Assessment of the in vitro acaricidal activity of Bravecto® (fluralaner) and a proposed orange oil-based formulation vehicle for the treatment of Sarcoptes scabiei.

BACKGROUND: Sarcoptic mange is a serious animal welfare concern in bare-nosed wombats (Vombatus ursinus). Fluralaner (Bravecto®) is a novel acaricide that has recently been utilised for treating mange in wombats. The topical 'spot-on' formulation of fluralaner can limit treatment delivery options in situ, but dilution to a volume for 'pour-on' delivery is one practicable solution. This study investigated the in vitro acaricidal activity of Bravecto, a proposed essential oil-based diluent (Orange Power®), and two of its active constituents, limonene and citral, against Sarcoptes scabiei. METHODS: Sarcoptes scabiei were sourced from experimentally infested pigs. In vitro assays were performed to determine the lethal concentration (LC50) and survival time of the mites when exposed to varying concentrations of the test solutions. RESULTS: All compounds were highly effective at killing mites in vitro. The LC50 values of Bravecto, Orange Power, limonene and citral at 1 h were 14.61 mg/ml, 4.50%, 26.53% and 0.76%, respectively. The median survival times of mites exposed to undiluted Bravecto, Orange Power and their combination were 15, 5 and 10 min, respectively. A pilot survival assay of mites collected from a mange-affected wombat showed survival times of < 10 min when exposed to Bravecto and Orange Power and 20 min when exposed to moxidectin. CONCLUSIONS: These results confirm the acaricidal properties of Bravecto, demonstrate acaricidal properties of Orange Power and support the potential suitability of Orange Power and its active constituents as a diluent for Bravecto. As well as killing mites via direct exposure, Orange Power could potentially enhance the topical delivery of Bravecto to wombats by increasing drug penetration in hyperkeratotic crusts. Further research evaluating the physiochemical properties and modes of action of Orange Power and its constituents as a formulation vehicle would be of value.

Polyoxygenated cyclohexene derivatives and other constituents of Uvaria rufa stem.

Six undescribed compounds, uvarirufols D and E, (+)-uvarigranol B, (-)-uvarigranol E, 6-acetoxy-5-hydroxy-7-methoxyflavanone and cherrevenaphthalene D, along with twelve known compounds, including polyoxygenated cyclohexenes, flavonoids, and lignans, were isolated from the methanol extract of Uvaria rufa stems. Their structures were elucidated by spectroscopic analyses and the absolute configurations were determined using electronic circular dichroism. Several isolates were evaluated for cytotoxic, antitubercular and anti-inflammatory potentials. (-)-6-Acetylzeylenol showed moderate inhibitory activity against Mycobacterium tuberculosis, with MIC value of 47.10 µg/mL. Cherrevenaphthalene D exhibited weak antimycobacterial activity and potent inhibitory effect on lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 cells (EC50 = 8.54 µM). 8-Hydroxy-5,7-dimethoxyflavanone displayed moderate level of NO inhibition (EC50 = 43.62 µM) with little cytotoxicity. The polyoxygenated cyclohexenes and lignans were inactive against HCT 116 and 22Rv1 cancer cells (IC50 > 100 µM).

Dulcisenes C-E, polyoxygenated cyclohexenes, from Uvaria dulcis dunal and their cytotoxic activity.

Dulcisenes C-E, undescribed polyoxygenated cyclohexenes and twenty-one known compounds were isolated from the dichloromethane extract of the leaves of Uvaria dulcis Dunal. The structures of these undescribed compounds were determined by spectroscopic data analyses, including 1D and 2D NMR, IR, and MS techniques; their absolute configurations were analyzed by NOESY and ECD spectra. Cytotoxicity of sixteen more abundant isolates was evaluated. Cherrevenone and 2',3'-dihydroxy-4',6'-dimethoxychalcone exhibited cytotoxic activity against some cancer cell lines with IC50 values in the range of 3.3-11.8 µM.

Nm23-H1 activator phenylbutenoid dimer exerts cytotoxic effects on metastatic breast cancer cells by inducing mitochondrial dysfunction only under glucose starvation.

Mitochondrial oxidative phosphorylation (OXPHOS) has become an attractive target in anti-cancer studies in recent years. In this study, we found that a small molecule phenylbutenoid dimer NMac1 (Nm23-H1 activator 1), (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, a previously identified anti-metastatic agent, has novel anti-proliferative effect only under glucose starvation in metastatic breast cancer cells. NMac1 causes significant activation of AMPK by decreasing ATP synthesis, lowers mitochondrial membrane potential (MMP, ΔΨm), and inhibits oxygen consumption rate (OCR) under glucose starvation. These effects of NMac1 are provoked by a consequence of OXPHOS complex I inhibition. Through the structure-activity relationship (SAR) study of NMac1 derivatives, NMac24 was identified as the most effective compound in anti-proliferation. NMac1 and NMac24 effectively suppress cancer cell proliferation in 3D-spheroid in vivo-like models only under glucose starvation. These results suggest that NMac1 and NMac24 have the potential as anti-cancer agents having cytotoxic effects selectively in glucose restricted cells.

Oxygenated Cyclohexene Derivatives from the Stem and Root Barks of Uvaria pandensis.

Five new cyclohexene derivatives, dipandensin A and B (1 and 2) and pandensenols A-C (3-5), and 16 known secondary metabolites (6-21) were isolated from the methanol-soluble extracts of the stem and root barks of Uvaria pandensis. The structures were characterized by NMR spectroscopic and mass spectrometric analyses, and that of 6-methoxyzeylenol (6) was further confirmed by single-crystal X-ray crystallography, which also established its absolute configuration. The isolated metabolites were evaluated for antibacterial activity against the Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis and the Gram-negative bacteria Enterococcus raffinosus, Escherichia coli, Paraburkholderia caledonica, Pectobacterium carotovorum, and Pseudomonas putida, as well as for cytotoxicity against the MCF-7 human breast cancer cell line. A mixture of uvaretin (20) and isouvaretin (21) exhibited significant antibacterial activity against B. subtilis (EC50 8.7 µM) and S. epidermidis (IC50 7.9 µM). (8'α,9'ß-Dihydroxy)-3-farnesylindole (12) showed strong inhibitory activity (EC50 9.8 µM) against B. subtilis, comparable to the clinical reference ampicillin (EC50 17.9 µM). None of the compounds showed relevant cytotoxicity against the MCF-7 human breast cancer cell line.

Antidepressant mechanism and active compounds of saffron from network pharmacology study.

Saffron has been applied in depression treatment, but its antidepressant compounds and mechanisms are unclear. In this research, a network pharmacology-based method was proposed to screen the active compounds and the potential mechanisms of saffron for depression treatment. Firstly, the chemical compounds of saffron were collected from literature and filtered by drug-like prediction. Secondly, common targets, by comparing the targets of saffron predicted by Pharm Mapper server with targets associated with depression collected from Genecards, were regarded as the antidepressant targets of saffron. Thirdly, common targets were mapped to KEGG pathways, considered as the pathways related with the antidepressant effects of saffron. Finally, the network of compounds-targets-pathways was constructed and analyzed by cytoscape 3.4.0. Ten compounds including crocetin, picrocrocin, (1R, 5S, 6R)-5-(hydroxymethyl)- 4, 4, 6-trimethyl-7-Oxabicyclo[4.1.0]heptan-2-one and its glycoside were screened as the main antidepressant compounds, some of which were reported for the first time. They might have effective treatment for depression by acting on targets, such as MAP2K1, MAPK1, HRAS, PIK3R1, ALB and AKT1 and pathways related with immune system, signal transduction and so on. This study provided a new insight into the antidepressant mechanism and active compounds of saffron, which also had a guiding effect on later experiments.

Effect of ZnSO4, MnSO4 and FeSO4 on the Partial Hydrogenation of Benzene over Nano Ru-Based Catalysts.

Nano Ru-based catalysts, including monometallic Ru and Ru-Zn nanoparticles, were synthesized via a precipitation method. The prepared catalysts were evaluated on partial hydrogenation of benzene towards cyclohexene generation, during which the effect of reaction modifiers, i.e., ZnSO4, MnSO4, and FeSO4, was investigated. The fresh and the spent catalysts were thoroughly characterized by XRD, TEM, SEM, XPS, XRF, and DFT studies. It was found that Zn2+ or Fe2+ could be adsorbed on the surface of a monometallic Ru catalyst, where a stabilized complex could be formed between the cations and the cyclohexene. This led to an enhancement of catalytic selectivity towards cyclohexene. Furthermore, electron transfer was observed from Zn2+ or Fe2+ to Ru, hindering the catalytic activity towards benzene hydrogenation. In comparison, very few Mn2+ cations were adsorbed on the Ru surface, for which no cyclohexene could be detected. On the other hand, for Ru-Zn catalyst, Zn existed as rodlike ZnO. The added ZnSO4 and FeSO4 could react with ZnO to generate (Zn(OH)2)5(ZnSO4)(H2O) and basic Fe sulfate, respectively. This further benefited the adsorption of Zn2+ or Fe2+, leading to the decrease of catalytic activity towards benzene conversion and the increase of selectivity towards cyclohexene synthesis. When 0.57 mol·L-1 of ZnSO4 was applied, the highest cyclohexene yield of 62.6% was achieved. When MnSO4 was used as a reaction modifier, H2SO4 could be generated in the slurry via its hydrolysis, which reacted with ZnO to form ZnSO4. The selectivity towards cyclohexene formation was then improved by the adsorbed Zn2+.

Synthetic Spirocyclohexadienones as New Anti-Migratory Compounds in Triple- Negative Breast Cancer Cell Migration.

BACKGROUND: Triple-negative BC is the most aggressive type of breast cancer and its lack of responsiveness to conventional therapies requires screening of new chemical entities. Anti-migratory compounds are promising to treat metastatic cancer since they inhibit one of the main steps of the metastatic cascade. Spirocyclic compounds are non-conventional structures used as building blocks for the synthesis of biologically active molecules and considered interesting structures in the search for new targets in cancer research. OBJECTIVE: Here, we evaluated the potential of eight synthetic spirocyclohexadienones as cell migration inhibitors. METHODS: The anti-migratory ability of compounds was tested by wound healing and Boyden chamber approaches. Experiments in tubulin were performed by fluorescence and tubulin polymerization techniques. Finally, compounds were submitted to cell proliferation inhibition and flow cytometry assays to explore the mechanism by which they inhibit cell migration. RESULTS: Four compounds inhibited cell migration significantly. Analogs containing the 3,4,5-trimethoxyphenil ring at R1 position were the most potent and, thus, selected for additional experiments. Tubulin polymerization and fluorescence assays highlighted a possible binding of spirocyclohexadienones in the colchicine binding site; however, these compounds did not affect the cell cycle to the same extent as colchicine. Cell proliferation was affected and, notably, the most potent analogs induced apoptosis of tumor cells, suggesting a different mechanism by which they inhibit cell migration. CONCLUSION: We presented, for the first time, a series of eight synthetic spirocyclohexadienones with the ability to inhibit TNBC cell migration. These compounds represent a new category to be explored as anticancer agents.

Efficacy of novel methylenecyclohexenone derivatives as TrxR inhibitors in suppressing the proliferation and metastasis of human cancer cells.

A series of mono- and di-methylenecyclohexenone derivatives, 3a-f and 4a-f, respectively, were designed and synthesized from piperlongumine (PL) and their in vitro and in vivo pharmacological properties were evaluated. A majority of the compounds exhibited a potent antiproliferative effect on five human cancer cell lines, especially those causing breast cancer. Compound 4f showed the highest antiproliferative potency among all of the compounds, almost a 10-fold higher inhibitory potency against thioredoxin reductase (TrxR) compared with PL in cells causing breast cancer. In addition, 4f was found to increase the levels of reactive oxygen species (ROS), thus leading to more potent antiproliferative effects. More importantly, the suppression assays of migration and invasion revealed that compound 4f could reverse the epithelial-mesenchymal transition induced by the transforming growth factor ß1, and exhibit prominent anti-metastasis effects. Compound 4f also showed strong inhibition potency toward solid tumors of breast cancer in vivo. Our findings show that compound 4f is a promising therapeutic candidate in the treatment of breast cancer, which, however, needs further research to be proved.

TMPE Derived from Saffron Natural Monoterpene as Cytotoxic and Multidrug Resistance Reversing Agent in Colon Cancer Cells.

Terpenes constitute one of the largest groups of natural products. They exhibit a wide range of biological activities including antioxidant, anticancer, and drug resistance modulating properties. Saffron extract and its terpene constituents have been demonstrated to be cytotoxic against various types of cancer cells, including breast, liver, lung, pancreatic, and colorectal cancer. In the present work, we have studied anticancer properties of TMPE, a newly synthesized monoterpene derivative of ß-cyclocitral-the main volatile produced by the stigmas of unripe crocuses. TMPE presented selective cytotoxic activity to doxorubicin-resistant colon cancer cells and was identified to be an effective MDR modulator in doxorubicin-resistant cancer cells. Synergy between this derivative and doxorubicin was observed. Most probably, TMPE inhibited transport activity of ABCB1 protein without affecting its expression level. Analysis of TMPE physicochemical parameters suggested it was not likely to be transported by ABCB1. Molecular modeling showed TMPE being more reactive molecule than the parental compound-ß-cyclocitral. Analysis of electrostatic potential maps of both compounds prompted us to hypothesize that reduced reactivity as well as susceptibility to electrophilic attack were related to the lower general toxicity of ß-cyclocitral. All of the above pointed to TMPE as an interesting candidate molecule for MDR reversal in cancer cells.

Anti-Breast Cancer Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione in vivo and in vitro Through MAPK Signaling Pathway.

BACKGROUND: 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) has been reported to inhibit a variety of cancer cell lines. The purpose of this study was to investigate the effects of DMDD on 4T1 breast cancer cells and the effects of DMDD on 4T1 breast cancer in mice and its molecular mechanisms. METHODS: 4T1 breast cancer cells were treated with different concentrations of DMDD, and their proliferation, apoptosis, cell-cycle distribution, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT, Acridine orange and ethidium bromide dual staining analysis (AO/EB) dual staining, flow cytometry, scratch test, and the Transwell assay. Relative quantitative real-time qPCR analysis and Western blot were applied to examine the expression levels of related genes and proteins. In animal experiments, we established a xenograft model to assess the anti-breast cancer effects of DMDD by evaluating the inhibition rate. The apoptotic activity of DMDD was evaluated by hematoxylin-eosin (HE) staining, transmission electron microscope (TEM) analysis and TdT-mediated dUTP nick end labeling (TUNEL) assays. The mRNA expression levels of MAPK pathway components were detected by relative quantitative real-time qPCR. In addition, the protein expression levels of MAPK pathway components were assessed through immunohistochemical assays and Western blotting. RESULTS: Experiments showed that DMDD could inhibit the proliferation, migration, invasion of 4T1 cells and induce cellular apoptosis and G1 cell cycle arrest. Moreover, DMDD down-regulated the mRNA expressions of raf1, mek1, mek2, erk1, erk2, bcl2, and up-regulated the mRNA expression of bax. DMDD reduced the protein expressions of p-raf1, p-mek, p-erk, p-p38, Bcl2, MMP2, MMP9 and increased the protein expressions of Bax and p-JNK. The results showed that DMDD can effectively reduce the tumor volume and weight of breast cancer in vivo, up-regulate the expression of IL-2, down-regulate the expression of IL-4 and IL-10, induce the apoptosis of breast cancer cells in mice, and regulate the expression of genes and proteins of the MAPK pathway. CONCLUSION: Our study indicates that DMDD can inhibit proliferation, migration, and invasion and induces apoptosis and cell-cycle arrest of 4T1 breast cancer cells. Also, our findings indicate that DMDD induces the apoptosis of breast cancer cells and inhibits the growth in mice. Its mechanism may be related to the MAPK pathway.

Preparation of cyclohexene isotopologues and stereoisotopomers from benzene.

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease2, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.

Platinum(IV) Complexes of trans-1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance.

Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5-8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells.

Marine biomaterials: Biomimetic and pharmacological potential of cultivated Aplysina aerophoba marine demosponge.

Marine demosponges of the Verongiida order are considered a gold-mine for bioinspired materials science and marine pharmacology. The aim of this work was to simultaneously isolate selected bromotyrosines and unique chitinous structures from A. aerophoba and to propose these molecules and biomaterials for possible application as antibacterial and antitumor compounds and as ready-to-use scaffolds for cultivation of cardiomyocytes, respectively. Among the extracted bromotyrosines, the attention has been focused on aeroplysinin-1 that showed interesting unexpected growth inhibition properties for some Gram-negative clinical multi-resistant bacterial strains, such as A. baumannii and K. pneumoniae, and on aeroplysinin-1 and on isofistularin-3 for their anti-tumorigenic activity. For both compounds, the effects are cell line dependent, with significant growth inhibition activity on the neuroblastoma cell line SH-SY5Y by aeroplysinin-1 and on breast cancer cell line MCF-7 by isofistularin-3. In this study, we also compared the cultivation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) on the A. aerophoba chitinous scaffolds, in comparison to chitin structures that were pre-coated with Geltrex™, an extracellular matrix mimetic which is used to enhance iPSC-CM adhesion. The iPSC-CMs on uncoated and pure chitin structures started contracting 24 h after seeding, with comparable behaviour observed on Geltrex-coated cell culture plates, confirming the biocompatibility of the sponge biomaterial with this cell type. The advantage of A. aerophoba is that this source organism does not need to be collected in large quantities to supply the necessary amount for further pre-clinical studies before chemical synthesis of the active compounds will be available. A preliminary analysis of marine sponge bioeconomy as a perspective direction for application of biomaterials and secondary bioactive metabolites has been finally performed for the first time.

In vitro and computational studies of natural products related to perezone as anti-neoplastic agents.

Many natural phyto-products as perezone (Per) exhibit anti-cancer activities. Using experimental and computational studies, it was described that Poly ADP-ribose polymerase 1(PARP-1) inhibition and the induction of oxidative stress state explain the pro-apoptotic activity of Per. The aim of this study was to evaluate two phyto-products related to Per as anti-cancer agents: hydroxyperezone (OHPer) and its monoangelate (OHPer-MAng). These molecules were structurally characterized employing thermal analysis, IR spectrophotometry and X-ray diffraction techniques. The phyto-compounds evaluated in vitro in six cancer cell lines (K562, MCF-7, MDA-MB-231, HeLa, U373, A549) and non-malignant cells determinate their cytotoxicity, type of induced cell death, ability to avoid cell migration and changes at the redox status of the cell. Using, in vitro and computational studies provided the inhibition of PARP-1 and its potential binding mode. Cell proliferation assays demonstrated that OHPer-MAng treatment significantly induces apoptosis in triple negative breast cancer (TNBC) cell line (MDA-MB-231 IC50 = 3.53 µM), being particularly less cytotoxic to Vero cells (IC50 = 313.92 µM), human lymphocytes (IC50 = 221.46 µM) and rat endothelial cells (IC50=> 400 µM). The treatment of MDA-MB-231 cells with OHPer-MAng showed inhibition of migration by cancer cells. The induction of an oxidative stress state, similar to other quinones and PARP-1 inhibition explains the pro-apoptotic activity of OHPer-MAng. Docking studies showed that OHPer-MAng establishes great non-bonding interactions with the lateral chains of Tyr235, Hys201, Tyr246, Ser203, Asn207, and Gly233 located at the catalytic site of PARP-1, also demonstrating the anti-cancer activity of OHPer-MAng in TNBC cell line.

Oxygenated Cyclohexene Derivatives and Other Constituents from the Roots of Monanthotaxis trichocarpa.

Three new oxygenated cyclohexene derivatives, trichocarpeols A (1), B (2), and C (3), along with nine known secondary metabolites, were isolated from the methanolic root extract of Monanthotaxis trichocarpa. They were identified by NMR spectroscopic and mass spectrometric analyses, and the structure of trichocarpeol A (1) was confirmed by single-crystal X-ray diffraction. Out of the 12 isolated natural products, uvaretin (4) showed activity against the Gram-positive bacterium Bacillus subtilis with a MIC value of 18 µM. None of the isolated metabolites was active against the Gram-negative Escherichia coli at a ∼5 mM (2000 µg/mL) concentration. Whereas 4 showed cytotoxicity at EC50 10.2 µM against the MCF-7 human breast cancer cell line, the other compounds were inactive or not tested.

Improving Effects of Hop-Derived Bitter Acids in Beer on Cognitive Functions: A New Strategy for Vagus Nerve Stimulation.

Dementia and cognitive decline are global public health problems. Moderate consumption of alcoholic beverages reduces the risk of dementia and cognitive decline. For instance, resveratrol, a polyphenolic compound found in red wine, has been well studied and reported to prevent dementia and cognitive decline. However, the effects of specific beer constituents on cognitive function have not been investigated in as much detail. In the present review, we discuss the latest reports on the effects and underlying mechanisms of hop-derived bitter acids found in beer. Iso-α-acids (IAAs), the main bitter components of beer, enhance hippocampus-dependent memory and prefrontal cortex-associated cognitive function via dopamine neurotransmission activation. Matured hop bitter acids (MHBAs), oxidized components with ß-carbonyl moieties derived from aged hops, also enhance memory functions via norepinephrine neurotransmission-mediated mechanisms. Furthermore, the effects of both IAAs and MHBAs are attenuated by vagotomy, suggesting that these bitter acids enhance cognitive function via vagus nerve stimulation. Moreover, supplementation with IAAs attenuates neuroinflammation and cognitive impairments in various rodent models of neurodegeneration including Alzheimer's disease. Daily supplementation with hop-derived bitter acids (e.g., 35 mg/day of MHBAs) may be a safe and effective strategy to stimulate the vagus nerve and thus enhance cognitive function.

A computational study of regioselectivity in aluminum hydride ring-opening of cis- and trans-4-t-butyl and 3-methylcyclohexene oxides.

Nucleophilic ring opening of cyclohexene oxides is known to proceed preferentially through the trans-diaxial pathway (the Fürst-Plattner rule). This preference, however, is not absolute, and can be affected by substituents on the cyclohexene oxide ring, as illustrated by LiAlH4 ring-opening of the cis- and trans-isomers of 4-t-butyl- and 3-methylcyclohexene oxide (cis- and trans-1, cis- and trans-2). We performed B3LYP/6-31+G*(PCM) geometry optimizations to locate the chair-like and twist-boat-like transition structures for the hydride attacks on the pseudoaxial and pseudoequatorial conformers of these epoxides. Our calculations are consistent with the experimental observation of effective Fürst-Plattner control of AlH4--opening of cis-1, trans-1, and cis-2, but low selectivity in ring-opening of trans-2. Our data at B3LYP/6-31+G*(PCM) suggests this reduction in selectivity is due to a diminished pseudoequatorial preference of the 3-methyl group in trans-2 relative to that in cis-2. The two calculated chair-like transition structures for hydride opening of trans-2 differ in activation energy free energy (ΔΔG‡) by only 0.4 kcal mol-1. Thus, these calculations account for the reduced regioselectivity of ring opening seen for trans-2 by AlH4- and other nucleophiles.

Antimicrobial and antioxidant activities of hydrocarbon and oxygenated monoterpenes against some foodborne pathogens through in vitro and in silico studies.

The present work describes the antimicrobial action of 25 monoterpenes (six hydrocarbons, five ketones, two aldehydes, six alcohols and six acetate analogues) against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus and antifungal activity against Aspergillus flavus. The antibacterial activity was evaluated by broth microdilution technique as a minimum inhibitory concentration (MIC) and the antifungal activity was performed by mycelia radial growth technique as the effective concentration causing 50% inhibition of the mycelial growth (EC50). The results showed that thymol and α-terpineol were the most potent against E. coli (MIC = 45 and 55 mg/L, respectively) and S. aureus (MIC = 135 and 225 mg/L, respectively). The results also showed that thymol displayed the maximum antifungal action against A. flavus with EC50 20 mg/L. Furthermore, the antioxidant activity was determined using N,N-dimethyl-1,4-phenylenediamine (DMPD) and the results showed that geraniol were the most potent compound (IC50 = 19 mg/L). Molecular docking studies indicated that the compounds displayed different binding interactions with the amino acid residues at the catalytic sites of N5-carboxyaminoimidazole synthetase and oxysterol binding protein Osh4 enzymes. Non-covalent interactions including van der Waals, hydrogen bonding as well as hydrophobic were observed between the compounds and the enzymes. A significant relationship was found between the docking score and the biological activity of the tested monoterpenes compared to the ceftriaxone and carbendazim as standard bactericide and fungicide, respectively. In silico ADMET properties were also performed and displayed potential for the development of promising antimicrobial agents. For these reasons, these compounds may be considered as potential ecofriendly alternatives in food preservation to delay or prevent the microbial infection and prolong the shelf life of food products.

Correlation between Chemical Composition and Antifungal Activity of Clausena lansium Essential Oil against Candida spp.

Essential oils (EOs) have been shown to have a diversity of beneficial human health effects. Clausena is a large and highly diverse genus of plants with medicinal and cosmetic significance. The aim of this study was to analyze the composition of Clausena lansium EOs and to investigate their potential antifungal effects. The chemical compositions of Clausena lansium EOs obtained by hydrodistillation were analyzed by gas chromatography-mass spectrometry (GC-MS). A total of 101 compounds were identified among the diverse extracts of C. lansium. EOs of leaves and pericarps from different cultivars (Hainan local wampee and chicken heart wampee) collected in Hainan (China) were classified into four clusters based on their compositions. These clusters showed different antifungal activities against five Candida species (C. albicans, C. tropicalis, C. glabrata, C. krusei and C. parapsilosis) using the disc diffusion method. Clausena lansium EOs of pericarps displayed noteworthy antifungal activitives against all the tested Candida strains with inhibition zone diameters in the range of 11.1­23.1 mm. EOs of leaves showed relatively low antifungal activities with inhibition zone diameters in the range of 6.5­22.2 mm. The rank order of antifungal activities among the four EO clusters was as follows: Cluster IV> Cluster III > Cluster I ≥ Cluster II. These results represent the first report about the correlation between chemical composition of C. lansium EOs and antifungal activity. Higher contents of ß-phellandrene, ß-sesquiphellandrene and ß-bisabolene in EOs of pericarps were likely responsible for the high antifungal activity of Cluster IV EOs. Taken together, our results demonstrate the chemical diversity of Clausena lansium EOs and their potential as novel antifungal agents for candidiasis caused by Candida spp. Furthermore, the obtained results showing a wide spectrum of antifungal activities provide scientific evidence for the traditional use of these plants.