0000000000202408
AUTHOR
Mustapha Cherkaoui Malki
Resveratrol, a chemopreventive agent, disrupts the cell cycle control of human SW480 colorectal tumor cells
Resveratrol is a natural polyphenolic compound produced by a number of plants and found in high amount in peanuts, seeds, grapes or berries as source of human nutrition. Epidemiological studies strongly suggest that resveratrol may act as a cancer chemopreventive compound. The mechanism by which resveratrol inhibits cell proliferation was studied in human colorectal tumor SW480 cell line. The results show that resveratrol strongly inhibits cell proliferation at the micromolar range in a time- and dose-dependent manner. Resveratrol appears to block the cell cycle at the transition --> G2/M since inhibition of [(3)H]-thymidine incorporation is not observed, while there is an increase of the c…
An expeditious synthesis of spinasterol and schottenol, two phytosterols present in argan oil and in cactus pear seed oil, and evaluation of their biological activities on cells of the central nervous system
International audience; Spinasterol and schottenol, two phytosterols present in argan oil and in cactus pear seed oil, were synthesized from commercially available stigmasterol by a four steps reactions. In addition, the effects of these phytosterols on cell growth and mitochondrial activity were evaluated on 158N murine oligodendrocytes, C6 rat glioma cells, and SK-N-BE human neuronal cells with the crystal violet test and the MTT test, respectively. The effects of spinasterol and schottenol were compared with 7-ketocholesterol (71CC) and ferulic acid, which is also present in argan and cactus pear seed oil. Whatever the cells considered, dose dependent cytotoxic effects of 71CC were obser…
Toxicological evaluation of peroxisome proliferators. Further cellular and molecular aspects.
International audience
Molecular analysis on the chemopreventive properties of resveratrol, a plant polyphenol microcomponent.
As a plant microcomponent, resveratrol is a polyphenolic compound produced by several species and found especially in Polygonum roots, peanuts seeds, berries and also grape and therefore can be present in human diet or beverages (red wine, for instance). Traditional chinese medicine and more recent epidemiological studies strongly suggested that resveratrol may act as a cancer chemopreventive compound. The biochemical mechanism by which resveratrol inhibits cell proliferation was provided by studies in numerous human cell lines including our work in hepatoblastoma HepG2 and colorectal tumor SW480 cells. The results show that resveratrol strongly inhibits cell proliferation at the micromolar…
Transcriptional and post-transcriptional analysis of peroxisomal protein encoding genes from rat treated with an hypolipemic agent, ciprofibrate
The treatment of rats with ciprofibrate, a potent peroxisome proliferator, led to increased levels of the peroxisomal acyl-CoA oxidase (ACO) mRNA. How ciprofibrate functions to elevate ACO mRNA is not known. To help determine the mechanism of ciprofibrate action, in vitro transcription assays were performed. It was determined that ciprofibrate was responsible for a 3.5-fold stimulation of the rate of ACO transcription within 24 hr of ingestion. It was also observed that the transcription rate stimulation following a 2-week ciprofibrate treatment of Wistar rats was maintained following 4 weeks of ciprofibrate withdrawal. Re-introduction of the drug after the 4-week pause resulted in greater …
Differential proto-oncogene mRNA induction from rats treated with peroxisome proliferators
After experimental treatment of rats with clofibrate or ciprofibrate, two peroxisomes proliferators with hypolipidemic activity, RNAs were prepared from liver, kidney, heart and brain; hybridization was done with DNA probes for c-myc and c-Ha-ras oncogenes and for cyanide insensitive Acyl CoA oxidase, a peroxisomal protein. c-myc mRNA is highly abundant in liver and at a lower extent in kidney, especially after treatment with ciprofibrate; clofibrate also allows a c-myc mRNA increase, but at a lower extent. c-Ha-ras, which is already expressed in all tested tissues from control animals, is stimulated by clofibrate and ciprofibrate treatments. Comparatively these compounds stimulate the cyan…
Phosphorylation of peroxisome proliferator-activated receptor α in rat Fao cells and stimulation by ciprofibrate
The basic mechanism(s) by which peroxisome proliferators activate peroxisome proliferator-activated receptors (PPARs) is (are) not yet fully understood. Given the diversity of peroxisome proliferators, several hypotheses of activation have been proposed. Among them is the notion that peroxisome proliferators could activate PPARs by changing their phosphorylation status. In fact, it is well known that several members of the nuclear hormone receptor superfamily are regulated by phosphorylation. In this report, we show that the rat Fao hepatic-derived cell line, known to respond to peroxisome proliferators, exhibited a high content of PPARalpha. Alkaline phosphatase treatment of Fao cell lysat…
Expression of R-3-hydroxybutyrate dehydrogenase, a ketone body converting enzyme in heart and liver mitochondria of ruminant and non-ruminant mammals
1. The properties of rat liver and bovine heart R-3-hydroxybutyrate dehydrogenase (BDH) have been extensively studied in the past 20 years, but little is known concerning the biogenesis and the regulation of this dehydrogenase over different species. 2. In addition, controversial results were often reported concerning the activity, the level and the subcellular location of this enzyme in ruminants. 3. BDH activity found in liver and kidney mitochondria from ruminants (cow and sheep) is low, while it is much higher in rat. 4. However, the enzyme activity is detected in microsomes and in cytosol of liver and of kidney cells from ruminants. These activities are not correlated to ketonaemia lev…
Expression of liver peroxisomal proteins as compared to other organelle marker enzymes in rats treated with hypolipidemic agents.
Abstract Peroxisome proliferation induced by 2 hypolipidemic agents (clofibrate and ciprofibrate) was studied in rats by complementary approaches, ie cell fractionation, electron microscopy, marker enzyme activities, immunoblotting and nucleic acid hybridization techniques. Administration of clofibrates for 2 and 52 weeks in doses of 500 ppm and 50 ppm respectively, or ciprofibrate for 2,28 and 52 weeks in doses of 250, 25 and 25 ppm respectively, did not alter the behavior of the peroxisomes after induction as shown by ultracentrifugation profiles. The peroxisome mass was increased as shown by the purification procedure. Specific enzymes (catalase and mostly cyanide insensitive palmitoyl C…
Response of genetically obese Zucker rats to ciprofibrate, a hypolipidemic agent, with peroxisome proliferation activity as compared to Zucker lean and Sprague-Dawley rats.
Genetically obese Zucker (fa/fa) rats were used as an experimental model to study the effects of hypolipidemic agents on peroxisome proliferation; comparison was made with Zucker lean phenotype (Fa/-) and Sprague-Dawley strain/phenotype. The pharmacokinetics of a single administration of ciprofibrate (1 or 3 mg/kg), appeared to be similar in all strains/phenotypes. After a 2-week oral administration at the same dosages, there were dosage-related increases in hepatocellular peroxisomal yield and in the hepatic enzymes' cyanide-insensitive acyl-CoA oxidase and catalase. The peroxisomal yield was less increased in Zucker than in Sprague-Dawley rats, while the enzyme activities were similarly i…
Delayed effects of ciprofibrate on rat liver peroxisomal properties and proto-oncogene expression.
Peroxisome proliferators (PPs) are non-genotoxic carcinogens in rodents. Their reversible effects on rat liver have been studied with ciprofibrate and fenofibrate. We found that with the hypolipemic drug fenofibrate a pause of 28 days is sufficient for a return to normal status, whereas with the highly potent PP ciprofibrate, the stimulation of ACO mRNA levels remains after its withdrawal. We investigated the effects of the renewal of the treatment with PPs on other peroxisomal parameters and proto-oncogene expression using Wistar rats. Interestingly, c-myc expression was enhanced even upon drug withdrawal, and was more stimulated by the second exposure to ciprofibrate, while c-fos expressi…
Gene Regulation of Peroxisomal Enzymes by Nutrients, Hormones and Nuclear Signalling Factors in Animal and Human Species
Many peroxisomal enzymes are controlled at the transcriptional level. This gene regulation is well documented in liver from rodent species and is more important upon peroxisome proliferation, although both phenomena are not always associated. Understanding of this regulation comes largely from studies on PPARs (Peroxisome Proliferator-Activated Receptors). Other transcription factors including thyroid hormone receptors, glucocorticoid receptors, LXR, also influence peroxisomal gene expression often in combination with tissue specific cofactors (co-activators or co-repressors). In human tissues and cells, inducibility of peroxisomal enzymes often has not been investigated. De Craemer (1995) …
Regulation of the peroxisomal β-oxidation-dependent pathway by peroxisome proliferator-activated receptor α and kinases
The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green (Nature 347:645-650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT x TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710-16714, 1998). After the first discovery, severa…