Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease

Farnesol antimicrobial role as biofilm cell detachment inducer in S. epidermidis biofilms

Objetives: Farnesol is a naturally-occurring sesquiterpene that was originally isolated from essential oils found in many plants has been described to have antimicrobial potential against several bacteria, including S. epidermidis. However, farnesol mechanism of action is not yet fully understood and some contradictory findings have been reported. We recently described that while farnesol was not efficient at killing biofilm bacteria, a strong reduction on biofilm biomass was detected, and we hypothesize that farnesol could be inducing biofilm detachment. Here, we address this hypothesis. Methods: To test our hypothesis we used 36 representative clinical strains of S. epidermidis from different parts of the world and characterized them in terms of genetic variability, biofilm formation and on the effect of farnesol on biofilm physiology and gene expression. Results: Farnesol had no bactericidal effect on stationary phase populations equal or above 108 CFU/mL. In exponential phase planktonic bacteria, farnesol showed a bacteriostatic effect after cell density reached 108 CFU/mL. In any of the growth phases studied, farnesol was effective in killing above 90% of bacteria in 4 h when cell density was 107 CFU/mL or below. Confocal microscopy and flow citometry analysis confirmed that in biofilms bacteria were not killed by farnesol but nevertheless cell wall integrity was affected. Gene expression studies revealed differential responses to farnesol, depending on the bacterial strain tested. Farnesol cell detachement from biofilms was also straindependent. Conclusions: We found that while farnesol cannot kill high density bacterial communities, such as biofilms, it was nevertheless able to induce biofilm detachment in 50% of the strains that formed biofilm

Biotransformasi 2E-6E-Farnesol Oleh Jamur Endofit Botryosphaeria SP. CA2C-3 Yang Diisolasi Dari Temu Hitam (Curcuma Aeruginosa ROXB.)

The objective of study was to investigate the microbial transformation reaction of 2E-6E-farnesol by the endophyticfungi isolated from temu hitam (Curcuma aeruginosa ROXB. The transformation was carried out in PDB with (2E-6E-farnesol), incubated at room temperature (25-32o C) under shaking condition at 120 rpm for two days produceda major biotransformed product. Structure elucidation based on 1D- and 13C-NMR analysis showed that the biotransformedproduct was 10,11-dihydroxi-2E-6E-farnesol. It It was verified that biotransformation reaction of 2E-6E-farnesol into 10,11-dihydroxi-2E-6E-farnesol through an intermediate 10,11-epoxi-2E-6E-farnesol

Elucidating Signal Transduction Modulatory Drug Target Network of Colon Cancer: A Network Biology Approach

Latest evaluation and validation of cancer drugs and their targets has demonstrated the lack and inadequate development of new and better drugs, based on available protocols. Even though the specificity of drug targets is a great challenge in the pharmaco-proteomics field of cancer biology, for eradicating such hurdles and paving the way for the drugs of future, a novel step has been envisaged here to study the relation between drug target network and the corresponding drug network using the advanced concepts of proteomics and network biology. The literature mining was done for the collection of receptors and the ligands. About 1000 natural compounds were collected and out of those 300 molecules showed anti-cancer activity against colon cancer. Ligand Vs multiple receptor docking was done using the software Quantum 3.3.0; the results were further used for the designing of a well connected Protein Ligand Interaction (PLI) network of colon cancer. The obtained network is then extrapolated to sort out the receptors expressed in the specific cancer type. The network is then statistically analyzed and represented by the graphical interpretation, in order to ascertain the hub nodes and their locally parsed neighbours. Based on the best docking scores, the graphs obtained from the docking analysis are statistically validated with the help of VisANT. In the network three hub nodes Neutrophil cytosol factor 2, UV excision repair protein RAD23 homolog A, & Receptor-type tyrosine-protein phosphatase eta were identified, which showed the highest interaction with the ligands. Butyrate and Farnesol showed highest interaction as ligands. Multiple Sequence Alignment was done of the binding site sequence of the drug targets to find out the evolutionary closeness of the binding sites. The phylogenetic tree was also constructed to further validate the observation. Further in-vitro and in-vivo studies needs to be done to analyse the receptor specificity and anti tumor activity of these compounds in Colon cancer

Effect of farnesol on Candida dubliniensis morphogenesis

Cell–cell signalling in Candida albicans is a known phenomenon and farnesol was identified as a quorum sensing molecule determining the yeast morphology. The aim of this work was to verify if farnesol had a similar effect on Candida dubliniensis, highlighting the effect of farnesol on Candida spp. morphogenesis. Methods and Results: Two different strains of C. dubliniensis and one of C. albicans were grown both in RPMI 1640 and in serum in the presence of absence of farnesol. At 150 μmol l -1 farnesol the growth rate of both Candida species was not affected. On the contrary, farnesol inhibited hyphae and pseudohyphae formation in C. dubliniensis. Conclusion: Farnesol seems to mediate cell morphology in both Candida species. Significance and Impact of the Study: The effect of farnesol on C. dubliniensis morphology was not reported previously.Fundação para a Ciência e a Tecnologia (FCT

Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons.

In the Drosophila antenna, different subtypes of olfactory receptor neurons (ORNs) housed in the same sensory hair (sensillum) can inhibit each other non-synaptically. However, the mechanisms underlying this underexplored form of lateral inhibition remain unclear. Here we use recordings from pairs of sensilla impaled by the same tungsten electrode to demonstrate that direct electrical ("ephaptic") interactions mediate lateral inhibition between ORNs. Intriguingly, within individual sensilla, we find that ephaptic lateral inhibition is asymmetric such that one ORN exerts greater influence onto its neighbor. Serial block-face scanning electron microscopy of genetically identified ORNs and circuit modeling indicate that asymmetric lateral inhibition reflects a surprisingly simple mechanism: the physically larger ORN in a pair corresponds to the dominant neuron in ephaptic interactions. Thus, morphometric differences between compartmentalized ORNs account for highly specialized inhibitory interactions that govern information processing at the earliest stages of olfactory coding

Response of Staphylococcus epidermidis biofilms cells to the effect of farnesol

Objective:Staphylococcus epidermidis is a leading cause of medical-device-related infections, especially in immunocompromised patients. The treatment of these infections is further complicated by the emergence of multiresistant strains. The ability of S. epidermidis to form biofilms on biotic and abiotic surfaces is believed to contribute significantly to the pathogenesis of these infections. Biofilms are notoriously difficult to eradicate and are often resistant to systemic antibiotic therapy. Recently, farnesol has been described as having antimicrobial properties, and therefore a possible action on the prevention of S. epidermidis related infections. In previous studies it was shown that 300 microM farnesol was effective against S. epidermidis planktonic cells but having only a slight effect on biofilm cells. So, the goal of this study was to assess the antimicrobial activity of higher farnesol concentrations (1 and 100 mM) against biofilm cells of S. epidermidis. Methods: Two S. epidermidis strains biofilm-producing (9142 and 1457) were used in this study. Farnesol (0, 1 mM, 100 mM) was added to 24 h biofilm cells. Biofilm formation was assessed through crystal violet (CV) staining that measure total biomass of biofilm and cellular viability through XTT and colony-forming units (CFU/ml). Results: The results didn't show a significant effect of both farnesol concentrations on biofilm biomass and activity. In fact, biofilm cell reduction was less than 2 Log, similarly to most antibiotics (e.g. tetracycline and vancomycin). Conclusion: Although the reduction promoted by farnesol was less than 3 Log as requested for an antibiotic agent, its efficacy is similar to vancomycin. On account of that we are now testing the combined effect of farnesol with agents that disrupt the biofilm matrix