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At least 505 records · Page 28Linked to original sources
PubMed2006

Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane IGF-I receptor, MMP2 activity and HSP27 expression.

BACKGROUND: Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase, the rate-limiting enzyme of the mevalonate pathway, and are used successfully in the treatment of hypercholesterolaemia. Statins are contraindicated during pregnancy. Lately, we have shown that simvastatin has adverse affects on human first trimester placental explants' proliferation and migration. The objective of the present study was to investigate the molecules involved in mediating simvastatin's effect on trophoblast cell migration. We hypothesized that simvastatin attenuates insuline-like growth factor-I (IGF-I) receptor expression (involved in trophoblast motility), matrix metalloproteinase (MMP) activities, and heat shock protein 27 (HSP27) levels (whose mRNA is actively transcribed during trophoblast differentiation) in trophoblast cells thus consequently effecting their migration. METHODS: Human placental explants were cultured above a matrigel with/without simvastatin (10 microM) for 5 days. In this model, trophoblast migrates from the villi into the matrigel. Western-blot and immunohistochemistry served for analysing HSP27 expression. Immunohistochemistry was used for assessing IGF-I receptor localization. MMPs activity was assayed by gel zymography. RESULTS: Simvastatin reduced IGF-I receptor membranal expression, MMP2 activity and HSP27 expression in trophoblast cells (P < 0.05). CONCLUSIONS: The inhibitory effect of simvastatin on trophoblast cell migration is associated with a significant decrease in the tested molecules, which probably contributes to the impaired migration.

Blotting, Western↗
PubMed2004

Relationship between intron 4b splicing of the rat geranylgeranyl diphosphate synthase gene and the active enzyme expression level.

Geranylgeranyl diphosphate synthase (GGPS) is a branch point enzyme in the mevalonate pathway that catalyzes the synthesis of geranylgeranyl diphosphate used for the geranylgeranylation of Rho, Rac and Rab proteins. The current study showed the production of multiple forms of GGPS mRNA from a single GGPS gene in rat. The mRNAs resulted from combinations of multiple alternative introns and two poly(A) sites in the 3'-translated and 3'-untranslated regions. These are classified into 1a-type and 1b-type mRNAs, based on the splicing of intron 4b resulting in the difference in deduced amino acid sequence between the C-terminal regions. The 1a-type and 1b-type proteins expressed in both Escherichia coli and HeLa cells were active and inactive, respectively. In the case of HeLa cells, the latter protein expression level was about 10% relative to the former one. This was also observed for Cos-7 and 293 cells. When fusions of beta-galactosidase with C-terminal regions differing between the 1a-type and 1b-type proteins were expressed in HeLa cells, the expressed fusion proteins were both found to be active but the latter fusion protein expression level was considerably low compared with the former one. The expression level of 1a-type mRNA was higher than that of 1b-type mRNA in brain, liver, heart, and thymus, but the two expression levels were the same in testis and ovary. During testis development the total GGPS mRNA expression level increased, accompanied by an increase in 1b-type mRNA, the expression level of 1a-type mRNA encoding active GGPS remaining kept unchanged. These results indicate that the expression level of rat active GGPS is at least regulated through the splicing of intron 4b of its gene.

3' Untranslated Regions↗
PubMed2001

Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling.

Vitamin E, the most important lipid-soluble antioxidant, was discovered at the University of California at Berkeley in 1922 in the laboratory of Herbert M. Evans (Science 1922, 55: 650). At least eight vitamin E isoforms with biological activity have been isolated from plant sources. Since its discovery, mainly antioxidant and recently also cell signaling aspects of tocopherols and tocotrienols have been studied. Tocopherols and tocotrienols are part of an interlinking set of antioxidant cycles, which has been termed the antioxidant network. Although the antioxidant activity of tocotrienols is higher than that of tocopherols, tocotrienols have a lower bioavailability after oral ingestion. Tocotrienols penetrate rapidly through skin and efficiently combat oxidative stress induced by UV or ozone. Tocotrienols have beneficial effects in cardiovascular diseases both by inhibiting LDL oxidation and by down-regulating 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG CoA) reductase, a key enzyme of the mevalonate pathway. Important novel antiproliferative and neuroprotective effects of tocotrienols, which may be independent of their antioxidant activity, have also been described.

Animals↗
PubMed2005

Tocotrienols: constitutional effects in aging and disease.

Tocotrienols, a class of vitamin E analogs, modulate several mechanisms associated with the aging process and aging-related diseases. Most studies compare the activities of tocotrienols with those of tocopherols ("classical vitamin E"). However, some biological effects were found to be unique for tocotrienols. Although the absorption mechanisms are essentially the same for all vitamin E analogs, tocotrienols are degraded to a greater extent than tocopherols. The levels of tocotrienols in the plasma of animals and humans were estimated to reach low micromolar concentrations. One hallmark in the origin of disease and aging is the overproduction of reactive oxygen species (ROS). Tocotrienols possess excellent antioxidant activity in vitro and have been suggested to suppress ROS production more efficiently than tocopherols. In addition, tocotrienols show promising nonantioxidant activities in various in vitro and in vivo models. Most notable are the interactions of tocotrienols with the mevalonate pathway leading to the lowering of cholesterol levels, the prevention of cell adhesion to endothelial cells, and the suppression of tumor cell growth. Furthermore, glutamate-induced neurotoxicity is suppressed in the presence of tocotrienols. This review summarizes the main antioxidant and nonantioxidant effects of tocotrienols and assesses their potential as health-maintaining compounds.

Aging↗
PubMed1994

Two separate sites contribute to AP-1 activation of the promoter for 3-hydroxy-3-methylglutaryl coenzyme A synthase.

Metabolic flux into the mevalonate pathway is regulated by end product repression and cell growth. In the experiments reported here the transcriptional promoter for an early enzyme of the pathway, 3-hydroxy-3-methylglutaryl coenzyme A synthase, is shown to be activated by the growth stimulatory agent tetraphorbol acetate (TPA). We show that TPA has a direct stimulatory action on the promoter and further that this is mediated by the AP-1 transcription factor. In addition, we show that there are two separate cis-acting sites that bind AP-1 and both are required for maximal stimulation. We further show that in AP-1-deficient cells ectopic expression of AP-1 stimulates synthetic promoters containing two copies of each synthase element upstream of a minimal promoter. The physiological rationale of having both end product repression and direct activation by growth stimulatory cues is discussed.

Animals↗
PubMed2001

Isolation of NPC1-deficient Chinese hamster ovary cell mutants by gene trap mutagenesis.

Chinese hamster ovary cell mutants defective in the NPC1 gene (NPC1-trap) were generated by retrovirus-mediated gene trap mutagenesis from a parental cell line JP17 expressing an ecotropic retrovirus receptor. Insertion of the gene trap vector in the NPC1 gene and the absence of the gene product were verified by 5'RACE and immunological analyses, respectively. NPC1-trap cells showed intracellular accumulation of low-density lipoprotein (LDL)-derived cholesterol and had an increased level of unesterified cellular cholesterol. Cholesterol biosynthesis through the mevalonate pathway was upregulated in the mutant cells as assessed by [(14)C]acetate incorporation into cellular sterols. When JP17 cells were depleted of lipoproteins and then loaded with LDL, cell surface LDL receptors were promptly downregulated and the mature form of the sterol regulatory element-binding protein-1 disappeared from the nucleus. These responses to LDL were obviously retarded in NPC1-trap cells, suggesting an impaired response of the cholesterol-regulatory system to LDL. NPC1-trap cells will be a useful tool to study the regulation of cellular cholesterol homeostasis and the pathogenesis of Niemann-Pick disease type C.

Animals↗
PubMed2002

Mechanisms of bisphosphonate effects on osteoclasts, tumor cell growth, and metastasis.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption that also exhibit antitumor activity. There is now extensive in vitro evidence that bisphosphonates inhibit proliferation and induce apoptosis of tumor cell lines. In addition, they appear to inhibit tumor cell adhesion and invasion of the extracellular matrix. These data are supported by a growing body of evidence from animal models demonstrating that bisphosphonates can reduce skeletal tumor burden. This may reflect direct antitumor effects or indirect effects via osteoclast inhibition and alteration of the bone microenvironment. Research has begun to shed light on the complex mechanisms by which bisphosphonates inhibit bone resorption and interfere with the formation and growth of bone lesions. Nitrogen-containing bisphosphonates inhibit protein prenylation and thereby short-circuit intracellular signaling via small guanine triphosphatases, such as Ras, which require membrane localization. As a result of these biochemical effects on the mevalonate pathway, bisphosphonates appear to modulate the expression of bcl-2 leading to caspase-dependent apoptosis, inhibit matrix metalloproteinases, downregulate alphavbeta3 and alphavbeta5 integrins, and increase expression of osteoprotegerin, thereby antagonizing osteoclastogenesis. Further preclinical studies are ongoing to fully elucidate these biochemical mechanisms, and well-designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates can be realized in the clinical setting.

Adjuvants, Immunologic↗
PubMed2002

Bisphosphonates in cancer therapy.

Bisphosphonates inhibit osteoclast-mediated bone resorption in metastatic bone disease. A wealth of preclinical data have begun to shed light on the complex mechanisms by which bisphosphonates inhibit bone resorption and interfere with the formation and growth of bone metastases. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway, which results in the inhibition of osteoclast function and the induction of apoptosis in osteoclasts and tumor cells alike. There is now extensive evidence that bisphosphonates have cytostatic activity against tumor cell lines and inhibit tumor cell adhesion and invasion of the extracellular matrix. These data are supported by a growing body of evidence from animal models demonstrating that bisphosphonates can reduce skeletal tumor burden. However, it remains unclear whether this reduction reflects a direct antitumor effect or an indirect effect via osteoclast inhibition and alteration of the bone microenvironment. Further preclinical studies are needed to elucidate these biochemical mechanisms fully; ultimately, well-controlled clinical trials will be required to investigate whether the antitumor potential of bisphosphonates translates into a significant clinical benefit for patients with cancer.

Animals↗
PubMed2001

The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro.

Bisphosphonates (BPs), such as pamidronate and clodronate, are an important class of drugs for the treatment of bone diseases. It is widely recognized that they inhibit bone resorption by suppressing the action of osteoclasts through antagonizing the mevalonate pathway, thereby reducing osteolytic bone metastases derived from different cancers, i.e. breast carcinoma and multiple myeloma. In contrast, the effects of BPs on primary bone tumors is an issue still to be resolved. Therefore, a systematic approach was set up to test the hypothesis that BPs could act directly on osteosarcoma cells. The effects of pamidronate and clodronate on seven osteosarcoma cell lines (HOS, MG-63, OST, SaOS-2, SJSA-1, U(2)OS and ZK-58) were studied. Pamidronate inhibited cell growth in a time- and dose-dependent manner, and decreased proliferation for up to 73% at 50 microM after 72 h, whereas its monophosphonate analog 3-aminopropyl phosphonate did not reduce cell viability at concentrations up to 2 mM. Clodronate showed less inhibitory effects (maximally 38% reduction at 1 mM after 72 h). Importantly, cell growth of fibroblasts was only very weakly affected by treatment with pamidronate. These results suggest that pamidronate may be a useful agent for the treatment of patients with osteosarcoma.

Antineoplastic Agents↗
PubMed1998

Genetic analysis of hydroxymethylglutaryl-coenzyme A reductase regulated degradation.

Hydroxymethylglutaryl-coenzyme A reductase degradation occurs in the endoplasmic reticulum, and is regulated by the mevalonate pathway. In order to discover the molecules that mediate the degradation process and its control, we conducted a genetic analysis of the degradation of the yeast Hmg2p isozyme of hydroxymethylglutaryl-coenzyme A reductase. Hmg2p degradation occurs by the action of HRD genes that direct Hmg2p to the ubiquitin-proteasome pathway. Regulation of HRD-dependent Hmg2p degradation appears to occur by the action of a separate set of CRD genes.

Animals↗
PubMed2003

HMG-CoA reductase inhibition: anti-inflammatory effects beyond lipid lowering?

Atherosclerosis has many features of a chronic inflammatory disease. Atherosclerotic lesions contain inflammatory cells. Systemic markers of inflammation, such as white blood cells, C-reactive protein, serum amyloid A, interleukin-6, and soluble adhesion molecules are predictive of future cardiovascular events. Atherogenic lipoprotein particles, in particular modified low-density lipoproteins (LDL), elicit pro-inflammatory responses of cellular elements of the vessel wall, including endothelial dysfunction and activation of monocyte-derived macrophages. High-density lipoproteins (HDL) oppose these effects by inhibiting the oxidation of LDL, and by down-regulating the expression of adhesion molecules and selectins. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has proven the most successful strategy to reduce the concentration of LDL in the circulation. These compounds lower LDL cholesterol by inhibiting the mevalonate pathway in the liver. Prospective clinical trials have convincingly demonstrated that HMG-CoA reductase inhibitors can effectively lower the incidence of cardiovascular events in primary and secondary prevention. Post hoc analyses of these trials suggest that the clinical benefit brought about by statins may not entirely be due to their effect on the levels of circulating lipoproteins. In vitro observations of anti-inflammatory actions of statins on vascular cells may contribute to explain effects beyond lipid lowering. It is, however, not clear whether these findings are relevant to the in vivo situation. Further investigation is now necessary in order to determine the relative significance of cholesterol lowering and of ancillary effects on the net clinical benefit of statin treatment.

Animals↗
PubMed2002

Inhibition of squalene synthase and squalene epoxidase in tobacco cells triggers an up-regulation of 3-hydroxy-3-methylglutaryl coenzyme a reductase.

To get some insight into the regulatory mechanisms controlling the sterol branch of the mevalonate pathway, tobacco (Nicotiana tabacum cv Bright Yellow-2) cell suspensions were treated with squalestatin-1 and terbinafine, two specific inhibitors of squalene synthase (SQS) and squalene epoxidase, respectively. These two enzymes catalyze the first two steps involved in sterol biosynthesis. In highly dividing cells, SQS was actively expressed concomitantly with 3-hydroxy-3-methylglutaryl coenzyme A reductase and both sterol methyltransferases. At nanomolar concentrations, squalestatin was found to inhibit efficiently sterol biosynthesis as attested by the rapid decrease in SQS activity and [(14)C]radioactivity from acetate incorporated into sterols. A parallel dose-dependent accumulation of farnesol, the dephosphorylated form of the SQS substrate, was observed without affecting farnesyl diphosphate synthase steady-state mRNA levels. Treatment of tobacco cells with terbinafine is also shown to inhibit sterol synthesis. In addition, this inhibitor induced an impressive accumulation of squalene and a dose-dependent stimulation of the triacylglycerol content and synthesis, suggesting the occurrence of regulatory relationships between sterol and triacylglycerol biosynthetic pathways. We demonstrate that squalene was stored in cytosolic lipid particles, but could be redirected toward sterol synthesis if required. Inhibition of either SQS or squalene epoxidase was found to trigger a severalfold increase in enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, giving first evidence for a positive feedback regulation of this key enzyme in response to a selective depletion of endogenous sterols. At the same time, no compensatory responses mediated by SQS were observed, in sharp contrast to the situation in mammalian cells.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed1996

Light suppresses 3-Hydroxy-3-methylglutaryl coenzyme A reductase gene expression in Arabidopsis thaliana.

3-Hydroxy-3-methylglutaryl (HMG) coenzyme A reductase mRNA accumulates preferentially in dark-grown Arabidopsis plants. As one step toward understanding the role that light plays in the regulation of the mevalonate pathway in plants, we characterized the suppression of HMG1 gene expression in response to illumination wavelength, duration, and fluence rate. The accumulation of HMG1 mRNA by dark treatment is suppressed by continuous exposure to white light and is dependent on the amount of light perceived during the period of illumination. By using promoter/reporter gene fusions we also demonstrate that this reaction is mediated by cis-acting elements that reside in the Arabidopsis HMG1 promoter and, therefore, is likely to be controlled at the transcriptional level. HMG1 expression is differentially responsive to continuous blue and red light but not to far-red light. In contrast, changes in HMG1 mRNA levels were not observed in response to brief light pulses of any spectrum, suggesting that continuous illumination is required for sustained and maximal suppression of HMG coenzyme A reductase expression. Taken together, these data indicate that light-mediated control of the HMG1 gene is mediated by a regulatory circuit that monitors aspects of both spectral quality and fluence and involves either multiple photoreceptors or a single photoreceptor that is differentially sensitive to both blue and red light.

Arabidopsis↗
PubMed1998

Dedicated roles of plastid transketolases during the early onset of isoprenoid biogenesis in pepper fruits1.

Isopentenyl diphosphate (IPP), which is produced from mevalonic acid or other nonmevalonic substrates, is the universal precursor of isoprenoids in nature. Despite the presence of several isoprenoid compounds in plastids, enzymes of the mevalonate pathway leading to IPP formation have never been isolated or identified to our knowledge. We now describe the characterization of two pepper (Capsicum annuum L.) cDNAs, CapTKT1 and CapTKT2, that encode transketolases having distinct and dedicated specificities. CapTKT1 is primarily involved in plastidial pentose phosphate and glycolytic cycle integration, whereas CapTKT2 initiates the synthesis of isoprenoids in plastids via the nonmevalonic acid pathway. From pyruvate and glyceraldehyde-3-phosphate, CapTKT2 catalyzes the formation of 1-deoxy-xylulose-5-phosphate, the IPP precursor. CapTKT1 is almost constitutively expressed during the chloroplast-to-chromoplast transition, whereas CapTKT2 is overexpressed during this period, probably to furnish the IPP necessary for increased carotenoid biosynthesis. Because deoxy-xylulose phosphate is shared by the plastid pathways of isoprenoid, thiamine (vitamin B1), and pyridoxine (vitamin B6) biosynthesis, our results may explain why albino phenotypes usually occur in thiamine-deficient plants.

Amino Acid Sequence↗
PubMed2000

Compartmentation of ATP:citrate lyase in plants.

Extracts prepared from young leaves of Pea (Pisum sativum), tobacco (Nicotiana tabacum), rape (Brassica napus), and spinach (Spinacia oleracea) all contained ATP:citrate lyase (ACL) activity, which was most active in rape leaflets (130 nmol min(-1) g fresh weight). In rape and spinach, ACL activity was predominantly localized in the plastids (between about 78% and 90% of the total activity), whereas in pea and tobacco, distribution was mainly cytosolic (about 85% and 78%, respectively, of the total). These distributions were calculated from the relative distributions of plastid and cytosol marker enzymes. Cross-reactivity between plant and rat ACL antibody was carried out by immunoblot analysis and, in rape and spinach, showed that a 120-kD protein, presumably indicating homomeric ACL proteins, was present in both cytosolic and plastidic fractions. In pea, two cross-reacting proteins were detected, the major material being in the cytosol fraction. Therefore, ACL occurs both in the cytosol and plastids of higher plants, but the distribution of activity changes according to the species. The plastidic ACL is proposed to function for the supply of acetyl-coenzyme A for lipid biosynthesis de novo, whereas the cytosolic ACL may provide acetyl-coenzyme A for the mevalonate pathway or fatty acid elongation.

ATP Citrate (pro-S)-Lyase↗
PubMed2005

A preliminary crystallographic analysis of the putative mevalonate diphosphate decarboxylase from Trypanosoma brucei.

Mevalonate diphosphate decarboxylase catalyses the last and least well characterized step in the mevalonate pathway for the biosynthesis of isopentenyl pyrophosphate, an isoprenoid precursor. A gene predicted to encode the enzyme from Trypanosoma brucei has been cloned, a highly efficient expression system established and a purification protocol determined. The enzyme gives monoclinic crystals in space group P2(1), with unit-cell parameters a = 51.5, b = 168.7, c = 54.9 A, beta = 118.8 degrees. A Matthews coefficient VM of 2.5 A3 Da(-1) corresponds to two monomers, each approximately 42 kDa (385 residues), in the asymmetric unit with 50% solvent content. These crystals are well ordered and data to high resolution have been recorded using synchrotron radiation.

Animals↗
PubMed2005

Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia.

BACKGROUND: By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity. METHODS: In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 +/- 7 years) were randomized to rosuvastatin 40 mg day(-1) or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic-hyperinsulinaemic clamp after 12 weeks of both treatment periods. RESULTS: Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides -28%; LDL-c -50%; VLDL-c -56%, VLDL-TG -39%) and both parameters of low-grade inflammation (as measured by hsCRP, -16%) and oxidative stress (as measured by plasma-oxLDL, -55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41.7 +/- 17.4 vs. 40.6 +/- 11.1 L kg(-1) min(-1), placebo vs. rosuvastatin, P = 0.71). CONCLUSION: Despite marked improvements in lipid and lipoprotein values, low-grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH.

Blood Glucose↗
PubMed2006

Isolation, endocrine regulation and mRNA distribution of the 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-S) gene from the pine engraver, Ips pini (Coleoptera: Scolytidae).

We isolated a full-length cDNA encoding 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-S) from the pine engraver beetle, Ips pini (Say), and examined its genomic structure. The intron-less gene has a predicted 460 amino acid cytosolic protein product with 73% identity to HMG-S from Dendroctonus jeffreyi, and high identity (58-64%) with other insect HMG-Ss. Topically applied juvenile hormone (JH) III induced HMG-S mRNA levels up to 6.5-fold in both sexes, mostly in the anterior midgut, though there were differences between males and females in the timing, sensitivity to JH III dose and tissue distribution of HMG-S mRNA. These data further validate the coordinate regulation of mevalonate pathway genes for de novo isoprenoid pheromone production in bark beetles.

Amino Acid Sequence↗