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PubMed2005

The effect of farnesol on amino acid incorporation by a wild-type and cell-wall variant strain of Candida albicans.

Farnesol, a quorum sensing (QS) signal, is produced by Candida albicans during high density growth and has been found to inhibit morphogenesis. This QS auto-inducing signal was discovered to increase amino acid incorporation by C. albicans when concentrations of farnesol increased to 10 microg/mL in yeast nitrogen broth. Farnesol concentrations greater than 10 microg/mL abolished the enhanced incorporation, and the magnitude of the increased incorporation was dependent on cell-surface hydrophobicity.

Amino Acids↗
PubMed2003

Circadian rhythms in Neurospora crassa: farnesol or geraniol allow expression of rhythmicity in the otherwise arrhythmic strains frq10, wc-1, and wc-2.

In Neurospora crassa, the circadian rhythm can be seen in the bd (band) strain as a series of "bands" or conidiation (spore-forming) regions on the surface of an agar medium. Certain mutations at 3 different genes (frq, wc-1, or wc-2) lead to the loss of the circadian rhythm. In this study, it was found that the addition of 10(-4) to 10(-5) M of geraniol or farnesol restored rhythmic banding to strains that lack a circadian rhythm due to mutations in any 1 of these 3 genes. These 3 conditionally arrhythmic strains now exhibited robust, free-running conidiation rhythms. Their rhythms were neither temperature-compensated nor obviously sensitive to light, so the full properties of a circadian rhythm were not restored. At 20 degrees C, in growth tubes, farnesol treatment gave periods of 28, 26, and 22 h for the frq10, wc-1, and wc-2 strains, respectively. Geraniol treatment at 20 degrees C gave periods of 23, 25.5, and 24.5 h for the frq10, wc-1, and wc-2 strains, respectively. A PRC for temperature pulses (1 h, 20 to 40 degrees C) for the frq10 strain grown in the presence of geraniol showed strong resetting (type 0), suggesting that a temperature-sensitive oscillator was present. Farnesol and geraniol are related to known intermediates in the steroid (or mevalonate) pathway. These data are interpreted in terms of a 2-oscillator model, in which farnesol/geraniol activate or amplify a remaining oscillator (a postulated frq-less oscillator).

Activity Cycles↗
PubMed1976

The in vitro effects of farnesol and derivatives on Hymenolepis diminuta.

Employing an in vitro maintenance system, in which 8-day-old Hymenolepis diminuta survives for 24 hr (Fioravanti and MacInnis, 1976), it was found that farnesol or farnesal supplementation of the medium had no beneficial effects on maintenance and these substances induced necrosis at higher concentrations. Similar experiments utilizing Schiller's (1965) culture system demonstrated that neither farnesol, farnesal, nor farnesyl methyl ether exhibited growth promoting effects and were toxic to the worms at higher concentrations. In addition, neither the 2-cis, 6-trans nor the 2-trans, 6-trans-isomers of farnesol promoted growth in the Schiller system and at higher concentrations resulted in severe necrosis within 24 hr.

Animals↗
PubMed2004

Enzymatic cyclization reactions of geraniol, farnesol and geranylgeraniol, and those of truncated squalene analogs having C20 and C25 by recombinant squalene cyclase.

The substrate specificity of squalene-hopene cyclase was investigated using the C10-C25 analogs including naturally occurring substances, e.g. geraniol (C10), farnesol (C15) and geranylgeraniol (C20). No cyclization occurred for geraniol, but a significantly high conversion ratio (64%) was observed for farnesol, yielding the cyclic sesquiterpenes consisting of 6/6-fused bicyclic ring systems. Among them, an attractive compound having C30 was produced, in the structure of which acyclic the farnesol unit is linked to the bicyclic skeleton through ether linkage. Conversion of geranylgeraniol was low (ca. 12%). The squalene analogs having C20 and C25 also were cyclized in yields of ca. 33-36%, but the analogs having the methyl group at C7 and/or at C11 underwent no cyclization; the large steric bulk size of C7-Me and/or C11-Me, which is arranged in [small alpha]-disposition for all the pre-chair conformation, would have interacted repulsively with the cyclase recognition site near to the C7 and/or C11, resulting in no construction of the all-chair conformation inside the reaction cavity. A relatively low yield of geranylgeraniol indicated that a less bulky hydrogen atom must be located at C14 for the efficient polycyclization reaction. The squalene cyclase shows remarkably broad substrate specificity to accept the truncated analogs having carbon-chain lengths of C(15)-C25 in addition to C30.

Journal Article↗
PubMed1994

Phosphorylation of farnesol by a cell-free system from Botryococcus braunii.

Farnesol was incorporated into squalene as well as botryococcenes when the alcohol was fed to the culture of Botryococcus braunii B race strain. In in vitro experiments with a 10,000 x g supernatant of cell homogenate, squalene was synthesized from farnesyl diphosphate in the presence of NADPH or NADH, but botryococcenes were not synthesized under the same conditions. A 100,000 x g pelet fraction was able to phosphorylate farnesol to give its mono- and diphosphate esters in a CTP dependent manner.

Cytidine Triphosphate↗
PubMed1995

Identification of a nuclear receptor that is activated by farnesol metabolites.

Nuclear hormone receptors comprise a superfamily of ligand-modulated transcription factors that mediate the transcriptional activities of steroids, retinoids, and thyroid hormones. A growing number of related proteins have been identified that possess the structural features of hormone receptors, but that lack known ligands. Known as orphan receptors, these proteins represent targets for novel signaling molecules. We have isolated a mammalian orphan receptor that forms a heterodimeric complex with the retinoid X receptor. A screen of candidate ligands identified farnesol and related metabolites as effective activators of this complex. Farnesol metabolites are generated intracellularly and are required for the synthesis of cholesterol, bile acids, steroids, retinoids, and farnesylated proteins. Intermediary metabolites have been recognized as transcriptional regulators in bacteria and yeast. Our results now suggest that metabolite-controlled intracellular signaling systems are utilized by higher organisms.

Amino Acid Sequence↗
PubMed2005

Monitoring farnesol-induced toxicity in tobacco BY-2 cells with a fluorescent analog.

In a previous study (A. Hemmerlin, T.J. Bach, Plant Physiol. 123 (2000) 1257-1268), we have demonstrated that above a critical concentration, treatment with all-trans-farnesol induces cell-death in Nicotiana tabacum L. cv Bright Yellow-2 (TBY-2) cells. Now we used a fluorescent analog of farnesol (Fol(FLUO)), in which an isoprene unit is replaced by the fluorochrome 7-nitrobenz-2-oxa-1,3-diazol-4-yl, to visualize how cell integrity is affected. Fol(FLUO) exhibited the same toxicity as the natural compound and was shown to be readily taken up by TBY-2 cells, followed by integration into subcellular membrane structures. Although the plasma membrane seemed not to be labeled, Fol(FLUO) was associated with the tonoplast, endoplasmic reticulum, and Golgi apparatus or lipid bodies. Longer exposure times and increased Fol(FLUO) accumulation triggered the formation and proliferation of new membrane structures of as yet unknown function. Finally, at even higher and clearly cytotoxic concentrations of the analog, the cell contents became clearly disorganized, with cell swelling and ultimately plasmolysis.

Apoptosis↗
PubMed1992

Growth inhibition of leukemia cell line CEM-C1 by farnesol: effects of phosphatidylcholine and diacylglycerol.

Acute leukemia cells of the established line CEM-C1 were treated during growth in serum-free medium with various concentrations of trans-trans farnesol. At concentrations ranging from 9.0 to 31.5 microM, farnesol inhibited growth of these cells without causing cell lysis. This effect was preceded by very rapid inhibition of choline incorporation in cellular lipid fraction. The growth inhibitory effect was prevented to a large extent by incubation with phosphatidylcholine or diacylglycerol.

Acyclic Monoterpenes↗
PubMed1998

Improvement of nitrergic relaxation by farnesol of the sphincter of Oddi from hypercholesterolaemic rabbits.

Field stimulation relaxed the rabbit sphincter of Oddi muscle rings after incubation with atropine (1 microM) and guanethidine (4 microM) with a threefold increase in tissue cyclic cGMP content, a response previously shown to be essentially nitrergic. Preparations from hypercholesterolaemic rabbits (1.5% dietary cholesterol load over 8 weeks increasing serum total cholesterol from pre-diet 1.4+/-0.3 to 22.6+/-3.8 mmol/l) exhibited contractions with no change in cyclic GMP content under the same conditions. The nitrergic relaxation was recaptured with a twofold increase in tissue cyclic GMP content in preparations from hypercholesterolaemic rabbits undergone a treatment with 30 microM/kg farnesol i.v. twice a day over the last 3 days of the dietary period. We conclude that farnesol treatment restores nitrergic relaxation of the sphincter of Oddi in hypercholesterolaemia.

Animals↗
PubMed2003

The adenosine inhibition of glutamate exocytosis in synaptosomes is removed by the collapse of the vesicle-cytosol deltapH plus the opening of farnesol-sensitive Ca(2+) channels.

Adenosine inhibits synaptosomal exocytosis of glutamate, triggered by KCl or by the K(+) channel inhibitor, 4-aminopyridine (4-AP), without affecting Ca(2+) influx. Its effect is removed by the activation of protein kinase C (PKC). We show that in the presence of the protein kinase inhibitor, staurosporine, the adenosine inhibition is removed also by collapsing deltapH between secretory vesicle and the cytosol with methylamine (MA), provided that exocytosis is triggered by KCl (which activates an initial transient spike of Ca(2+) influx) but not by 4-AP. If KCl is supplied prior to Ca(2+), the spike of Ca(2+) influx is absent and the adenosine inhibition is maintained. MA can remove the adenosine inhibition also with 4-AP, provided that tetraethylammonium (TEA), an inhibitor of a different class of K(+) channels, is supplied together with 4-AP. TEA promotes a further increase of cytosolic free Ca(2+) concentration ([Ca(2+)](i)), which adds to the 4-AP-induced Ca(2+) influx. Farnesol (5-10 microM), a physiological derivative of farnesyl pyrophosphate of the sterol biosynthetic pathway, specifically inhibits the Ca(2+) spike after KCl as well as the TEA-promoted Ca(2+) increase. At the same time, it prevents the removal of the adenosine inhibition by MA. We conclude that the adenosine inhibition is removed by the coincidence of two signals, the alkalinization of secretory vesicles and the opening of a particular class of Ca(2+) channels associated to the TEA-sensitive K(+) channels, equivalent to the Ca(2+) spike after KCl, and sensitive to farnesol.

4-Aminopyridine↗
PubMed1990

Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation.

Oncogenic forms of ras proteins are synthesized in the cytosol and must become membrane associated to cause malignant transformation. Palmitic acid and an isoprenoid (farnesol) intermediate in cholesterol biosynthesis are attached to separate cysteine residues near the C termini of H-ras, N-ras, and Kirsten-ras (K-ras) exon 4A-encoded proteins. These lipid modifications have been suggested to promote or stabilize the association of ras proteins with membranes. Because preventing isoprenylation also prevents palmitoylation, examining the importance of isoprenylation alone has not been possible. However, the oncogenic human [Val12]K-ras 4B protein is not palmitoylated but is isoprenylated, membrane associated, and fully transforming. We therefore constructed mutant [Val12]K-ras 4B proteins that were not isoprenylated to examine the effects of isoprenylation in the absence of palmitoylation. The nonisoprenylated mutant proteins both failed to associate with membranes and did not transform NIH 3T3 cells. In addition, inhibition of isoprenoid and cholesterol synthesis with the drug compactin also decreased [Val12]K-ras 4B protein isoprenylation and membrane association. These results unequivocally demonstrate that isoprenylation, rather than palmitoylation, is essential for ras membrane binding and ras transforming activity. These findings clearly indicate the biological significance of ras protein modification by farnesol and suggest that this modification may be important for facilitating the processing, trafficking, and biological activity of other isoprenylated proteins. Because K-ras is the most frequently activated oncogene in a wide spectrum of human malignancies, study of this pathway could lead to important therapeutic treatments.

Animals↗
PubMed2006

Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21(Cip1) and p27(Kip1) in human pancreatic adenocarcinoma cells.

Pancreatic cancer, the fourth leading cause of cancer-associated mortality in the United States, usually presents in an advanced stage and is generally refractory to chemotherapy. As such, there is a great need for novel therapies for this disease. The naturally derived isoprenoids perillyl alcohol, farnesol, and geraniol have chemotherapeutic potential in pancreatic and other tumor types. However, their mechanisms of action in these systems are not completely defined. In this study, we investigated isoprenoid effects on the cell cycle and observed a similar antiproliferative mechanism of action among the three compounds. First, when given in combination, the isoprenoids exhibited an additive antiproliferative effect against MIA PaCa-2 human pancreatic cancer cells. Furthermore, all three compounds induced a G(0)/G(1) cell cycle arrest that coincided with an increase in the expression of the cyclin kinase inhibitor proteins p21(Cip1) and p27(Kip1) and a reduction in cyclin A, cyclin B1, and cyclin-dependent kinase (Cdk) 2 protein levels. Immunoprecipitation studies demonstrated increased association of both p21(Cip1) and p27(Kip1) with Cdk2 as well as diminished Cdk2 kinase activity after isoprenoid exposure, indicating a cell cycle-inhibitory role for p21(Cip1) and p27(Kip1) in pancreatic adenocarcinoma cells. When siRNA was used to inhibit expression of p21(Cip1) and p27(Kip1) proteins in MIA PaCa-2 cells, conditional resistance to all three isoprenoid compounds was evident. Given similar findings in this cell line and in BxPC-3 human pancreatic adenocarcinoma cells, we conclude that the chemotherapeutic isoprenoid compounds perillyl alcohol, farnesol, and geraniol invoke a p21(Cip1)- and p27(Kip1)-dependent antiproliferative mechanism in human pancreatic adenocarcinoma cells.

Acyclic Monoterpenes↗
PubMed2003

Sensitization of Staphylococcus aureus and Escherichia coli to antibiotics by the sesquiterpenoids nerolidol, farnesol, bisabolol, and apritone.

The sesquiterpenoids nerolidol, farnesol, bisabolol, and apritone were investigated for their abilities to enhance bacterial permeability and susceptibility to exogenous antimicrobial compounds. Initially, it was observed by flow cytometry that these sesquiterpenoids promoted the intracellular accumulation of the membrane-impermeant nucleic acid stain ethidium bromide by live cells of Lactobacillus fermentum, suggesting that enhanced permeability resulted from disruption of the cytoplasmic membrane. The ability of these sesquiterpenoids to increase bacterial susceptibility to a number of clinically important antibiotics was then investigated. In disk diffusion assays, treatment with low concentrations (0.5 to 2 mM) of nerolidol, bisabolol, or apritone enhanced the susceptibility of Staphylococcus aureus to ciprofloxacin, clindamycin, erythromycin, gentamicin, tetracycline, and vancomycin. Nerolidol and farnesol also sensitized Escherichia coli to polymyxin B. Our results indicate the practical utility of sensitizing bacteria to antimicrobials with sesquiterpenoids that have traditionally been used as flavorants and aroma compounds in the food and perfume industries.

Anti-Bacterial Agents↗
PubMed2005

Apigenin and tt-farnesol with fluoride effects on S. mutans biofilms and dental caries.

Apigenin (Api) and tt-farnesol (Far) are two naturally occurring agents that affect the development of cariogenic biofilms. Fluoride (F) interferes physicochemically with caries development and also exhibits antibacterial activity. We examined whether the association of Api and Far enhance the anti-caries properties of F by acting cooperatively on the expression of virulence of Streptococcus mutans. The biological effects of each of the agents were greatly enhanced when used in combination with F. In general, biofilms treated with Api and/or Far in combination with F displayed less biomass and fewer insoluble glucans and iodophilic polysaccharides than did those treated with the test agents alone (P < 0.05). The combination of the test agents with F was highly effective in preventing caries development in rats, especially Api+Far+F, and results were comparable with those observed with chlorhexidine + F (positive control). Results from these studies showed that apigenin and tt-farnesol may enhance the cariostatic effectiveness of fluoride.

Animals↗
PubMed2003

Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes.

We recently demonstrated that squalene synthase (SQS) inhibitors reduce plasma triglyceride through an LDL receptor-independent mechanism in Watanabe heritable hyperlipidemic rabbits (Hiyoshi et al. 2001. Eur. J. Pharmacol. 431: 345-352). The present study deals with the mechanism of the inhibition of triglyceride biosynthesis by the SQS inhibitors ER-27856 and RPR-107393 in rat primary cultured hepatocytes. Atorvastatin, an HMG-CoA reductase inhibitor, had no effect on triglyceride biosynthesis, but reversed the inhibitory effect of the SQS inhibitors. A squalene epoxidase inhibitor, NB-598, affected neither triglyceride biosynthesis nor its inhibition by ER-27856 and RPR-107393. The reduction of triglyceride biosynthesis by ER-27856 and RPR-107393 was potentiated by mevalonolactone supplementation. Treatment of hepatocytes with farnesol and its derivatives reduced triglyceride biosynthesis. In addition, we found that ER-27856 and RPR-107393 significantly reduced the incorporation of [1-(14)C]acetic acid into oleic acid, but not the incorporation of [1-(14)C]oleic acid into triglyceride. Though ER-27856 and RPR-107393 increased mitochondrial fatty acid beta-oxidation, the inhibition of beta-oxidation by RS-etomoxir had little effect on their inhibition of triglyceride biosynthesis. These results suggest that SQS inhibitors reduce triglyceride biosynthesis by suppressing fatty acid biosynthesis via an increase in intracellular farnesol and its derivatives.

Animals↗
PubMedDate not supplied

[The action of a juvenile hormone synthetic analog--ether-farnesol on Xenopsylla cheopis fleas].

The authors tested the effect of the analogue of juvenile hormone (AJH), ether-farnesol, synthesized at the Institute of Chemistry of the Academy of Sciences of ESSR (the city of Tallin), on immature stages of X. cheopis. When testing the following doses of AJH (0.0025, 0.00025, 0.000025, 0.0000025 ml per lg of substrate, consisting of sand and dry bull blood, for feeding larvae) it was established that the dose of 0.0025 ml/g causes 100% mortality of insects on the 2nd day of the experiment. 10 fold decrease in ether-farnesol dose causes the mortality of the majority of larvae. Only 13.6% of them formed cocoons, which failed to produce mature individuals. A repeated 10 and 100 fold decrease of AJH caused mortality in 50.0 and 46.7% of insects, respectively. The effect of the preparation stipulated the disturbance of the normal course of metamorphosis (changes in the data of phases replacement and the mortality of insects during their moulting).

Animals↗
PubMed1988

Isopentenoid synthesis in isolated embryonic Drosophila cells. Farnesol catabolism and omega-oxidation.

Kc cells divert minimally 40% of their mevalonate carbon to n-fatty acids and unidentified compounds covalently linked to macromolecules (Havel, C., Rector, E. R., II, and Watson, J. A. (1986) J. Biol. Chem. 261, 10150-10156). Furthermore mevalonate carbon diversion appears to occur at the polyprenyl 1-pyrophosphate level. This report summarizes initial efforts to define the mevalonate carbon diversion pathway. We demonstrate that Kc cell extracts readily metabolize [14C]farnesyl 1-pyrophosphate and [14C]farnesol, via common intermediates, to identical 14C-products. Two of the major 14C-products were identified as trans,trans-3,7,11-trimethyl-2,6,10-dodecatrien-1,12-dioic acid and trans-3,7-dimethyl-2,6-decadien-1,10-dioic acid. Similar acids were also synthesized by supplemented rat liver extracts incubated with [14C]farnesol. We conclude that (a) mevalonate carbon diversion at the level of polyprenyl 1-pyrophosphate is a viable metabolic strategy, (b) polyprenols are oxidized to alpha,omega-prenyl dicarboxylic acids which are catabolized from the omega-terminus, and (c) this metabolic process is not limited to insect cells.

Animals↗
PubMedDate not supplied

[Activity of the octanol dehydrogenase, of the alcool dehydrogenase and aldehyde dehydrogenase on the farnesol metabolism. Photoperiodic and neurhormonale regulation, controlling the metabolism of the juvenile hormone, in Pieris brassicae (author's transl)].

The antagonistic photoperiodic behaviour of the farnesol dehydrogenases indicates that the photonic control mechanism of the brain acts on the farnesol derivates. This cerebral control is double. The first system, linked at the allatotrope function is proportionnal at the photoperiod and acts on the octanol dehydrogenase 0,32. The second system controle the deshydrogenases ADH bands 0,50--0,58, is linked at the darkness. It is linked also at the neurocerebral activity then it stops its activity at the 4th day of the 5th stage. This last seems to be the determinating control for the establishment of the diapause since in short photoperiod, when the inhibition by this system ends, the alcool dehydrogenases 0,50-0,58 series is suractivated in rate with the lasting of the scotophase. In darkness, the 1st system functionnes cyclically and has a maximum synchron with the single maximum of the 2nd system. Inversally, in continuous light, the 2nd system is synchronisated with the 1st which has a prolongated action, maybe linked with a prolongated activity of the neurosecretory cells of the pars intercerebralis and corpora allata.

Animals↗