Identifying the Key Role of Plutella xylostella General Odorant Binding Protein 2 in Perceiving a Larval Attractant, (E,E)-2,6-Farnesol.

There is currently a lack of effective olfaction-based techniques to control diamondback moth (DBM) larvae. Identifying behaviorally active odorants for DBM larvae and exploring their recognition mechanisms can provide insights into olfaction-based larval control strategies. Through the two-choice assay, (E,E)-2,6-farnesol (farnesol) was identified as a compound exhibiting significant attractant activity toward DBM larvae, achieving an attraction index of 0.48 ± 0.13. PxylGOBP1 and PxylGOBP2, highly expressed in the antennae of DBM larvae, both showed high affinity toward farnesol. RNAi technology was used to knock down PxylGOBP1 and PxylGOBP2, revealing that the attraction of DBM larvae to farnesol nearly vanished following the knockdown of PxylGOBP2, indicating its critical role in recognizing farnesol. Further investigation into the PxylGOBP2-farnesol interaction revealed the importance of residues like Thr9, Trp37, and Phe118 in PxylGOBP2's binding to farnesol. This research is significant for unveiling the olfactory mechanisms of DBM larvae and developing larval behavior regulation techniques.

Studying mixed-species biofilms of Candida albicans and Staphylococcus aureus using evolutionary game theory.

Mixed-species biofilms of Candida albicans and Staphylococcus aureus pose a significant clinical challenge due to their resistance to the human immune system and antimicrobial therapy. Using evolutionary game theory and nonlinear dynamics, we analyse the complex interactions between these organisms to understand their coexistence in the human host. We determine the Nash equilibria and evolutionary stable strategies of the game between C. albicans and S. aureus and point out different states of the mixed-species biofilm. Using replicator equations we study the fungal-bacterial interactions on a population level. Our focus is on the influence of available nutrients and the quorum sensing molecule farnesol, including the potential therapeutic use of artificially added farnesol. We also investigate the impact of the suggested scavenging of C. albicans hyphae by S. aureus. Contrary to common assumptions, we confirm the hypothesis that under certain conditions, mixed-species biofilms are not universally beneficial. Instead, different Nash equilibria occur depending on encountered conditions (i.e. varying farnesol levels, either produced by C. albicans or artificially added), including antagonism. We further show that the suggested scavenging of C. albicans' hyphae by S. aureus does not influence the overall outcome of the game. Moreover, artificially added farnesol strongly affects the dynamics of the game, although its use as a medical adjuvant (add-on medication) may pose challenges.

Comparative transcriptional analysis of Candida auris biofilms following farnesol and tyrosol treatment.

Candida auris is frequently associated with biofilm-related invasive infections. The resistant profile of these biofilms necessitates innovative therapeutic options, where quorum sensing may be a potential target. Farnesol and tyrosol are two fungal quorum-sensing molecules with antifungal effects at supraphysiological concentrations. Here, we performed genome-wide transcript profiling with C. auris biofilms following farnesol or tyrosol exposure using transcriptome sequencing (RNA-Seq). Since transition metals play a central role in fungal virulence and biofilm formation, levels of intracellular calcium, magnesium, and iron were determined following farnesol or tyrosol treatment using inductively coupled plasma optical emission spectrometry. Farnesol caused an 89.9% and 73.8% significant reduction in the calcium and magnesium content, respectively, whereas tyrosol resulted in 82.6%, 76.6%, and 81.2% decrease in the calcium, magnesium, and iron content, respectively, compared to the control. Genes involved in biofilm events, glycolysis, ergosterol biosynthesis, fatty acid oxidation, iron metabolism, and autophagy were primarily affected in treated cells. To prove ergosterol quorum-sensing molecule interactions, microdilution-based susceptibility testing was performed, where the complexation of farnesol, but not tyrosol, with ergosterol was impeded in the presence of exogenous ergosterol, resulting in a minimum inhibitory concentration increase in the quorum-sensing molecules. This study revealed several farnesol- and tyrosol-specific responses, which will contribute to the development of alternative therapies against C. auris biofilms. IMPORTANCE: Candida auris is a multidrug-resistant fungal pathogen, which is frequently associated with biofilm-related infections. Candida-derived quorum-sensing molecules (farnesol and tyrosol) play a pivotal role in the regulation of fungal morphogenesis and biofilm development. Furthermore, they may have remarkable anti-biofilm effects, especially at supraphysiological concentrations. Innovative therapeutic approaches interfering with quorum sensing may be a promising future strategy against C. auris biofilms; however, limited data are currently available concerning farnesol-induced and tyrosol-related molecular effects in C. auris. Here, we detected several genes involved in biofilm events, glycolysis, ergosterol biosynthesis, fatty acid oxidation, iron metabolism, and autophagy, which were primarily influenced following farnesol or tyrosol exposure. Moreover, calcium, magnesium, and iron homeostasis were also significantly affected. These results reveal those molecular and physiological events, which may support the development of novel therapeutic approaches against C. auris biofilms.

Transdermal administration of farnesol-ethosomes enhances the treatment of cutaneous candidiasis induced by Candida albicans in mice.

Cutaneous candidiasis, caused by Candida albicans, is a severe and frustrating condition, and finding effective treatments can be challenging. Therefore, the development of farnesol-loaded nanoparticles is an exciting breakthrough. Ethosomes are a novel transdermal drug delivery carrier that incorporates a certain concentration (10-45%) of alcohols into lipid vesicles, resulting in improved permeability and encapsulation rates compared to conventional liposomes. Farnesol is a quorum-sensing molecule involved in morphogenesis regulation in C. albicans, and these ethosomes offer a promising new approach to treating this common fungal infection. This study develops the formulation of farnesol-loaded ethosomes (farnesol-ethosomes) and assesses applications in treating cutaneous candidiasis induced by C. albicans in vitro and in vivo. Farnesol-ethosomes were successfully developed by ethanol injection method. Therapeutic properties of farnesol-ethosomes, such as particle size, zeta potential, and morphology, were well characterized. According to the results, farnesol-ethosomes demonstrated an increased inhibition effect on cells' growth and biofilm formation in C. albicans. In Animal infection models, treating farnesol-ethosomes by transdermal administration effectively relieved symptoms caused by cutaneous candidiasis and reduced fungal burdens in quantity. We also observed that ethosomes significantly enhanced drug delivery efficacy in vitro and in vivo. These results indicate that farnesol-ethosomes can provide future promising roles in curing cutaneous candidiasis. IMPORTANCE: Cutaneous candidiasis attributed to Candida infection is a prevalent condition that impacts individuals of all age groups. As a type of microbial community, biofilms confer benefits to host infections and mitigate the clinical effects of antifungal treatments. In C. albicans, the yeast-to-hypha transition and biofilm formation are effectively suppressed by farnesol through its modulation of multiple signaling pathway. However, the characteristics of farnesol such as hydrophobicity, volatility, degradability, and instability in various conditions can impose limitations on its effectiveness. Nanotechnology holds the potential to enhance the efficiency and utilization of this molecule. Treatment of farnesol-ethosomes by transdermal administration demonstrated a very remarkable therapeutic effect against C. albicans in infection model of cutaneous candidiasis in mice. Many patients suffering fungal skin infection will benefit from this study.

Farnesol remodels the peritoneal cavity immune environment influencing Candida albicans pathogenesis during intra-abdominal infection.

Candida albicans is a lifelong member of the mycobiome causing mucosal candidiasis and life-threatening, systemic, and intra-abdominal disease in immunocompromised and transplant patients. Despite the clinical importance of intra-abdominal candidiasis with mortality rates between 40% and 70%, the contribution of fungal virulence factors and host immune responses to disease has not been extensively studied. Secretion of the quorum-sensing molecule, farnesol, acts as a virulence factor for C. albicans during systemic infection, while inducing local, protective innate immune responses in oral models of infection. Previously, we reported that farnesol recruits macrophages to the peritoneal cavity in mice, suggesting a role for farnesol in innate immune responses. Here, we expand on our initial findings, showing that farnesol profoundly alters the peritoneal cavity microenvironment promoting innate inflammation. Intra-peritoneal injection of farnesol stimulates rapid local death of resident peritoneal cells followed by recruitment of neutrophils and inflammatory macrophages into the peritoneal cavity and peritoneal mesothelium associated with an early increase in chemokines followed by proinflammatory cytokines. These rapid inflammatory responses to farnesol significantly increase morbidity and mortality of mice with intra-abdominal candidiasis associated with increased formation of peritoneal adhesions, despite similar rates of fungal clearance from the peritoneal cavity and retro-peritoneal organs. C. albicans ddp3Δ/ddp3Δ knockout and reconstituted strains recapitulate these findings. This indicates that farnesol may be detrimental to the host during intra-abdominal infections. Importantly, our results highlight a need to understand how C. albicans virulence factors modulate the host immune response within the peritoneum, an exceedingly common site of Candida infection.

Pterodon emarginatus Seed Preparations: Antiradical Activity, Chemical Characterization, and In Silico ADMET Parameters of ß-caryophyllene and Farnesol.

The study of medicinal plants and their active compounds is relevant to maintaining knowledge of traditional medicine and to the development of new drugs of natural origin with lower environmental impact. From the seeds of the Brazilian plant Pterodon emarginatus, six different preparations were obtained: essential oil (EO), ethanol extract (EthE) prepared using the traditional method, and four extracts using solvents at different polarities, such as n-hexane, chloroform, ethyl acetate, and methanol (HexE, ChlE, EtAE, and MetE). Chemical characterization was carried out with gas chromatography, allowing the identification of several terpenoids as characteristic components. The two sesquiterpenes ß-caryophyllene and farnesol were identified in all preparations of Pterodon emarginatus, and their amounts were also evaluated. Furthermore, the total flavonoid and phenolic contents of the extracts were assessed. Successively, the antiradical activity with DPPH and ORAC assays and the influence on cell proliferation by the MTT test on the human colorectal adenocarcinoma (HT-29) cell line of the preparations and the two compounds were evaluated. Lastly, an in silico study of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) showed that ß-caryophyllene and farnesol could be suitable candidates for development as drugs. The set of data obtained highlights the potential medicinal use of Pterodon emarginatus seeds and supports further studies of both plant preparations and isolated compounds, ß-caryophyllene and farnesol, for their potential use in disease with free radical involvement as age-related chronic disorders.

Comparative Antibacterial and Efflux Pump Inhibitory Activity of Isolated Nerolidol, Farnesol, and α-Bisabolol Sesquiterpenes and Their Liposomal Nanoformulations.

The efflux systems are considered important mechanisms of bacterial resistance due to their ability to extrude various antibiotics. Several naturally occurring compounds, such as sesquiterpenes, have demonstrated antibacterial activity and the ability to inhibit efflux pumps in resistant strains. Therefore, the objective of this research was to analyze the antibacterial and inhibitory activity of the efflux systems NorA, Tet(K), MsrA, and MepA by sesquiterpenes nerolidol, farnesol, and α-bisabolol, used either individually or in liposomal nanoformulation, against multi-resistant Staphylococcus aureus strains. The methodology consisted of in vitro testing of the ability of sesquiterpenes to reduce the Minimum Inhibitory Concentration (MIC) and enhance the action of antibiotics and ethidium bromide (EtBr) in broth microdilution assays. The following strains were used: S. aureus 1199B carrying the NorA efflux pump, resistant to norfloxacin; IS-58 strain carrying Tet(K), resistant to tetracyclines; RN4220 carrying MsrA, conferring resistance to erythromycin. For the EtBr fluorescence measurement test, K2068 carrying MepA was used. It was observed the individual sesquiterpenes exhibited better antibacterial activity as well as efflux pump inhibition. Farnesol showed the lowest MIC of 16.5 µg/mL against the S. aureus RN4220 strain. Isolated nerolidol stood out for reducing the MIC of EtBr to 5 µg/mL in the 1199B strain, yielding better results than the positive control CCCP, indicating strong evidence of NorA inhibition. The liposome formulations did not show promising results, except for liposome/farnesol, which reduced the MIC of EtBr against 1199B and RN4220. Further research is needed to evaluate the mechanisms of action involved in the inhibition of resistance mechanisms by the tested compounds.

Biological effects of trans, trans-farnesol in Leishmania amazonensis.

Introduction: Farnesol, derived from farnesyl pyrophosphate in the sterols biosynthetic pathway, is a molecule with three unsaturations and four possible isomers. Candida albicans predominantly secretes the trans, trans-farnesol (t, t-FOH) isomer, known for its role in regulating the virulence of various fungi species and modulating morphological transition processes. Notably, the evolutionary divergence in sterol biosynthesis between fungi, including Candida albicans, and trypanosomatids resulted in the synthesis of sterols with the ergostane skeleton, distinct from cholesterol. This study aims to assess the impact of exogenously added trans, trans-farnesol on the proliferative ability of Leishmania amazonensis and to identify its presence in the lipid secretome of the parasite. Methods: The study involved the addition of exogenous trans, trans-farnesol to evaluate its interference with the proliferation of L. amazonensis promastigotes. Proliferation, cell cycle, DNA fragmentation, and mitochondrial functionality were assessed as indicators of the effects of trans, trans-farnesol. Additionally, lipid secretome analysis was conducted, focusing on the detection of trans, trans-farnesol and related products derived from the precursor, farnesyl pyrophosphate. In silico analysis was employed to identify the sequence for the farnesene synthase gene responsible for producing these isoprenoids in the Leishmania genome. Results: Exogenously added trans, trans-farnesol was found to interfere with the proliferation of L. amazonensis promastigotes, inhibiting the cell cycle without causing DNA fragmentation or loss of mitochondrial functionality. Despite the absence of trans, trans-farnesol in the culture supernatant, other products derived from farnesyl pyrophosphate, specifically α-farnesene and ß-farnesene, were detected starting on the fourth day of culture, continuing to increase until the tenth day. Furthermore, the identification of the farnesene synthase gene in the Leishmania genome through in silico analysis provided insights into the enzymatic basis of isoprenoid production. Discussion: The findings collectively offer the first insights into the mechanism of action of farnesol on L. amazonensis. While trans, trans-farnesol was not detected in the lipid secretome, the presence of α-farnesene and ß-farnesene suggests alternative pathways or modifications in the isoprenoid metabolism of the parasite. The inhibitory effects on proliferation and cell cycle without inducing DNA fragmentation or mitochondrial dysfunction raise questions about the specific targets and pathways affected by exogenous trans, trans-farnesol. The identification of the farnesene synthase gene provides a molecular basis for understanding the synthesis of related isoprenoids in Leishmania. Further exploration of these mechanisms may contribute to the development of novel therapeutic strategies against Leishmania infections.

Antiparasitic effect of Farnesol against Leishmania major: A rationale from in vitro and in silico investigations.

Leishmaniasis is a vector-borne parasitic infection caused by the infective bite of female Phlebotomine sandflies. Treatment of leishmaniasis by conventional synthetic compounds is met by challenges pertaining to adverse effects which call for the discovery of newer anti-leishmanial molecules. This study was performed to evaluate the effect and modes of action of a sesquiterpene alcoholic molecule Farnesol on Leishmania major, the causative agent of Zoonotic CL. The cytotoxic effect of Farnesol against L.major promastigotes, amastigotes and macrophages was assessed by MTT test and counting. The IC50 on promastigotes by Farnesol on L.major was also evaluated by flow cytometry. In the findings, promastigotes were reduced at 167µM. The mean numbers of L.major amastigotes in macrophages were significantly decreased on exposure to Farnesol at 172µM. In addition, Farnesol induced significant apoptosis dose-dependent on L.major promastigotes. In silico protein-ligand_binding analyses indicated the effect of Farnesol in perturbation of the ergosterol synthesis pathway of Leishmania with attributes suggesting inhibition of Lanosterol-α-demethylase, the terminal enzyme of ergosterol synthesis machinery. Findings from flow cytometry reveal the role of Farnesol in apoptosis-induced killing in promastigotes. Farnesol was effective at very lower concentrations when compared to Paromomycin. Further studies are crucial to evaluate the therapeutic potential of Farnesol alone or in combination with other conventional drugs in animal models.

Vasorelaxant effect of (E,E)-farnesol in human umbilical vein ex vivo assays.

(E,E)-farnesol is a sesquiterpene acyclic alcohol produced by bacteria, protozoa, fungi, plants, and animals. The literature describes its applications in food, pharmaceutical, and cosmetic industries, and also in the pharmacological context with a vasorelaxant effect. However, its effects on human umbilical vessels remain poorly investigated. Thus, this study aims to investigate, in a new way, the vasorelaxant effect of (E,E)-farnesol in human umbilical veins (HUV) from healthy donors. Rings obtained from isolated HUV were suspended in an organ bath to record their isometric tension in different experimental sections. (E,E)-farnesol (1 µmol/L to 1 mmol/L) promoted vasorelaxant effect in venous preparations contracted by depolarization (KCl 60 mmol/L) or pharmacological agonism (5-HT 10 µmol/L), with EC50 values of 239.9 µmol/L and 424 µmol/L, respectively. In calcium-free solution, this effect was also observable. (E,E)-farnesol was able to suppress contractions evoked by CaCl2 and BaCl2 suggesting a blockade of voltage-dependent (especially L-type) calcium channels. The vasorelaxant efficacy and potency of (E,E)-farnesol were affected in the presence of tetraethylammonium (1 and 10 mmol/L), glibenclamide (10 µmol/L) and BaCl2 (1 mmol/L) indicating a possible involvement of potassium channels (BKCa, KATP and KIR) in this effect. Our data suggest that (E,E)-farnesol has a promising potential to be applicable as a vasodilator in hypertensive conditions in pregnancy that alter HUV reactivity.

Farnesol brain transcriptomics in CNS inflammatory demyelination.

BACKGROUND: Farnesol (FOL) prevents the onset of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). OBJECTIVE: We examined the transcriptomic profile of the brains of EAE mice treated with daily oral FOL using next-generation sequencing (RNA-seq). METHODS: Transcriptomics from whole brains of treated and untreated EAE mice at the peak of EAE was performed. RESULTS: EAE-induced mice, compared to naïve, healthy mice, overall showed increased expression in pathways for immune response, as well as an increased cytokine signaling pathway, with downregulation of cellular stress proteins. FOL downregulates pro-inflammatory pathways and attenuates the immune response in EAE. FOL downregulated the expression of genes involved in misfolded protein response, MAPK activation/signaling, and pro-inflammatory response. CONCLUSION: This study provides insight into the molecular impact of FOL in the brain and identifies potential therapeutic targets of the isoprenoid pathway in MS patients.

The fungal quorum-sensing molecule, farnesol, regulates the immune response of vaginal epithelial cells against Candida albicans.

BACKGROUND: Farnesol is a Candida-secreted quorum-sensing molecule of great interest as a potential antifungal agent for serious and hardly curable infections-candidiasis, especially vulvovaginal candidiasis (VVC). METHODS: The effect of farnesol on cellular morphology and viability and evaluated the production of Th1 (IL-2), Th2 (IL-4), proinflammatory (IL-6), chemotactic (IL-8), and Th17 (IL-17) cytokines in the culture supernatants of vaginal epithelial cell line (VK2) were evaluated. Moreover, we tested the inhibitory effect of farnesol on C. albicans adhesion. Scanning electron microscopy was conducted to observe any VK2 cell ultrastructural changes. RESULTS: Only low concentrations (≤ 50 µmol/L) of farnesol did not affect the morphology and viability of the VK2 cells (P > 0.05). Farnesol reduced the adhesion of C. albicans to the VK2 cells. When treated with farnesol, statistical elevated levels of both IL-4 and IL-17 secreted by the infected VK2 cells were present in the culture supernatants (P < 0.05). CONCLUSIONS: Farnesol acts as a stimulator to up-regulate the Th17-type innate immune response, as well as Th2-type humoral immunity following C. albicans infection. Further research is required to select the optimal therapeutic dose to develop efficacious and safe mucosal immune adjuvant for treating VVCs.

Evaluation of farnesol orally and topically against experimental cutaneous leishmaniasis: In -vivo analysis.

Leishmaniasis is a zoonotic disease transmitted by an obligate intra-macrophage protozoan of the genus Leishmania through the infective bite of a vector sandfly. This study investigated the therapeutic efficacy of farnesol, a sesquiterpene compound, for the treatment of cutaneous leishmaniasis (CL) using in vivo BALB/c mouse model. In this study, farnesol's efficacy was compared with the standard drug, paromomycin. It was observed that farnesol significantly reduced lesion sizes and footpad thickness compared to the control group (paromomycin). Lymph node size was also significantly reduced in farnesol-treated mice, indicating its ability to control infection spread. Combination therapy with farnesol and Paromomycin did not demonstrate synergistic effects. These results highlight the potential of farnesol as an alternative therapeutic agent for CL. Further investigations are required to elucidate its mechanism of action and assess potential off-target effects. Optimization of oral delivery methods should be explored to enhance bioavailability. Overall, our findings support farnesol's efficacy in CL treatment, offering promising prospects for improved disease management.

Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity.

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.

Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions, such as neurodegenerative diseases and diabetes; thus, elevating PGC-1α abundance might be a promising strategy to treat muscle aging. Here, we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1α. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farnesol treatment accelerated the recovery of muscle injury associated with enhanced muscle stem cell function. The protein expression of Parkin-interacting substrate (PARIS/Zfp746), a transcriptional repressor of PGC-1α, was elevated in aged muscles, likely contributing to PGC-1α reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1α suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS expression in the muscles of aged mice, leading to the elevation of PGC-1α. Collectively, the current study demonstrated that the PARIS-PGC-1α pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS.

Concurrent administration of farnesol protects acetaminophen-induced acute hepatic necrosis in mice.

Acetaminophen (APAP) is known to cause acute liver injury and acute liver failure in Western countries. This study investigates the protective role of farnesol (FAR) (C15 H26 O), a natural sesquiterpene alcohol in essential oils, against APAP-induced acute liver necrosis in mice. Mice were injected with a single dose of APAP (300 mg/kg) via an intraperitoneal route. Different groups of mice were concurrently treated with a single dose of FAR 25 mg/kg, FAR 50 mg/kg, and N-acetylcysteine. APAP administration caused a significant increase in transaminase activities and malondialdehyde (MDA) levels in the serum and liver tissue, respectively, with a concomitant decrease in intracellular antioxidants, including reduced glutathione (GSH) in the liver tissue. APAP intoxication upregulated proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1ß (IL-1ß), IL-6, nuclear factor-κB (NF-κB), and IκB kinase ß in the liver tissue. FAR and N-acetylcysteine (NAC) administrations concurrently with APAP prevented serum transaminase increase in serum and MDA levels in the liver tissue. A high dose of FAR and NAC treatments significantly inhibited GSH and other antioxidant depletion. FAR and NAC treatments also downregulated the expression of proinflammatory markers. FAR treatments protects against APAP-induced acute liver injury and offers antioxidant and anti-inflammatory effects by inhibiting the NF-κB pathway involved in the transcription of genes responsible for inflammatory cytokine synthesis.

Inhibitory effects of a maleimide compound on the virulence factors of Candida albicans.

Candidiasis caused by Candida albicans infection has long been a serious human health problem. The pathogenicity of C. albicans is mainly due to its virulence factors, which are novel targets of antifungal drugs for low risk of resistance development. In this study, we identified a maleimide compound [1-(4-methoxyphenyl)-1hydro-pyrrole-2,5-dione, MPD] that exerts effective anti-virulence activity. It could inhibit the process of adhesion, filamentation, and biofilm formation in C. albicans. In addition, it exhibited low cytotoxicity, hemolytic activity, and drug resistance development. Moreover, in Galleria mellonella-C. albicans (in vivo) infection model, the survival time of infected larvae was significantly prolonged under the treatment of MPD. Further, mechanism research revealed that MPD increased farnesol secretion by upregulating the expression of Dpp3. The increased farnesol inhibited the activity of Cdc35, which then decreased the intracellular cAMP content resulting in the inhibition of virulence factors via the Ras1-cAMP-Efg1 pathway. In all, this study evaluated the inhibitory effect of MPD on various virulence factors of C. albicans and identified the underlying mechanisms. This suggests a potential application of MPD to overcome fungal infections in clinics.

Bioactivity of select essential oil constituents against life stages of Anopheles arabiensis (Diptera: Culicidae).

Malaria is transmitted by infected female Anopheles mosquitoes, and An. arabiensis is a main malaria vector in arid African countries. Like other anophelines, its life cycle comprises of three aquatic stages; egg, larva, and pupa, followed by a free flying adult stage. Current vector control interventions using synthetic insecticides target these stages using adulticides or less commonly, larvicides. With escalating insecticide resistance against almost all conventional insecticides, identification of agents that simultaneously act at multiple stages of Anopheles life cycle presents a cost-effective opportunity. A further cost-effective approach would be the discovery of such insecticides from natural origin. Interestingly, essential oils present as potential sources of cost-effective and eco-friendly bioinsecticides. This study aimed to identify essential oil constituents (EOCs) with potential toxic effects against multiple stages of An. arabiensis life cycle. Five EOCs were assessed for inhibition of Anopheles egg hatching and ability to kill larvae, pupae and adult mosquitoes of An. arabiensis species. One of these EOCs, namely methyleugenol, exhibited potent Anopheles egg hatchability inhibition with an IC50 value of 0.51 ± 0.03 µM compared to propoxur (IC50: 5.13 ± 0.62 µM). Structure-activity relationship study revealed that methyleugenol and propoxur share a 1,2-dimethoxybenze moiety that may be responsible for the observed egg-hatchability inhibition. On the other hand, all five EOCs exhibited potent larvicidal activity with LC50 values less than 5 µM, with four of them; cis-nerolidol, trans-nerolidol, (-)-α-bisabolol, and farnesol, also possessing potent pupicidal effects (LC50 < 5 µM). Finally, all EOCs showed only moderate lethality against adult mosquitoes. This study reports for the first time, methyleugenol, (-)-α-bisabolol and farnesol as potent bioinsecticides against early life stages of An. arabiensis. This synchronized activity against Anopheles aquatic stages shows a prospect to integrate EOCs into existing adulticide-based vector control interventions.

Synergy with farnesol rejuvenates colistin activity against Colistin-resistant Gram-negative bacteria in vitro and in vivo.

Colistin (COL) is considered the last line of treatment against infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB). However, the increasing number of colistin-resistant (COL-R) bacteria is a great threat to public health. In this study, a strategy of combining farnesol (FAR), which has anti-inflammatory and antitumor properties, with COL to restart COL activity was proposed. The synergistic effect of FAR combined with COL against COL-R GNB in vivo and in vitro were investigated. The excellent synergistic antibacterial activity of the COL-FAR combination was confirmed by performing the checkerboard assay, time-killing assay, and LIVE/DEAD bacterial cell viability assay. Crystal violet staining and scanning electron microscopy results showed that COL-FAR prevented biofilm formation and eradicated pre-existing mature biofilm. Cytotoxicity assay showed that FAR at 64 µg/mL was not cytotoxic to RAW264.7 cells. In vivo infection experiments showed that COL-FAR increased the survival rate of infected Galleria mellonella and decreased the bacterial load in a mouse thigh infection model. These results indicate that COL-FAR is a potentially effective therapeutic option for combating COL-R GNB infections.

Combination of Farnesol with Common Antifungal Drugs: Inhibitory Effect against Candida Species Isolated from Women with RVVC.

Background and Objectives: Vulvovaginal candidiasis (VVC) is a mucous membrane infection, with an increased rate of antifungal resistance of Candida species. In this study, the in vitro efficacy of farnesol alone or in combination with traditional antifungals was assessed against resistant Candida strains recovered from women with VVC. Materials and Methods: Eighty Candida isolates were identified by multiplex polymerase chain reaction (PCR), and the antifungal susceptibility to amphotericin B (AMB), fluconazole (FLU), itraconazole (ITZ), voriconazole (VOR), clotrimazole (CTZ), and farnesol was tested by the standard microdilution method. The combinations of farnesol with each antifungal were calculated based on the fractional inhibitory concentration index (FICI). Result: Candida glabrata was the predominant species (48.75%) isolated from vaginal discharges, followed by C. albicans (43.75%), C. parapsilosis (3.75%), a mixed infection of C. albicans and C. glabrata (2.5%) and C. albicans and C. parapsilosis (1%). C. albicans and C. glabrata isolates had lower susceptibility to FLU (31.4% and 23.0%, respectively) and CTZ (37.1% and 33.3%, respectively). Importantly, there was "synergism" between farnesol-FLU and farnesol-ITZ against C. albicans and C. parapsilosis (FICI = 0.5 and 0.35, respectively), reverting the original azole-resistant profile. Conclusion: These findings indicate that farnesol can revert the resistance profile of azole by enhancing the activity of FLU and ITZ in resistant Candida isolates, which is a clinically promising result.