[Show abstract][Hide abstract] ABSTRACT: Geraniol (G)-a natural compound present in the essential oils of many aromatic plants-has attracted interest for its potential antitumor effects. The molecular mechanisms of the growth inhibition and apoptosis induced by G in cancer cells, however, remain unclear. In this study, we investigated the effects of G on cell proliferation in culture in A549 cells and in vivo in those same tumor cells implanted in nude mice fed diets supplemented with 25, 50, and 75 mmol G/kg. We demonstrated that G caused a dose- and time-dependent growth inhibition of A549 cells and tumor growth in vivo along with an induction of apoptosis. Moreover, further in vivo assays indicated that G decreased the levels of 3-hydroxymethylglutarylcoenzyme-A reductase-the rate-limiting enzyme in cholesterogenesis-in a dose-dependent manner along with cholesterogenesis and cholesterolemia in addition to reducing the amount of membrane-bound Ras protein. These results showed that the doses of G used in this work, though nontoxic to animals, clearly inhibited the mevalonate pathway, which is closely linked to cell proliferation and increased apoptosis in A549 tumors, but not in normal mouse-liver cells. Accordingly, we suggest that G displays significant antitumor activity and should be a promising candidate for cancer chemotherapy.
Nutrition and Cancer 05/2014; 66(5):1-8. DOI:10.1080/01635581.2014.916320 · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Monoterpenes are naturally occurring plant hydrocarbons with multiple effects on the mevalonate pathway (MP), while statins competitively inhibit hydroxymethylglutarylcoenzyme-A reductase (HMGCR), the rate-limiting enzyme in the MP. Monoterpenes and statins proved capable of inhibiting both proliferation and cholesterogenesis. In the present study we assess the in-vitro antiproliferative and anticholesterogenic effects of two monoterpenes: linalool and 1,8-cineole-either alone, in combination with each other, or combined individually with simvastatin-on liver-derived (HepG2) and extrahepatic (A549) cell lines. The three compounds alone inhibited cell proliferation in a dose-dependent fashion, while their pairwise combination produced synergistic antiproliferative effects in both cell lines. Incorporation experiments with [(14)C]acetate revealed that linalool and 1,8-cineole inhibited the MP, probably at different points, resulting in a reduction in cholesterogenesis and an accumulation of other MP intermediates and products. Linalool or 1,8-cineole, either together or individually with simvastatin, synergistically inhibited cholesterol synthesis. At low concentrations both monoterpenes inhibited steps specifically involved in cholesterol synthesis, whereas at higher concentrations HMGCR levels became down-regulated. Added exogenous mevalonate failed to reverse the inhibition of proliferation exerted by linalool and 1,8-cineole, suggesting that HMGCR inhibition alone is not responsible for the antiproliferative activity of those agents. This work demonstrates that monoterpenes in combination with each other, or individually in combination with simvastatin synergistically inhibits proliferation and cholesterogenesis in the human cell lines investigated, thus contributing to a clearer understanding of the action of essential-oil components, and their combination with the statins, in the targeting of specific points within a complex metabolic pathway.
[Show abstract][Hide abstract] ABSTRACT: Several agrochemicals like organophosphates are extensively used to control pests in agricultural practices but they also adversely affect non-target fauna. The effect of organophosphorous fenitrothion on the prawn Macrobrachium borellii was evaluated. The 96-h LC50 was determined. Activity of superoxide dismutase, catalase, glutathione-S-transferase and lipid oxidation levels, were evaluated in the hepatopancreas from adults exposed to sublethal fenitrothion concentrations for 1, 2, 4 and 7 days. In addition, superoxide dismutase mRNA expression, acetylcholinesterase inhibition and haemocyte DNA damage were determined. The 96-h LC50 was 4.24μg/l of fenitrothion. Prawn exposed to sublethal FS concentrations showed an increase of both catalase and superoxide dismutase activities, mainly after 2 and 4 days exposure and an increase of glutathione-S-transferase activity from day 2 to day 7 while lipid oxidation levels increased mainly on day 1. Superoxide dismutase transcripts were significantly higher in fenitrothion -treated prawns, indicating an induction mechanism. Hemolymph analysis showed that while acetylcholinesterase activity decreased after 2 days, haemocytes displayed most DNA damage after 7-day exposure to fenitrothion. These results indicate that prawn enzymes are highly sensitive to fenitrothion exposure, and these biological responses in M. borellii could be valuable biomarkers to monitor organophosphorous contamination in estuarine environments.
[Show abstract][Hide abstract] ABSTRACT: Geraniol, present in the essential oils of many aromatic plants, has in vitro and in vivo antitumor activity against several cell lines. We investigated the effects of geraniol on lipid metabolic pathways involved in Hep-G2 cell proliferation and found that geraniol inhibits the mevalonate pathway, phosphatidylcholine biosynthesis, cell growth, and cell cycle progression (with an arrest occurring at the G0/G1 interphase) and increases apoptosis. The expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting step in cholesterol synthesis, was inhibited at the transcriptional and posttranscriptional levels, as assessed by real-time RT-PCR, Western blots, and [(14)C]HMG-CoA-conversion radioactivity assays. That geraniol decreased cholesterogenesis but increased the incorporation of [(14)C]acetate into other nonsaponifiable metabolites indicated the existence of a second control point between squalene and cholesterol involved in redirecting the flow of cholesterol-derived carbon toward other metabolites of the mevalonate pathway. That exogenous mevalonate failed to restore growth in geraniol-inhibited cells suggests that, in addition to the inhibition of HMGCR, other dose-dependent actions exist through which geraniol can impact the mevalonate pathway and consequently inhibit cell proliferation. These results suggest that geraniol, a nontoxic compound found in many fruits and herbs, exhibits notable potential as a natural agent for combatting cancer and (or) cardiovascular diseases.
[Show abstract][Hide abstract] ABSTRACT: Statins are competitive inhibitors of HMG-CoA reductase used in hypercholesterolemic patients. Monoterpenes are non-nutritive dietary components found in the essential oils of many plants with pharmacologic effects on mevalonate metabolism. The study is centered on the effects and action mechanisms of the monoterpene components of essential oils and the combination of monoterpenes between them and combined with simvastatin on cholesterogenesis, lipid metabolism and cellular proliferation in vitro using two established cell lines, Hep G2 (derived from a human hepatoblastoma), A549 (derived from a human lung adenocarcinoma) and in vivo in no host and host nude mice carrying implanted tumors derived from A549. This opens up great expectations about the potential of co-administration of different natural isoprenoids and essential oils in improving anti-cholesterolemic therapies and/or cancer treatment as well as in the potential synergism with statins as an alternative to lower effective doses, decreasing the likelihood of undesired and/or toxic effects.
[Show abstract][Hide abstract] ABSTRACT: Simvastatin is a competitive inhibitor of 3-hydroxymethylglutaryl coenzyme A reductase activity, whereas geraniol is a monoterpene with multiple pharmacologic effects on mevalonate metabolism. Both of them inhibit growth and proliferation of many cell lines. The present study was designed to determine the action of geraniol, in combination with simvastatin, by assessing their effects in vitro on human hepatocarcinoma cell line (Hep G2). The treatment of Hep G2 cells with concentrations of simvastatin or geraniol that did not inhibit cell proliferation (5 µmol·l⁻¹ of simvastatin and 50 µmol·l⁻¹ of geraniol) resulted in a significant inhibition of cell proliferation. We also examined the effect of simvastatin, geraniol and the combination of both on the biosynthesis of lipids from [¹⁴C]-acetate. Our results demonstrate that the combination of simvastatin and geraniol synergistically inhibited cholesterol biosynthesis and proliferation of Hep G2 cell line, contributing to a better understanding of the action of a component of essential oils targeting a complex metabolic pathway, which would improve the use of drugs or their combination in the fight against cancer and/or cardiovascular diseases.
Cell Biochemistry and Function 08/2011; 29(6):452-8. DOI:10.1002/cbf.1772 · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ulomoides dermestoides (Fairmaire, 1893) is a cosmopolitan tenebrionid beetle reared by Argentine people who consume them alive as an alternative medicine in the treatment of different illnesses such as asthma, Parkinson's, diabetes, arthritis, HIV and specially cancer.
To evaluate the cytotoxicity and DNA damage of the major volatile components released by Ulomoides dermestoides on human lung carcinoma epithelial cell line A549.
The defence compounds of Ulomoides dermestoides were extracted with dichloromethane and analyzed and quantified by capillary gas chromatography. The toxicity effects of the beetle's extract against A549 cell line were evaluated. Cytotoxicity was evaluated by MTT test and Trypan blue assay and genotoxicity was evaluated by the comet assay. The synthetic compounds, individually or combined, were also tested in A549 cells and normal mononuclear human cells.
The defence compounds of Ulomoides dermestoides extracted with dichloromethane (methyl-1,4-benzoquinones, ethyl-1,4-benzoquinones and 1-pentadecene as major components) showed cytotoxic activity on A549 cells demonstrated by MTT test and Trypan blue assay, with IC(50) values of 0.26equivalent/ml and 0.34equivalent/ml, respectively (1equivalent=amount of components extracted per beetle). The inhibition of A549 cell proliferation with the synthetic blend (1,4-benzoquinone and 1-pentadecene) or 1,4-benzoquinone alone was similar to that obtained with the insect extract. 1-Pentadecene showed no inhibitory effect. Low doses of insect extract or synthetic blend (0.15equivalent/ml) inhibited mononuclear cell proliferation by 72.2±2.7% and induced significant DNA damage both in tumor and mononuclear cells.
Results of this study demonstrated that defence compounds of Ulomoides dermestoides reduced cell viability and induced DNA damage. We also concluded that the insect benzoquinones are primarily responsible for inducing cytotoxicity and genotoxicity in culture cells.
Journal of ethnopharmacology 06/2011; 136(1):204-9. DOI:10.1016/j.jep.2011.04.056 · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of α-D-hex-2-enopyranosyl sulfonamides was evaluated for their antiproliferative activity against human hepatocellular liver carcinoma (HepG2) and human lung adenocarcinoma (A549) cell lines. The most potent compound (2,4,6-tri-O-acetyl-3-deoxy-α-D-erythro-hex-2-enopyranosyl ethanesulfonamide) showed antiproliferative properties in the micromolar range. The SARs of these sulfonamidoglycoside which includes the influence of carbohydrate rings and sulfonamide class are described.
[Show abstract][Hide abstract] ABSTRACT: The composition of volatile organic compounds (VOC) released by the entomopathogenic fungus Beauveria bassiana (Hyphomycete: Deuteromycotina) utilizing two different carbon sources was investigated. Analyses were performed by solid-phase microextraction (SPME) coupled to capillary gas chromatography (CGC) and CGC-mass spectrometry (MS). Major components in glucose-grown cultures were diisopropyl naphthalenes, ethanol, and sesquiterpenes. Alkane-grown fungal VOC switched to a fingerprint with prevalence of n-decane. This is the first report on the volatiles released by entomopathogenic fungi.
Microbiological Research 02/2008; 163(2):148-51. DOI:10.1016/j.micres.2006.03.013 · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The biochemical interaction between fungal pathogens and their insect host epicuticle was studied by examining fungal hydrocarbon degrading ability. As a contact insecticide, entomopathogenic fungi invade their host through the cuticle, covered by an outermost lipid layer mainly composed of highly stable, very long chain structures. Strains of Beauveria bassiana and Metarhizium anisopliae (Deuteromycotina: Hyphomycetes), pathogenic both to the blood-sucking bug Triatoma infestans (Hemiptera: Reduviidae) and the bean-weevil Acanthoscelides obtectus (Coleoptera, Bruchidae), were grown on different carbon sources. Alkane-grown cells showed a lipid pattern different from that of glucose-grown cells, evidenced by a major switch in the triacylglycerol and sterol components. Radiolabelled hydrocarbons were used to investigate the catabolic pathway and the by-product incorporation into fungal cellular components. The first oxidation round is presumably carried out by a cytochrome P450 enzyme system, the metabolites will traverse the peroxisomal membrane, and after successive transformations will eventually provide the appropriate fatty acyl CoA for complete degradation in the peroxisomes, the site of beta-oxidation in fungi. In this review, we will show the relationship between fungal ability to catabolize very long chain hydrocarbons and virulence parameters.
Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology 07/2007; 146(1-2):124-37. DOI:10.1016/j.cbpc.2006.08.003 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Entomopathogenic fungi adapt to growth in a culture medium containing an insect-like hydrocarbon as the sole carbon source inducing the beta-oxidation pathway during the alkane degradation. The effect of two carbon sources on the catalase activity was studied in the entomopathogenic fungus Beauveria bassiana. Catalase activity was detected both in the peroxisomal and cytosolic fraction. A significant increment in the specific activity of the peroxisomal fraction (12.6-fold) was observed when glucose was replaced by an insect-like hydrocarbon, whereas the specific activity in the cytosol diminished more than 1.2-fold in the same culture condition. After purification to homogeneity by gel filtration and strong anion exchange chromatography, an apparent molecular mass of 54.7 and 84.0 kDa per subunit were determined respectively for the peroxisomal and cytosolic catalase. The enzymes showed different biochemical and kinetic characteristics, but both were inhibited by 3-amino-1,2,4 triazole. Peroxisomal catalase was sensitive to pH, heat and high concentration of the hydrogen peroxide substrate. Inversely the cytosolic isoform exhibited a broad range of optimal pH (6.0-10.0), high thermostability (<55 C) and remained fully active at least up to 70 mM hydrogen peroxide. Measurement of catalase activity is a new approach for evaluating fungal ability to degrade hydrocarbons.
[Show abstract][Hide abstract] ABSTRACT: The effect of alkane-growth induction of theentomopathogenic fungus Beauveria bassiana(Balsamo) Vuillemin (Deuteromycotina:Hyphomycetes), on the ability to kill the beanweevil Acanthoscelides obtectus Say(Coleoptera: Bruchidae), was tested. Adultinsects were sprayed with an 0.01% Tween 20aqueous suspension of 4 106 conidia/ml.The performance of fungi grown in complete agarmedium containing glucose as carbon source(FS0) was compared to that of alkane-grownfungi (FS1) with n-hexadecane as the onlycarbon source. Mortality increased (p< 0.05) from 22 4.5% to 44 11.4% at day 7, and from 26 5.5% to 60 7.1% 14 days after treatment withFS0 or FS1 respectively. The insectepicuticular hydrocarbons were analysed bycapillary gas chromatography (CGC); majorcomponents were saturated hydrocarbons, 27 to29 carbons in length. A variety ofmethyl-branched isomers of C27 were theprevailing structures, and nC27 was the majorstraight chain component. Whole insecthydrocarbons were qualitatively identical tothose of the epicuticular surface. Oleic,linoleic and palmitic acids accounted foralmost 88% of the fungal fatty acids,irrespective of the carbon source used forgrowth; however, the unsaturated/saturatedratio diminished markedly from 4.32(FS0) to 2.47 (FS1). These resultsindicate that alkane supplementation of culturemedia might be a tool to improve the virulenceof some mycoinsecticides.
[Show abstract][Hide abstract] ABSTRACT: The pathogenicity of Metarhizium anisopliae (Ma) and Beauveria bassiana (Bb) isolates against Triatoma infestans, the major vector of Chagas disease in Argentina is reported. A 100% mortality was achieved with mean lethal times varying form 5.8 (Ma6) to 7.7 (Bb5) or 11.1 days (Bb10). The fatty acid, hydrocarbon, and total lipid patterns were compared for glucose-grown and alkane-grown Bb10 cultures. The alkane-grown cells showed a lipid pattern different from that of glucose-grown cells, with triacylglyercol as the major lipid fraction, whereas sterols prevailed in the glucose-grown cells. A significant reduction in the relative amounts of linoleic acid diminished the unsaturated/saturated fatty acid ratio for alkane-grown cells; in addition, large amounts of heptacosanoic and eicosanoic acids were detected in the saturated fraction. The hydrocarbon profile of Bb10 showed a saturated chain length distribution,with a marked prevalence for straight chains, ranging from n-C18 to n-C37 in the carbon skeleton, with n-C22 as the major component. Alkane-grown cells showed no qualitative changes in their hydrocarbon fraction, but a similar ratio for odd/even carbon chains. After 48-h incubation assays,[1-(14)C]acetate uptake was largely diminished following a period of alkane growth induction. Glucose-grown cells readily incorporated 19% of the labelinto phospholipids, hydrocarbons, triacylglycerols, and free fatty acids. In contrast, incorporation was reduced to 5.3% for alkane-grown cells, accounting only for phospholipid synthesis.
[Show abstract][Hide abstract] ABSTRACT: The biochemical interaction between fungal pathogens and their insect host cuticle was studied by examining fungal hydrocarbon degrading activity, and the chain length of the lipid metabolites produced. Either n-octacosane or n-tetracosane substrate - of like chain length as the epicuticular straight chain hydrocarbons of Triatoma infestans - was used. Metarhizium anisopliae and Beauveria bassiana strains cultured on glucose-containing agar were able to degrade [³H] octacosane mainly into free fatty acids, phospholipids and acylglycerols. Volatile organic compounds (VOC) were also produced through β-oxidation reactions. When fungi were induced to grow on a hydrocarbon-enriched agar as the sole carbon source, hydrocarbon degrading activity was noticeably increased. The absence of very long chain fatty acids of like carbon skeleton as the supplemented hydrocarbon, i.e., the putative direct oxidation product, together with the large amounts of [³H]acetic acid produced, are supporting evidence for β-oxidation mechanisms going to completion, thus providing the acetyl-CoA units for de novo synthesis of fatty acids. Electron microscopy examination of 3,3′-diaminobenzidine-treated cells showed peroxisomal proliferation upon alkane-growth induction. These data provide the first insight on fatty acyl metabolites produced by fungal catabolism of insect-derived very long chain alkanes.
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