Socialane, a Nonaprenyl Terpene Hydrocarbon Surface Lipid from the Collembola Hypogastrura socialis.

Springtails use unique compounds for their outermost epicuticular wax layer, often of terpenoid origin. We report here the structure and synthesis of socialane, the major cuticular constituent of the Collembola Hypogastrura socialis. Socialane is also the first regular nonaprenyl terpene with a cyclic head group. The saturated side chain has seven stereogenic centers, making the determination of the configuration difficult. We describe here the identification of socialane and a synthetic approach using the building blocks farnesol and phytol, enantioselective hydrogenation, and α-alkylation of sulfones for the synthesis of various stereoisomers. NMR experiments showed the presence of an anti-configuration of the methyl groups closest to the benzene ring and that the other methyl groups of the polyprenyl side-chain are not uniformly configured. Furthermore, socialane is structurally different from [6+2]-terpene viaticene of the closely related H. viatica, showing species specificity of the epicuticular lipids of this genus and hinting at a possible role of surface lipids in the communication of these gregarious arthropods.

Farnesol delivery via polymeric nanoparticle carriers inhibits cariogenic cross-kingdom biofilms and prevents enamel demineralization.

Streptococcus mutans and Candida albicans are frequently detected together in the plaque from patients with early childhood caries (ECC) and synergistically interact to form a cariogenic cross-kingdom biofilm. However, this biofilm is difficult to control. Thus, to achieve maximal efficacy within the complex biofilm microenvironment, nanoparticle carriers have shown increased interest in treating oral biofilms in recent years. Here, we assessed the anti-biofilm efficacy of farnesol (Far), a hydrophobic antibacterial drug and repressor of Candida filamentous forms, against cross-kingdom biofilms employing drug delivery via polymeric nanoparticle carriers (NPCs). We also evaluated the effect of the strategy on teeth enamel demineralization. The farnesol-loaded NPCs (NPC+Far) resulted in a 2-log CFU/mL reduction of S. mutans and C. albicans (hydroxyapatite disc biofilm model). High-resolution confocal images further confirmed a significant reduction in exopolysaccharides, smaller microcolonies of S. mutans, and no hyphal form of C. albicans after treatment with NPC+Far on human tooth enamel (HT) slabs, altering the biofilm 3D structure. Furthermore, NPC+Far treatment was highly effective in preventing enamel demineralization on HT, reducing lesion depth (79% reduction) and mineral loss (85% reduction) versus vehicle PBS-treated HT, while NPC or Far alone had no differences with the PBS. The drug delivery via polymeric NPCs has the potential for targeting bacterial-fungal biofilms associated with a prevalent and costly pediatric oral disease, such as ECC.

Therapeutic Efficacy of Sesquiterpene Farnesol in Treatment of Cutibacterium acnes-Induced Dermal Disorders.

Acne vulgaris is a highly prevalent skin disorder requiring treatment and management by dermatologists. Antibiotics such as clindamycin are commonly used to treat acne vulgaris. However, from both medical and public health perspectives, the development of alternative remedies has become essential due to the increase in antibiotic resistance. Topical therapy is useful as a single or combined treatment for mild and moderate acne and is often employed as maintenance therapy. Thus, the current study investigated the anti-inflammatory, antibacterial, and restorative effects of sesquiterpene farnesol on acne vulgaris induced by Cutibacterium acnes (C. acnes) in vitro and in a rat model. The minimum inhibitory concentration (MIC) of farnesol against C. acnes was 0.14 mM, and the IC50 of 24 h exposure to farnesol in HaCaT keratinocytes was approximately 1.4 mM. Moreover, 0.8 mM farnesol exhibited the strongest effects in terms of the alleviation of inflammatory responses and abscesses and necrotic tissue repair in C.acnes-induced acne lesions; 0.4 mM farnesol and clindamycin gel also exerted similar actions after a two-time treatment. By contrast, nearly doubling the tissue repair scores, 0.4 mM farnesol displayed great anti-inflammatory and the strongest reparative actions after a four-time treatment, followed by 0.8 mM farnesol and a commercial gel. Approximately 2-10-fold decreases in interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, found by Western blot analysis, were predominantly consistent with the histopathological findings and tissue repair scores. The basal hydroxypropyl methylcellulose (HPMC) gel did not exert anti-inflammatory or reparative effects on rat acne lesions. Our results suggest that the topical application of a gel containing farnesol is a promising alternative remedy for acne vulgaris.

Antifungal activity of farnesol incorporated in liposomes and associated with fluconazole.

Candida infections represent a threat to human health. Candida albicans is the main causative agent of invasive candidiasis, especially in immunosuppressed patients. The emergence of resistant strains has required the development of new therapeutic strategies. In this context, the use of liposomes as drug carrier systems is a promising alternative in drug development. Thus, considering the evidence demonstrating that sesquiterpene farnesol is a bioactive compound with antifungal properties, this study evaluated the activity farnesol-containing liposomes against different Candida strains. The IC50 of farnesol and its liposomal formulation was assessed in vitro using cultures of Candida albicans, Candida tropicalis, and Candida krusei. The Minimum Fungicidal Concentration (MFC) was established by subculture in solid medium. The occurrence of fungal dimorphism was analyzed using optical microscopy. The effects on antifungal resistance to fluconazole were assessed by evaluating the impact of combined therapy on the growth of Candida strains. The characterization of liposomes was carried out considering their vesicular size, polydispersion index, and zeta medium potential, in addition to electron microscopy analysis. Farnesol exerted an antifungal activity that might be associated with the inhibition of fungal dimorphism, especially in Candida albicans. The incorporation of farnesol into liposomes significantly increased its antifungal activity against C. albicans, C. tropicalis, and C. krusei. In addition, liposomal farnesol potentiated the action of fluconazole against C. albicans and C. tropicalis. On the other hand, the association of unconjugated farnesol with fluconazole resulted in antagonistic effects. In conclusion, farnesol-containing liposomes have the potential to be used in antifungal drug development. However, further research is required to investigate how the antifungal properties of farnesol are affected by the interaction with liposomes, contributing to the modulation of antifungal resistance to conventional drugs.

Farnesyl glycosides and one new triterpenoid saponin from the roots of Lecaniodiscus cupanioides Planch. ex Benth.

Chemical investigation of the methanol extract of the roots of Lecaniodiscus cupanioides led to the isolation and characterisation of three new sesquiterpene glycosides, named cupanioidesosides A (1), B (2) and C (3), together with one new triterpenoid saponin named lecanioside A (4), Their structures were established by extensive analysis of spectroscopic methods including 1D and 2D NMR techniques (COSY, NOESY, TOCSY, HSQC, and HMBC) and HRESIMS. The four new compounds were evaluated for their antiproliferative activity against the Caco-2 cell line (human epithelial cell line). None of the isolated compounds showed positive activity in our assay. Our findings represent a valuable contribution to the chemotaxonomy Lecaniodiscus genus of the subfamily of Sapindoideae of Sapindaceae family, known to be a rich source of farnesol glycosides.

Farnesal-loaded pH-sensitive polymeric micelles provided effective prevention and treatment on dental caries.

BACKGROUND: Farnesol is a sesquiterpene from propolis and citrus fruit that shows promising anti-bacterial activity for caries treatment and prevention, but its hydrophobicity limits the clinical application. We aimed to develop the novel polymeric micelles (PMs) containing a kind of derivative of farnesol and a ligand of pyrophosphate (PPi) that mediated PMs to adhere tightly with the tooth enamel. RESULTS: Farnesal (Far) was derived from farnesol and successfully linked to PEG via an acid-labile hydrazone bond to form PEG-hyd-Far, which was then conjugated to PPi and loaded into PMs to form the aimed novel drug delivery system, PPi-Far-PMs. The in vitro test about the binding of PPi-Far-PMs to hydroxyapatite showed that PPi-Far-PMs could bind rapidly to hydroxyapatite and quickly release Far under the acidic conditions. Results from the mechanical testing and the micro-computed tomography indicated that PPi-Far-PMs could restore the microarchitecture of teeth with caries. Moreover, PPi-Far-PMs diminished the incidence and severity of smooth and sulcal surface caries in rats that were infected with Streptococcus mutans while being fed with a high-sucrose diet. The anti-caries efficacy of free Far can be improved significantly by PPi-Far-PMs through the effective binding of it with tooth enamel via PPi. CONCLUSIONS: This novel drug-delivery system may be useful for the treatment and prevention of dental caries as well as the targeting therapy of anti-bacterial drugs in the oral disease.

Synthetic Derivatives of (+)-epi-α-Bisabolol Are Formed by Mammalian Cytochromes P450 Expressed in a Yeast Reconstituted Pathway.

Identification of the enzyme(s) involved in complex biosynthetic pathways can be challenging. An alternative approach might be to deliberately diverge from the original natural enzyme source and use promiscuous enzymes from other organisms. In this paper, we have tested the ability of a series of human and animal cytochromes P450 involved in xenobiotic detoxification to generate derivatives of (+)-epi-α-bisabolol and attempt to produce the direct precursor of hernandulcin, a sweetener from Lippia dulcis for which the last enzymatic steps are unknown. Screening steps were implemented in vivo in S. cerevisiae optimized for the biosynthesis of oxidized derivatives of (+)-epi-α-bisabolol by coexpressing two key enzymes: the (+)-epi-α-bisabolol synthase and the NADPH cytochrome P450 reductase. Five out of 25 cytochromes P450 were capable of producing new hydroxylated regioisomers of (+)-epi-α-bisabolol. Of the new oxidized bisabolol products, the structure of one compound, 14-hydroxy-(+)-epi-α-bisabolol, was fully elucidated by NMR while the probable structure of the second product was determined. In parallel, the production of (+)-epi-α-bisabolol derivatives was enhanced through the addition of a supplementary genomic copy of (+)-epi-α-bisabolol synthase that augmented the final titer of hydroxylated product to 64 mg/L. We thus demonstrate that promiscuous drug metabolism cytochromes P450 can be used to produce novel compounds from a terpene scaffold.

Antiaging and smoothness-improving properties of farnesol-based facial masks on rat skin exposed to ultraviolet B.

BACKGROUND: Farnesol is an acyclic sesquiterpene presents in various natural sources including fruits, vegetables, and herbs. In this study, we successfully prepared a farnesol-containing gel with ultraviolet B-screening and skin-repairing capabilities. Furthermore, the advantageous potential of farnesol-containing facial masks for UVB-caused sunburnt skin was evaluated. AIMS: Thus, the objectives of this study are to design and prepare optimal facial masks possessing collagen production and smoothness-enhancing capabilities for the skin. METHODS: A series of formulations consisting of hydroxypropyl methylcellulose, hyaluronan, and farnesol were used to prepare the facial masks. The effects of the facial masks on collagen production by skin fibroblasts in vitro were examined. The effects of the prepared masks on collagen synthesis, smoothness, and inflammation of the skin were further evaluated in vivo using two modes (mask administration interspersed with UVB exposure and mask administration after UVB exposure) of a rat model. RESULTS: Facial masks containing both 0.3 and 0.8 mM farnesol improved skin smoothness and enhanced collagen content and arrangement in the skin of rats with mask administration interspersed with and after UVB exposure. The masks containing 0.8 mM farnesol exerted the greatest effects on collagen production/arrangement and smoothness improvement in vivo model. Histopathologically observed inflammation was alleviated, and interleukin (IL)-6 was decreased in the 0.8 mM farnesol-containing facial mask-covered skin compared with that without facial masks. CONCLUSIONS: The farnesol-containing facial masks prepared in this study may have collagen production-increasing, smoothness-improving, and anti-inflammatory properties for UVB-caused sunburn; thus, farnesol is potentially a beneficial component in facial masks.

Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-ß (Aß) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aß1-42-injected mice (Aß1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deficits. MATERIALS AND METHODS: AD model mice were manufactured through intracerebroventricular injection of Aß1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot. RESULTS: The results demonstrated that FTS could prevent Aß1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aß1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aß1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aß, which is the underlying molecular mechanism. CONCLUSION: In conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

beta-caryophyllene oxide and trans-nerolidol affect enzyme activity of CYP3A4 - in vitro and in silico studies.

Evaluation of possible interactions with enzymes of drug metabolism is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. Here, focus is given on interactions of three sesquiterpenes (beta-caryophyllene oxide (CAO), trans-nerolidol (tNER) and farnesol (FAR)) with CYP3A4. To determine the CYP3A4 activity, specific substrates testosterone (TES) and midazolam (MDZ) were used. In human liver microsomes, the CAO inhibited the MDZ 1´-hydroxylation by mixed type inhibition and K(i) 46.6 microM; TES 6beta-hydroxylation was inhibited more strongly by tNER by the same mechanism and with K(i) of 32.5 microM. Results indicated a possibility of different mode of interaction of both compounds within the active site of CYP3A4 and this was why the molecular docking study was done. The docking experiments showed that the studied sesquiterpenes (CAO and tNER) bound to the CYP3A4 active site cause a significant decrease of binding affinity of substrates tested which corresponded well to the inhibition studies. The inhibition observed, however, most probably does not pose a real harm to microsomal drug metabolism as the levels of sesquiterpenes in plasma (assuming the use of these compounds as spices or flavoring additives) does not usually exceed micromolar range. Hence, the interaction of drugs metabolized by CYP3A4 with sesquiterpenes is less probable.

Multiple Signaling Pathways Involved in Human Dendritic Cell Maturation Are Affected by the Fungal Quorum-Sensing Molecule Farnesol.

The quorum-sensing molecule farnesol is produced by the opportunistic human fungal pathogen Candida albicans Aside from its primary function of blocking the transition from yeast to hyphal morphotype, it has an immunomodulatory role on human dendritic cells (DC) through the alteration of surface markers, cytokine secretion, and their ability to activate T cells. Nonetheless, the molecular mechanisms by which farnesol modulates DC differentiation and maturation remained unknown. In this study, we demonstrate through transcriptional and functional assays that farnesol influences several signaling pathways during DC differentiation and in response to TLR agonists. In particular, farnesol increases the expression of the Ag-presenting glycoprotein CD1d through the nuclear receptors PPARγ and RARα, as well as p38 MAPK. However, the higher expression of CD1d did not confer these DC with an enhanced capacity to activate CD1d-restricted invariant NKT cells. In the presence of farnesol, there is reduced secretion of the Th1-inducing cytokine, IL-12, and increased release of proinflammatory cytokines, as well as the anti-inflammatory cytokine IL-10. These changes are partially independent of nuclear receptor activity but, in the case of TNF-α and IL-10, dependent on NF-κB and MAPK pathways. Interestingly, renewal of the IL-12/IL-10 milieu restores the ability of farnesol-differentiated DC to activate invariant NKT, Th1, and FOXP3+ regulatory T cells. Our results show that farnesol modulates nuclear receptors, NF-κB, and MAPK-signaling pathways, thereby impairing the capacity of DC to activate several T cells subsets and potentially conferring C. albicans, an advantage in overcoming DC-mediated immunity.

The Addition of a Pheromone to a Floral Lure Increases Catches of Females of the Click Beetle Agriotes ustulatus (Schaller) (Coleoptera: Elateridae).

Agriotes ustulatus is an economically important click beetle in Europe. A female-produced pheromone, (E,E)-farnesyl acetate, has been identified and is used for monitoring and detecting males. More recently, a floral lure targeting females with modest, but significant, activity has been described. Based on preliminary data, we hypothesized, that similar to the effects on the congeneric A. brevis, addition of the pheromone to the floral lure should improve female A. ustulatus catches. Also, as click beetles have been reported to respond to white light, we studied possible interactions between visual and chemical cues. In field trials, the addition of the synthetic pheromone to the floral lure resulted in a dramatic increase in the number of females trapped, whereas male catches remained unaffected and equal to those in traps baited with pheromone only. A white visual cue did not influence trap catches. Maximum catches of both sexes of A. ustulatus can be achieved using the pheromone and the floral lure inside the same trap. Furthermore, the compounds can be formulated in a single polyethylene bag dispenser, making handling of the trap easier. Due to a much larger proportion of females in the catch, this improved trap may be a promising tool for semiochemical-based, environmentally sound agricultural practice against this important pest.

Design and synthesis of mucoadhesive nanogel containing farnesol: investigation of the effect on HWP1, SAP6 and Rim101 genes expression of Candida albicans in vitro.

The evolution of drug resistance of Candida species to conventional antifungal agents has been a major medical challenge worldwide; attempt to use the potential antifungal agents with appropriate therapy efficacy and minimum effects is considerably growing. This study was conducted to evaluate the use of nanogel as a nanocarrier for pharmaceutical application of farnesol. The nanogels were synthetized using alginate (AL) and chitosan (CS) polymers containing 300 µM of farnesol in the nano-range 42-70 nm size. In vitro release studies indicated that release of farnesol from CS and AL nanogels was as 58% and 37%, respectively. Chitosan nanogel showed more in inhibitory zone as compared to AL nanogel (9 mm). Also, cytotoxicity assay showed no significant difference between control and treatment groups (p>.05). Finally, the effect of nanogels on genes expression of HWP1, SAP6 and Rim101 in Candida albicans ATCC10231 was assessed using real-time polymerase chain reaction (PCR). Expression of HWP1 and SAP6 genes in C. albicans treated with CS nanogel was significantly decreased (p<.01). In general, the obtained finding showed that, CS nanogel contains farnesol with proper antifungal activity and as a new approach used in pharmaceutical applications against C. albicans; however, more studies in vitro and in vivo are needed in the future.

Development, characterization, and in vitro-in vivo evaluation of polymeric nanoparticles containing miconazole and farnesol for treatment of vulvovaginal candidiasis.

Vulvovaginal candidiasis (VVC) is caused mainly by the opportunistic fungus Candida albicans, and its yeast to hyphae transition is considered a major virulence factor. Farnesol is a molecule that inhibits yeast to hyphae transition. The increased incidence of VVC has influenced a need for developing new therapeutic strategies. The objective was to develop a mucoadhesive nanostructured system composed of miconazole and farnesol co-encapsulated within chitosan nanoparticles. The miconazole presented a minimal inhibitory concentration (MIC) of 1 µg/ml against C. albicans. The farnesol was capable of inhibiting yeast to hyphae transition at levels greater or equal to 300 µM. The combination of miconazole and farnesol showed no change in miconazole MIC. Chitosan nanoparticles containing miconazole and farnesol were prepared by ionic gelation and showed favorable characteristics for use on mucous membranes. They showed size variation and polydispersion index (PDI) after 30 days, but the efficiency of drug encapsulation was maintained. Regarding toxicity in cultured fibroblasts (BALB/c 3T3) the nanoparticles were considered nontoxic. The nanoparticles showed antifungal activity against the C. albicans strain used with MICs of 2.5 µg/ml and 2 µg/ml for nanoparticles containing miconazole or miconazole/farnesol, respectively. Nanoparticles containing farnesol inhibited yeast to hyphae transition at concentrations greater than or equal to 240 µM. The in vivo antifungal activity was assessed in the murine model for VVC. The results suggested that chitosan nanoparticles containing miconazole and farnesol were effective at inhibiting fungal proliferation. Additionally, chitosan nanoparticles containing farnesol were capable of decreasing the pathogenicity of infection, demonstrated through the absence of inflammation.

Enhanced design and formulation of nanoparticles for anti-biofilm drug delivery.

Biofilms are surface-bound, structured microbial communities underpinning persistent bacterial infections. Biofilms often create acidic pH microenvironments, providing opportunities to leverage responsive drug delivery systems to improve antibacterial efficacy. Here, the antibacterial efficacy of novel formulations containing pH-responsive polymer nanoparticle carriers (NPCs) and farnesol, a hydrophobic antibacterial drug, were investigated. Multiple farnesol-loaded NPCs, which varied in overall molecular weight and corona-to-core molecular weight ratios (CCRs), were tested using standard and saturated drug loading conditions. NPCs loaded at saturated conditions exhibited ∼300% greater drug loading capacity over standard conditions. Furthermore, saturated loading conditions sustained zero-ordered drug release over 48 hours, which was 3-fold longer than using standard farnesol loading. Anti-biofilm activity of saturated NPC loading was markedly amplified using Streptococcus mutans as a biofilm-forming model organism. Specifically, reductions of ∼2-4 log colony forming unit (CFU) were obtained using microplate and saliva-coated hydroxyapatite biofilm assays. Mechanistically, the new formulation reduced total biomass by disrupting insoluble glucan formation and increased NPC-cell membrane localization. Finally, thonzonium bromide, a highly potent, FDA-approved antibacterial drug with similar alkyl chain structure to farnesol, was also loaded into NPCs and used to treat S. mutans biofilms. Similar to farnesol-loaded NPCs, thonzonium bromide-loaded NPCs increased drug loading capacity ≥2.5-fold, demonstrated nearly zero-order release kinetics over 96 hours, and reduced biofilm cell viability by ∼6 log CFU. This work provides foundational insights that may lead to clinical translation of novel topical biofilm-targeting therapies, such as those for oral diseases.

Chemistry and Biology of Farnesol and its Derivatives: Quorum Sensing Molecules with Immense Therapeutic Potential.

BACKGROUND: Farnesol is an acyclic sesquiterpene alcohol, endogenously synthesized via the ergosterol pathway. It is a quorum sensing molecule (QSM) that was first discovered in C. albicans, and is involved in the inhibition of hyphae formation. METHODS: This review focuses on the comprehensive details of occurrence, chemical/biological synthesis of farnesol and its derivatives, and the factors involved in the regulation of their production. Further, the review also presents their cellular functions and diversified biomedical applications. RESULTS: Large-scale production of farnesol can be achieved using chemical synthesis and metabolic engineering approach. Farnesol is involved in the regulation of various physiological processes including filamentation, biofilm development, drug efflux, and apoptosis, etc. Farnesol and its derivatives/ analogues have also been reported to exhibit anti-biofilm, anti-cancer, anti-tumor and fungicidal properties. The antimicrobial potential of farnesol has been enhanced by synergizing it with known antifungal drugs, and also through nano-formulation(s). CONCLUSION: Apart from its quorum sensing activity, farnesol can be used as an effective anti-microbial, anti-inflammatory, ant-allergic, anti-cancerous, and anti-obesity agent.

Selective Inhibition of Human AKR1B10 by n-Humulone, Adhumulone and Cohumulone Isolated from Humulus lupulus Extract.

Hop-derived compounds have been subjected to numerous biomedical studies investigating their impact on a wide range of pathologies. Isomerised bitter acids (isoadhumulone, isocohumulone and isohumulone) from hops, used in the brewing process of beer, are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies. However, the closely related reductases AKR1A1 and AKR1B1, which fulfil important roles in the detoxification of endogenous and xenobiotic carbonyl compounds oftentimes crossreact with inhibitors designed to target AKR1B10. Accordingly, there is an ongoing search for selective AKR1B10 inhibitors that do not interact with endogeneous AKR1A1 and AKR1B1-driven detoxification systems. In this study, unisomerised α-acids (adhumulone, cohumulone and n-humulone) were separated and tested for their inhibitory potential on AKR1A1, AKR1B1 and AKR1B10. Also AKR1B10-mediated farnesal reduction was effectively inhibited by α-acid congeners with Ki-values ranging from 16.79 ± 1.33 µM (adhumulone) to 3.94 ± 0.33 µM (n-humulone). Overall, α-acids showed a strong inhibition with selectivity (115⁻137 fold) for AKR1B10. The results presented herein characterise hop-derived α-acids as a promising basis for the development of novel and selective AKR1B10-inhibitors.

Potential Anti-Inflammatory and Anti-Cancer Properties of Farnesol.

Farnesol, an acyclic sesquiterpene alcohol, is predominantly found in essential oils of various plants in nature. It has been reported to exhibit anti-cancer and anti-inflammatory effects, and also alleviate allergic asthma, gliosis, and edema. In numerous tumor cell lines, farnesol can modulate various tumorigenic proteins and/or modulates diverse signal transduction cascades. It can also induce apoptosis and downregulate cell proliferation, angiogenesis, and cell survival. To exert its anti-inflammatory/anti-oncogenic effects, farnesol can modulate Ras protein and nuclear factor kappa-light-chain-enhancer of activated B cells activation to downregulate the expression of various inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin-6. In this review, we describe the potential mechanisms of action underlying the therapeutic effects of farnesol against cancers and inflammatory disorders. Furthermore, these findings support the clinical development of farnesol as a potential pharmacological agent in clinical studies.

Farnesylthiosalicylic acid-loaded lipid-polyethylene glycol-polymer hybrid nanoparticles for treatment of glioblastoma.

OBJECTIVES: We aimed to develop lipid-polyethylene glycol (PEG)-polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid (FTA) for treatment of glioblastoma. METHOD: Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy (PEG)-2000] ammonium salt (PLGA-DSPE-PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 (RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. KEY FINDINGS: Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250-300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. CONCLUSION: Farnesylthiosalicylic acid-loaded PLGA-DSPE-PEG-DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments.