Dietary nutrients with ability to reverse adverse epigenetic events have great potential for cancer chemoprevention. Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) ...is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1-driven mechanisms in pre-clinical models of prostate cancer and whether pterostilbene, a natural potent analog of resveratrol, may effectively target MTA1 to prevent prostate cancer development and progression. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. In addition, loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis, thereby restraining prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice by 50% and reducing tumor development and progression in prostate specific Pten-null mice by 52%. Taken together, our pre-clinical findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression and offer pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.
Glyphosate-resistant (GR) soybean Glycine max (L.) Merr. was developed by stable integration of a foreign gene that codes insensitive enzyme 5-enolpyruvylshikimate-3-phosphate synthase, an enzyme in ...the shikimate pathway, the target pathway of glyphosate. Application of glyphosate to GR soybean results in injury under certain conditions. It was hypothesized that if GR soybean is completely resistant to the glyphosate, injury could be caused by a metabolite of glyphosate, aminomethylphosphonic acid (AMPA), a known phytotoxin. Glyphosate and AMPA effects on one- to two-trifoliolate leaf stage (16−18-days old) GR and non-GR soybean were examined in the greenhouse. In GR soybean, a single application of glyphosate−isopropylammonium (1.12−13.44 kg/ha) with 0.5% Tween 20 did not significantly reduce the chlorophyll content of the second trifoliolate leaf at 7 days after treatment (DAT) or the shoot dry weight at 14 DAT compared with Tween 20 alone. A single application of AMPA (0.12−8.0 kg/ha) with 0.5% Tween 20 reduced the chlorophyll content of the second trifoliolate leaf by 0−52% at 4 DAT and reduced shoot fresh weight by 0−42% at 14 DAT in both GR and non-GR soybeans compared with Tween 20 alone. AMPA at 0.12 and 0.50 kg/ha produced injury in GR and non-GR soybean, respectively, similar to that caused by glyphosate−isopropylammonium at 13.44 kg/ha in GR soybean. AMPA levels found in AMPA-treated soybean of both types and in glyphosate-treated GR soybean correlated similarly with phytotoxicity. These results suggest that soybean injury to GR soybean from glyphosate is due to AMPA formed from glyphosate degradation. Keywords: Aminomethylphosphonic acid; chlorophyll; glyphosate; herbicide-resistant crop; shikimic acid; transgenic crop
Controversy continues to exist regarding whether the transgene for glyphosate resistance (GR) and/or glyphosate applied to GR crops adversely affect plant mineral content. Field studies were ...conducted in 2013 and 2014 in Stoneville, MS and Urbana, IL to examine this issue in maize. At each location, the experiment was conducted in fields with no history of glyphosate application and fields with several years of glyphosate use preceding the study. Neither glyphosate nor the GR transgene affected yield or mineral content of leaves or seed, except for occasional (<5%) significant effects that were inconsistent across minerals, treatments, and environments. Glyphosate and AMPA (aminomethylphosphonic acid), a main degradation product of glyphosate, were found in leaves from treated plants, but little or no glyphosate and no AMPA was found in maize seeds. These results show that the GR transgene and glyphosate application, whether used for a single year or several years, have no deleterious effect on mineral nutrition or yield of GR maize.
Abstract Objectives Oxidative damage to lipids, proteins, and nucleic acids in the brain often causes progressive neuronal degeneration and death that are the focal traits of chronic and acute ...pathologies, including those involving cognitive decline. The aim of this study was to investigate the specific effects of both Euterpe oleracea and Euterpe precatoria açaí fruit pulp on restoring stressor-induced calcium dysregulation, stunted growth of basal dendrites, and autophagy inhibition using embryonic hippocampal and HT22 hippocampal neurons. Methods Water-soluble whole fruit pulp extracts from two açaí species were applied to rat primary neurons and HT22 hippocampal neurons with varied time and concentrations. Recovery of neurons from dopamine-induced Ca2+ dysregulation was measured by live cell imaging using fluorescent microscopy. The effect of açaí fruit pulp extracts on neurons following chemically-induced autophagy inhibition was measured using both immunofluorescence and immunohistochemical techniques. Results It has been postulated that at least part of the loss of cognitive function in aging may depend on a dysregulation in calcium ion (Ca2+ ) homeostasis and a loss of autophagy function in the brain, which affects numerous signaling pathways and alters protein homeostasis. In the present study, polyphenol-rich fruit pulp extracts from two species of açaí, Euterpe precatoria and Euterpe oleracea , when applied to rat hippocampal primary neuronal cells (E18), caused a significant ( P < 0.05) recovery of depolarized brain cells from dopamine-induced Ca2+ influx. Autophagy, a protein homeostasis mechanism in brain, when blocked by known inhibitors such as bafilomycin A1 or wortmannin, caused a significant reduction in the growth of primary basal dendrites in rodent primary hippocampal neurons and significant accumulation of polyubiquitinated proteins in mouse HT22 hippocampal neurons in culture. However, pretreatment with açaí extracts up to 1 mg/mL significantly increased the length of basal dendrites and attenuated the inhibitor-induced autophagy dysfunction. Açaí extracts activated the phosphorylation of mammalian target of rapamycin, increased the turnover of autophagosomes and MAP1 B LC3-II, and decreased accumulation of LC3-ubiquitin binding P62/SQSTM1. Conclusion Although the polyphenol profile of Euterpe precatoria showed substantially higher concentrations of major flavonoids han Euterpe oleracea , the relative effects were essentially similar for both species. The study adds to growing evidence that supports the putative health effects of açaí fruit species on brain cells.
A series of trans-stilbene derivatives containing 4′-methylthio substituent were synthesized and evaluated for inhibitory activities on human recombinant cytochrome P450(s): CYP1A1, CYP1A2, and ...CYP1B1. CYP1A2-related metabolism of stilbene derivatives was estimated by using NADPH oxidation assay. Additionally, for CYP1A2 and CYP1B1 molecular docking analysis was carried out to provide information on enzyme–ligand interactions and putative site of metabolism.
3,4,5-Trimethoxy-4′-methylthio-trans-stilbene, an analogue of DMU-212 (3,4,5,4′-tetramethoxy-trans-stilbene) was an effective inhibitor of all CYP1 enzymes. On the other hand, 2,3,4-trimethoxy-4′-methylthio-trans-stilbene, appeared to be the most selective inhibitor of the isozymes CYP1A1 and CYP1B1, displaying extremely low affinity towards CYP1A2. Molecular modeling suggested that the most probable binding poses of the methylthiostilbene derivatives in CYP1A2 active sites are those with the methylthio substituent directed towards the heme iron. Products of CYP1A2-catalyzed oxidation of 2,4,5-trimethoxy-4′-methylthiostilbene and 3,4,5-trimethoxy-4′-methylthiostilbene were identified as monohydroxylated compounds. Other studied derivatives appeared to be poor substrates of CYP1A2. Structure–activity relationship analysis rendered better understanding of the mechanism of action of xenobiotic-metabolizing enzymes crucial at the early stage of carcinogenesis.
Hairy root cultures of peanut were established and elicited to produce
trans-resveratrol. Sodium acetate increased the levels of
trans-resveratrol in the medium by almost 60-fold in comparison to ...non-elicited cultures.
Resveratrol and its derivatives are natural stilbenes associated with many health benefits that include those conferred by their antioxidant and anticancer properties. While stilbenes can be recovered as an extract from a selected number of plants, these products are not suitable for many applications in the food/pharmaceutical sectors due to high levels of impurities as well as the overall low concentration of resveratrol and its derivatives in the extract. To deliver a highly defined and enriched resveratrol product, hairy root cultures of peanut (
Arachis hypogaea) were established and tested as a bioproduction system for resveratrol and associated derivatives. Analyses by HPTLC and GC–MS of ethyl acetate extracts showed that a single 24
h sodium acetate elicitation resulted in a 60-fold induction and secretion of
trans-resveratrol into the medium of peanut hairy root cultures.
trans-Resveratrol accumulated to levels of 98
μg/mg of the dried extract from the medium representing 99% of the total resveratrol produced. Other stilbenes, including
trans-pterostilbene, were also detected in the medium. Our results demonstrate the capacity of hairy root cultures as an effective bioprocessing system for valued nutraceuticals like resveratrol and resveratrol derivatives. In being able to effectively induce and recover high levels of resveratrol and associated derivatives from the media fraction, hairy roots may offer a scalable and continuous product recovery platform for naturally-derived, high quality, enriched nutraceuticals.
Research suggests that polyphenolic compounds contained in fruits and vegetables that are rich in color may have potent antioxidant and anti-inflammatory activities. The present studies determined if ...stilbene (e.g., resveratrol) compounds would be efficacious in reversing the deleterious effects of aging in 19 month old Fischer 344 rats. Experiment I utilized resveratrol and six resveratrol analogues and examined their efficacies in preventing dopamine-induced decrements in calcium clearance following oxotremorine-induced depolarization in COS-7 cells transfected with M1 muscarinic receptors (MAChR) that we have shown previously to be sensitive to oxidative stressors. Experiment II utilized the most efficacious analogue (pterostilbene) from experiment I and fed aged rats a diet with a low (0.004%) or a high (0.016%) concentration of pterostilbene. Results indicated that pterostilbene was effective in reversing cognitive behavioral deficits, as well as dopamine release, and working memory was correlated with pterostilbene levels in the hippocampus.
Stilbenes are phytoalexins that become activated when plants are stressed. These compounds exist in foods and are widely consumed. Resveratrol is a grape-derived stilbene, which possesses a wide ...range of health-promoting activities, including anticancer properties. Several other stilbenes structurally similar to resveratrol are also available in food, but their biological activities remain largely unknown. In this study, we compared the effects of resveratrol and its natural derivatives pterostilbene, trans-resveratrol trimethylether, trans-pinostilbene and trans-desoxyrhapontigenin on androgen-responsive human prostate cancer LNCaP cells. We found that these compounds exert differential effects on LNCaP cell growth, cell cycle and apoptosis. Trans-resveratrol trimethylether appeared to be the most potent compound among the stilbenes tested. Treatment of LNCaP cells with trans-resveratrol trimethylether resulted in G2/M blockage while other compounds, including resveratrol, induced G1/S arrest. Moreover, different from other compounds, trans-resveratrol trimethylether induced apoptosis. At the molecular level, the effects of these compounds on cell cycle correlated with induction of the cyclin-dependent kinase inhibitor 1A and B mRNA levels. Additionally, these compounds also inhibited both androgen- as well as estrogen-mediated pathways. These results provide mechanistic information on how resveratrol and its methylether analogs may act to contribute to potential antiprostate cancer activity.
CYP1A1 and CYP1B1 are the inducible forms of cytochrome P450 expressed in extrahepatic tissues, which are responsible for the biotransformation of polycyclic aromatic hydrocarbons, heterocyclic ...amines and estradiol to the carcinogenic intermediates. The aim of our research was to determine and compare the inhibitory effect of naturally occurring analogues of trans-resveratrol on the catalytic activities of human recombinant CYP1A1 and CYP1B1. Pinostilbene (3,4'-dihydroxy-5-methoxystilbene), desoxyrhapontigenin (3,5-dihydroxy-4'-methoxystilbene), and pterostilbene (3,5-dimethoxy-4'-hydroxystilbene) appeared to be very potent inhibitors of CYP1A1 catalytic activity with Ki values of 0.13, 0.16 and 0.57 micromolar, respectively. Results from this study indicate that trans-resveratrol analogues in which the hydroxy groups are substituted by methoxy groups exhibit a remarkably stronger inhibitory effect towards CYP1A1 in comparison to the parent compound. On the contrary, the potency of pinostilbene, desoxyrhapontigenin and pterostilbene towards CYP1B1 with Ki values of 0.90, 2.06 and 0.91 micromolar, respectively, was comparable to that of resveratrol. It appears that between these analogues, inhibition of CYP1A1 and CYP1B1 catalytic activities does not vary much regardless of the number and position of methylether substitution. The results suggest that the trans-resveratrol analogues: pinostilbene, desoxyrhapontigenin and pterostilbene, which occur in some food plants, might be considered as promising chemopreventive agents.
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