance is correctly treated in simulations, it is not possible to generate a physically meaningful model for the enzyme that can accurately reproduce activity and selectivity trends. We also expand our understanding of other catalytic residues, demonstrating in particular the role of a noncanonical residue, E35, as a "backup base" in the absence of H300. Our results provide a detailed view of the main factors driving catalysis and regioselectivity in this enzyme and identify targets for subsequent enzyme design efforts.

  13. 7,12-dimethylbenz[a]anthracene-induced malignancies in a mouse model of menopause.

    PubMed

    Marion, Samuel L; Watson, Jennifer; Sen, Nivedita; Brewer, Molly A; Barton, Jennifer K; Hoyer, Patricia B

    2013-02-01

    Ovarian cancer has a high mortality rate because there are few symptoms in early disease development. The incidence of ovarian cancer increases in women after menopause. Understanding early events in this disease can best be achieved by using animal models. Therefore, the objective of this study was to develop and track the onset of ovarian tumorigenesis in mice mimicking characteristics of postmenopausal epithelial cancer in women. Female B6C3F1 mice (age, 28 d) received 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg IV daily for 20 d) to cause ovarian failure. Four months after VCD treatment, via surgical intervention, each mouse received a single injection of 7,12-dimethylbenz[a]anthracene (DMBA) or vehicle control (sesame oil) under the bursa of the right ovary to cause ovarian neoplasms. The experimental groups were untreated controls (Con-Con), DMBA-treatment only (Con-DMBA), VCD treatment only (VCD-Con), and VCD+DMBA-treated (VCD+DMBA) mice. At 3, 5, 7, and 9 mo after DMBA injection, ovaries were collected for histologic and immunohistochemical evaluation. No tumors developed in Con-Con mice. All VCD-treated mice (with or without DMBA) exhibited ovarian failure. Mice that received both VCD and DMBA exhibited tumors at 3 mo (50%), 5 mo (14%), 7 mo (90%), and 9 mo (57%) after DMBA treatment; 31% of the tumors were epithelial in origin. Our findings confirm that inducing ovarian tumors in mice by chemical means is an effective method for studying early stages of tumor development that may be relevant to epithelial ovarian cancers that arise in postmenopausal women.

  14. Structural insights into human microsomal epoxide hydrolase by combined homology modeling, molecular dynamics simulations, and molecular docking calculations.

    PubMed

    Saenz-Méndez, Patricia; Katz, Aline; Pérez-Kempner, María Lucía; Ventura, Oscar N; Vázquez, Marta

    2017-04-01

    A new homology model of human microsomal epoxide hydrolase was derived based on multiple templates. The model obtained was fully evaluated, including MD simulations and ensemble-based docking, showing that the quality of the structure is better than that of only previously known model. Particularly, a catalytic triad was clearly identified, in agreement with the experimental information available. Analysis of intermediates in the enzymatic mechanism led to the identification of key residues for substrate binding, stereoselectivity, and intermediate stabilization during the reaction. In particular, we have confirmed the role of the oxyanion hole and the conserved motif (HGXP) in epoxide hydrolases, in excellent agreement with known experimental and computational data on similar systems. The model obtained is the first one that fully agrees with all the experimental observations on the system. Proteins 2017; 85:720-730. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  15. Experimental verification, and domain definition, of structural alerts for protein binding: epoxides, lactones, nitroso, nitros, aldehydes and ketones.

    PubMed

    Nelms, M D; Cronin, M T D; Schultz, T W; Enoch, S J

    2013-01-01

    This study outlines how a combination of in chemico and Tetrahymena pyriformis data can be used to define the applicability domain of selected structural alerts within the profilers of the OECD QSAR Toolbox. Thirty-three chemicals were profiled using the OECD and OASIS profilers, enabling the applicability domain of six structural alerts to be defined, the alerts being: epoxides, lactones, nitrosos, nitros, aldehydes and ketones. Analysis of the experimental data showed the applicability domains for the epoxide, nitroso, aldehyde and ketone structural alerts to be well defined. In contrast, the data showed the applicability domains for the lactone and nitro structural alerts needed modifying. The accurate definition of the applicability domain for structural alerts within in silico profilers is important due to their use in the chemical category in predictive and regulatory toxicology. This study highlights the importance of utilizing multiple profilers in category formation.

  16. Extremely efficient crystallization of HKUST-1 and Keggin-loaded related phases through the epoxide route.

    PubMed

    Oestreicher, Víctor; Jobbágy, Matías

    2017-03-25

    Highly crystalline HKUST-1 and COK-16-like phases were obtained based on a mild in situ alkalinization one-pot epoxide driven method. A slurry composed of finely ground trimesic acid, H 3 BTC, dispersed in a CuCl 2 aqueous solution quantitatively developed well crystallized HKUST-1 after the addition of propylene oxide. The use of solid H 3 BTC ensures a low concentration of free linker, favoring crystalline growth over the precipitation of amorphous or metastable impurities. An extreme space-time yield of 2.1 × 10 5 kg m -3 day -1 was reached, with no linker excess and minimum use of solvent. The method was equally efficient in the achievement of pure NENU/COK-16 phases, containing [PW 12 O 40 ] 3- , [PMo 12 O 40 ] 3- and [SiMo 12 O 40 ] 4- polyoxometalates.

  17. Effects of 7,8-benzoflavone of skin tumor-initiating activities of various 7- and 12-substituted derivatives of 7,12-dimenthylbenz(a)anthracene in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    DiGiovanni, J.; Slaga, T.J.; Viaje, A.

    1978-07-01

    The skin tumor-initiating activities of various 7- and 12-substituted derivatives of 7,12-dimethylbenz(a)anthracene (DMBA) were investigated in female outbred Charles River CD-1 mice. 7-Formyl-12-methylbenz(a)anthracene (7-CHO-12-MBA) at 740 nmoles/mouse was an effective tumor initiator, at a dose 74-fold greater than that of DMBA. 7,8-Benzoflavone (7,8-BF) inhibited the tumor-initiating activity of 7-CHO-12-MBA by 51%. 12-Formyl-7-methylbenz(a)anthranene and 7,12-diformylbenz(a)anthracene, applied at initiating doses of 740 nmoles and 704 nmoles/mouse, respectively, were much less active than 7-CHO-12-MBA. 7-Bromomethyl-12-methylbenz(a)anthracene (7-BRME-12-MBA) and 7-bromomethylbenz(a)anthracene (7-BRMEBA) were also investigated. 7-BRME-12-MBA was a more effective tumor initiator than 7-BRMEBA, but both were less active than DMBA. 7,8-BF inhibited the tumor-initiating activitymore » of 7-BRME- 12-MBA and 7-BRMEBA by 34 and 54%, respectively. 12-Bromomethyl-7-methylbenz(a)anthracene (12-BRME-7-MBA) was as active an initiator as 7-BRME-12-MBA. 7,8-BF inhibited tumor initiation with 12-BRME-7-MBA by 29%. Three naturally occurring flavones, quercetin, myricetin, and 4',5,7-trihydroxyflavonone, and the cytochrome P/sub 450/, inhibitor 1-benzylimidazole were investigated after topical application(100 ..mu..g) for their effects on tumor initiation with DMBA. Quercetin inhibited tumor initiation with DMBA. Quercetin inhibited tumor initiation with DMBA by 22%, whereas myricetin and 4',5,7-trihydroxyflavanone enhanced tumor initiation with DMBA by 54 and 29%, respectively. 1-Benzylimidazole had no effect. The abilities of the flavones and 1-benzylimidazole to inhibit aryl hydrocarbon hydroxylase in vitro did not correlate with their effects on tumor initiation with DMBA.« less

  18. Impact of obesity on 7,12-dimethylbenz[a]anthracene-induced altered ovarian connexin gap junction proteins in female mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Nteeba, Jackson, E-mail: nteeba@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    The ovarian gap junction proteins alpha 4 (GJA4 or connexin 37; CX37), alpha 1 (GJA1 or connexin 43; CX43) and gamma 1 (GJC1 or connexin 45; CX45) are involved in cell communication and folliculogenesis. 7,12-dimethylbenz[a]anthracene (DMBA) alters Cx37 and Cx43 expression in cultured neonatal rat ovaries. Additionally, obesity has an additive effect on DMBA-induced ovarian cell death and follicle depletion, thus, we investigated in vivo impacts of obesity and DMBA on CX protein levels. Ovaries were collected from lean and obese mice aged 6, 12, 18, or 24 wks. A subset of 18 wk old mice (lean and obese) weremore » dosed with sesame oil or DMBA (1 mg/kg; ip) for 14 days and ovaries collected 3 days thereafter. Cx43 and Cx45 mRNA and protein levels decreased (P < 0.05) after 18 wks while Cx37 mRNA and protein levels decreased (P < 0.05) after 24 wks in obese ovaries. Cx37 mRNA and antral follicle protein staining intensity were reduced (P < 0.05) by obesity while total CX37 protein was reduced (P < 0.05) in DMBA exposed obese ovaries. Cx43 mRNA and total protein levels were decreased (P < 0.05) by DMBA in both lean and obese ovaries while basal protein staining intensity was reduced (P < 0.05) in obese controls. Cx45 mRNA, total protein and protein staining intensity level were decreased (P < 0.05) by obesity. These data support that obesity temporally alters gap junction protein expression and that DMBA-induced ovotoxicity may involve reduced gap junction protein function. - Highlights: • Ovarian gap junction proteins are affected by ovarian aging and obesity. • DMBA exposure negatively impacts gap junction proteins. • Altered gap junction proteins may contribute to infertility.« less

  19. Precursor effect on the property and catalytic behavior of Fe-TS-1 in butadiene epoxidation

    NASA Astrophysics Data System (ADS)

    Wu, Mei; Zhao, Huahua; Yang, Jian; Zhao, Jun; Song, Huanling; Chou, Lingjun

    2017-11-01

    The effect of iron precursor on the property and catalytic behavior of iron modified titanium silicalite molecular sieve (Fe-TS-1) catalysts in butadiene selective epoxidation has been studied. Three Fe-TS-1 catalysts were prepared, using iron nitrate, iron chloride and iron sulfate as precursors, which played an important role in adjusting the textural properties and chemical states of TS-1. Of the prepared Fe-TS-1 catalysts, those modified by iron nitrate (FN-TS-1) exhibited a significant enhanced performance in butadiene selective epoxidation compared to those derived from iron sulfate (FS-TS-1) or iron chloride (FC-TS-1) precursors. To obtain a deep understanding of their structure-performance relationship, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Temperature programmed desorption of NH3 (NH3-TPD), Diffuse reflectance UV-Vis spectra (DR UV-Vis), Fourier transformed infrared spectra (FT-IR) and thermal gravimetric analysis (TGA) were conducted to characterize Fe-TS-1 catalysts. Experimental results indicated that textural structures and acid sites of modified catalysts as well as the type of Fe species influenced by the precursors were all responsible for the activity and product distribution.

  20. Chloroquine Binding Reveals Flavin Redox Switch Function of Quinone Reductase 2*

    PubMed Central

    Leung, Kevin K. K.; Shilton, Brian H.

    2013-01-01

    Quinone reductase 2 (NQO2) is an FAD-linked enzyme and the only known human target of two antimalarial drugs, primaquine (PQ) and chloroquine (CQ). The structural differences between oxidized and reduced NQO2 and the structural basis for inhibition by PQ and CQ were investigated by x-ray crystallography. Structures of oxidized NQO2 in complex with PQ and CQ were solved at 1.4 Å resolution. CQ binds preferentially to reduced NQO2, and upon reduction of NQO2-CQ crystals, the space group changed from P212121 to P21, with 1-Å decreases in all three unit cell dimensions. The change in crystal packing originated in the negative charge and 4–5º bend in the reduced isoalloxazine ring of FAD, which resulted in a new mode of CQ binding and closure of a flexible loop (Phe126–Leu136) over the active site. This first structure of a reduced quinone reductase shows that reduction of the FAD cofactor and binding of a specific inhibitor lead to global changes in NQO2 structure and is consistent with a functional role for NQO2 as a flavin redox switch. PMID:23471972

  1. 40 CFR 63.1427 - Process vent requirements for processes using extended cookout as an epoxide emission reduction...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... = Concentration of epoxide in the reactor liquid at the beginning of the time period, weight percent. k = Reaction rate constant, 1/hr. t = Time, hours. Note: This equation assumes a first order reaction with respect... process knowledge, reaction kinetics, and engineering knowledge, in accordance with paragraph (a)(2)(i) of...

  2. 40 CFR 63.1427 - Process vent requirements for processes using extended cookout as an epoxide emission reduction...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... = Concentration of epoxide in the reactor liquid at the beginning of the time period, weight percent. k = Reaction rate constant, 1/hr. t = Time, hours. Note: This equation assumes a first order reaction with respect... process knowledge, reaction kinetics, and engineering knowledge, in accordance with paragraph (a)(2)(i) of...

  3. Modulatory efficacy of green tea polyphenols on glycoconjugates and immunological markers in 4-Nitroquinoline 1-oxide-induced oral carcinogenesis-A therapeutic approach.

    PubMed

    Srinivasan, Periasamy; Sabitha, Kuruvimalai Ekambaram; Shyamaladevi, Chennam Srinivasulu

    2006-08-25

    Green tea polyphenols (GTP) has been used as a chemopreventive agent world wide against chemically induced cancer. The present study is aimed to understand the therapeutic action of GTP on glycoconjugates and immunological markers in 4-Nitroquinoline 1-oxide (4-NQO)-induced oral cancer over a period of 30 days at 200mg/kg, p.o., Oral cancer was induced by painting 4-NQO for 8 weeks followed by administration of GTP after 22 weeks, for 30 days. Glycoconjugates such as hexose, hexosamine, sialicacid, fucose and mucoprotein were analysed. Expression of glycoconjugates was examined through histology and SDS-PAGE. Immunological markers such as circulating immune complex and mast cell density were studied. Oral cancer-induced animals showed a significant increase in levels of glycoconjugates and its expression, similar to that observed for immunological markers. Treatment with GTP altered the expression of glycoconjugates as well as immunological markers. The results suggest that GTP modulates both the expression of glycoconjugates and immunological markers resulting in regression of oral cancer.

  4. Epoxy Resins Toughened with Surface Modified Epoxidized Natural Rubber Fibers by One-Step Electrospinning.

    PubMed

    Kim, Joo Ran; Kim, Jung J

    2017-04-27

    Epoxidized natural rubber fibers (ERFs) are developed through one-step electrospinning and directly deposited into epoxy resins without collecting and distributing of fibers. The shape of ERFs shows rough surface due to different evaporation rate of solvent mixture consisting of chloroform and dichloromethane and the average diameter of ERFs is 6.2 µm. The increase of ERFs loading from 0 to 20 wt % into the epoxy resin increases the fracture strain significantly from 1.2% to 13% and toughness from 0.3 MPa to 1.9 MPa by a factor of 7. However, the tensile strength and Young's modulus decrease about 34% from 58 MPa to 34 MPa and from 1.4 GPa to 0.9 GPa, respectively. Due to the crosslinking reactions between oxirane groups of ERFs and amine groups in the resin, surface roughness and the high aspect ratio of ERFs, ERFs result in more effective toughening effect with the minimum loss of tensile properties in epoxy resins.

  5. Epoxy Resins Toughened with Surface Modified Epoxidized Natural Rubber Fibers by One-Step Electrospinning

    PubMed Central

    Kim, Joo Ran; Kim, Jung J.

    2017-01-01

    Epoxidized natural rubber fibers (ERFs) are developed through one-step electrospinning and directly deposited into epoxy resins without collecting and distributing of fibers. The shape of ERFs shows rough surface due to different evaporation rate of solvent mixture consisting of chloroform and dichloromethane and the average diameter of ERFs is 6.2 µm. The increase of ERFs loading from 0 to 20 wt % into the epoxy resin increases the fracture strain significantly from 1.2% to 13% and toughness from 0.3 MPa to 1.9 MPa by a factor of 7. However, the tensile strength and Young’s modulus decrease about 34% from 58 MPa to 34 MPa and from 1.4 GPa to 0.9 GPa, respectively. Due to the crosslinking reactions between oxirane groups of ERFs and amine groups in the resin, surface roughness and the high aspect ratio of ERFs, ERFs result in more effective toughening effect with the minimum loss of tensile properties in epoxy resins. PMID:28772822

  6. 7,12-Dimethylbenz[a]anthracene-Induced Malignancies in a Mouse Model of Menopause

    PubMed Central

    Marion, Samuel L; Watson, Jennifer; Sen, Nivedita; Brewer, Molly A; Barton, Jennifer K; Hoyer, Patricia B

    2013-01-01

    Ovarian cancer has a high mortality rate because there are few symptoms in early disease development. The incidence of ovarian cancer increases in women after menopause. Understanding early events in this disease can best be achieved by using animal models. Therefore, the objective of this study was to develop and track the onset of ovarian tumorigenesis in mice mimicking characteristics of postmenopausal epithelial cancer in women. Female B6C3F1 mice (age, 28 d) received 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg IV daily for 20 d) to cause ovarian failure. Four months after VCD treatment, via surgical intervention, each mouse received a single injection of 7,12-dimethylbenz[a]anthracene (DMBA) or vehicle control (sesame oil) under the bursa of the right ovary to cause ovarian neoplasms. The experimental groups were untreated controls (Con–Con), DMBA-treatment only (Con–DMBA), VCD treatment only (VCD–Con), and VCD+DMBA-treated (VCD+DMBA) mice. At 3, 5, 7, and 9 mo after DMBA injection, ovaries were collected for histologic and immunohistochemical evaluation. No tumors developed in Con–Con mice. All VCD-treated mice (with or without DMBA) exhibited ovarian failure. Mice that received both VCD and DMBA exhibited tumors at 3 mo (50%), 5 mo (14%), 7 mo (90%), and 9 mo (57%) after DMBA treatment; 31% of the tumors were epithelial in origin. Our findings confirm that inducing ovarian tumors in mice by chemical means is an effective method for studying early stages of tumor development that may be relevant to epithelial ovarian cancers that arise in postmenopausal women. PMID:23561932

  7. Reduction of the 20-Carbonyl Group of C-21 Steroids by Spores of Fusarium solani and Other Microorganisms. I. Side-Chain Degradation, Epoxide Cleavage, and Substrate Specificity

    PubMed Central

    Plourde, Rosaire; El-Tayeb, Ossama M.; Hafez-Zedan, Hamdallah

    1972-01-01

    The spores of Fusarium solani reduced the C2-carbonyl group, 1-dehydrogenated ring „A” and cleaved the side chain of 16α, 17α-oxidopregn-4-ene-3, 20-dione (16α, 17α-oxidoprogesterone)(I) to give the following products: 20α-hydroxy-16α, 17α-oxidopregn-4-en-3-one(II); 20α-hydroxy-16α, 17α-oxidopregna-1, 4-dien-3-one(III); 16α-hydroxy-17a-oxa-androsta-1, 4-diene-3, 17-dione (16α-hydroxy-1-dehydrotestololactone)(IV); and 16α, 17β-dihydroxy-androsta-1, 4-dien-3-one (16α-hydroxy-1-dehydrotestosterone)(V). When II was used as a substrate, it was metabolized into III, IV, and V at a slower rate than I. Furthermore, 16α-hydroxy-androst-4-ene-3, 17-dione (16α-hydroxyandrostenedione)(X) was transformed into IV and V. Pregn-4-ene-3, 20-dione (progesterone)(XII) was transformed into androsta-1, 4-diene-3, 17-dione (androstadienedione)(VIII) and 17a-oxa-androsta-1, 4-diene-3, 17-dione (1-dehydrotestololactone)(IX), while 17α-hydroxy-pregn-4-ene-3, 20-dione (17α-hydroxyprogesterone)(VI) was converted into its 1-dehydro analogue (VII) without accumulation of any 20-dihydro compounds. Substrate specificity in the 20-reductase system of F. solani, Cylindrocarpon radicicola, Septomyxa affinis, Bacillus lentus, and three strains of B. sphaericus are demonstrated. The 20-reductase is active only on steroids having the 16α, 17α-oxido, and Δ4-3-keto functions. Evidence of competition between side-chain degrading enzymes and the 20-reductase for the steroid molecule and evidence of side-chain degradation followed by epoxide cleavage (and not the reverse) are presented. A mechanism for the epoxide opening by nongerminating spores of F. solani is postulated. PMID:5021973

  8. Collapse of the native structure caused by a single amino acid exchange in human NAD(P)H:quinone oxidoreductase(1.).

    PubMed

    Lienhart, Wolf-Dieter; Gudipati, Venugopal; Uhl, Michael K; Binter, Alexandra; Pulido, Sergio A; Saf, Robert; Zangger, Klaus; Gruber, Karl; Macheroux, Peter

    2014-10-01

    Human quinone oxidoreductase 1 (NQO1) is essential for the antioxidant defense system, stabilization of tumor suppressors (e.g. p53, p33, and p73), and activation of quinone-based chemotherapeutics. Overexpression of NQO1 in many solid tumors, coupled with its ability to convert quinone-based chemotherapeutics into potent cytotoxic compounds, have made it a very attractive target for anticancer drugs. A naturally occurring single-nucleotide polymorphism (C609T) leading to an amino acid exchange (P187S) has been implicated in the development of various cancers and poor survival rates following anthracyclin-based adjuvant chemotherapy. Despite its importance for cancer prediction and therapy, the exact molecular basis for the loss of function in NQO1 P187S is currently unknown. Therefore, we solved the crystal structure of NQO1 P187S. Surprisingly, this structure is almost identical to NQO1. Employing a combination of NMR spectroscopy and limited proteolysis experiments, we demonstrated that the single amino acid exchange destabilized interactions between the core and C-terminus, leading to depopulation of the native structure in solution. This collapse of the native structure diminished cofactor affinity and led to a less competent FAD-binding pocket, thus severely compromising the catalytic capacity of the variant protein. Hence, our findings provide a rationale for the loss of function in NQO1 P187S with a frequently occurring single-nucleotide polymorphism. Structural data are available in the Protein Data Bank under the accession numbers 4cet (P187S variant with dicoumarol) and 4cf6 (P187S variant with Cibacron blue). NQO1 P187S and NQO1 P187S bind by nuclear magnetic resonance (View interaction) NQO1 P187S and NQO1 P187S bind by x-ray crystallography (1, 2) NQO1 and NQO1 bind by molecular sieving (1, 2). © 2014 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS.

  9. Modulation of miR-203 and its regulators as a function of time during the development of 7, 12 dimethylbenz [a] anthracene induced mouse skin tumors in presence or absence of the antitumor agents

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tiwari, Prakash; Gupta, Krishna P., E-mail: krishnag522@yahoo.co.in

    2014-07-15

    We investigated the chemopreventive effects of naturally occurring compounds like butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) individually or in combination in 7, 12-dimethylbenz [a] anthracene (DMBA) treated mouse skin at 4 and 16 weeks, the time before and after the tumor development. DMBA application did not show any skin tumors at 4 weeks but well defined tumors appeared at 16 weeks. BA, NA or CAG prevented the tumor development significantly but the protection was highly enhanced when all these compounds were given together. In order to see the molecular changes progressing with tumors, we showed the downregulationmore » of tumor suppressor miR-203 at 16 weeks and upregulation of histone deacetylases (HDAC), DNA methyltransferase, promoter methylation of miR-203 at 4 or 16 weeks. Regulators of micro RNA biogenesis such as DICER1 and Ago2 were also deregulated by DMBA. Proto-oncogene c-myc and BMI1 were upregulated and tumor suppressor gene p16 was downregulated by DMBA as a function of time. Effects of BA, NA or CAG were more pronounced after 16 weeks as compared to 4 weeks in preventing the tumor development and altered gene expression. Concomitant administration of BA, NA and CAG tried to prevent these alterations more effectively than that of individual compound possibly by regulating miR-203 status through epigenetic or biogenetic modulations before and after the tumor development. Study provides a rationale for chemoprevention by combination of different compounds targeting miR-203. - Highlights: • DMBA modulates miR-203 and its regulator before and after the onset of tumors. • Suppression of miR-203 and p16 could be the result of gene promoter methylation. • BA, NA or CAG prevents the effects of DMBA. • Combination of BA, NA or CAG is more effective in preventing the DMBA modulations.« less

  10. 3-D QSAR ANALYSIS OF INHIBITION OF MURINE SOLUBLE EPOXIDE HYDROLASE (MSEH) BY BENZOYLUREAS, ARYLUREAS, AND THEIR ANALOGUES. (R825433)

    EPA Science Inventory

    Two hundred and seventy-one compounds including benzoylureas, arylureas and related compounds were assayed using recombinant murine soluble epoxide hydrolase (MsEH) produced from a baculovirus expression system. Among all the insect growth regulators assayed, 18 benzoylphenylu...

  11. α-Mangostin inhibits DMBA/TPA-induced skin cancer through inhibiting inflammation and promoting autophagy and apoptosis by regulating PI3K/Akt/mTOR signaling pathway in mice.

    PubMed

    Wang, Fei; Ma, Hongxia; Liu, Zhaoguo; Huang, Wei; Xu, Xiaojing; Zhang, Xuemei

    2017-08-01

    Skin cancer is the most common form of cancer responsible for considerable morbidity and mortality, the treatment progress of which remains slow though. Therefore, studies identifying anti-skin cancer agents that are innocuous are urgently needed. α-Mangostin, a natural product isolated from the pericarp of mangosteen fruit, has potent anti-cancer activity. However, its role in skin cancer remains unclear. The aim of this study was to evaluate the treatment effect of α-mangostin on skin tumorigenesis induced by 9,10-dimethylbenz[a]anthracene (DMBA)/TPA in mice and the potential mechanism. Treatment with α-mangostin significantly suppressed tumor formation and growth, and markedly reduced the incidence rate. α-Mangostin not only inhibited the expressions of pro-inflammatory factors, but also promoted the production of anti-inflammatory factors in tumor and blood. It induced autophagy of skin tumor and regulated the expressions of autophagy-related proteins. The protein expressions of LC3, LC3-II and Beclin1 increased whereas those of LC3-I and p62 decreased after treatment with α-mangostin. Moreover, α-mangostin promoted the apoptosis of skin tumor dose-dependently by up-regulating of Bax, cleaved caspase-3, cleaved PARP and Bad, and down-regulating of Bcl-2 and Bcl-xl. Furthermore, showed α-mangostin inhibited the PI3K/AKT/mTOR (mammalian target of rapamycin) signaling pathway, as evidenced by decreased expressions of phospho-PI3K (p-PI3K), p-Akt and p-mTOR, but did not affect the expressions of t-PI3K, t-Akt or t-mTOR. Collectively, α-mangostin suppressed murine skin tumorigenesis induced by DMBA/TPA through inhibiting inflammation and promoting autophagy and apoptosis by regulating the PI3K/Akt/mTOR signaling pathway, as a potential candidate for future clinical therapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Carbamazepine and its 10,11-epoxide metabolite in acute mania: clinical and pharmacokinetic correlates.

    PubMed

    Petit, P; Lonjon, R; Cociglio, M; Sluzewska, A; Blayac, J P; Hue, B; Alric, R; Pouget, R

    1991-01-01

    The study was designed to investigate the antimanic profile of carbamazepine as a first-line drug in affective or schizoaffective disorders, to correlate the clinical efficacy with the plasma level of carbamazepine and its 10,11-epoxide metabolite, and to test the potential value of monitoring the salivary level. It was administered alone for 3 weeks to 21 acute manic inpatients. During the first week, the dosage was rapidly increased to 800 mg/day in order to produce steady-state plasma levels of carbamazepine on Day 7. The individual dose was then adjusted to maintain the therapeutic range of 8-12 mg/l. Plasma and saliva levels of the drug and its metabolite, as well as clinical status were assessed weekly. Overall, there was 62% globally improved patients and 77% in affective disorders. The improvement of manic symptoms was significantly lower in schizoaffective than in affective disorders, whereas the dropout rate and the need for antipsychotic medication was higher in the former group. The antimanic response was significantly correlated with the plasma levels both of carbamazepine and its epoxide metabolite, with a time-lag consistent with a delayed drug effect. Drug and metabolite concentrations in saliva were close to their plasma free fraction and were strongly correlated with their plasma levels, suggesting the potential value of salivary drug monitoring.

  13. Anti-tumorigenic effect of nano formulated peptide pACC1 by diminishing de novo lipogenisis in DMBA induced mammary carcinoma rat model.

    PubMed

    Kaliaperumal, Jagatheesh; Padarthi, Pavankumar; Elangovan, Namasivayam; Hari, Natarajan

    2014-07-01

    At present, the majority of established treatments for breast cancer are based on clinical manifestations, some fundamental of molecular and cellular biology of cancer. In recent times, the therapy is moving towards personalized medicines. Nevertheless, both the methodologies have own demerits. In the present study, we proposed a novel idea of targeted therapy with twin pharmacological potential by a peptide pACC1. The peptide was formulated with chitosan and evaluated with DMBA induced mammary carcinoma. Results suggest that the peptide holds great control on tumor cell multiplication, fatty acid synthesis and lactate levels. In addition, peptide also brings normal metabolic signs in glycolytic and glycogenic pathways. Histological studies confirm the dual pharmacological actions. Further, it is also proven that the peptide controls membrane receptor levels of HER2 and EGFR. In conclusion, that the peptide pACC1 could be employed as greater therapeutic adjuvant with currently established drugs without considering the stage of the cancer. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. A copper-phosphonate network as a high-performance heterogeneous catalyst for the CO2 cycloaddition reactions and alcoholysis of epoxides.

    PubMed

    Ai, Jing; Min, Xue; Gao, Chao-Ying; Tian, Hong-Rui; Dang, Song; Sun, Zhong-Ming

    2017-05-23

    A novel 3D copper-phosphonate network, with the general formula Cu 7 (H 1 L) 2 (TPT) 3 (H 2 O) 6 , namely compound 1, has been synthesized using a rigid tetrahedral linker tetraphenylsilane tetrakis-4-phosphonic acid (H 8 L) and a nitrogen-containing ancillary ligand (TPT: [5-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1H-tetrazole]) under hydrothermal conditions. The compound was fully characterized using PXRD, ICP, IR, TGA and elemental analysis. Compound 1 can be used as an efficient catalyst for the CO 2 coupling reaction that is greatly superior to many conventional MOF-based catalysts, where porosity is always mentioned and used. In addition, it shows excellent catalytic performance for ring-opening reactions with epoxides under ambient conditions. Additionally, compound 1 can be recycled at least three times without a significant compromise in the activity in the two catalytic reactions.

  15. Significance of the lipid phase in the dynamics and functions of the xanthophyll cycle as revealed by PsbS overexpression in tobacco and in-vitro de-epoxidation in monogalactosyldiacylglycerol micelles.

    PubMed

    Hieber, A David; Kawabata, Osamu; Yamamoto, Harry Y

    2004-01-01

    The dynamics of the xanthophyll cycle relative to non-photochemical quenching (NPQ) were examined in tobacco plants overexpressing violaxanthin de-epoxidase (VDE), PsbS and PsbS+VDE for effects on NPQ and violaxanthin (V) de-epoxidation over a range of light intensities. Induction of de-epoxidation and NPQ increased in overexpressed VDE and PsbS plants, respectively. Surprisingly, under low light, overexpressing PsbS enhanced de-epoxidation in addition to NPQ. The effect was hypothesized as due to PsbS binding zeaxanthin (Z) or inducing the binding of Z within the quenching complex, thus shifting the equilibrium toward higher de-epoxidation states. Studies in model systems show that Z can stereospecifically inhibit VDE activity against violaxanthin. This effect, observed under conditions of limiting lipid concentration, was interpreted as product feedback inhibition. These results support the hypothesis that the capacity of the thylakoid lipid phase for xanthophylls is limited and modulates xanthophyll-cycle activity, in conjunction with the release of V and binding of Z by pigment-binding proteins. These modulating factors are incorporated into a lipid-matrix model that has elements of a signal transduction system wherein the light-generated protons are the signal, VDE the signal receptor, Z the secondary messenger, the lipid phase the transduction network, and Z-binding proteins the targets.

  16. Combination of natural fiber Boehmeria nivea (ramie) with matrix epoxide for bullet proof vest body armor

    NASA Astrophysics Data System (ADS)

    Anggoro, Didi Dwi; Kristiana, Nunung

    2015-12-01

    Ballistic protection equipment, such as a bulletproof vest, is a soldier's most important means of preserving life and survivability in extreme combat conditions. The bulletproof vests are designed to protect the user's chest from injury without disturbing the ability to perform his duties. Aromatic polyamide or aramid fibers known under the trade name Kevlar, Trawon and so is synthetic fiber materials commonly used in the manufacture of bulletproof vests. This synthetic fibers have high tensile strength and ductility. Kevlar is expensive and imported material. In this study, will introduce local natural raw materials, ramie fiber (Boehmeria nivea) which is cheaper and environmentally friendly. It has enough tenacity and tensile strength as a bulletproof vest. This experiment uses two panels, there are Panel A as front surface of Panel B. Panel A is a combination of ramie and epoxide matrix, while panel B is only ramie. From several variations of experimental combinations between Panel A and Panel B, optimal combination obtained with 16 layers of panel A and 31-34 layers of panel B which is able to protect againts cal. 7.65 mm × 17 mm (.32 ACP) bullet fired through pistol .32 Pindad from a distance of 20 meters. Panel with a size of 20 cm × 20 cm has a total thickness between 12,922 to13,745 mm and a total weight between 506,26 to 520,926gram. Scanning electron microscopy (SEM) observations indicated that the porosity and surface area of the ramie fiber is smooth, fiber surfaces showed topography with micropores. SEM also showed well-arranged structure of fibers bonding. Energy Dispersive X-ray (EDX) analysis indicated 100 % carbon contents in ramie fiber. Test result indicates that panel from composite ramie-epoxide can reach the level 1of International Standard of NIJ - 010104. Compared to panel from polyester fiber, the panel from composite ramie-epoxide (0,50-0,52 kg) is lighter weight than panel polyester fiber (1,642 kg).

  17. Nanobody based immunoassay for human soluble epoxide hydrolase detection using polyHRP for signal enhancement—the rediscovery of polyHRP

    USDA-ARS?s Scientific Manuscript database

    Soluble epoxide hydrolase (sEH) is a potential pharmacological target for treating hypertension, vascular inflammation, cancer, pain and multiple cardiovascular related diseases. A variable domain of a heavy chain only antibody (termed sdAb, nanobody or VHH) possesses advantages of small size, high ...

  18. UVB induces atypical melanocytic lesions and melanoma in human skin.

    PubMed Central

    Atillasoy, E. S.; Seykora, J. T.; Soballe, P. W.; Elenitsas, R.; Nesbit, M.; Elder, D. E.; Montone, K. T.; Sauter, E.; Herlyn, M.

    1998-01-01

    A direct causal relationship between ultraviolet (UV) light in the B range and melanoma development has not been demonstrated in humans; this study aims to establish causality. A total of 158 RAG-1 mice, grafted with human newborn foreskin, were separated into four groups and observed for a median of 10 months: 1) no treatment, 2) a single treatment with 7,12-dimethyl(a)benzanthracene (DMBA), 3) UVB irradiation at 500 J/m2 alone, three times weekly, and 4) a combination of DMBA and UVB. Twenty-three percent of 40 normal human skin grafts treated with UVB only and 38% of 48 grafts treated with the combination of DMBA and UVB developed solar lentigines within 5 to 10 months of treatment. Melanocytic hyperplasia was found in 73% of all UVB-treated xenografts. Histological melanocytic changes resembling lentigo and lentigo maligna were seen in several skin grafts treated with both DMBA and UVB. In one graft of an animal treated with a combination of DMBA and UVB, a human malignant melanoma, nodular type, developed. This experimental system demonstrates that chronic UVB irradiation with or without an initiating carcinogen can induce human melanocytic lesions, including melanoma. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:9588887

  19. Is the mu-oxo-mu-peroxodiiron intermediate of a ribonucleotide reductase biomimetic a possible oxidant of epoxidation reactions?

    PubMed

    de Visser, Sam P

    2008-01-01

    Density functional calculations on a mu-oxo-mu-peroxodiiron complex (1) with a tetrapodal ligand BPP (BPP=N,N-bis(2-pyridylmethyl)-3-aminopropionate) are presented that is a biomimetic of the active site region of ribonucleotide reductase (RNR). We have studied all low-lying electronic states and show that it has close-lying broken-shell singlet and undecaplet (S=0, 5) ground states with essentially two sextet spin iron atoms. In strongly distorted electronic systems in which the two iron atoms have different spin states, the peroxo group moves considerably out of the plane of the mu-oxodiiron group due to orbital rearrangements. The calculated absorption spectra of (1,11)1 are in good agreement with experimental studies on biomimetics and RNR enzyme systems. Moreover, vibrational shifts in the spectrum due to (18)O(2) substitution of the oxygen atoms in the peroxo group follow similar trends as experimental observations. To identify whether the mu-oxo-mu-1,2-peroxodiiron or the mu-oxo-mu-1,1-peroxodiiron complexes are able to epoxidize substrates, we studied the reactivity patterns versus propene. Generally, the reactions are stepwise via radical intermediates and proceed by two-state reactivity patterns on competing singlet and undecaplet spin state surfaces. However, both the mu-oxo-mu-1,2-peroxodiiron and mu-oxo-mu-1,1-peroxodiiron complex are sluggish oxidants with high epoxidation barriers. The epoxidation barriers for the mu-oxo-mu-1,1-peroxodiiron complex are significantly lower than the ones for the mu-oxo-mu-1,2-peroxodiiron complex but still are too high to be considered for catalytic properties. Thus, theory has ruled out two possible peroxodiiron catalysts as oxidants in RNR enzymes and biomimetics and the quest to find the actual oxidant in the enzyme mechanism continues.

  20. Use of dimethyldioxirane in the epoxidation of the main constituents of the essential oils obtained from Tagetes lucida, Cymbopogon citratus, Lippia alba and Eucalyptus citriodora.

    PubMed

    Veloza, Luz A; Orozco, Lina M; Sepúlveda-Arias, Juan C

    2011-07-01

    Dimethyldioxirane (DMDO), a widely used oxidant in organic synthesis is considered an environmentally friendly oxygen transfer reagent because acetone is the only byproduct formed in its oxidation reactions. This work describes the isolation of the main constituents (terpenes) in the essential oils obtained from Tagetes lucida, Cymbopogon citratus, Lippia alba and Eucalyptus citriodora, their epoxidation with DMDO in acetone solution and the characterization of the resulting epoxides by GC-MS (EI) and NMR. This is one of the first reports involving the application of dioxirane chemistry to essential oils in order to generate modified compounds with potential uses in several areas of medicine and industry.

  1. Chemopreventive effect of Lagenaria siceraria in two stages DMBA plus croton oil induced skin papillomagenesis.

    PubMed

    Kumar, Navneet; Kale, Raosaheb K; Tiku, Ashu B

    2013-01-01

    Cancer chemoprevention is a dietary or therapeutic strategy to prevent, suppress, or delay carcinogenesis either at initiation or progression level with nontoxic agents. Use of natural dietary compounds has been a major chemopreventive approach to modulate tumorigenic pathways. In the present study, we have evaluated Lagenaria siceraria (bottle gourd), a common vegetable of Indian household for its chemomodulatory potential. The fruit has been used in traditional medicine for a very long time for health benefits and to cure pain, ulcers, fever, cough, asthma, and other bronchial disorders. However, despite its reported beneficial effect the chemo modulatory potential of this plant has not been reported. Therefore chemopreventive effect of bottle gourd juice (BGJ) was studied against 7,12-dimethylbenz(a)anthracene (DMBA) plus croton oil induced skin papillomagenesis in Swiss albino mice. The effect was studied both at antiinitiation and antiinitiation/promotion level followed by histopathological study. A dose of 2.5% and 5% given in drinking water showed significant decrease in papilloma number, papilloma incidence, papilloma multiplicity, papilloma latency, papilloma volume, and papilloma size in different size range. Histopathological study showed chemopreventive effect by minimizing loss of stratification, a decrease in number of epithelial layers, reducing dermal infiltration and protection for various cytoplasmic changes. Higher dose of BGJ was found to be more effective than lower dose and the chemopreventive effect was maximum for antiinitiation/promotion treatment. Altogether, this study reports the chemopreventive effect of Lagenaria siceraria on skin papillomagenesis for the first time and suggests that its consumption may help in suppression of skin cancer.

  2. Benzo(a)pyrene diol epoxides as intermediates in nucleic acid binding in vitro and in vivo.

    PubMed

    Weinstein, I B; Jeffrey, A M; Jennette, K W; Blobstein, S H; Harvey, R G; Harris, C; Autrup, H; Kasai, H; Nakanishi, K

    1976-08-13

    Evidence has been obtained that a specific isomer of a diol epoxide derivative of benzo(a)pyrene, (+/-)-7 beta,8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, is an intermediate in the binding of benzo(a)pyrene to RNA in cultured bovine bronchial mucosa. An adduct is formed between position 10 of this derivative and the 2-amino group of guanine.

  3. Synthesis of a highly dispersed CuO catalyst on CoAl-HT for the epoxidation of styrene.

    PubMed

    Hu, Rui; Yang, Pengfei; Pan, Yongning; Li, Yunpeng; He, Yufei; Feng, Junting; Li, Dianqing

    2017-10-10

    A highly dispersed CuO catalyst was prepared by the deposition-precipitation method and evaluated for the catalytic epoxidation of styrene with tert-butyl hydroperoxide (TBHP) as the oxidant under solvent acetonitrile conditions. Compared with MgAl hydrotalcite (MgAl-HT)-, MgO-, TiO 2 -, C-, and MCM-22-supported catalysts, CuO/CoAl-HT exhibited preferable activity and selectivity towards styrene oxide (72% selectivity at 99.5% styrene conversion) due to its high dispersion of CuO and surface area of Cu. The improved dispersion of CuO/CoAl-HT could be ascribed to the nature of HT support, especially the synergistic effect of acidic and basic sites on the surface, which facilitated the formation of highly dispersed CuO species. A structure-performance relationship study indicated that copper(ii) in CuO was the active site for the epoxidation and oxidation of styrene, and that Cu II of rich electronic density favored the improvement of selectivity of styrene oxide. Based on these results, a reaction mechanism was proposed. Moreover, the preferred catalytic performance of CuO/CoAl-HT could be maintained in five reused cycles.

  4. On the relevance of genotoxicity for fish populations I: effects of a model genotoxicant on zebrafish (Danio rerio) in a complete life-cycle test.

    PubMed

    Diekmann, Markus; Hultsch, Veit; Nagel, Roland

    2004-05-28

    Genotoxicity may be detected in surface waters by means of various genotoxicity assays. In order to enable an ecotoxicological assessment of the consequences of such genotoxic potential for fish populations, a complete life-cycle test with zebrafish (Danio rerio) and the model genotoxicant 4-nitroquinoline-1-oxide (NQO) was conducted. Zebrafish (f1) were continuously exposed to NQO (i.e. 0.1, 0.3, 1.1, 2.9, and 14.6 microg/l, respectively) from fertilised eggs until sexual maturity. In addition to reproduction studies in the f1-generation, f2-fish were exposed to NQO during the first 6 weeks of development. Up to 2.9 microg/l NQO, fish did not display differences in survival and growth (P < 0.05). A NQO concentration of 14.6 microg/l, however, was lethal. Female fish exposed to all NQO concentrations up to 2.9 microg/l displayed a significant reduction in egg production (P < 0.05). A mathematical simulation revealed that exposure to weak concentrations of NQO is leading to an elevated extinction risk. Copyright 2004 Elsevier B.V.

  5. Quantum chemical study of the mechanism of action of vitamin K epoxide reductase (VKOR)

    NASA Astrophysics Data System (ADS)

    Deerfield, David, II; Davis, Charles H.; Wymore, Troy; Stafford, Darrel W.; Pedersen, Lee G.

    Possible model, but simplistic, mechanisms for the action of vitamin K epoxide reductase (VKOR) are investigated with quantum mechanical methods (B3LYP/6-311G**). The geometries of proposed model intermediates in the mechanisms are energy optimized. Finally, the energetics of the proposed (pseudo-enzymatic) pathways are compared. We find that the several pathways are all energetically feasible. These results will be useful for designing quantum mechanical/molecular mechanical method (QM/MM) studies of the enzymatic pathway once three-dimensional structural data are determined and available for VKOR.

  6. QbD-based development of α-linolenic acid potentiated nanoemulsion for targeted delivery of doxorubicin in DMBA-induced mammary gland carcinoma: in vitro and in vivo evaluation.

    PubMed

    Tripathi, Chandra Bhushan; Parashar, Poonam; Arya, Malti; Singh, Mahendra; Kanoujia, Jovita; Kaithwas, Gaurav; Saraf, Shubhini A

    2018-05-10

    Breast cancer is the most common cancer of occurrence in women and has the highest mortality incidence rate therein. The present study envisaged to develop doxorubicin (Dox) loaded folate functionalized nanoemulsion (NE) for profound therapeutic activity against mammary gland cancer. NE was prepared using pseudo-ternary phase diagrams utilizing α-linolenic acid (ALA) as lipid phase, to further enhance the anticancer potential of Dox. Box-Behnken design was employed to systematically develop the NE. Optimized NE (f-Dox-NE) was evaluated for in vitro and in vivo performance. f-Dox-NE, with globule size 55.2 ± 3.3 nm, zeta potential - 31 ± 2 mV, entrapment 92.51 ± 3.62%, drug loading 0.42 ± 0.08% and percent drug release 94.86 ± 1.87% in 72 h, was capable of reducing cell viability in MCF-7 cell lines vis-à-vis pure and marketed drug. Further, mechanistic studies in MCF-7 cell lines demonstrated that f-Dox-NE induces cellular apoptosis by reactive oxygen species generated and mitochondrial membrane mediated apoptosis. The antitumor effect was evaluated in 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland tumor in female Albino Wistar rats. f-Dox-NE exhibited enhanced antitumor targeting potential, therapeutic safety and efficacy vis-à-vis pure and marketed drug, as revealed by tumor volume, animal survival, weight variation, cardiotoxicity and biodistribution studies. f-Dox-NE restored the biochemical parameters viz., SOD, catalase, TBARS and protein carbonyl, towards normal levels in comparison to DMBA induced animal group. f-Dox-NE displayed downregulation of anti-apoptotic (Bcl-2 and MMP-9) proteins and upregulation of pro-apoptotic proteins (caspase-9 and BAX). The experimental results suggest that ALA augmented folate functionalized NE are able to overcome the challenges of developing safe and effective delivery system with enhanced potential for mammary gland carcinoma therapy.

  7. Lutein from deepoxidation of lutein epoxide replaces zeaxanthin to sustain an enhanced capacity for nonphotochemical chlorophyll fluorescence quenching in avocado shade leaves in the dark.

    PubMed

    Förster, Britta; Pogson, Barry James; Osmond, Charles Barry

    2011-05-01

    Leaves of avocado (Persea americana) that develop and persist in deep shade canopies have very low rates of photosynthesis but contain high concentrations of lutein epoxide (Lx) that are partially deepoxidized to lutein (L) after 1 h of exposure to 120 to 350 μmol photons m(-2) s(-1), increasing the total L pool by 5% to 10% (ΔL). Deepoxidation of Lx to L was near stoichiometric and similar in kinetics to deepoxidation of violaxanthin (V) to antheraxanthin (A) and zeaxanthin (Z). Although the V pool was restored by epoxidation of A and Z overnight, the Lx pool was not. Depending on leaf age and pretreatment, the pool of ΔL persisted for up to 72 h in the dark. Metabolism of ΔL did not involve epoxidation to Lx. These contrasting kinetics enabled us to differentiate three states of the capacity for nonphotochemical chlorophyll fluorescence quenching (NPQ) in attached and detached leaves: ΔpH dependent (NPQ(ΔpH)) before deepoxidation; after deepoxidation in the presence of ΔL, A, and Z (NPQ(ΔLAZ)); and after epoxidation of A+Z but with residual ΔL (NPQ(ΔL)). The capacity of both NPQ(ΔLAZ) and NPQ(ΔL) was similar and 45% larger than NPQ(ΔpH), but dark relaxation of NPQ(ΔLAZ) was slower. The enhanced capacity for NPQ was lost after metabolism of ΔL. The near equivalence of NPQ(ΔLAZ) and NPQ(ΔL) provides compelling evidence that the small dynamic pool ΔL replaces A+Z in avocado to "lock in" enhanced NPQ. The results are discussed in relation to data obtained with other Lx-rich species and in mutants of Arabidopsis (Arabidopsis thaliana) with increased L pools.

  8. Characteristics of polyaniline cobalt supported catalysts for epoxidation reactions.

    PubMed

    Kowalski, Grzegorz; Pielichowski, Jan; Grzesik, Mirosław

    2014-01-01

    A study of polyaniline (PANI) doping with various cobalt compounds, that is, cobalt(II) chloride, cobalt(II) acetate, and cobalt(II) salen, is presented. The catalysts were prepared by depositing cobalt compounds onto the polymer surface. PANI powders containing cobalt ions were obtained by one- or two-step method suspending PANI in the following acetonitrile/acetic acid solution or acetonitrile and then acetic acid solution. Moreover different ratios of Co(II) : PANI were studied. Catalysts obtained with both methods and at all ratios were investigated using various techniques including AAS and XPS spectroscopy. The optimum conditions for preparation of PANI/Co catalysts were established. Catalytic activity of polyaniline cobalt(II) supported catalysts was tested in dec-1-ene epoxidation with molecular oxygen at room temperature. The relationship between the amount of cobalt species, measured with both AAS and XPS techniques, and the activity of PANI-Co catalysts has been established.

  9. Characteristics of Polyaniline Cobalt Supported Catalysts for Epoxidation Reactions

    PubMed Central

    Kowalski, Grzegorz; Pielichowski, Jan; Grzesik, Mirosław

    2014-01-01

    A study of polyaniline (PANI) doping with various cobalt compounds, that is, cobalt(II) chloride, cobalt(II) acetate, and cobalt(II) salen, is presented. The catalysts were prepared by depositing cobalt compounds onto the polymer surface. PANI powders containing cobalt ions were obtained by one- or two-step method suspending PANI in the following acetonitrile/acetic acid solution or acetonitrile and then acetic acid solution. Moreover different ratios of Co(II) : PANI were studied. Catalysts obtained with both methods and at all ratios were investigated using various techniques including AAS and XPS spectroscopy. The optimum conditions for preparation of PANI/Co catalysts were established. Catalytic activity of polyaniline cobalt(II) supported catalysts was tested in dec-1-ene epoxidation with molecular oxygen at room temperature. The relationship between the amount of cobalt species, measured with both AAS and XPS techniques, and the activity of PANI-Co catalysts has been established. PMID:24701183

  10. Lipoxin Generation Is Related to Soluble Epoxide Hydrolase Activity in Severe Asthma

    PubMed Central

    Ono, Emiko; Dutile, Stefanie; Kazani, Shamsah; Wechsler, Michael E.; Yang, Jun; Hammock, Bruce D.; Douda, David Nobuhiro; Tabet, Yacine; Khaddaj-Mallat, Rayan; Sirois, Marco; Sirois, Chantal; Rizcallah, Edmond; Rousseau, Éric; Martin, Richard; Sutherland, E. Rand; Castro, Mario; N. Jarjour, Nizar; Israel, Elliot

    2014-01-01

    Rationale: Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established. Objectives: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma. Methods: Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte–platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections. Measurements and Main Results: 8-Isoprostane levels in sputum supernatants were inversely related to LXA4 in severe asthma (r = −0.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA4 and 15-epi-LXA4 biosynthesis by peripheral blood leukocytes. LXA4 and 15-epi-LXA4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte–platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited platelet-activating factor–induced increases in leukocyte–platelet aggregates (70.8% inhibition [LXA4 100 nM], 78.3% inhibition [15-epi-LXA4 100 nM]) and 15-epi-LXA4 markedly inhibited tumor necrosis factor-α–induced increases in bronchial contraction. Conclusions: LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach

  11. Efficient asymmetric hydrolysis of styrene oxide catalyzed by Mung bean epoxide hydrolases in ionic liquid-based biphasic systems.

    PubMed

    Chen, Wen-Jing; Lou, Wen-Yong; Zong, Min-Hua

    2012-07-01

    The asymmetric hydrolysis of styrene oxide to (R)-1-phenyl-1,2-ethanediol using Mung bean epoxide hydrolases was, for the first time, successfully conducted in an ionic liquid (IL)-containing biphasic system. Compared to aqueous monophasic system, IL-based biphasic systems could not only dissolve the substrate, but also effectively inhibit the non-enzymatic hydrolysis, and therefore markedly improve the reaction efficiency. Of all the tested ILs, the best results were observed in the biphasic system containing C(4)MIM·PF(6), which exhibited good biocompatibility with the enzyme and was an excellent solvent for the substrate. In the C(4)MIM·PF(6)/buffer biphasic system, it was found that the optimal volume ratio of IL to buffer, reaction temperature, buffer pH and substrate concentration were 1/6, 35°C, 6.5 and 100 mM, respectively, under which the initial reaction rate, the yield and the product e.e. were 18.4 mM/h, 49.4% and 97.0%. The biocatalytic process was shown to be feasible on a 500-mL preparative scale. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Overexpression of Catalase Enhances Benzo(a)pyrene Detoxification in Endothelial Microsomes.

    PubMed

    Yang, Fang; Yang, Hong; Ramesh, Aramandla; Goodwin, J Shawn; Okoro, Emmanuel U; Guo, ZhongMao

    2016-01-01

    We previously reported that overexpression of catalase upregulated xenobiotic- metabolizing enzyme (XME) expression and diminished benzo(a)pyrene (BaP) intermediate accumulation in mouse aortic endothelial cells (MAECs). Endoplasmic reticulum (ER) is the most active organelle involved in BaP metabolism. To examine the involvement of ER in catalase-induced BaP detoxification, we compared the level and distribution of XMEs, and the profile of BaP intermediates in the microsomes of wild-type and catalase transgenic endothelial cells. Our data showed that endothelial microsomes were enriched in cytochrome P450 (CYP) 1A1, CYP1B1 and epoxide hydrolase 1 (EH1), and contained considerable levels of quinone oxidoreductase-1 (NQO1) and glutathione S-transferase-pi (GSTP). Treatment of wild-type MAECs with 1μM BaP for 2 h increased the expression of microsomal CYP1A1, 1B1 and NQO1 by ~300, 64 and 116%, respectively. However, the same treatment did not significantly alter the expression of EH1 and GSTP. Overexpression of catalase did not significantly increase EH1, but upregulated BaP-induced expression of microsomal CYP1A1, 1B1, NQO1 and GSTP in the following order: 1A1>NQO1>GSTP>1B1. Overexpression of catalase did not alter the distribution of each of these enzymes in the microsomes. In contrast to our previous report showing lower level of BaP phenols versus BaP diols/diones in the whole-cell, this report demonstrated that the sum of microsomal BaP phenolic metabolites were ~60% greater than that of the BaP diols/diones after exposure of microsomes to BaP. Overexpression of catalase reduced the concentrations of microsomal BaP phenols and diols/diones by ~45 and 95%, respectively. This process enhanced the ratio of BaP phenol versus diol/dione metabolites in a potent manner. Taken together, upregulation of phase II XMEs and CYP1 proteins, but not EH1 in the ER might be the mechanism by which overexpression of catalase reduces the levels of all the BaP metabolites, and

  13. Enantioselective syntheses of aeruginosin 298-A and its analogues using a catalytic asymmetric phase-transfer reaction and epoxidation.

    PubMed

    Ohshima, Takashi; Gnanadesikan, Vijay; Shibuguchi, Tomoyuki; Fukuta, Yuhei; Nemoto, Tetsuhiro; Shibasaki, Masakatsu

    2003-09-17

    We developed a versatile synthetic process for aeruginosin 298-A as well as several attractive analogues, in which all stereocenters were controlled by a catalytic asymmetric phase-transfer reaction and epoxidation. Furthermore, drastic counteranion effects in phase-transfer catalysis were observed for the first time, making it possible to three-dimensionally fine-tune the catalyst (ketal part, aromatic part, and counteranion).

  14. Synthesis, docking, cytotoxicity, and LTA4H inhibitory activity of new gingerol derivatives as potential colorectal cancer therapy.

    PubMed

    El-Naggar, Mai H; Mira, Amira; Abdel Bar, Fatma M; Shimizu, Kuniyoshi; Amer, Mohamed M; Badria, Farid A

    2017-02-01

    Leukotriene A4 hydrolase (LTA 4 H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene which may play an important role in chronic inflammation associated carcinogenesis. [6]-gingerol, the major bioactive compound of Zingiber officinale, is a potential inhibitor of LTA 4 H, a highly expressed enzyme in colorectal carcinoma. Eighteen compounds; seven of natural origin (including [4]-, [6]-, [8]-, and [10]-gingerol), five new and six known semi-synthesized [6]-gingerol derivatives were examined using docking, in vitro cytotoxicity against human colon cancer cells (HCT-116) and LTA 4 H aminopeptidase and epoxide hydrolase inhibitory studies. Methyl shogoal (D8) showed to be the most potent compound against HCT-116 cells (IC 50 ; 1.54μM). Remarkably, D8 proved to be non-cytotoxic to normal cells; (TIG-1) and (HF-19) with high selective index (SI; 52.3). Furthermore [6]-gingerol derivatives showed potent LTA 4 H inhibitory activities in comparison to the universal positive controls (bestatin and 4BSA). Among the natural gingerols, [10]-gingerol (N3) exhibited the highest LTA 4 H aminopeptidase and epoxide hydrolase inhibitory activities with IC 50 ; 21.59 and 15.24μM, respectively. Meanwhile, methyl shogoal (D8) and 4'-O-prenyl-[6]-gingerol (D10) retained the highest inhibition with IC 50 ; 4.92 and 3.01μM, for aminopeptidase, and 11.27 and 7.25μM for epoxide hydrolase activities, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Oil-in-Water Emulsions Stabilized by Saponified Epoxidized Soybean Oil-Grafted Hydroxyethyl Cellulose.

    PubMed

    Huang, Xujuan; Li, Qiaoguang; Liu, He; Shang, Shibin; Shen, Minggui; Song, Jie

    2017-05-03

    An oil-in-water emulsion stabilized by saponified epoxidized soybean oil-grafted hydroxyethyl cellulose (H-ESO-HEC) was investigated. By using an ultrasonic method, oil-in-water emulsions were prepared by blending 50 wt % soybean oil and 50 wt % H-ESO-HEC aqueous suspensions. The influence of H-ESO-HEC concentrations on the properties of oil-in-water emulsions was examined. The H-ESO-HEC concentrations in the aqueous phase varied from 0.02 to 0.40 wt %. When the H-ESO-HEC concentration was 0.4 wt %, the emulsion remained stable for >80 days. The mean droplet sizes of the emulsions decreased by increasing the H-ESO-HEC concentration and extending the ultrasonic time. The adsorption amounts of H-ESO-HEC at the oil-water interface increased when the H-ESO-HEC concentrations in the aqueous phase increased. The rheological property revealed that the apparent viscosity of the H-ESO-HEC-stabilized oil-in-water emulsions increased when the H-ESO-HEC concentrations increased. Steady flow curves indicated an interfacial film formation in the emulsions. The evolution of G', G″, and tan η indicated the predominantly elastic behaviors of all the emulsions.

  16. The potential of shark bone powder in breast cancer inhibition (pre-clinical study in DMBA-Induced Sprague Dawly Rats)

    NASA Astrophysics Data System (ADS)

    Bintari, S. H.; Parman, S.; Dafip, M.

    2018-03-01

    Breast cancer is a malignant disease, which lead to second cause of that after cervical cancer in women. To date, lots of drugs and supplement have been developed and consumed by patients. Shark bone is one of the supplements that might inhibit the proliferation of cancer cells. The application of shark bone powder for supplementation in breast cancer cases still becomes controversy; but until now people are still many who consume as a supplement. This study aimed to prove the potency of shark bone powder in the inhibition of breast cancer proliferation and to propose the possibility of its biological mechanism. The pre-clinical experimental study used a controlled posttest controlled design with 25 white rats strains of DML-induced Sprague-Dawley strains. The cancer markers observed were p53, AgNORs, VEGF, Bcl-2, and Cas-3. The test subjects were divided into 3 groups: control group and 2 treatment groups fed modified with 60% and 90% respectively. A pre-clinical trial of shark bone powder showed that there was significant inhibition for the DMBA-induced anti proliferation and breast cell cancer (p <0.05) parameters. Optimal concentration of shark bone powder to inhibit breast cancer proliferation lies in concentration 30mg/BB/day.

  17. erbB expression changes in ethanol and 7, 12- dimethylbenz (a) anthracene-induced oral carcinogenesis

    PubMed Central

    Jacinto-Alemán, Luis F.; García-Carrancá, Alejandro; Leyba-Huerta, Elba R.; Zenteno-Galindo, Edgar; Jiménez-Farfán, María D.

    2013-01-01

    Objetive: The aim of this study was to determine erbB expression in normal mucosa, oral dysplasia, and invasive carcinomas developed in the hamster’s buccal pouch chemical carcinogenesis model. Study design: Fifty Syrian golden hamsters were equally divided in five groups (A-E); two controls and three experimental group exposed to alcohol, DMBA, or both for 14 weeks. Number of tumors per cheek, volume, histological condition, erbB expression were determined and results were analyzed by the Mann–Whitney U and Dunn’s test. Results: Control groups and those exposed to alcohol (A, B and C respectively) only presented clinical and histological normal mucosa; while those exposed to DMBA or DMBA plus alcohol (D and E groups) developed dysplasia and invasive carcinomas. erbB2, erbB3, and erbB4 increased their expression in alcohol-exposed mucosa, dysplasia, and invasive carcinomas. We observed a similar expression level for erbB2 in dysplasia and carcinomas; while, erbB3 and erbB4 were similar only in carcinomas. Conclusion: The DMBA and alcohol can be considered as carcinogen and promoter for oral carcinogenesis. The erbB expression is different according to their histological condition, suggesting differential participation of the erbB family in oral carcinogenesis induced by alcohol and DMBA. Key words:erbB, 7,12- dimethylbenz(a)anthracene, oral squamous cell carcinoma. PMID:23229248

  18. Two conformers of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene spiro-linked with homobenzoquinone epoxide.

    PubMed

    Asahara, Haruyasu; Koizumi, Takuya; Mochizuki, Eiko; Oshima, Takumi

    2006-03-01

    The crystal structures of the two thermally equilibrated conformational isomers of the epoxide 1',5'-dimethylspiro[10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,8'-4'-oxatricyclo[5.1.0.0(3,5)]octane]-2',6'-dione, C23H20O3, have been determined by X-ray diffraction. In the tricyclic dione skeleton, the oxirane and cyclopropane rings adopt an anti structure with respect to the conjunct quinone frame. The spiro-linked 10,11-dihydro-5H-dibenzo[a,d]cycloheptene ring of the major isomer has a fairly twisted boat form, folding opposite to the adjoining cyclopropane methyl substituent, whereas the seven-membered ring of the minor isomer has an almost ideal twist-boat form, inversely folding to the side of the relevant methyl group. The conformational structures of these isomers have been compared with those of the corresponding isomers of the unepoxidized homobenzoquinone.

  19. The stability of the three transmembrane and the four transmembrane human vitamin K epoxide reductase models

    NASA Astrophysics Data System (ADS)

    Wu, Sangwook

    2016-04-01

    The three transmembrane and the four transmembrane helix models are suggested for human vitamin K epoxide reductase (VKOR). In this study, we investigate the stability of the human three transmembrane/four transmembrane VKOR models by employing a coarse-grained normal mode analysis and molecular dynamics simulation. Based on the analysis of the mobility of each transmembrane domain, we suggest that the three transmembrane human VKOR model is more stable than the four transmembrane human VKOR model.

  20. Stereoselective construction of the 5-hydroxy diazabicyclo[4.3.1]decane-2-one scaffold, a privileged motif for FK506-binding proteins.

    PubMed

    Bischoff, Matthias; Sippel, Claudia; Bracher, Andreas; Hausch, Felix

    2014-10-17

    A stereoselective synthesis of a derivatized bicyclic [4.3.1]decane scaffold based on an acyclic precursor is described. The key steps involve a Pd-catalyzed sp(3)-sp(2) Negishi-coupling, an asymmetric Shi epoxidation, and an intramolecular epoxide opening. Representative derivatives of this novel scaffold were synthesized and found to be potent inhibitors of the psychiatric risk factor FKBP51, which bound to FKBP51 with the intended molecular binding mode.

  1. Inhibition of soluble epoxide hydrolase limits niacin-induced vasodilation in mice

    PubMed Central

    Inceoglu, A. B.; Clifton, H.L.; Yang, J.; Hegedus, C.; Hammock, B. D.; Schaefer, S.

    2012-01-01

    Background The use of niacin in the treatment of dyslipidemias is limited by the common side effect of cutaneous vasodilation, commonly termed flushing. Flushing is thought to be due to release of the vasodilatory prostanoids PGD2 and PGE2 from arachidonic acid metabolism through the cyclooxygenase (COX) pathway. Arachidonic acid is also metabolized by the cytochrome P450 system which is regulated, in part, by the enzyme soluble epoxide hydrolase (sEH). Methods: These experiments used an established murine model in which ear tissue perfusion was measured by laser Doppler to test the hypothesis that inhibition of sEH would limit niacin-induced flushing. Results: Niacin-induced flushing was reduced from 506 ± 126 to 213 ± 39 % in sEH knockout animals. Pharmacologic treatment with 3 structurally distinct sEH inhibitors similarly reduced flushing in a dose dependent manner, with maximal reduction to 143±15% of baseline flow using a concentration of 1 mg/kg TPAU (1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea). Systemically administered PGD2 caused ear vasodilation which was not changed by either pharmacologic sEH inhibition or by sEH gene deletion. Conclusions: Inhibition of sEH markedly reduces niacin-induced flushing in this model without an apparent effect on the response to PGD2. sEH inhibition may be a new therapeutic approach to limit flushing in humans. PMID:22526297

  2. Lutein from Deepoxidation of Lutein Epoxide Replaces Zeaxanthin to Sustain an Enhanced Capacity for Nonphotochemical Chlorophyll Fluorescence Quenching in Avocado Shade Leaves in the Dark1

    PubMed Central

    Förster, Britta; Pogson, Barry James; Osmond, Charles Barry

    2011-01-01

    Leaves of avocado (Persea americana) that develop and persist in deep shade canopies have very low rates of photosynthesis but contain high concentrations of lutein epoxide (Lx) that are partially deepoxidized to lutein (L) after 1 h of exposure to 120 to 350 μmol photons m−2 s−1, increasing the total L pool by 5% to 10% (ΔL). Deepoxidation of Lx to L was near stoichiometric and similar in kinetics to deepoxidation of violaxanthin (V) to antheraxanthin (A) and zeaxanthin (Z). Although the V pool was restored by epoxidation of A and Z overnight, the Lx pool was not. Depending on leaf age and pretreatment, the pool of ΔL persisted for up to 72 h in the dark. Metabolism of ΔL did not involve epoxidation to Lx. These contrasting kinetics enabled us to differentiate three states of the capacity for nonphotochemical chlorophyll fluorescence quenching (NPQ) in attached and detached leaves: ΔpH dependent (NPQΔpH) before deepoxidation; after deepoxidation in the presence of ΔL, A, and Z (NPQΔLAZ); and after epoxidation of A+Z but with residual ΔL (NPQΔL). The capacity of both NPQΔLAZ and NPQΔL was similar and 45% larger than NPQΔpH, but dark relaxation of NPQΔLAZ was slower. The enhanced capacity for NPQ was lost after metabolism of ΔL. The near equivalence of NPQΔLAZ and NPQΔL provides compelling evidence that the small dynamic pool ΔL replaces A+Z in avocado to “lock in” enhanced NPQ. The results are discussed in relation to data obtained with other Lx-rich species and in mutants of Arabidopsis (Arabidopsis thaliana) with increased L pools. PMID:21427278

  3. BENZO[A]PYRENE AND BENZO[C]PHENANTHRENE: THE EFFECT OF STRUCTURE ON THE BINDING OF WATER MOLECULES TO THE DIOL EPOXIDES

    EPA Science Inventory

    ABSTRACT
    The interaction with water of the diol epoxides (DEs) of both a planar and a non-planar PAH have been examined using molecular dynamics. To determine probable water locations around the DE for later use in the study of DE protonation, molecular dynamics simulations u...

  4. Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation-Structure-Based Hit Evaluation and Chemistry Exploration.

    PubMed

    Xue, Yafeng; Olsson, Thomas; Johansson, Carina A; Öster, Linda; Beisel, Hans-Georg; Rohman, Mattias; Karis, David; Bäckström, Stefan

    2016-03-04

    Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Gaucher disease types 1, 2, and 3: differential mutations of the acid beta-glucosidase active site identified with conduritol B epoxide derivatives and sphingosine.

    PubMed Central

    Grabowski, G A; Dinur, T; Osiecki, K M; Kruse, J R; Legler, G; Gatt, S

    1985-01-01

    To elucidate the genetic heterogeneity in Gaucher disease, the residual beta-glucosidase in cultured fibroblasts from affected patients with each of the major phenotypes was investigated in vitro and/or in viable cells by inhibitor studies using the covalent catalytic site inhibitors, conduritol B epoxide or its bromo derivative, and the reversible cationic inhibitor, sphingosine. These studies delineated three distinct groups (designated A, B, and C) of residual activities with characteristic responses to these inhibitors. Group A residual enzymes had normal I50 values (i.e., the concentration of inhibitor that results in 50% inhibition) for the inhibitors and normal or nearly normal t1/2 values for conduritol B epoxide. All neuronopathic (types 2 and 3) and most non-Jewish nonneuronopathic (type 1) patients had group A residual activities and, thus, could not be distinguished by these inhibitor studies. Group B residual enzymes had about four- to fivefold increased I50 values for the inhibitors and similarly increased t1/2 values for conduritol B epoxide. All Ashkenazi Jewish type 1 and only two non-Jewish type 1 patients had group B residual activities. The differences in I50 values between groups A and B also were confirmed by determining the uninhibited enzyme activity after culturing the cells in the presence of bromo-conduritol B epoxide. Group C residual activity had intermediate I50 values for the inhibitors and represented a single Afrikaner type 1 patient: this patient was a genetic compound for the group A (type 2) and group B (type 1) mutations. These inhibition studies indicated that: Gaucher disease type 1 is biochemically heterogeneous, neuronopathic and non-Jewish nonneuronopathic phenotypes cannot be reliably distinguished by these inhibitor studies, and the Ashkenazi Jewish form of Gaucher disease type 1 results from a unique mutation in a specific active site domain of acid beta-glucosidase that leads to a defective enzyme with a decreased Vmax

  6. Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE{sub 2} induced pain model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Goswami, Sumanta Kumar; Inceoglu, Bora; Yang, Jun

    Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100 mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3 mg/kg/day, p.o.) and OME (100 mg/kg/day, p.o., 7 days) + TPPU (3 mg/kg/day,more » p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE{sub 2} was monitored. While OME treatment by itself exhibited variable effects on PGE{sub 2} induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME + TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study. - Highlights: • The soluble epoxide hydrolase (sEH) inhibitor TPPU is anti-hyperalgesic. • Omeprazole potentiates the anti-hyperalgesic actions of TPPU. • This potentiation is associated with increased P450 activity. • The potentiation is associated with an increase in fatty acid epoxide/diol ratio. • Joint use of sEH inhibitors and P450 inducers could result in drug–drug interactions.« less

  7. Application of Fourier transform infrared (FT-IR) spectroscopy to the study of the modification of epoxidized sunflower oil by acrylation.

    PubMed

    Irinislimane, Ratiba; Belhaneche-Bensemra, Naima

    2012-12-01

    Commercial sunflower oil was epoxidized at the laboratory-scale. The epoxidized sunflower oil (ESFO) was modified following the acrylation reaction. Modification was carried out simultaneously using acrylic acid (AA) and triethylamine (TEA). To optimize the reaction conditions, the effects of four temperatures (40, 60, 80, and 100 °C), the ESFO:AA (100:100) ratio, and 0.2% TEA were investigated. The rate of conversion was analyzed with both FT-IR and titration of the oxirane ring. After that, the temperature with the highest conversion was selected and used throughout for all modification reactions. Then, four ratios (100:100, 100:90, 100:80, and 100:75) of ESFO:AA were analyzed at four different concentrations of TEA (0.2, 0.3, 0.4, and 0.5%) to determine the best estimate for both the ESFO:AA ratio and the catalyst concentration. Conversion rate was analyzed using FT-IR spectroscopy by measuring the concentrations of ester, carbonyl, and alcohol groups. Moreover, oxirane-ring concentration was estimated using the titration method (with gentian violet as indicator) and FT-IR spectroscopy (epoxy ring absorptions at 1270 cm(-1) and 877 cm(-1)). Based on conversion yield, the optimum ESFO:AA ratio corresponds to 100:80; the best temperature reaction was at 60 °C, and the best TEA concentration was 0.2%. The critical amounts of reactants needed to reach maximum conversion were established. The final acid value of the acrylated ESFO after washing (pH = 7) was 2.1 mg potassium hydroxide (KOH)·g(-1). All results show that FT-IR spectroscopy is a simple, low-cost, rapid method for investigating the kinetics of a reaction.

  8. Leukotriene C4 production by murine mast cells: evidence of a role for extracellular leukotriene A4.

    PubMed Central

    Dahinden, C A; Clancy, R M; Gross, M; Chiller, J M; Hugli, T E

    1985-01-01

    The glutathione-containing leukotriene C4 (LTC4) is a major mediator of smooth muscle contraction and is released by mast cells when antigen interacts with cell-bound IgE. Antigen-stimulated mast cells undergo phospholipase activation. We report a pathway of LTC4 production by mast cells that does not require phospholipase activation but depends on the interaction of activated neutrophils with unstimulated mast cells, using as an intermediate extracellular leukotriene A4 (LTA4). The epoxide LTA4 is released by neutrophils and, together with leukotriene B4 and 5-hydroxyeicosatetraenoic acid, constitutes the major lipoxygenase metabolites found in supernatants of stimulated neutrophils. Five minutes after activation of neutrophils by calcium ionophore A23187 we measured 136 pmol of extracellular LTA4 per 10(7) neutrophils (range 40-300, n = 7) by trapping the epoxide with alcohols. Therefore, we conclude that LTA4 is not just an intracellular leukotriene precursor but is released as a lipoxygenase metabolite. LTA4 is known to be stabilized by albumin and is efficiently converted by mast cells into LTC4 even at low LTA4 concentrations. The LTA4 complexed to albumin is converted into LTC4 rapidly and completely within 10-15 min. More than 50% of the LTA4 presented to mast cells is metabolized to LTC4 at concentrations of LTA4 between 0.2 and 2 nmol of LTA4 per 10(7) mast cells. This observation establishes a potential physiologic role for extracellular LTA4. Therefore, interactions between various cell types that release or utilize LTA4 may provide an important metabolic pathway for the production of leukotrienes. PMID:2995976

  9. Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

    NASA Astrophysics Data System (ADS)

    Temml, Veronika; Garscha, Ulrike; Romp, Erik; Schubert, Gregor; Gerstmeier, Jana; Kutil, Zsofia; Matuszczak, Barbara; Waltenberger, Birgit; Stuppner, Hermann; Werz, Oliver; Schuster, Daniela

    2017-02-01

    Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N’-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.

  10. Thermoset coatings from epoxidized sucrose soyate and blocked, bio-based dicarboxylic acids.

    PubMed

    Kovash, Curtiss S; Pavlacky, Erin; Selvakumar, Sermadurai; Sibi, Mukund P; Webster, Dean C

    2014-08-01

    A new 100% bio-based thermosetting coating system was developed from epoxidized sucrose soyate crosslinked with blocked bio-based dicarboxylic acids. A solvent-free, green method was used to block the carboxylic acid groups and render the acids miscible with the epoxy resin. The thermal reversibility of this blocking allowed for the formulation of epoxy-acid thermoset coatings that are 100% bio-based. This was possible due to the volatility of the vinyl ethers under curing conditions. These systems have good adhesion to metal substrates and perform well under chemical and physical stress. Additionally, the hardness of the coating system is dependent on the chain length of the diacid used, making it tunable. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Metal (2) 4,4',4",4'" phthalocyanine tetraamines as curing agents for epoxy resins

    NASA Technical Reports Server (NTRS)

    Achar, B. N.; Fohlen, G. M.; Parker, J. A. (Inventor)

    1985-01-01

    Metal, preferably divalent copper, cobalt or nickel, phthalocyanine tetraamines are used as curing agents for epoxides. The resulting copolymers have high thermal and chemical resistance and are homogeneous. They are useful as binders for laminates, e.g., graphite cloth laminate.

  12. Identification of α-tocotrienolquinone epoxides and development of an efficient molecular distillation procedure for quantitation of α-tocotrienol oxidation products in food matrices by high-performance liquid chromatography with diode array and fluorescence detection.

    PubMed

    Büsing, Anne; Drotleff, Astrid M; Ternes, Waldemar

    2012-08-29

    The aim of this study was to investigate the most important oxidation products of α-tocotrienol (α-T3) along with other tocochromanols in lipid matrices and tocotrienol-rich foods. For this purpose, an efficient molecular distillation procedure was developed for the extraction of analytes, and α-T3-spiked and thermally oxidized natural lipids (lard and wheat germ oil) and α-T3-rich foods (wholemeal rye bread and oil from dried brewer's spent grain) were investigated through HPLC-DAD-F. The following α-T3 oxidation products were extractable from lipid matrices along with tocochromanols: α-tocotrienolquinone (α-T3Q), α-tocotrienolquinone-4a,5-epoxide (α-T3Q-4a,5-E), α-tocotrienolquinone-7,8-epoxide (α-T3Q-7,8-E), 7-formyl-β-tocotrienol (7-FβT3), and 5-formyl-γ-tocotrienol (5-FγT3). Recovery rates were as high as 88% and enrichment factors up to 124. The proposed method allows the investigation of α-T3Q, α-T3Q-4a,5-E, α-T3Q-7,8-E, 7-FβT3, and 5-FγT3 in small quantities (<0.78 μg/g) in lipid matrices, which is necessary for the investigation and analysis of the formation kinetics of these oxidation products in fat, oils, and tocotrienol-rich foods.

  13. A comparison of RS4-type resistant starch to RS2-type resistant starch in suppressing oxidative stress in high-fat-diet-induced obese rats.

    PubMed

    Si, Xu; Zhou, Zhongkai; Strappe, Padraig; Blanchard, Chris

    2017-01-25

    The anti-obesity effects of two types of resistant starch (RS) in high-fat-diet-induced obese rats were investigated. The serum triglycerides, total cholesterol and malondialdehyde concentrations were significantly reduced, and the total antioxidant capacity, superoxide dismutase levels and glutathione peroxidase activity were increased by RS2 and RS4 consumption compared to the obesity group. A significant reduction in the serum glucose level and elevations in hepatic lipid metabolic enzyme activities were observed only for RS4 administration. Moreover, the expression levels of the fatty acid synthesis associated genes ACC and Fads1, the triglyceride synthesis and metabolism-related gene SREBP-1, the adipocyte differentiation gene PPARγ, the cholesterol synthesis associated gene HMGCR, and the gluconeogenesis associated gene GAPDH were all significantly down-regulated, whilst the lipid oxidation gene Acox1 and the liver function genes Gsta2, Nqo1, and Gclm were up-regulated in both administered groups. Additionally, RS4 performed well in up-regulating the expressions of Gsta2, Gsta3, Nqo1, and Egfr, and down-regulating LXRα, Igfbp1, and Pml. RS4 exhibited great advantages in reducing oxidative stress compared with RS2.

  14. Antioxidative effects of the spice cardamom against non-melanoma skin cancer by modulating nuclear factor erythroid-2-related factor 2 and NF-κB signalling pathways.

    PubMed

    Das, Ila; Acharya, Asha; Berry, Deborah L; Sen, Supti; Williams, Elizabeth; Permaul, Eva; Sengupta, Archana; Bhattacharya, Sudin; Saha, Tapas

    2012-09-28

    The role of dietary factors in inhibiting or delaying the development of non-melanoma skin cancer (NMSC) has been investigated for many years. Cardamom, which is a dietary phytoproduct, has been commonly used in cuisines for flavour and has numerous health benefits, such as improving digestion and stimulating metabolism and having antitumorigenic effects. We have investigated the efficacy of dietary cardamom against 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin papillomatogenesis in Swiss albino mice that closely resembles human NMSC. Mice were grouped into normal wild type (untreated), vehicle-treated (acetone), carcinogen-treated (DMBA), and DMBA and cardamom-treated (DMBA+CARD) to delineate the role of cardamom against DMBA-induced papillomatogenesis. Oral administration of cardamom to DMBA-treated mice up-regulated the phase II detoxification enzymes, such as glutathione-S-transferase and glutathione peroxidase, probably via activation of nuclear factor erythroid-2-related factor 2 transcription factor in 'DMBA+CARD' mice. Furthermore, reduced glutathione, glutathione reductase, superoxide dismutase and catalase were also up-regulated by cardamom in the same 'DMBA+CARD' group of mice compared with DMBA-treated mice. Cardamom ingestion in DMBA-treated mice blocked NF-κB activation and down-regulated cyclo-oxygenase-2 expression. As a consequence, both the size and the number of skin papillomas generated on the skin due to the DMBA treatment were reduced in the 'DMBA+CARD' group. Thus, the results from the present study suggest that cardamom has a potential to become a pivotal chemopreventive agent to prevent papillomagenesis on the skin.

  15. A PLS-based extractive spectrophotometric method for simultaneous determination of carbamazepine and carbamazepine-10,11-epoxide in plasma and comparison with HPLC

    NASA Astrophysics Data System (ADS)

    Hemmateenejad, Bahram; Rezaei, Zahra; Khabnadideh, Soghra; Saffari, Maryam

    2007-11-01

    Carbamazepine (CBZ) undergoes enzyme biotransformation through epoxidation with the formation of its metabolite, carbamazepine-10,11-epoxide (CBZE). A simple chemometrics-assisted spectrophotometric method has been proposed for simultaneous determination of CBZ and CBZE in plasma. A liquid extraction procedure was operated to separate the analytes from plasma, and the UV absorbance spectra of the resultant solutions were subjected to partial least squares (PLS) regression. The optimum number of PLS latent variables was selected according to the PRESS values of leave-one-out cross-validation. A HPLC method was also employed for comparison. The respective mean recoveries for analysis of CBZ and CBZE in synthetic mixtures were 102.57 (±0.25)% and 103.00 (±0.09)% for PLS and 99.40 (±0.15)% and 102.20 (±0.02)%. The concentrations of CBZ and CBZE were also determined in five patients using the PLS and HPLC methods. The results showed that the data obtained by PLS were comparable with those obtained by HPLC method.

  16. Structure of a bacterial homologue of vitamin K epoxide reductase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Weikai; Schulman, Sol; Dutton, Rachel J.

    Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain {gamma}-carboxylation of many blood coagulation factors. Here, we report the 3.6 {angstrom} crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins tomore » reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anticoagulant.« less

  17. Altered cytokeratin expression during chemoprevention of experimental hamster buccal pouch carcinogenesis by garlic.

    PubMed

    Balasenthil, S; Rao, K S; Nagini, S

    2002-03-01

    Cytokeratins (also known as keratins (K)) are members of the family of intermediate filaments and form major components of the mammalian epithelial cell cytoskeleton. Cytokeratins have emerged as reliable cellular markers of oral cancer development and chemoprevention because of their abundance, stability and high antigenicity. We investigated the effect of aqueous garlic extract on cytokeratin expression during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Hamsters were divided into four groups of six animals. Animals in group 1 were painted with a 0.5% solution of DMBA in liquid paraffin, on the right buccal pouches, three times a week for 14 weeks. Group 2 animals were painted with DMBA as in group 1 and also received 250 mg/kg body weight aqueous garlic extract orally on alternate days to the DMBA application. Group 3 animals received garlic extract only, as in group 2. Group 4 animals received neither DMBA nor garlic extract and served as the control. The hamsters were killed after an experimental period of 14 weeks. Cytokeratin expression was studied using human monoclonal antibodies AE1 and AE3, which react with type I and II keratins. In DMBA-induced squamous cell carcinomas, decreased expression of high molecular weight keratins was observed. Administration of garlic extract to animals painted with DMBA suppressed HBP carcinomas and restored normal cytokeratin expression. The results of the present study suggest that inhibition of HBP carcinogenesis by garlic may be due to its regulatory effects on differentiation, tumour invasiveness, migratory and metastatic potential. We suggest that one of the mechanisms of tumour inhibition by garlic is an influence on cellular differentiation.

  18. One-Pot Conversion of Epoxidized Soybean Oil (ESO) into Soy-Based Polyurethanes by MoCl₂O₂ Catalysis.

    PubMed

    Pantone, Vincenzo; Annese, Cosimo; Fusco, Caterina; Fini, Paola; Nacci, Angelo; Russo, Antonella; D'Accolti, Lucia

    2017-02-21

    An innovative and eco-friendly one-pot synthesis of bio-based polyurethanes is proposed via the epoxy-ring opening of epoxidized soybean oil (ESO) with methanol, followed by the reaction of methoxy bio-polyols intermediates with 2,6-tolyl-diisocyanate (TDI). Both synthetic steps, methanolysis and polyurethane linkage formation, are promoted by a unique catalyst, molybdenum(VI) dichloride dioxide (MoCl₂O₂), which makes this procedure an efficient, cost-effective, and environmentally safer method amenable to industrial scale-up.

  19. Abnormal responses to the carcinogen 4-nitroquinoline 1-oxide of cultured fibroblasts from patients with dysplastic nevus syndrome and hereditary cutaneous malignant melanoma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smith, P.J.; Greene, M.H.; Adams, D.

    The dysplastic nevus syndrome (DNS) is a preneoplastic melanocyte abnormality which occurs in families affected by hereditary cutaneous malignant melanoma (HCMM). A putative role of host-environmental interactions in the etiology of hereditary melanoma has been strengthened by the recent finding that fibroblasts derived from HCMM/DNS patients demonstrated enhanced sensitivity to u.v.-irradiation in vitro. An extension of these studies is reported in which we have examined the invitro responses to a model environmental carcinogen, 4-nitroquinoline 1-oxide (4NQO), of six non-tumor skin fibroblast strains from HCMM/DNS patients representing five families. Three of the six HCMM/DNS strains showed enhanced cell killing with sensitivitiesmore » greater than that of a xeroderma pigmentosum (XP) variant strain but less than those of ataxia telangiectasia and XP Group D cell strains. The inhibition and recovery of de novo DNA synthesis, together with the expression of repair synthesis, following 4NQO exposure appeared to be normal in HCMM/DNS strains, irrespective of their subsequent clonogenic potential. The data point to a metabolic anomaly which may contribute to the carcinogenic risk of the melanoma prone preneoplastic state presented by some DNS patients.« less

  20. Overexpression of CYB5R3 and NQO1, two NAD+ -producing enzymes, mimics aspects of caloric restriction.

    PubMed

    Diaz-Ruiz, Alberto; Lanasa, Michael; Garcia, Joseph; Mora, Hector; Fan, Frances; Martin-Montalvo, Alejandro; Di Francesco, Andrea; Calvo-Rubio, Miguel; Salvador-Pascual, Andrea; Aon, Miguel A; Fishbein, Kenneth W; Pearson, Kevin J; Villalba, Jose Manuel; Navas, Placido; Bernier, Michel; de Cabo, Rafael

    2018-04-28

    Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b 5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD + /sirtuin pathway. The results highlight the importance of these NAD + producers for the promotion of health and extended lifespan. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  1. MODULATION BY IONIC STRENGTH AND SUPERHELICITY OF BENZO[a]PYRENE DIOL EPOXIDE INDUCED DNA ALKYLATION AND UNWINDING

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gamper, Howard B.; Straub, Kenneth; Calvin, Melvin

    Superhelical and partially relaxed SV40 DNA were reacted in vitro with (+)7{beta}, 8{alpha}-dihydroxy-9{alpha},10{alpha}-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP diol epoxide). The modified DNA contained N{sup 2} guanine and N{sup 6} adeninte hydrocarbon adducts in the ratio 86:14. Superhelical SV40 DNA was approximately 6% more susceptible to modification than partially relaxed viral DNA. Counterions inhibited DNA alkylation by up to 90%, Mg{sup 2+} being 50-fold more effective than Na{sup +}. The sensitivity of covalent binding to helix stability is consistent with a reaction complex in which BaP diol epoxide is intercalated. The superhelical density of the modified DNA substrates was determined electrophoretically relative to partiallymore » relaxed standards and an unwinding angle for the hydrocarbon adducts was calculated. The angle was dependent upon the superhelicity of the DNA molecule and ranged from 330{sup o} to 30{sup o}. This data indicates that the modified base pairs are disrupted and, in the presence of torsional strain, act as centers for the further denaturation of up to 8 adjacent base pairs. In the absence of such strain the alkylation sites have an ordered structure with the attached hydrocarbon probably oriented in the minor or major groove of the helix.« less

  2. Gas-phase and solution-phase polymerization of epoxides by Cr(salen) complexes: evidence for a dinuclear cationic mechanism.

    PubMed

    Schön, Eva; Zhang, Xiangyang; Zhou, Zhiping; Chisholm, Malcolm H; Chen, Peter

    2004-11-15

    The gas-phase reactions of a series of mass-selected mononuclear and dinuclear Cr(salen) complexes with propylene oxide suggest that the enhanced reactivity of the dinuclear complexes in gas-phase and in solution may derive from a dicationic mechanism in which the alkoxide chain is mu(2)-coordinated to two Lewis acidic metal centers. The double coordination is proposed to suppress backbiting, and hence chain-transfer in the gas-phase homopolymerization of epoxides.

  3. Vitamin K3-2,3-epoxide induction of apoptosis with activation of ROS-dependent ERK and JNK protein phosphorylation in human glioma cells.

    PubMed

    Wu, Jender; Chien, Chih-Chiang; Yang, Liang-Yo; Huang, Guan-Cheng; Cheng, Min-Chi; Lin, Che-Tong; Shen, Shing-Chuan; Chen, Yen-Chou

    2011-08-15

    2-Methyl-1,4-naphthoquinone (menadione or vitamin K3; EPO) and K3-2,3-epoxide (EPO1), but not vitamin K3-3-OH (EPO2), exhibited cytotoxicity that caused DNA fragmentation and chromatin condensation in U87 and C6 cells. EPO1 showed more-potent cytotoxicity than EPO, and the IC(50) values of EPO and EPO1 in U87 cells were 37.5 and 15.7μM, respectively. Activation of caspase 3 enzyme activity with cleavage of caspase 3 protein was detected in EPO1-treated U87 and C6 cells, and the addition of the caspase 3 peptidyl inhibitor, DEVD-FMK, reduced the cytotoxic effect of EPO1. An increase in the intracellular ROS level by EPO1 was observed in the DCHF-DA analysis, and EPO1-induced apoptosis and caspase 3 protein cleavage were prevented by adding the antioxidant, N-acetyl-cysteine (NAC), with decreased ROS production elicited by EPO1. Activation of ERK and JNK, but not p38, via phosphorylation induction was identified in EPO1- but not EPO- or EPO2-treated U87 and C6 cells, and this was blocked by adding NAC. However, the ERK inhibitor, PD98059, and the JNK inhibitor, SP600125, showed no effect on EPO1-induced cytotoxicity in either cell type. Our findings demonstrate that 2,3-epoxide substitution significantly potentiates the apoptotic effect of vitamin K3 via stimulating ROS production, which may be useful in the chemotherapy of glioblastoma cells. Copyright © 2011. Published by Elsevier Ireland Ltd.

  4. Altered soluble epoxide hydrolase-derived oxylipins in patients with seasonal major depression: An exploratory study.

    PubMed

    Hennebelle, Marie; Otoki, Yurika; Yang, Jun; Hammock, Bruce D; Levitt, Anthony J; Taha, Ameer Y; Swardfager, Walter

    2017-06-01

    Many cytochrome p450-derived lipids promote resolution of inflammation, in contrast to their soluble epoxide hydrolase(sEH)-derived oxylipin breakdown products. Here we compare plasma oxylipins and precursor fatty acids between seasons in participants with major depressive disorder with seasonal pattern (MDD-s). Euthymic participants with a history of MDD-s recruited in summer-fall were followed-up in winter. At both visits, a structured clinical interview (DSM-5 criteria) and the Beck Depression Inventory II (BDI-II) were administered. Unesterified and total oxylipin pools were assayed by liquid chromatography tandem mass-spectrometry (LC-MS/MS). Precursor fatty acids were measured by gas chromatography. In nine unmedicated participants euthymic at baseline who met depression criteria in winter, BDI-II scores increased from 4.9±4.4 to 19.9±7.7. Four sEH-derived oxylipins increased in winter compared to summer-fall with moderate to large effect sizes. An auto-oxidation product (unesterified epoxyketooctadecadienoic acid) and lipoxygenase-derived 13-hydroxyoctadecadienoic acid also increased in winter. The cytochrome p450-derived 20-COOH-leukotriene B4 (unesterified) and total 14(15)-epoxyeicosatetraenoic acid, and the sEH-derived 14,15-dihydroxyeicostrienoic acid (unesterified), decreased in winter. We conclude that winter depression was associated with changes in cytochrome p450- and sEH-derived oxylipins, suggesting that seasonal shifts in omega-6 and omega-3 fatty acid metabolism mediated by sEH may underlie inflammatory states in symptomatic MDD-s. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  5. STAT3 as a Chemoprevention Target in Carcinogen-Induced Head and Neck Squamous Cell Carcinoma.

    PubMed

    Peyser, Noah D; Wang, Lin; Zeng, Yan; Acquafondata, Marie; Freilino, Maria; Li, Hua; Sen, Malabika; Gooding, William E; Satake, Masanobu; Wang, Zhenghe; Johnson, Daniel E; Grandis, Jennifer R

    2016-08-01

    Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal disease due, in large part, to a high rate of second primary tumor (SPT) formation. The 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis provides a robust system in which to study chemopreventive agents in the context of chemically induced HNSCC tumors. STAT3 is a potent oncogene that is hyperactivated by tyrosine phosphorylation early in HNSCC carcinogenesis and is a rational therapeutic target. We recently reported that loss-of-function of the STAT3 phosphatase PTPRT promotes STAT3 activation in HNSCC tumors and preclinical models and may serve as a predictive biomarker of response to STAT3 inhibitors, including the small-molecule Stattic. We therefore investigated the hypothesis that Ptprt-knockout (KO) mice would be more susceptible to 4-NQO-induced oral carcinogenesis and more sensitive to Stattic-mediated chemoprevention compared with wild-type (WT) mice. Herein, we demonstrate that Ptprt WT and KO mice develop similar spectra of HNSCC disease severity upon 12 weeks of 4-NQO administration, with no apparent effect of Ptprt genotype on carcinogenesis or treatment outcome. Targeting of STAT3 with Stattic resulted in a chemopreventive effect against 4-NQO-induced oral cancer (P = 0.0402). While these results do not support a central role for PTPRT in 4-NQO-induced HNSCC carcinogenesis, further investigation of STAT3 as a chemoprevention target in this cancer is warranted. Cancer Prev Res; 9(8); 657-63. ©2016 AACR. ©2016 American Association for Cancer Research.

  6. A DFT-Based Computational-Experimental Methodology for Synthetic Chemistry: Example of Application to the Catalytic Opening of Epoxides by Titanocene.

    PubMed

    Jaraíz, Martín; Enríquez, Lourdes; Pinacho, Ruth; Rubio, José E; Lesarri, Alberto; López-Pérez, José L

    2017-04-07

    A novel DFT-based Reaction Kinetics (DFT-RK) simulation approach, employed in combination with real-time data from reaction monitoring instrumentation (like UV-vis, FTIR, Raman, and 2D NMR benchtop spectrometers), is shown to provide a detailed methodology for the analysis and design of complex synthetic chemistry schemes. As an example, it is applied to the opening of epoxides by titanocene in THF, a catalytic system with abundant experimental data available. Through a DFT-RK analysis of real-time IR data, we have developed a comprehensive mechanistic model that opens new perspectives to understand previous experiments. Although derived specifically from the opening of epoxides, the prediction capabilities of the model, built on elementary reactions, together with its practical side (reaction kinetics simulations of real experimental conditions) make it a useful simulation tool for the design of new experiments, as well as for the conception and development of improved versions of the reagents. From the perspective of the methodology employed, because both the computational (DFT-RK) and the experimental (spectroscopic data) components can follow the time evolution of several species simultaneously, it is expected to provide a helpful tool for the study of complex systems in synthetic chemistry.

  7. Identification and characterization of epoxide hydrolase activity of polycyclic aromatic hydrocarbon-degrading bacteria for biocatalytic resolution of racemic styrene oxide and styrene oxide derivatives.

    PubMed

    Woo, Jung-Hee; Kwon, Tae-Hyung; Kim, Jun-Tae; Kim, Choong-Gon; Lee, Eun Yeol

    2013-04-01

    A novel epoxide hydrolase (EHase) from polycyclic aromatic hydrocarbon (PAH)-degrading bacteria was identified and characterized. EHase activity was identified in four strains of PAH-degrading bacteria isolated from commercial gasoline and oil-contaminated sediment based on their growth on styrene oxide and its derivatives, such as 2,3- and 4-chlorostyrene oxides, as a sole carbon source. Gordonia sp. H37 exhibited high enantioselective hydrolysis activity for 4-chlorostyrene oxide with an enantiomeric ratio of 27. Gordonia sp. H37 preferentially hydrolyzed the (R)-enantiomer of styrene oxide derivatives resulting in the preparation of a (S)-enantiomer with enantiomeric excess greater than 99.9 %. The enantioselective EHase activity was identified and characterized in various PAH-degrading bacteria, and whole cell Gordonia sp. H37 was employed as a biocatalyst for preparing enantiopure (S)-styrene oxide derivatives.

  8. Resveratrol pretreatment attenuates injury and promotes proliferation of neural stem cells following oxygen-glucose deprivation/reoxygenation by upregulating the expression of Nrf2, HO-1 and NQO1 in vitro.

    PubMed

    Shen, Changbo; Cheng, Wei; Yu, Pingping; Wang, Li; Zhou, Lulin; Zeng, Li; Yang, Qin

    2016-10-01

    There is considerable interest in the use of drugs and other methods for protecting implanted neural stem cells (NSCs) from the adverse environment of injured tissue for successful cell therapy. Resveratrol can modify cardiac stem cells to enhance their survival and differentiation, however, its effect and the mechanism underlying its neuroprotective effect on NSCs following stroke remain to be fully elucidated. Nuclear factor erythroid 2‑related factor 2 (Nrf‑2) signaling is important in antioxidative stress, and the role of Nrf‑2 signaling in the enhanced neuroprotection of NSCs by resveratrol following stroke also remains to be elucidated. In the present study, NSCs were pretreated with resveratrol prior to oxygen‑glucose deprivation/reoxygenation (OGD/R) in vitro. The survival, apoptosis and proliferation of the NSCs were assessed using an MTT assay, Hoechst 33258 staining of nuclei and flow cytometry, respectively. In addition, the activity of superoxide dismutase (SOD), level of malondiadehyde (MDA) and content of glutathione (GSH) were determined. The protein expressions levels of Nrf‑2, NAD(P)H:quinone oxidoreductase 1 (NQO‑1), and heme oxygenase 1 (HO‑1) were detected using western blot analysis. It was found that resveratrol markedly enhanced NSC survival and proliferation, decreased apoptosis and the levels of MDA, and increased the activity of SOD and content of GSH in a concentration‑dependent manner following OGD/R injury in vitro. In addition, the protein expression levels of Nrf2, HO‑1 and NQO1 were significantly upregulated. These findings suggested that resveratrol attenuated injury and promoted proliferation of the NSCs, at least in part, by upregulating the expression of Nrf2, HO‑1 and NQO1 following OGD/R injury in vitro.

  9. Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase.

    PubMed

    Kim, In-Hae; Park, Yong-Kyu; Nishiwaki, Hisashi; Hammock, Bruce D; Nishi, Kosuke

    2015-11-15

    Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Investigation of miscibility of p(3hydroxybutyrate-co-3hydroxyhexanoate) and epoxidized natural rubber blends

    NASA Astrophysics Data System (ADS)

    Akram, Faridah; Chan, Chin Han; Natarajan, Valliyappan David

    2015-08-01

    Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate [P(3HB-co-3HHx)] produced by C. necator PHB-4 harboring phaCcs from crude palm kernel oil with 21 mol% of 3-hydroxyhexanoate and epoxidized natural rubber with 25 mol% of epoxy content (ENR-25) were used to study the miscibility of the blends by attenuated total reflection-Fourier transform infrared (ATR-FTIR) and differential scanning calorimetry (DSC). The polymers used were purified and the blends were prepared by solution casting method. Nuclear magnetic resonance (NMR) spectra confirm the purity and molecular structures of P(3HB-co-3HHx) and ENR-25. FTIR spectra for different compositions of P(3HB-co-3HHx) and ENR-25 blends show absorbance change of the absorbance bands but with no significant shifting of the absorbance bands as the P(3HB-co-3HHx) content decreases, which shows that there is no intermolecular interaction between the parent polymer blends. On top of that, there are two Tgs present for the blends and both remain constant for different compositions which corresponds to the Tgs of the parent polymers. This indicates that the blends are immiscible.

  11. Ethyl 2-(4-meth-oxy-phen-yl)-6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxyl-ate: crystal structure and Hirshfeld analysis.

    PubMed

    Zukerman-Schpector, Julio; Sugiyama, Fabricia H; Garcia, Ariel L L; Correia, Carlos Roque D; Jotani, Mukesh M; Tiekink, Edward R T

    2017-07-01

    The title compound, C 14 H 17 NO 4 , features an epoxide-O atom fused to a pyrrolidyl ring, the latter having an envelope conformation with the N atom being the flap. The 4-meth-oxy-phenyl group is orthogonal to [dihedral angle = 85.02 (6)°] and lies to the opposite side of the five-membered ring to the epoxide O atom, while the N-bound ethyl ester group (r.m.s. deviation of the five fitted atoms = 0.0187 Å) is twisted with respect to the ring [dihedral angle = 17.23 (9)°]. The most prominent inter-actions in the crystal are of the type methine-C-H⋯O(carbon-yl) and these lead to the formation of linear supra-molecular chains along the c axis; weak benzene-C-H⋯O(epoxide) and methine-C-H⋯O(meth-oxy) inter-actions connect these into a three-dimensional architecture. The analysis of the Hirshfeld surface confirms the presence of C-H⋯O inter-actions in the crystal, but also the dominance of H⋯H dispersion contacts.

  12. Food-Associated Lactobacillus plantarum and Yeasts Inhibit the Genotoxic Effect of 4-Nitroquinoline-1-Oxide

    PubMed Central

    Prete, Roberta; Tofalo, Rosanna; Federici, Ermanno; Ciarrocchi, Aurora; Cenci, Giovanni; Corsetti, Aldo

    2017-01-01

    Lactic acid bacteria and yeasts, representing the prevailing microbiota associated with different foods generally consumed without any cooking, were identified and characterized in vitro for some functional properties, such as acid-bile tolerance and antigenotoxic activity. In particular, 22 Lactobacillus plantarum strains and 14 yeasts were studied. The gastro-intestinal tract tolerance of all the strains was determined by exposing washed cell suspensions at 37°C to a simulated gastric juice (pH 2.0), containing pepsin (0.3% w/v) and to a simulated small intestinal juice (pH 8.0), containing pancreatin (1 mg mL-1) and bile extract (0.5%), thus monitoring changes in total viable count. In general, following a strain-dependent behavior, all the tested strains persisted alive after combined acid-bile challenge. Moreover, many strains showed high in vitro inhibitory activity against a model genotoxin, 4-nitroquinoline-1-oxide (4-NQO), as determined by the short-term method, SOS-Chromotest. Interestingly, the supernatants from bacteria- or yeasts-genotoxin co-incubations exhibited a suppression on SOS-induction produced by 4-NQO on the tester strain Escherichia coli PQ37 (sfiA::lacZ) exceeding, in general, the value of 75%. The results highlight that food associated microorganisms may reach the gut in viable form and prevent genotoxin DNA damage in situ. Our experiments can contribute to elucidate the functional role of food-associated microorganisms general recognized as safe ingested with foods as a part of the diet. PMID:29234315

  13. Engineering characterisation of epoxidized natural rubber-modified hot-mix asphalt

    PubMed Central

    Al-Mansob, Ramez A.; Ismail, Amiruddin; Yusoff, Nur Izzi Md.; Rahmat, Riza Atiq O. K.; Borhan, Muhamad Nazri; Albrka, Shaban Ismael; Azhari, Che Husna; Karim, Mohamed Rehan

    2017-01-01

    Road distress results in high maintenance costs. However, increased understandings of asphalt behaviour and properties coupled with technological developments have allowed paving technologists to examine the benefits of introducing additives and modifiers. As a result, polymers have become extremely popular as modifiers to improve the performance of the asphalt mix. This study investigates the performance characteristics of epoxidized natural rubber (ENR)-modified hot-mix asphalt. Tests were conducted using ENR–asphalt mixes prepared using the wet process. Mechanical testing on the ENR–asphalt mixes showed that the resilient modulus of the mixes was greatly affected by testing temperature and frequency. On the other hand, although rutting performance decreased at high temperatures because of the increased elasticity of the ENR–asphalt mixes, fatigue performance improved at intermediate temperatures as compared to the base mix. However, durability tests indicated that the ENR–asphalt mixes were slightly susceptible to the presence of moisture. In conclusion, the performance of asphalt pavement can be enhanced by incorporating ENR as a modifier to counter major road distress. PMID:28182724

  14. Engineering characterisation of epoxidized natural rubber-modified hot-mix asphalt.

    PubMed

    Al-Mansob, Ramez A; Ismail, Amiruddin; Yusoff, Nur Izzi Md; Rahmat, Riza Atiq O K; Borhan, Muhamad Nazri; Albrka, Shaban Ismael; Azhari, Che Husna; Karim, Mohamed Rehan

    2017-01-01

    Road distress results in high maintenance costs. However, increased understandings of asphalt behaviour and properties coupled with technological developments have allowed paving technologists to examine the benefits of introducing additives and modifiers. As a result, polymers have become extremely popular as modifiers to improve the performance of the asphalt mix. This study investigates the performance characteristics of epoxidized natural rubber (ENR)-modified hot-mix asphalt. Tests were conducted using ENR-asphalt mixes prepared using the wet process. Mechanical testing on the ENR-asphalt mixes showed that the resilient modulus of the mixes was greatly affected by testing temperature and frequency. On the other hand, although rutting performance decreased at high temperatures because of the increased elasticity of the ENR-asphalt mixes, fatigue performance improved at intermediate temperatures as compared to the base mix. However, durability tests indicated that the ENR-asphalt mixes were slightly susceptible to the presence of moisture. In conclusion, the performance of asphalt pavement can be enhanced by incorporating ENR as a modifier to counter major road distress.

  15. Synthesis and field screening of chiral monounsaturated epoxides as lepidopteran sex attractants and sex pheromone components.

    PubMed

    Millar, J G; Giblin, M; Barton, D; Underhill, E W

    1991-05-01

    Enantiomerically enriched forms of (Z)-6-cis-9,10-epoxymonoenes and (Z)-9-cis-6,7-epoxymonoenes of chain lengths C17-20 were synthesized by Sharpless asymmetric epoxidation of allylic alcohol intermediates, followed by tosylation or halogenation and chain extension. The resulting monounsaturated epoxides were field tested as sex attractants for lepidopteran species.Euchlaena madusaria Walker males were attracted to blends of the enantiomers of (Z)-6- cis- 9,10-epoxynonadecene 6Z-cis-9,10-epoxy-19:H; IUPAC name [2α,3α(Z)]-2-pentyl-3-(2-dodecenyI)oxirane in combination with 6Z,9Z-19: H. The response was antagonized by 9Z-cis-6,7-epoxy-19: H. 6Z,9Z-19: H was tentatively identified in pheromone gland extracts.Xanthotype sospeta Drury male moths were attracted to lures containing 6Z-9S,10R-epoxy-19: H; the response was antagonized by the opposite enantiomer.Pal-this angulalis Hübner males were attracted to 9Z-6S,7R-epoxy-19:H; the opposite enantiomer was antagonistic. 6Z,9Z-19:H and 9Z-cis-6,7-epoxy-19:H and 9Z-cis-6,7-epoxy-19:H were tentatively identified in pheromone gland extracts fromAnacamptodes humaria Guenée females. In field trails, 9Z-6R,7S-epoxy-19:H proved to be the attractive enantiomer, and the response was potentiated by 6Z,9Z-19:H. Mechanisms by which unique chemical communication channels are maintained by each species are discussed.

  16. The effects of combination of Eurycoma longifolia Jack ethanolic extract and doxorubicine on hematological profile in rats given by 7,12-dimethylbenz(a)anthracene

    NASA Astrophysics Data System (ADS)

    Nurani, L. H.; Mursyidi, A.; Widyarini, S.; Rohman, A.

    2017-11-01

    Doxorubicin (Dox) is known as anticancer drug commonly used for cancer treatment. Eurycoma longifolia Jack or Pasakbumi was reported to have chemopreventive effect. In cancer patients, there are some dysfunctions of blood parameter, therefore some hematologic tests are needed to monitor cancer patients. In this study, the effects of combination of ethanolic extract of E. longifolia Jack (EEE) and Dox on hematologic profiles were investigated in rats injected by DMBA. Rats were divided into eight groups. Group I was normal group; Group II, rats were treated with extract dose 100 mg/kgbw; Groups III, IV, V, VI, VII and VIII, rats were treated with Dox, DMBA, DMBA+Dox, DMBA+EEE, DMBA+Dox +EEE, and Dox+EEE, respectively. DMBA administration orally was conducted twice a week for 5 weeks. At 16th week of treatments, bloods were taken from orbitalis sinus for hematologicals profile (levels of Hb, erytrocyte, hematocrite, leukocyte, MCV, MCH, and differencial leucocyte count) measurements. These data were analyzed by one way ANOVA followed by LSD test. DMBA administration significantly decreased the hematological profiles compared to the normal group, except in lymphocyte level. Rats treated with extract and extract+Dox were able to increase the hematological profile compared to rats given by DMBA only. Based on these findings it can be concluded that the combination of EEE and Dox potentially increase hematological profile of rats given by DMBA.

  17. Calcium oxide supported gold nanoparticles as catalysts for the selective epoxidation of styrene by t-butyl hydroperoxide.

    PubMed

    Dumbre, Deepa K; Choudhary, Vasant R; Patil, Nilesh S; Uphade, Balu S; Bhargava, Suresh K

    2014-02-01

    Gold nanoparticles are deposited on basic CaO supports as catalysts for the selective conversion of styrene into styrene oxide. Synthetic methods, gold loading and calcination temperatures are varied to permit an understanding of their influence on gold nanoparticle size, the presence of cationic gold species and the nature of interaction between the gold nanoparticles and the CaO support. Based on these studies, optimal conditions are designed to make the Au/CaO catalyst efficient for the selective epoxidation of styrene. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Protective effects of new medicinal mushroom, Grifola gargal singer (higher Basidiomycetes), on induced DNA damage in somatic cells of Drosophila melanogaster.

    PubMed

    Postemsky, Pablo Daniel; Palermo, Ana Maria; Curvetto, Néstor Raúl

    2011-01-01

    Grifola gargal is an edible mushroom with attributed antioxidant properties. Different sources of G. gargal materials, i.e., fruit bodies and mycelia grown in liquid or solid media, were used to study its potential protective capacity when somatic mutation and recombination is induced in Drosophila melanogaster using DMBA (7-12-dimethyl-benz(α)anthracene) as promutagen. Heterozygote larvae (white/white+) were grown in media with different concentrations of DMBA. Grifola gargal fruit bodies (GgFB) or mycelia from liquid culture (GgLC) or from solid culture (GgWG), i.e., biotransformed wheat kernel flour, were added to the culture media in combined treatments with DMBA. Water, DMBA solvent, or wheat flour (WF) plus DMBA solvent were used as negative controls. Larval mortality increased from 9% to 11% in negative controls to 31% to 36% in DMBA treatments. The addition of GgFB, GgLC, or GgWG materials produced a protective effect on 25 μmol/vial DMBA-induced mortality. Mutations observed in SMART, as light spots per 100 eyes (LS/100 eyes), increased with increasing doses of DMBA; this was also true when considering the mutation incidence expressed as percentage of eyes exhibiting light spots (% eyes with LS). Interestingly, mycelia from GgFB, GgLC, or GgWG, in the presence of 25 μmol/vial DMBA, showed lower values in SMART of both the total LS/100 eyes and the percentage of eyes with LS. Thus, Grifola gargal materials were not only nontoxic, but in combination with 25 μmol/vial DMBA lowered the mortality induced by the promutagen and showed antimutagenic effects. Protective effects of G. gargal against DMBA are discussed in terms of the onset of desmutagenic and/or bioantimutagenic mechanisms of detoxification in the host organism, probably due to some bioactive compounds known to occur in higher mushrooms.

  19. Use of high frequency ultrasound to monitor cervical lymph node alterations in mice.

    PubMed

    Walk, Elyse L; McLaughlin, Sarah; Coad, James; Weed, Scott A

    2014-01-01

    Cervical lymph node evaluation by clinical ultrasound is a non-invasive procedure used in diagnosing nodal status, and when combined with fine-needle aspiration cytology (FNAC), provides an effective method to assess nodal pathologies. Development of high-frequency ultrasound (HF US) allows real-time monitoring of lymph node alterations in animal models. While HF US is frequently used in animal models of tumor biology, use of HF US for studying cervical lymph nodes alterations associated with murine models of head and neck cancer, or any other model of lymphadenopathy, is lacking. Here we utilize HF US to monitor cervical lymph nodes changes in mice following exposure to the oral cancer-inducing carcinogen 4-nitroquinoline-1-oxide (4-NQO) and in mice with systemic autoimmunity. 4-NQO induces tumors within the mouse oral cavity as early as 19 wks that recapitulate HNSCC. Monitoring of cervical (mandibular) lymph nodes by gray scale and power Doppler sonography revealed changes in lymph node size eight weeks after 4-NQO treatment, prior to tumor formation. 4-NQO causes changes in cervical node blood flow resulting from oral tumor progression. Histological evaluation indicated that the early 4-NQO induced changes in lymph node volume were due to specific hyperproliferation of T-cell enriched zones in the paracortex. We also show that HF US can be used to perform image-guided fine needle aspirate (FNA) biopsies on mice with enlarged mandibular lymph nodes due to genetic mutation of Fas ligand (Fasl). Collectively these studies indicate that HF US is an effective technique for the non-invasive study of cervical lymph node alterations in live mouse models of oral cancer and other mouse models containing cervical lymphadenopathy.

  20. Effect of epoxidation on 30% poly(methyl methacrylate)-grafted natural rubber polymer electrolytes

    NASA Astrophysics Data System (ADS)

    Nazir, Khuzaimah; Aziz, Ahmad Fairoz; Adam, Nurul Ilham; Yahya, Muhd Zu Azhan; Ali, Ab Malik Marwan

    2015-08-01

    Epoxidized 30% poly(methyl methacrylate)-grafted natural rubber (EMG 30) as a polymer host in solid polymer electrolytes (SPEs) has been investigated. EMG30 was synthesized via performicepoxidation method onto 30% poly(methyl methacrylate)-grafted natural rubber (MG30) and the formations of epoxy group were discussed. The EMG30 were characterized by proton nuclear magnetic resonance (1HNMR) to investigate their chemical structure and differential scanning calorimeter to determine their crystallinity. A new peak in 1HNMR spectra (2.71 ppm) confirmed the appearance of epoxy group. SPE based on EMG30 doped with 40 wt% LiCF3SO3 show the highest conductivity. The complexation between EMG30 and LiCF3SO3 were confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR).

  1. The main thylakoid membrane lipid monogalactosyldiacylglycerol (MGDG) promotes the de-epoxidation of violaxanthin associated with the light-harvesting complex of photosystem II (LHCII).

    PubMed

    Schaller, Susann; Latowski, Dariusz; Jemioła-Rzemińska, Małgorzata; Wilhelm, Christian; Strzałka, Kazimierz; Goss, Reimund

    2010-03-01

    In higher plants, the major part of the xanthophyll cycle pigment violaxanthin (Vx) is non-covalently bound to the main light-harvesting complex of PSII (LHCII). Under saturating light conditions Vx has to be released from its binding site into the surrounding lipid phase, where it is converted to zeaxanthin (Zx) by the enzyme Vx de-epoxidase (VDE). In the present study we investigated the influence of thylakoid lipids on the de-epoxidation of Vx, which was still associated with the LHCII. We isolated LHCII with different concentrations of native, endogenous lipids and Vx by sucrose gradient centrifugation or successive cation precipitation. Analysis of the different LHCII preparations showed that the concentration of LHCII-associated Vx was correlated with the concentration of the main thylakoid lipid monogalactosyldiacylglycerol (MGDG) associated with the complexes. Decreases in the MGDG content of the LHCII led to a diminished Vx concentration, indicating that a part of the total Vx pool was located in an MGDG phase surrounding the LHCII, whereas another part was bound to the LHCII apoproteins. We further studied the convertibility of LHCII-associated Vx in in-vitro enzyme assays by addition of isolated VDE. We observed an efficient and almost complete Vx conversion in the LHCII fractions containing high amounts of endogenous MGDG. LHCII preparations with low concentrations of MGDG exhibited a strongly reduced Vx de-epoxidation, which could be increased by addition of exogenous, pure MGDG. The de-epoxidation of LHCII-associated Vx was saturated at a much lower concentration of native, endogenous MGDG compared with the concentration of isolated, exogenous MGDG, which is needed for optimal VDE activity in in-vitro assays employing pure isolated Vx. Copyright 2009 Elsevier B.V. All rights reserved.

  2. Epoxide hydrolase Lsd19 for polyether formation in the biosynthesis of lasalocid A: direct experimental evidence on polyene-polyepoxide hypothesis in polyether biosynthesis.

    PubMed

    Shichijo, Yoshihiro; Migita, Akira; Oguri, Hiroki; Watanabe, Mami; Tokiwano, Tetsuo; Watanabe, Kenji; Oikawa, Hideaki

    2008-09-17

    Polyether metabolites are an important class of natural products. Although their biosynthesis, especially construction of polyether skeletons, attracted organic chemists for many years, no experimental data on the enzymatic polyether formation has been obtained. In this study, a putative epoxide hydrolase gene lsd19 found on the biosynthetic gene cluster of an ionophore polyether lasalocid was cloned and successfully overexpressed in Escherichia coli. Using the purified Lsd19, a proposed substrate, bisepoxyprelasalocid, and its synthesized analogue were successfully converted into lasalocid A and its derivative via a 6-endo-tet cyclization mode. On the other hand, treatment of the bisepoxide with trichloroacetic acid gave isolasalocid A via a 5-exo-tet cyclization mode. Therefore, the enzymatic conversion observed in this study unambiguously showed that the bisepoxyprelasalocid is an intermediate of the lasalocid biosynthesis and that Lsd19 catalyzes the sequential cyclic ether formations involving an energetically disfavored 6-endo-tet cyclization. This is the first example of the enzymatic epoxide-opening reactions leading to a polyether natural product.

  3. Interaction of benzo[a]pyrene diol epoxide isomers with human serum albumin: Site specific characterisation of adducts and associated kinetics

    NASA Astrophysics Data System (ADS)

    Motwani, Hitesh V.; Westberg, Emelie; Törnqvist, Margareta

    2016-11-01

    Carcinogenicity of benzo[a]pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)} involves DNA-modification by B[a]P diol epoxide (BPDE) metabolites. Adducts to serum albumin (SA) are not repaired, unlike DNA adducts, and therefore considered advantageous in assessment of in vivo dose of BPDEs. In the present work, kinetic experiments were performed in relation to the dose (i.e. concentration over time) of different BPDE isomers, where human SA (hSA) was incubated with respective BPDEs under physiological conditions. A liquid chromatography (LC) tandem mass spectrometry methodology was employed for characterising respective BPDE-adducts at histidine and lysine. This strategy allowed to structurally distinguish between the adducts from racemic anti- and syn-BPDE and between (+)- and (-)-anti-BPDE, which has not been attained earlier. The adduct levels quantified by LC-UV and the estimated rate of disappearance of BPDEs in presence of hSA gave an insight into the reactivity of the diol epoxides towards the N-sites on SA. The structure specific method and dosimetry described in this work could be used for accurate estimation of in vivo dose of the BPDEs following exposure to B[a]P, primarily in dose response studies of genotoxicity, e.g. in mice, to aid in quantitative risk assessment of PAHs.

  4. Cytologic Effects of Air Force Chemicals

    DTIC Science & Technology

    1978-09-01

    pCi/ml, 60 Ci/mmole), hydroxyurea (10- 2M) to suppress replicative DNA synthesis, and with or without 4-nitroquinoline-l-oxide (4NQO, a DNA-damaging...organ cultures. The tissues were minced in cold, buffered saline and then incubated with 3 H-thymidine, hydroxyurea and 4NQO to damage cellular DNA...incorporation under these conditions is taken as an indication of DNA repair activity, and incorporation of 3H-thymidine in the absence of hydroxyurea and

  5. Effect of Organo-Modified Nanoclay on the Thermal and Bulk Structural Properties of Poly(3-hydroxybutyrate)-Epoxidized Natural Rubber Blends: Formation of Multi-Components Biobased Nanohybrids.

    PubMed

    Salehabadi, Ali; Bakar, Mohamad Abu; Bakar, Noor Hana Hanif Abu

    2014-06-13

    Multi-component nanohybrids comprising of organo-modified montmorillonite (MMT) and immiscible biopolymer blends of poly(3-hydroxybutyrate) (PHB) and epoxidized natural rubber (ENR-50) were prepared by solvent casting technique. The one and three dimensional morphology of PHB/ENR-50/MMT systems were studied using Polarizing Optical Microscopy (POM) and Scanning Electron Microscopy (SEM). Differential scanning calorimetry (DSC) technique was used to evaluate the thermal properties of the nanohybrids. The melting temperature ( T m ) and enthalpy of melting (Δ H m ) of PHB decrease with respect to the increase in ENR-50 as well as MMT content. The non-isothermal decomposition of the nanohybrids was studied using thermogravimetric (TG-DTG) analysis. FTIR-ATR spectra supported ring opening of the epoxide group via reaction with carboxyl group of PHB and amines of organic modifier. The reaction mechanism towards the formation of the nanohybrids is proposed.

  6. Upregulation of intrinsic apoptotic pathway in NSAIDs mediated chemoprevention of experimental lung carcinogenesis.

    PubMed

    Setia, Shruti; Sanyal, Sankar N

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer. The role of COX-2 and apoptosis were evaluated in 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung cancer in rat and chemoprevention with indomethacin, a traditional NSAID and etoricoxib, a selective COX-2 inhibitor. The animals were divided into Control, DMBA, DMBA+ indomethacin and DMBA+ etoricoxib groups. They received a single intratracheal instillation of DMBA while NSAIDs were given orally daily for 32 weeks. Besides morphology and histology of lungs, RT-PCR, western blots and immunohistochemistry were performed for the expression of apoptotic proteins and COX enzymes. Apoptosis was studied by DNA fragmentation and fluorescent staining. The occurrence of tumors and lesions was noted in the DMBA animals, besides constricted alveolar spaces and hyperplasia. COX-1 was found to be uniformly expressed while COX-2 level was raised significantly in DMBA group. The apoptotic proteins, apaf-1, caspase-9 and caspase-3 were highly diminished in DMBA group but restored to normal level in NSAIDs groups. Also, apoptosis was suppressed in carcinogen group by DNA fragmentation analysis and fluorescent staining of the lung cells while co-administration of NSAIDs along with DMBA led to the restoration of apoptosis. DMBA administration to the rats led to tumorigenesis in the lungs, had no effects on COX-1 expression, while elevating the COX-2 levels and suppressing apoptosis. The treatment with NSAIDs led to the amelioration of these effects. However, etoricoxib which is a COX-2 specific inhibitor, was found to be more effective than the traditional NSAID, indomethacin.

  7. Crystallinity enhancement of Nafion electrolyte membranes assisted by a molecular gelator.

    PubMed

    Zhang, Wenjing; Yue, Po-Lock; Gao, Ping

    2011-08-02

    Nanocrystallites, acting as physical cross-links in Nafion membranes, play a crucial role in building blocks for improving mechanical durability and stopping fuel crossover. However, Nafion membranes suffer from low crystallinity due to the irregular pendent side chains, which hinder self-aggregation of the poly(tetrafluoroethylene) (PTFE) backbones. For the first time, a molecular gelator was introduced in the membrane casting process to enhance the rate of self-assembly of PTFE backbones so as to increase the membrane's crystallinity as well as proton conductivity without sacrificing the purity of Nafion. The molecular gelator used was 3,4-dimethylbenzaldehyde (DMBA). Addition of 0.5 wt % DMBA led to a 42% increase in crystallinity, a 32% increase in yield strength, a 22% increase in tensile modulus and an 18% increase in proton conductivity at 60 °C and 90% relative humidity. Additionally, the membrane electrode assembly (MEA) prepared from the membranes cast from the solution containing 0.5 wt % DMBA also showed an increase of 17% in maximum power density in comparison to the MEA prepared from pure Nafion membrane in a single cell polarization test without any external humidification. Transmission electron microscopy (TEM) and molecular dynamics simulation were used to elucidate the structural changes in Nafion membrane due to the introduction of DMBA. It was observed that the presence of DMBA gives wider crystalline regions under TEM. The molecular dynamics simulation at 500 K shows that the PTFE backbones become elongated in the presence of DMBA due to the enhanced mobility. This is consistent with the observed increase in crystallinity in the membrane as it means reduced entropic change upon crystallization.

  8. Ganoderma lucidum total triterpenes induce apoptosis in MCF-7 cells and attenuate DMBA induced mammary and skin carcinomas in experimental animals.

    PubMed

    Smina, T P; Nitha, B; Devasagayam, T P A; Janardhanan, K K

    2017-01-01

    Ganoderma lucidum total triterpenes were evaluated for its apoptosis-inducing and anti-cancer activities. Cytotoxicity and pro-apoptotic effect of total triterpenes were evaluated in human breast adenocarcinoma (MCF-7) cell line using MTT assay and DNA fragmentation analysis. Total triterpenes induced apoptosis in MCF-7 cells by down-regulating the levels of cyclin D1, Bcl-2, Bcl-xL and also by up-regulating the levels of Bax and caspase-9. Anti-carcinogenicity of total triterpenes was analysed using dimethyl benz [a] anthracene (DMBA) induced skin papilloma and mammary adenocarcinoma in Swiss albino mice and Wistar rats respectively. Topical application of 5mg, 10mg and 20mg total triterpenes reduced the incidence of skin papilloma by 62.5, 37.5 and 12.5% respectively. Incidence of the mammary tumour was also reduced significantly by 33.33, 66.67 and 16.67% in 10, 50 and 100mg/kg b.wt. total triterpenes treated animals respectively. Total triterpenes were also found to reduce the average number of tumours per animal and extended the tumour latency period in both the models. The results indicate the potential cytotoxicity and anti-cancerous activity of total triterpenes, there by opens up a path to the development of a safe and successive chemo preventive agent of natural origin. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Epoxide as a precursor to secondary organic aerosol formation from isoprene photooxidation in the presence of nitrogen oxides

    PubMed Central

    Lin, Ying-Hsuan; Zhang, Haofei; Pye, Havala O. T.; Zhang, Zhenfa; Marth, Wendy J.; Park, Sarah; Arashiro, Maiko; Cui, Tianqu; Budisulistiorini, Sri Hapsari; Sexton, Kenneth G.; Vizuete, William; Xie, Ying; Luecken, Deborah J.; Piletic, Ivan R.; Edney, Edward O.; Bartolotti, Libero J.; Gold, Avram; Surratt, Jason D.

    2013-01-01

    Isoprene is a substantial contributor to the global secondary organic aerosol (SOA) burden, with implications for public health and the climate system. The mechanism by which isoprene-derived SOA is formed and the influence of environmental conditions, however, remain unclear. We present evidence from controlled smog chamber experiments and field measurements that in the presence of high levels of nitrogen oxides (NOx = NO + NO2) typical of urban atmospheres, 2-methyloxirane-2-carboxylic acid (methacrylic acid epoxide, MAE) is a precursor to known isoprene-derived SOA tracers, and ultimately to SOA. We propose that MAE arises from decomposition of the OH adduct of methacryloylperoxynitrate (MPAN). This hypothesis is supported by the similarity of SOA constituents derived from MAE to those from photooxidation of isoprene, methacrolein, and MPAN under high-NOx conditions. Strong support is further derived from computational chemistry calculations and Community Multiscale Air Quality model simulations, yielding predictions consistent with field observations. Field measurements taken in Chapel Hill, North Carolina, considered along with the modeling results indicate the atmospheric significance and relevance of MAE chemistry across the United States, especially in urban areas heavily impacted by isoprene emissions. Identification of MAE implies a major role of atmospheric epoxides in forming SOA from isoprene photooxidation. Updating current atmospheric modeling frameworks with MAE chemistry could improve the way that SOA has been attributed to isoprene based on ambient tracer measurements, and lead to SOA parameterizations that better capture the dependency of yield on NOx. PMID:23553832

  10. Epoxide as a precursor to secondary organic aerosol formation from isoprene photooxidation in the presence of nitrogen oxides.

    PubMed

    Lin, Ying-Hsuan; Zhang, Haofei; Pye, Havala O T; Zhang, Zhenfa; Marth, Wendy J; Park, Sarah; Arashiro, Maiko; Cui, Tianqu; Budisulistiorini, Sri Hapsari; Sexton, Kenneth G; Vizuete, William; Xie, Ying; Luecken, Deborah J; Piletic, Ivan R; Edney, Edward O; Bartolotti, Libero J; Gold, Avram; Surratt, Jason D

    2013-04-23

    Isoprene is a substantial contributor to the global secondary organic aerosol (SOA) burden, with implications for public health and the climate system. The mechanism by which isoprene-derived SOA is formed and the influence of environmental conditions, however, remain unclear. We present evidence from controlled smog chamber experiments and field measurements that in the presence of high levels of nitrogen oxides (NO(x) = NO + NO2) typical of urban atmospheres, 2-methyloxirane-2-carboxylic acid (methacrylic acid epoxide, MAE) is a precursor to known isoprene-derived SOA tracers, and ultimately to SOA. We propose that MAE arises from decomposition of the OH adduct of methacryloylperoxynitrate (MPAN). This hypothesis is supported by the similarity of SOA constituents derived from MAE to those from photooxidation of isoprene, methacrolein, and MPAN under high-NOx conditions. Strong support is further derived from computational chemistry calculations and Community Multiscale Air Quality model simulations, yielding predictions consistent with field observations. Field measurements taken in Chapel Hill, North Carolina, considered along with the modeling results indicate the atmospheric significance and relevance of MAE chemistry across the United States, especially in urban areas heavily impacted by isoprene emissions. Identification of MAE implies a major role of atmospheric epoxides in forming SOA from isoprene photooxidation. Updating current atmospheric modeling frameworks with MAE chemistry could improve the way that SOA has been attributed to isoprene based on ambient tracer measurements, and lead to SOA parameterizations that better capture the dependency of yield on NO(x).

  11. Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

    PubMed

    Deng, Wensheng; Zhu, Yiming; Lin, Jiayun; Zheng, Lei; Zhang, Chihao; Luo, Meng

    2017-07-01

    Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Expression of Ki-67 and P16 INK4a in chemically-induced perioral squamous cell carcinomas in mice.

    PubMed

    Alves, Ângela Valéria Farias; Ribeiro, Danielle Rodrigues; Lima, Sonia Oliveira; Reis, Francisco Prado; Soares, Andréa Ferreira; Gomes, Margarete Zanardo; Albuquerque, Ricardo Luiz Cavalcanti de

    2016-01-01

    to evaluate the influence of Ki-67 and P16INK4a proteins immunohistochemical expressions on the clinical and morphological parameters of perioral squamous cell carcinoma induced with 9,10-dimethyl-1,2-benzanthracene (DMBA) in mice. we topically induced the lesions in the oral commissure of ten Swiss mice for 20 weeks, determining the time to tumors onset and the average tumor volume up to 26 weeks. In histopathological analysis, the variables studied were histological malignancy grade and the immunohistochemical expression of Ki-67 and P16INK4a proteins. The correlation between variables was determined by application of the Spearman correlation test. the mean time to onset of perioral lesions was 21.1 ± 2.13 weeks; mean tumor volume was 555.91 ± 205.52 mm3. Of the induced tumors, 80% were classified as low score and 20% high score. There was diffuse positivity for Ki-67 in 100% of lesions - Proliferation Index (PI) of 50.1 ± 18.0. There was a strong direct correlation between Ki-67 immunoreactivity and tumor volume (R = 0.702) and a low correlation with the malignancy score (R = 0.486). The P16INK4a protein expression was heterogeneous, showing a weak correlation with tumor volume (R = 0.334). There was no correlation between the immunohistochemical expression of the two proteins studied. in an experimental model of DMBA-induced perioral carcinogenesis, tumor progression was associated with the tumor proliferative fraction (Ki-67 positive cells) and with tumor histological grading, but not with P16INK4a expression. avaliar a influência da expressão imuno-histoquímica das proteínas Ki-67 e p16INK4a sobre parâmetros clínico-morfológicos em carcinomas espinocelulares periorais quimicamente induzidos com 9,10-dimetil-1,2-benzantraceno (DMBA) em modelo murino. as lesões foram induzidas topicamente na comissura labial de dez camundongos Swiss durante 20 semanas, sendo determinado o momento de surgimento dos tumores e volume tumoral médio até 26 semanas. Na

  13. Effect of epoxidation on 30% poly(methyl methacrylate)-grafted natural rubber polymer electrolytes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nazir, Khuzaimah; Aziz, Ahmad Fairoz; Adam, Nurul Ilham

    Epoxidized 30% poly(methyl methacrylate)-grafted natural rubber (EMG 30) as a polymer host in solid polymer electrolytes (SPEs) has been investigated. EMG30 was synthesized via performicepoxidation method onto 30% poly(methyl methacrylate)-grafted natural rubber (MG30) and the formations of epoxy group were discussed. The EMG30 were characterized by proton nuclear magnetic resonance ({sup 1}HNMR) to investigate their chemical structure and differential scanning calorimeter to determine their crystallinity. A new peak in {sup 1}HNMR spectra (2.71 ppm) confirmed the appearance of epoxy group. SPE based on EMG30 doped with 40 wt% LiCF{sub 3}SO{sub 3} show the highest conductivity. The complexation between EMG30 and LiCF{submore » 3}SO{sub 3} were confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR)« less

  14. Investigation of miscibility of p(3hydroxybutyrate-co-3hydroxyhexanoate) and epoxidized natural rubber blends

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Akram, Faridah; Chan, Chin Han; Natarajan, Valliyappan David

    Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate [P(3HB-co-3HHx)] produced by C. necator PHB{sup −}4 harboring phaC{sub cs} from crude palm kernel oil with 21 mol% of 3-hydroxyhexanoate and epoxidized natural rubber with 25 mol% of epoxy content (ENR-25) were used to study the miscibility of the blends by attenuated total reflection-Fourier transform infrared (ATR-FTIR) and differential scanning calorimetry (DSC). The polymers used were purified and the blends were prepared by solution casting method. Nuclear magnetic resonance (NMR) spectra confirm the purity and molecular structures of P(3HB-co-3HHx) and ENR-25. FTIR spectra for different compositions of P(3HB-co-3HHx) and ENR-25 blends show absorbance change of the absorbance bands but with nomore » significant shifting of the absorbance bands as the P(3HB-co-3HHx) content decreases, which shows that there is no intermolecular interaction between the parent polymer blends. On top of that, there are two T{sub g}s present for the blends and both remain constant for different compositions which corresponds to the T{sub g}s of the parent polymers. This indicates that the blends are immiscible.« less

  15. Conserved Loop Cysteines of Vitamin K Epoxide Reductase Complex Subunit 1-like 1 (VKORC1L1) Are Involved in Its Active Site Regeneration*

    PubMed Central

    Tie, Jian-Ke; Jin, Da-Yun; Stafford, Darrel W.

    2014-01-01

    Vitamin K epoxide reductase complex subunit 1 (VKORC1) reduces vitamin K epoxide in the vitamin K cycle for post-translational modification of proteins that are involved in a variety of biological functions. However, the physiological function of VKORC1-like 1 (VKORC1L1), a paralogous enzyme sharing about 50% protein identity with VKORC1, is unknown. Here we determined the structural and functional differences of these two enzymes using fluorescence protease protection (FPP) assay and an in vivo cell-based activity assay. We show that in vivo VKORC1L1 reduces vitamin K epoxide to support vitamin K-dependent carboxylation as efficiently as does VKORC1. However, FPP assays show that unlike VKORC1, VKORC1L1 is a four-transmembrane domain protein with both its termini located in the cytoplasm. Moreover, the conserved loop cysteines, which are not required for VKORC1 activity, are essential for VKORC1L1's active site regeneration. Results from domain exchanges between VKORC1L1 and VKORC1 suggest that it is VKORC1L1's overall structure that uniquely allows for active site regeneration by the conserved loop cysteines. Intermediate disulfide trapping results confirmed an intra-molecular electron transfer pathway for VKORC1L1's active site reduction. Our results allow us to propose a concerted action of the four conserved cysteines of VKORC1L1 for active site regeneration; the second loop cysteine, Cys-58, attacks the active site disulfide, forming an intermediate disulfide with Cys-139; the first loop cysteine, Cys-50, attacks the intermediate disulfide resulting in active site reduction. The different membrane topologies and reaction mechanisms between VKORC1L1 and VKORC1 suggest that these two proteins might have different physiological functions. PMID:24532791

  16. Conserved loop cysteines of vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) are involved in its active site regeneration.

    PubMed

    Tie, Jian-Ke; Jin, Da-Yun; Stafford, Darrel W

    2014-03-28

    Vitamin K epoxide reductase complex subunit 1 (VKORC1) reduces vitamin K epoxide in the vitamin K cycle for post-translational modification of proteins that are involved in a variety of biological functions. However, the physiological function of VKORC1-like 1 (VKORC1L1), a paralogous enzyme sharing about 50% protein identity with VKORC1, is unknown. Here we determined the structural and functional differences of these two enzymes using fluorescence protease protection (FPP) assay and an in vivo cell-based activity assay. We show that in vivo VKORC1L1 reduces vitamin K epoxide to support vitamin K-dependent carboxylation as efficiently as does VKORC1. However, FPP assays show that unlike VKORC1, VKORC1L1 is a four-transmembrane domain protein with both its termini located in the cytoplasm. Moreover, the conserved loop cysteines, which are not required for VKORC1 activity, are essential for VKORC1L1's active site regeneration. Results from domain exchanges between VKORC1L1 and VKORC1 suggest that it is VKORC1L1's overall structure that uniquely allows for active site regeneration by the conserved loop cysteines. Intermediate disulfide trapping results confirmed an intra-molecular electron transfer pathway for VKORC1L1's active site reduction. Our results allow us to propose a concerted action of the four conserved cysteines of VKORC1L1 for active site regeneration; the second loop cysteine, Cys-58, attacks the active site disulfide, forming an intermediate disulfide with Cys-139; the first loop cysteine, Cys-50, attacks the intermediate disulfide resulting in active site reduction. The different membrane topologies and reaction mechanisms between VKORC1L1 and VKORC1 suggest that these two proteins might have different physiological functions.

  17. Use of High Frequency Ultrasound to Monitor Cervical Lymph Node Alterations in Mice

    PubMed Central

    Walk, Elyse L.; McLaughlin, Sarah; Coad, James; Weed, Scott A.

    2014-01-01

    Cervical lymph node evaluation by clinical ultrasound is a non-invasive procedure used in diagnosing nodal status, and when combined with fine-needle aspiration cytology (FNAC), provides an effective method to assess nodal pathologies. Development of high-frequency ultrasound (HF US) allows real-time monitoring of lymph node alterations in animal models. While HF US is frequently used in animal models of tumor biology, use of HF US for studying cervical lymph nodes alterations associated with murine models of head and neck cancer, or any other model of lymphadenopathy, is lacking. Here we utilize HF US to monitor cervical lymph nodes changes in mice following exposure to the oral cancer-inducing carcinogen 4-nitroquinoline-1-oxide (4-NQO) and in mice with systemic autoimmunity. 4-NQO induces tumors within the mouse oral cavity as early as 19 wks that recapitulate HNSCC. Monitoring of cervical (mandibular) lymph nodes by gray scale and power Doppler sonography revealed changes in lymph node size eight weeks after 4-NQO treatment, prior to tumor formation. 4-NQO causes changes in cervical node blood flow resulting from oral tumor progression. Histological evaluation indicated that the early 4-NQO induced changes in lymph node volume were due to specific hyperproliferation of T-cell enriched zones in the paracortex. We also show that HF US can be used to perform image-guided fine needle aspirate (FNA) biopsies on mice with enlarged mandibular lymph nodes due to genetic mutation of Fas ligand (Fasl). Collectively these studies indicate that HF US is an effective technique for the non-invasive study of cervical lymph node alterations in live mouse models of oral cancer and other mouse models containing cervical lymphadenopathy. PMID:24955984

  18. Human cytochrome P450scc (CYP11A1) catalyzes epoxide formation with ergosterol.

    PubMed

    Tuckey, Robert C; Nguyen, Minh N; Chen, Jianjun; Slominski, Andrzej T; Baldisseri, Donna M; Tieu, Elaine W; Zjawiony, Jordan K; Li, Wei

    2012-03-01

    Cytochrome P450scc (P450scc) catalyzes the cleavage of the side chain of both cholesterol and the vitamin D(3) precursor, 7-dehydrocholesterol. The aim of this study was to test the ability of human P450scc to metabolize ergosterol, the vitamin D(2) precursor, and define the structure of the major products. P450scc incorporated into the bilayer of phospholipid vesicles converted ergosterol to two major and four minor products with a k(cat) of 53 mol · min(-1) · mol P450scc(-1) and a K(m) of 0.18 mol ergosterol/mol phospholipid, similar to the values observed for cholesterol metabolism. The reaction of ergosterol with P450scc was scaled up to make enough of the two major products for structural analysis. From mass spectrometry, NMR, and comparison of the NMR data to that for similar molecules, we determined the structures of the two major products as 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol and 22-keto-23-hydroxy-22,23-dihydroergosterol. Molecular modeling and nuclear Overhauser effect (or enhancement) spectroscopy spectra analysis helped to establish the configurations at C20, C22, and C23 and determine the final structures of major products as 22R,23S-epoxyergosta-5,7-diene-3β,20α-diol and 3β,23S-dihydroxyergosta-5,7-dien-22-one. It is likely that the formation of the second product is through a 22,23-epoxy (oxirane) intermediate followed by C22 hydroxylation with the formation of strained 22-hydroxy-22,23-epoxide (oxiranol), which is immediately transformed to the more stable α-hydroxyketone. Molecular modeling of ergosterol into the P450scc crystal structure positioned the ergosterol side chain consistent with formation of the above products. Thus, we have shown that P450scc efficiently catalyzes epoxide formation with ergosterol giving rise to novel epoxy, hydroxy, and keto derivatives, without causing cleavage of the side chain.

  19. Isolation and characterization of 9-lipoxygenase and epoxide hydrolase 2 genes: Insight into lactone biosynthesis in mango fruit (Mangifera indica L.).

    PubMed

    Deshpande, Ashish B; Chidley, Hemangi G; Oak, Pranjali S; Pujari, Keshav H; Giri, Ashok P; Gupta, Vidya S

    2017-06-01

    Uniqueness and diversity of mango flavour across various cultivars are well known. Among various flavour metabolites lactones form an important class of aroma volatiles in certain mango varieties due to their ripening specific appearance and lower odour detection threshold. In spite of their biological and biochemical importance, lactone biosynthetic pathway in plants remains elusive. Present study encompasses quantitative real-time analysis of 9-lipoxygenase (Mi9LOX), epoxide hydrolase 2 (MiEH2), peroxygenase, hydroperoxide lyase and acyl-CoA-oxidase genes during various developmental and ripening stages in fruit of Alphonso, Pairi and Kent cultivars with high, low and no lactone content and explains their variable lactone content. Study also covers isolation, recombinant protein characterization and transient over-expression of Mi9LOX and MiEH2 genes in mango fruits. Recombinant Mi9LOX utilized linoleic and linolenic acids, while MiEH2 utilized aromatic and fatty acid epoxides as their respective substrates depicting their role in fatty acid metabolism. Significant increase in concentration of δ-valerolactone and δ-decalactone upon Mi9LOX over-expression and that of δ-valerolactone, γ-hexalactone and δ-hexalactone upon MiEH2 over-expression further suggested probable involvement of these genes in lactone biosynthesis in mango. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. [Epoxide acrylate maleic resin and hydroxyapatite composite material as a bone graft substitute in surgical correction of orbital reconstruction].

    PubMed

    Mu, X; Dong, J; Wang, W

    1995-11-01

    This paper illustrates the results of surgical correction in 11 cases with orbital deformities such as periorbital deficiency after orbitotomy for retinoblastoma and orbital malposition after facial trauma. EH composite material, mixture of hydroxyapatite and epoxide acrylate maleic resin in constant proportion, was used as a good bone graft substitute in all 11 cases. This material was easier to be molded during surgery, safe to human body, had no toxic effects, no irritation and no implant-related complications. The early results obtained in these patients are encouraging.

  1. Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane

    PubMed Central

    Bauman, Julie E.; Zang, Yan; Sen, Malabika; Li, Changyou; Wang, Lin; Egner, Patricia A.; Fahey, Jed W.; Normolle, Daniel P.; Grandis, Jennifer R.; Kensler, Thomas W.; Johnson, Daniel E.

    2016-01-01

    Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSEs) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared to vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. PMID:27339168

  2. 18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase.

    PubMed

    Horti, Andrew G; Wang, Yuchuan; Minn, Il; Lan, Xi; Wang, Jian; Koehler, Raymond C; Alkayed, Nabil J; Dannals, Robert F; Pomper, Martin G

    2016-11-01

    Soluble epoxide hydrolase (sEH) is a bifunctional enzyme located within cytosol and peroxisomes that converts epoxides to the corresponding diols and hydrolyzes phosphate monoesters. It serves to inactivate epoxyeicosatrienoic acids (EETs), which are generated in the brain to couple neuronal activity and cerebral blood flow in normal and pathologic states. Altered regulation of sEH was observed previously in various neuropathologic disorders including vascular dementia and stroke. Inhibitors of sEH are pursued as agents to mitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)-6- 18 F-fluoronicotinamide ( 18 F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. 18 F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18 F-FNDP was measured using an sEH inhibitor screening assay kit. Biodistribution was undertaken in CD-1 mice. Binding specificity was assayed in CD-1 and sEH knock-out mice and Papio anubis (baboon) through pretreatment with an sEH inhibitor to block sEH binding. Dynamic PET imaging with arterial blood sampling was performed in 3 baboons, with regional tracer binding quantified using distribution volume. The metabolism of 18 F-FNDP in baboons was assessed using high-performance liquid chromatography. 18 F-FNDP (inhibition binding affinity constant, 1.73 nM) was prepared in 1 step in a radiochemical yield of 14% ± 7%, specific radioactivity in the range of 888-3,774 GBq/μmol, and a radiochemical purity greater than 99% using an automatic radiosynthesis module. The time of preparation was about 75 min. In CD-1 mice, regional uptake followed the pattern of striatum > cortex > hippocampus > cerebellum, consistent with the known brain distribution of sEH, with 5.2% injected dose per gram of tissue at peak uptake. Blockade of 80%-90% was demonstrated in all brain regions. Minimal radiotracer uptake was present in sEH knock-out mice. PET baboon

  3. Tuning graphitic oxide for initiator- and metal-free aerobic epoxidation of linear alkenes

    NASA Astrophysics Data System (ADS)

    Pattisson, Samuel; Nowicka, Ewa; Gupta, Upendra N.; Shaw, Greg; Jenkins, Robert L.; Morgan, David J.; Knight, David W.; Hutchings, Graham J.

    2016-09-01

    Graphitic oxide has potential as a carbocatalyst for a wide range of reactions. Interest in this material has risen enormously due to it being a precursor to graphene via the chemical oxidation of graphite. Despite some studies suggesting that the chosen method of graphite oxidation can influence the physical properties of the graphitic oxide, the preparation method and extent of oxidation remain unresolved for catalytic applications. Here we show that tuning the graphitic oxide surface can be achieved by varying the amount and type of oxidant. The resulting materials differ in level of oxidation, surface oxygen content and functionality. Most importantly, we show that these graphitic oxide materials are active as unique carbocatalysts for low-temperature aerobic epoxidation of linear alkenes in the absence of initiator or metal. An optimum level of oxidation is necessary and materials produced via conventional permanganate-based methods are far from optimal.

  4. Highly efficient sulfated Zr-doped titanoniobate nanoplates for the alcoholysis of styrene epoxide at room temperature

    NASA Astrophysics Data System (ADS)

    Zhang, Lihong; Hu, Chenhui; Mei, Weigang; Zhang, Junfeng; Cheng, Liyuan; Xue, Nianhua; Ding, Weiping; Chen, Jing; Hou, Wenhua

    2015-12-01

    Sulfated Zr-doped titanoniobate nanoplates were prepared and evaluated as a solid acid catalyst in the alcoholysis of styrene epoxide at room temperature. Compared with undoped and Zr-doped nanosheets, the resulting sulfated catalyst exhibited an excellent catalytic performance to afford corresponding β-alkoxyalcohols (99% yield with methanol as nucleophile in only 10 min) due to the high dispersion of zirconia species on nanosheets, appropriate Lewis acid strength and amount from the strong interaction between zirconia and sulfate species, and greatly increased surface area arisen from the exfoliation and house-of-cards restacking of nanosheets. The corresponding catalytic mechanism was proposed and discussed. The obtained material may act as a promising catalyst in many acid catalyzed reactions.

  5. Epigallocatechin-3-gallate reduces DNA damage induced by benzo[a]pyrene diol epoxide and cigarette smoke condensate in human mucosa tissue cultures.

    PubMed

    Baumeister, Philipp; Reiter, Maximilian; Kleinsasser, Norbert; Matthias, Christoph; Harréus, Ulrich

    2009-06-01

    Although epidemiological studies indicate cancer preventive effects of diets rich in fruit and vegetables, large clinical intervention studies conducted to evaluate dietary supplementation with micronutrients, mostly vitamins, showed disappointing results in large parts. In contrast, there is encouraging epidemiologic data indicating great chemopreventive potential of a large group of phytochemicals, namely polyphenols. This study shows the DNA protective effect epigallocatechin-3-gallate, a tea catechin, and one of the best-studied substances within this group, on carcinogen-induced DNA fragmentation in upper aerodigestive tract cells. Cell cultures from fresh oropharyngeal mucosa biopsies were preincubated with epigallocatechin-3-gallate in different concentrations before DNA damage was introduced with the metabolically activated carcinogen benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide or cigarette smoke condensate. Effects on resulting DNA fragmentation were measured using the alkaline single-cell microgel electrophoresis (comet assay). Epigallocatechin-3-gallate significantly reduced benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced DNA damage by up to 51% (P<0.001). Fragmentation induced by cigarette smoke condensate could be lowered by 47% (P<0.001). Data suggest a cancer preventive potential of epigallocatechin-3-gallate as demonstrated on a subcellular level. An additional mechanism of tea catechin action is revealed by using a primary mucosa culture model.

  6. Alkyl halide-free heteroatom alkylation and epoxidation facilitated by a recyclable polymer-supported oxidant for the in-flow preparation of diazo compounds.

    PubMed

    Nicolle, Simon M; Hayes, Christopher J; Moody, Christopher J

    2015-03-16

    Highly reactive metal carbenes, generated from simple ketones via diazo compounds, including diazo-amides and -phosphonates, using a recyclable reagent in-flow, are transient but versatile electrophiles for heteroatom alkylation reactions and for epoxide formation. The method produces no organic waste, with the only by-products being water, KI and nitrogen, without the attendant hazards of isolation of intermediate diazo compounds. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Nteeba, Jackson, E-mail: nteeba@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    7,12-Dimethylbenz[a]anthracene (DMBA) depletes ovarian follicles and induces DNA damage in extra-ovarian tissues, thus, we investigated ovarian DMBA-induced DNA damage. Additionally, since obesity is associated with increased offspring birth defect incidence, we hypothesized that a DMBA-induced DNA damage response (DDR) is compromised in ovaries from obese females. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice were dosed with sesame oil or DMBA (1 mg/kg; intraperitoneal injection) at 18 weeks of age, for 14 days. Total ovarian RNA and protein were isolated and abundance of Ataxia telangiectasia mutated (Atm), X-ray repair complementing defective repair in Chinese hamster cells 6more » (Xrcc6), breast cancer type 1 (Brca1), Rad 51 homolog (Rad51), poly [ADP-ribose] polymerase 1 (Parp1) and protein kinase, DNA-activated, catalytic polypeptide (Prkdc) were quantified by RT-PCR or Western blot. Phosphorylated histone H2AX (γH2AX) level was determined by Western blotting. Obesity decreased (P < 0.05) basal protein abundance of PRKDC and BRCA1 proteins but increased (P < 0.05) γH2AX and PARP1 proteins. Ovarian ATM, XRCC6, PRKDC, RAD51 and PARP1 proteins were increased (P < 0.05) by DMBA exposure in lean mice. A blunted DMBA-induced increase (P < 0.05) in XRCC6, PRKDC, RAD51 and BRCA1 was observed in ovaries from obese mice, relative to lean counterparts. Taken together, DMBA exposure induced γH2AX as well as the ovarian DDR, supporting that DMBA causes ovarian DNA damage. Additionally, ovarian DDR was partially attenuated in obese females raising concern that obesity may be an additive factor during chemical-induced ovotoxicity. - Highlights: • DMBA induces markers of ovarian DNA damage. • Obesity induces low level ovarian DNA damage. • DMBA-induced DNA repair response is altered by obesity.« less

  8. Engineering the lutein epoxide cycle into Arabidopsis thaliana.

    PubMed

    Leonelli, Lauriebeth; Brooks, Matthew D; Niyogi, Krishna K

    2017-08-15

    Although sunlight provides the energy necessary for plants to survive and grow, light can also damage reaction centers of photosystem II (PSII) and reduce photochemical efficiency. To prevent damage, plants possess photoprotective mechanisms that dissipate excess excitation. A subset of these mechanisms is collectively referred to as NPQ, or nonphotochemical quenching of chlorophyll a fluorescence. The regulation of NPQ is intrinsically linked to the cycling of xanthophylls that affects the kinetics and extent of the photoprotective response. The violaxanthin cycle (VAZ cycle) and the lutein epoxide cycle (LxL cycle) are two xanthophyll cycles found in vascular plants. The VAZ cycle has been studied extensively, owing in large part to its presence in model plant species where mutants are available to aid in its characterization. In contrast, the LxL cycle is not found in model plants, and its role in photosynthetic processes has been more difficult to define. To address this challenge, we introduced the LxL cycle into Arabidopsis thaliana and functionally isolated it from the VAZ cycle. Using these plant lines, we showed an increase in dark-acclimated PSII efficiency associated with Lx accumulation and demonstrated that violaxanthin deepoxidase is responsible for the light-driven deepoxidation of Lx. Conversion of Lx to L was reversible during periods of low light and occurred considerably faster than rates previously described in nonmodel species. Finally, we present clear evidence of the LxL cycle's role in modulating a rapid component of NPQ that is necessary to prevent photoinhibition in excess light.

  9. Engineering the lutein epoxide cycle into Arabidopsis thaliana

    DOE PAGES

    Leonelli, Lauriebeth; Brooks, Matthew D.; Niyogi, Krishna K.

    2017-07-31

    Although sunlight provides the energy necessary for plants to survive and grow, light can also damage reaction centers of photosystem II (PSII) and reduce photochemical efficiency. To prevent damage, plants possess photoprotective mechanisms that dissipate excess excitation. A subset of these mechanisms is collectively referred to as NPQ, or nonphotochemical quenching of chlorophyll a fluorescence. The regulation of NPQ is intrinsically linked to the cycling of xanthophylls that affects the kinetics and extent of the photoprotective response. The violaxanthin cycle (VAZ cycle) and the lutein epoxide cycle (LxL cycle) are two xanthophyll cycles found in vascular plants. The VAZ cyclemore » has been studied extensively, owing in large part to its presence in model plant species where mutants are available to aid in its characterization. In contrast, the LxL cycle is not found in model plants, and its role in photosynthetic processes has been more difficult to define. To address this challenge, we introduced the LxL cycle into Arabidopsis thaliana and functionally isolated it from the VAZ cycle. Using these plant lines, we showed an increase in dark-acclimated PSII efficiency associated with Lx accumulation and demonstrated that violaxanthin deepoxidase is responsible for the light-driven deepoxidation of Lx. Conversion of Lx to L was reversible during periods of low light and occurred considerably faster than rates previously described in nonmodel species. Finally, we present clear evidence of the LxL cycle’s role in modulating a rapid component of NPQ that is necessary to prevent photoinhibition in excess light.« less

  10. Distribution and ultrastructural characteristics of dark cells in squamous metaplasias of the respiratory tract epithelium.

    PubMed Central

    Klein-Szanto, A. J.; Nettesheim, P.; Pine, A.; Martin, D.

    1981-01-01

    Dark epithelial basal cells were found in both carcinogen-induced and non-carcinogen-induced squamous metaplasias of the tracheal epithelium. Formaldehyde-induced squamous metaplasias exhibited 4% dark cells in the basal layer. Metaplasias induced by vitamin A deficiency and those induced by dimethylbenz(alpha)anthracene (DMBA) without atypia showed 18--20% basal dark cells. DMBA-induced metaplasias with moderate to severe atypia exhibited 50% basal dark cells. The labeling index of basal cells in metaplastic epithelia, regardless of the inducing agent, was 16--18%, ie, the same as that of the normal esophageal stratified squamous epithelium. The percentage of labeled dark basal cells per total dark cell population was approximately 19% in the non-carcinogen-induced metaplasias and in the DMBA-induced metaplasias without atypia. In the atypical metaplasias induced by DMA this percentage increased to 26. On the basis of ultrastructural observations, five types of dark epithelial cells could be distinguished in the metaplastic epithelia: Type I (ovoid or fusiform dark cell with abundant cytoplasmic filaments, desmosomes, and free ribosomes--dark keratinocyte type); Type II (ovoid or spherical small cell with scant cytoplasm with few organelles--basal respiratory type); Type III (irregular or ovoid, few cytoplasmic filaments and organelles and desmosomes, extremely abundant free ribosomes--dedifferentiated type); Type IV (fusiform or ovoid, large mitochondria, prominent ergastoplasm, secretion droplets--mucous cell type); and type V (irregular shape, organelle remnants, vacuoles, pyknotic nuclei--involutional-cell type). Type I was the predominant cell type in formaldehyde-induced metaplasias and was also commonly seen in DMBA-induced metaplasias without atypia. Type II predominated in metaplasias induced by vitamin A deficiency. Type III was seen in DMBA-induced metaplasias and was the predominant cell type in the atypical epithelial alterations. Type IV cells

  11. Devonian post-orogenic extension-related volcano-sedimentary rocks in the northern margin of the Tibetan Plateau, NW China: Implications for the Paleozoic tectonic transition in the North Qaidam Orogen

    NASA Astrophysics Data System (ADS)

    Qin, Yu; Feng, Qiao; Chen, Gang; Chen, Yan; Zou, Kaizhen; Liu, Qian; Jiao, Qianqian; Zhou, Dingwu; Pan, Lihui; Gao, Jindong

    2018-05-01

    The Maoniushan Formation in the northern part of the North Qaidam Orogen (NQO), NW China, contains key information on a Paleozoic change in tectonic setting of the NQO from compression to extension. Here, new zircon U-Pb, petrological, and sedimentological data for the lower molasse sequence of the Maoniushan Formation are used to constrain the timing of this tectonic transition. Detrital zircons yield U-Pb ages of 3.3-0.4 Ga with major populations at 0.53-0.4, 1.0-0.56, 2.5-1.0, and 3.3-2.5 Ga. The maximum depositional age of the Maoniushan Formation is well constrained by a youngest detrital zircon age of ∼409 Ma. Comparing these dates with geochronological data for the region indicates that Proterozoic-Paleozoic zircons were derived mainly from the NQO as well as the Oulongbuluk and Qaidam blocks, whereas Archean zircons were probably derived from the Oulongbuluk Block and the Tarim Craton. The ∼924, ∼463, and ∼439 Ma tectonothermal events recorded in this region indicate that the NQO was involved in the early Neoproterozoic assembly of Rodinia and early Paleozoic microcontinental convergence. A regional angular unconformity between Devonian and pre-Devonian strata within the NQO suggests a period of strong mountain building between the Oulongbuluk and Qaidam blocks during the Silurian, whereas an Early Devonian post-orogenic molasse, evidence of extensional collapse, and Middle to Late Devonian bimodal volcanic rocks and Carboniferous marine carbonate rocks clearly reflect long-lived tectonic extension. Based on these results and the regional geology, we suggest that the Devonian volcano-sedimentary rocks within the NQO were formed in a post-orogenic extensional setting similar to that of the East Kunlun Orogen, indicating that a major tectonic transition from compression to extension in these two orogens probably commenced in the Early Devonian.

  12. Direct and indirect antioxidant activity of polyphenol- and isothiocyanate-enriched fractions from Moringa oleifera.

    PubMed

    Tumer, Tugba Boyunegmez; Rojas-Silva, Patricio; Poulev, Alexander; Raskin, Ilya; Waterman, Carrie

    2015-02-11

    Moringa oleifera Lam. is a fast-growing, tropical tree with various edible parts used as nutritious food and traditional medicine. This study describes an efficient preparatory strategy to extract and fractionate moringa leaves by fast centrifugal partition chromatography (FCPC) to produce polyphenol and isothiocyanate (ITC) rich fractions. Characterization and further purification of these fractions showed that moringa polyphenols were potent direct antioxidants assayed by oxygen radical absorbance capacity (ORAC), whereas moringa ITCs were effective indirect antioxidants assayed by induction of NAD(P)H quinone oxidoreductase 1 (NQO1) activity in Hepa1c1c7 cells. In addition, purified 4-[(α-l-rhamnosyloxy)benzyl]isothiocyanate and 4-[(4'-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate were further evaluated for their ORAC and NQO1 inducer potency in comparison with sulforaphane (SF). Both ITCs were as potent as SF in inducing NQO1 activity. These findings suggest that moringa leaves contain a potent mixture of direct and indirect antioxidants that can explain its various health-promoting effects.

  13. Autonomous healing materials based on epoxidized natural rubber and ethylene methacrylic acid ionomers

    NASA Astrophysics Data System (ADS)

    Arifur Rahman, Md; Penco, Maurizio; Peroni, Isabella; Ramorino, Giorgio; Janszen, Gerardus; Di Landro, Luca

    2012-03-01

    The development of autonomous healing material has an enormous scientific and technological interest. In this context, this research work deals with the investigation of autonomous healing behavior of epoxidized natural rubber (ENR) and its blends with ethylene methacrylic acid ionomers. The autonomous healing behavior of ENR and its blends containing two different ionomers [poly(ethylene-co-methacrylic acid sodium salt) (EMNa) and poly(ethylene-co-methacrylic acid zinc salt) (EMZn)] has been studied by ballistic puncture tests. Interestingly, EMNa/ENR blends exhibit complete healing just after the ballistic test but EMZn/ENR blends do not show full self-repairing. The healing efficiency has been evaluated by optical microscopy and a depressurized air-flow test. The healing mechanism has been investigated by characterizing thermal and mechanical properties of the blends. The chemical structure studied by FTIR and thermal analysis show that the ion content of ionomers and functionality of ENR has a significant influence on the self-healing behavior.

  14. Inhibitors of soluble epoxide hydrolase minimize ischemia-reperfusion-induced cardiac damage in normal, hypertensive, and diabetic rats.

    PubMed

    Islam, Oliul; Patil, Prashanth; Goswami, Sumanta K; Razdan, Rema; Inamdar, Mohammed N; Rizwan, Mohammed; Mathew, Jubin; Inceoglu, Bora; Stephen Lee, Kin S; Hwang, Sung H; Hammock, Bruce D

    2017-06-01

    We designed a study to evaluate the cardioprotective effect of two soluble epoxide hydrolase (sEH) inhibitors, 1-(1-propanoylpiperidin-4-yl)-3-(4-trifluoromethoxy)phenyl)urea (TPPU) and trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB), in ischemia-reperfusion (IR) model. Cardioprotective effects of the sEH inhibitors were evaluated against IR-induced myocardial damage in hearts from normal, hypertensive, and diabetic rats using Langendorff's apparatus. In addition, the effect of sEH inhibitors on endothelial function was evaluated in vitro and ex vivo using isolated rat thoracic aorta. Ischemia-reperfusion (IR) increased the myocardial damage in hearts from normal rats. IR-induced myocardial damage was augmented in hearts isolated from hypertensive and diabetic rats. Myocardial damage as evident from increase in the activities of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in heart perfusate was associated with significant decrease in the heart rate and developed tension, and increase in the resting tension in isolated heart. Both sEH inhibitors protected the heart in normal, hypertensive, and diabetic rats subjected to IR injury. The sEH inhibitor t-TUCB relaxed phenylephrine precontracted aorta from normal rats. Relaxant effect of acetylcholine (ACh) was reduced in aortas from diabetic and hypertensive rats compared to normal rats. Pretreatment of sEH inhibitors to diabetic and hypertensive rats increased relaxant effect of ACh on aortas isolated from these rats. Prophylactic treatment with sEH inhibitors decreased myocardial damage due to IR, hypertension and diabetes, and decreased endothelial dysfunction created by diabetes and hypertension. Therefore, inhibitors of sEH are useful probes to study cardiovascular pathology, and inhibition of the sEH is a potential approach in the management of IR-induced cardiac damage and endothelial dysfunction-related cardiovascular disorders. © 2017 John Wiley & Sons Ltd.

  15. Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane.

    PubMed

    Bauman, Julie E; Zang, Yan; Sen, Malabika; Li, Changyou; Wang, Lin; Egner, Patricia A; Fahey, Jed W; Normolle, Daniel P; Grandis, Jennifer R; Kensler, Thomas W; Johnson, Daniel E

    2016-07-01

    Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. Terreic acid, a quinone epoxide inhibitor of Bruton’s tyrosine kinase

    PubMed Central

    Kawakami, Yuko; Hartman, Stephen E.; Kinoshita, Eiji; Suzuki, Hidefumi; Kitaura, Jiro; Yao, Libo; Inagaki, Naoki; Franco, Alessandra; Hata, Daisuke; Maeda-Yamamoto, Mari; Fukamachi, Hiromi; Nagai, Hiroichi; Kawakami, Toshiaki

    1999-01-01

    Bruton’s tyrosine kinase (Btk) plays pivotal roles in mast cell activation as well as in B cell development. Btk mutations lead to severe impairments in proinflammatory cytokine production induced by cross-linking of high-affinity IgE receptor on mast cells. By using an in vitro assay to measure the activity that blocks the interaction between protein kinase C and the pleckstrin homology domain of Btk, terreic acid (TA) was identified and characterized in this study. This quinone epoxide specifically inhibited the enzymatic activity of Btk in mast cells and cell-free assays. TA faithfully recapitulated the phenotypic defects of btk mutant mast cells in high-affinity IgE receptor-stimulated wild-type mast cells without affecting the enzymatic activities and expressions of many other signaling molecules, including those of protein kinase C. Therefore, this study confirmed the important roles of Btk in mast cell functions and showed the usefulness of TA in probing into the functions of Btk in mast cells and other immune cell systems. Another insight obtained from this study is that the screening method used to identify TA is a useful approach to finding more efficacious Btk inhibitors. PMID:10051623

  17. Structure-Based Optimization of Arylamides as Inhibitors of Soluble Epoxide Hydrolase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Eldrup, Anne B.; Soleymanzadeh, Fariba; Taylor, Steven J.

    2009-11-04

    Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat livermore » microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.« less

  18. A Comparative Study on the Mechanical, Thermal and Morphological Characterization of Poly(lactic acid)/Epoxidized Palm Oil Blend

    PubMed Central

    Giita Silverajah, V. S.; Ibrahim, Nor Azowa; Yunus, Wan Md Zin Wan; Hassan, Hazimah Abu; Woei, Chieng Buong

    2012-01-01

    In this work, poly(lactic acid) (PLA) a fully biodegradable thermoplastic polymer matrix was melt blended with three different epoxidized palm oil (EPO). The aim of this research was to enhance the flexibility, mechanical and thermal properties of PLA. The blends were prepared at various EPO contents of 1, 2, 3, 4 and 5 wt% and characterized. The SEM analysis evidenced successful modification on the neat PLA brittle morphology. Tensile tests indicate that the addition of 1 wt% EPO is sufficient to improve the strength and flexibility compared to neat PLA. Additionally, the flexural and impact properties were also enhanced. Further, DSC analysis showed that the addition of EPO results in a decrease in Tg, which implies an increase in the PLA chain mobility. In the presence of 1 wt% EPO, TGA results revealed significant increase in the thermal stability by 27%. Among the three EPOs used, EPO(3) showed the best mechanical and thermal properties compared to the other EPO’s, with an optimum loading of 1 wt%. Conclusively, EPO showed a promising outcome to overcome the brittleness and improve the overall properties of neat PLA, thus can be considered as a potential plasticizer. PMID:22754338

  19. A comparative study on the mechanical, thermal and morphological characterization of poly(lactic acid)/epoxidized Palm Oil blend.

    PubMed

    Giita Silverajah, V S; Ibrahim, Nor Azowa; Yunus, Wan Md Zin Wan; Hassan, Hazimah Abu; Woei, Chieng Buong

    2012-01-01

    In this work, poly(lactic acid) (PLA) a fully biodegradable thermoplastic polymer matrix was melt blended with three different epoxidized palm oil (EPO). The aim of this research was to enhance the flexibility, mechanical and thermal properties of PLA. The blends were prepared at various EPO contents of 1, 2, 3, 4 and 5 wt% and characterized. The SEM analysis evidenced successful modification on the neat PLA brittle morphology. Tensile tests indicate that the addition of 1 wt% EPO is sufficient to improve the strength and flexibility compared to neat PLA. Additionally, the flexural and impact properties were also enhanced. Further, DSC analysis showed that the addition of EPO results in a decrease in T(g), which implies an increase in the PLA chain mobility. In the presence of 1 wt% EPO, TGA results revealed significant increase in the thermal stability by 27%. Among the three EPOs used, EPO(3) showed the best mechanical and thermal properties compared to the other EPO's, with an optimum loading of 1 wt%. Conclusively, EPO showed a promising outcome to overcome the brittleness and improve the overall properties of neat PLA, thus can be considered as a potential plasticizer.

  20. Stereochemical features of the hydrolysis of 9,10-epoxystearic acid catalysed by plant and mammalian epoxide hydrolases.

    PubMed Central

    Summerer, Stephan; Hanano, Abdulsamie; Utsumi, Shigeru; Arand, Michael; Schuber, Francis; Blée, Elizabeth

    2002-01-01

    cis-9,10-epoxystearic acid was used as a tool to probe the active sites of epoxide hydrolases (EHs) of mammalian and plant origin. We have compared the stereochemical features of the hydrolysis of this substrate catalysed by soluble and membrane-bound rat liver EHs, by soluble EH (purified to apparent homogeneity) obtained from maize seedlings or celeriac roots, and by recombinant soybean EH expressed in yeast. Plant EHs were found to differ in their enantioselectivity, i.e. their ability to discriminate between the two enantiomers of 9,10-epoxystearic acid. For example, while the maize enzyme hydrated both enantiomers at the same rate, the EH from soybean exhibited very high enantioselectivity in favour of 9R,10S-epoxystearic acid. This latter enzyme also exhibited a strict stereoselectivity, i.e. it hydrolysed the racemic substrate with a very high enantioconvergence, yielding a single chiral diol product, threo-9R,10R-dihydroxystearic acid. Soybean EH shared these distinctive stereochemical features with the membrane-bound rat liver EH. The stereochemical outcome of these enzymes probably results from a stereoselective attack by the nucleophilic residue on the oxirane ring carbon having the (S)-configuration, leading to the presumed (in plant EH) covalent acyl-enzyme intermediate. In sharp contrast, the reactions catalysed by cytosolic rat liver EH exhibited a complete absence of enantioselectivity and enantioconvergence; this latter effect might be ascribed to a regioselective formation of the acyl-enzyme intermediate involving C-10 of 9,10-epoxystearic acid, independent of its configuration. Thus, compared with soybean EH, the active site of rat liver soluble EH displays a very distinct means of anchoring the oxirane ring of the fatty acid epoxides, and therefore appears to be a poor model for mapping the catalytic domain of plant EHs. PMID:12020347