DHA-derived oxylipins, neuroprostanes and protectins, differentially and dose-dependently modulate the inflammatory response in human macrophages: Putative mechanisms through PPAR activation.

Whereas the anti-inflammatory properties and mechanisms of action of long chain ω3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. We conducted a dose-dependent and comparative study in human primary macrophages aiming to compare the anti-inflammatory activity of two types of DHA-derived oxylipins including the well-described protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A4t- and 4-F4t-NeuroP) formed through free-radical mediated oxygenation and expected to be new anti-inflammatory mediators. Considering the potential ability of these DHA-derived oxylipins to bind PPARs and knowing the central role of these transcription factors in the regulation of macrophage inflammatory response, we performed transactivation assays to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced mRNA levels of cytokines such as IL-6 and TNF-α, however not at the same doses. NPD1 showed the most effect at 0.1µM (-14.9%, p<0.05 for IL-6 and -26.7%, p<0.05 for TNF-α) while the three other molecules had greater effects at 10µM, with the strongest result due to the cyclopentenone neuroprostane, 14-A4t-NeuroP (-49.8%, p<0.001 and -40.8%, p<0.001, respectively). Part of the anti-inflammatory properties of the DHA-derived oxylipins investigated could be linked to their activation of PPARs. Indeed, all tested oxylipins significantly activated PPARγ, with 14-A4t-NeuroP leading to the strongest activation, and NPD1 and PDX also activated PPARα. In conclusion, our results show that neuroprostanes and more especially cyclopentenone neuroprostanes have potent anti-inflammatory activities similar or even more pronounced than protectins supporting that neuroprostanes should be considered as important contributors to the anti-inflammatory effects of DHA.

The main constituents of Tulipa systola Stapf. roots and flowers; their antioxidant activities.

People living on the mountains of the Kurdistan Region, Iraq make a large use of herbs in the local traditional medicine. Among them, Tulipa systola, which grows under and between rocks, is very popular as an anti-inflammatory remedy and pain-relief. The phytochemical study of an ethanolic extract obtained from flowers and roots of Tulip (T systola Stapf.) afforded three compounds, identified as (+)-1-O-E-feruloyl-3-O-E-p-coumaroylglycerol (1), (+)-6-tuliposide A (2), and (-)-kaempferol-3-O-rutinoside (3). The significant radical scavenging and antioxidant activity of the isolated compounds were evaluated on three tests, by determining the DPPH free radical scavenging activity, the total antioxidant activity and the hydrogen peroxide scavenging activity. Tuliposide A shows potent allergenic activity.

Chemical Characterization and in Vitro Antibacterial Activity of Myrcianthes hallii (O. Berg) McVaugh (Myrtaceae), a Traditional Plant Growing in Ecuador.

Myrcianthes hallii (O. Berg) McVaugh (Myrtaceae) is a plant native to Ecuador, traditionally used for its antiseptic properties. The composition of the hydro-methanolic extract of this plant was determined by submitting it to ultra-high performance liquid chromatography (UHPLC) hyphenated to heated-electrospray ionization mass spectrometry and UV detection. The presence of antimicrobial components prompted us to test the extract against methicillin-resistant and methicillin-susceptible Staphylococcus aureus, multidrug-resistant and susceptible Escherichia coli, Pseudomonas aeruginosa, Enterococcus spp. and Streptococcus pyogenes strains. The chromatographic analysis led to the identification of 38 compounds, including polyphenols and organic acids, and represents the first chemical characterization of this plant. The extract showed modest antibacterial activity against all tested bacteria, with the exception of E. coli which was found to be less sensitive. Whilst methicillin-resistant strains usually display resistance to several drugs, no relevant differences were observed between methicillin-susceptible and resistant strains. Considering its long-standing use in folk medicine, which suggests the relative safety of the plant, and the presence of many known antibacterial polyphenolic compounds responsible for its antibacterial activity, the results show that M. hallii extract could be used as a potential new antiseptic agent. Moreover, new anti-infective biomaterials and nanomaterials could be designed through the incorporation of M. hallii polyphenols. This prospective biomedical application is also discussed.

The Importance of the 5-Alkyl Substituent for the Violet Smell of Ionones: Synthesis of Racemic 5-Demethyl-α-ionone.

The synthesis and the odor tonalities of racemic 5-demethyl-α-ionone are described. This synthetic ionone derivative did not show the typical floral-woody violet smell of α-ionone, definitely proving the importance of a suitably sized and spatially oriented alkyl substituent at C(5) for stimulating olfactory receptors of ionones.

Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.

To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target.

Biomimetic cyclization of geraniol derivatives, a useful tool in the total synthesis of bioactive monocyclic terpenoids.

This review is a detailed account of authors' work in the field of biomimetic cyclization of geraniol-like dienes. The very high regio- and enantioselectivity achieved made these elegant reactions a viable tool for the synthesis of monocyclic building blocks used in the synthesis of valued terpenoids, like the precious aroma and perfume constituents' ionones and irones.

A new beta-D-glucopyranosyl 2-oxo-urs-12-en-28-oate from the Cameroonian plant Combretum bracteatum.

From the Cameroonian plant Combretum bracteatum (Laws.) Engl. and Diels a new compound, beta-D-glucopyranosyl 3 beta,19 alpha-dihydroxy-2-oxo-urs-12-en-28-oate, was isolated along with three known ursane and oleane triterpenes and two galactopyranosyl lipids. This represents the first example of a naturally occurring 2-oxo-urs-12-enoic acid derivative.

Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid.

The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) possesses potent anti-inflammatory properties and has shown therapeutic benefit in numerous inflammatory diseases. However, the molecular mechanisms of these anti-inflammatory properties are poorly understood. DHA is highly susceptible to peroxidation, which yields an array of potentially bioactive lipid species. One class of compounds are cyclopentenone neuroprostanes (A(4)/J(4)-NPs), which are highly reactive and similar in structure to anti-inflammatory cyclopentenone prostaglandins. Here we show that a synthetic A(4)/J(4)-NP, 14-A(4)-NP (A(4)-NP), potently suppresses lipopolysaccharideinduced expression of inducible nitric-oxide synthase and cyclooxygenase-2 in macrophages. Furthermore, A(4)-NP blocks lipopolysaccharide-induced NF-kappaB activation via inhibition of Ikappa kinase-mediated phosphorylation of IkappaBalpha. Mutation on Ikappa kinase beta cysteine 179 markedly diminishes the effect of A(4)-NP, suggesting that A(4)-NP acts via thiol modification at this residue. Accordingly, the effects of A(4)-NP are independent of peroxisome proliferator-activated receptor-gamma and are dependent on an intact reactive cyclopentenone ring. Interestingly, free radical-mediated oxidation of DHA greatly enhances its anti-inflammatory potency, an effect that closely parallels the formation of A(4)/J(4)-NPs. Furthermore, chemical reduction or conjugation to glutathione, both of which eliminate the bioactivity of A(4)-NP, also abrogate the anti-inflammatory effects of oxidized DHA. Thus, we have demonstrated that A(4)/J(4)-NPs, formed via the oxidation of DHA, are potent inhibitors of NF-kappaB signaling and may contribute to the anti-inflammatory actions of DHA. These findings have implications for understanding the anti-inflammatory properties of omega-3 fatty acids, and elucidate novel interactions between lipid peroxidation products and inflammation.

Fungitoxic metabolites from Erigeron apiculatus.

Four enyne derivatives (1-4) and quercitrin were isolated during a bioassay-guided chromatographic separation of a methanolic extract of Erigeron apiculatus. Matricarialactone (1) and lachnophyllumlactone (2) showed a high fungitoxic activity against Pyricularia oryzae. Matricaria acid methyl ester (3) and lachnophyllum acid methyl ester (4) were, instead, less active.