a genomics based approach identifies a thioviridamide like compound with selective anticancer activity

Thioviridamide is a structurally novel ribosomally synthesized and post-translational modified peptide (RiPP) produced by Streptomyces olivoviridis NA005001. It is characterized by a structure that features a series of thioamide groups and possesses potent antiproliferative activity in cancer cell lines. Its unusual structure allied to its promise as an anticancer compound led us to investigate the diversity of thioviridamide-like pathways across sequenced bacterial genomes. We have isolated and characterized three diverse members of this family of natural products. This characterization is supported by transformation-associated recombination cloning and heterologous expression of one of these compounds, thiostreptamide S4. Our work provides an insight into the diversity of this rare class of compound and indicates that the unusual N-terminus of thioviridamide is not introduced biosynthetically but is instead introduced during acetone extraction. A detailed analysis of the biological activity of one of th..

Tectonoelins, new norlignans from a bioactive extract of Tectona grandis

A phytochemical study on the most bioactive extract from Tectona grandis led to the isolation of two new norlignans, tectonoelin A and tectonoelin B, together with ten known compounds. The structures of the compounds were determined by a combination of 1D and 2D NMR techniques. This is the first time that this type of compound (C8–C80 linkage norlignans) has been isolated from a dicotyledon. The general bioactivities of the isolated compounds have been studied using etiolated wheat coleoptiles. The activities showed that the isolated lignans and norlignans should be part of the defence mechanisms of this plant

Caniferolide A, a Macrolide from Streptomyces caniferus, Attenuates Neuroinflammation, Oxidative Stress, Amyloid-Beta, and Tau Pathology in Vitro

The macrolide caniferolide A was isolated from extracts of a culture of the marine-derived actinomyceteStreptomyces caniferus, and its ability to ameliorate Alzheimer’s disease (AD) hallmarks was determined. The compound reducedneuroinflammatory markers in BV2 microglial cells activated with lipopolysaccharide (LPS), being able to block NFκB-p65translocation to the nucleus and to activate the Nrf2 pathway. It also produced a decrease in pro-inflammatory cytokines (IL-1β,IL-6, and TNF-α), reactive oxygen species (ROS) and nitric oxide release and inhibited iNOS, JNK, and p38 activities.Moreover, the compound blocked BACE1 activity and attenuated Aβ-activation of microglia by drastically diminishing ROSlevels. The phosphorylated state of the tau protein was evaluated in SH-SY5Y tau441 cells. Caniferolide A reduced Thr212 andSer214 phosphorylation by targeting p38 and JNK MAPK kinases. On the other side, the antioxidant properties of themacrolide were determined in an oxidative stress model with SH-SY5Y cells treated with H2O2. The compound diminishedROS levels and increased cell viability and GSH content by activating the nuclear factor Nrf2. Finally, the neuroprotectiveability of the compound was confirmed in two trans-well coculture systems with activated BV2 cells (both with LPS and Aβ)and wild type and transfected SH-SY5Y cells. The addition of caniferolide A to microglial cells produced a significant increase inthe survival of neuroblastoma in both cases. These results indicate that the compound is able to target many pathologicalmarkers of AD, suggesting that caniferolide A could be an interesting drug lead for a polypharmacological approach to theillnessThe research leading to these results has received funding from the following FEDER cofunded-grants, Consellería de Cultura, Educación e Ordenación Universitaria Xunta de Galicia, 2017 GRC GI-1682 (ED431C 2017/01); CDTI and Technological Funds, supported by Ministerio de Economía, Industria y Competitividad, AGL2014-58210-R, AGL2016-78728-R (AEI/FEDER, UE), ISCIII/PI16/01830, RTC-2016-5507-2, and ITC-20161072; and European Union POCTEP 0161-Nanoeaters-1-E-1, Interreg AlertoxNet EAPA-317-2016, Interreg Agritox EAPA-998-2018, H2020 778069-EMERTOX, and FP7 PharmaSea (Grant Agreement 312184).This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular pharmaceutics, copyright © 2019 American Chemical Society, after peer review and technical editing by the publisher.S

Streptocyclinones A and B ameliorate Alzheimer's disease pathological processes in vitro

Alzheimer's disease (AD) is a pathology characterized by the abnormal accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau. Oxidative stress and neuroinflammation are also strongly related to this disease. The ability of two new glycosylated angucyclinones, streptocyclinones A and B (1 and 2), isolated from Streptomyces sp to improve AD hallmarks was evaluated. Compounds were able to protect SH-SY5Y neuroblastoma cells from H2O2-induced oxidative injury by activating the nuclear factor E2-related factor (Nrf2). Their capacity to modulate neuroinflammation was tested in lipopolysaccharide-activated BV2 microglial cells. Compounds reduced the release of pro-inflammatory factors, inhibited the activation of NFκB and mitogen activated kinases (MAPK), and induced the translocation of Nrf2 to the nucleus of microglial cells. A trans-well co-culture was established to determine the effect of microglia treated with streptocyclinones on the survival of SH-SY5Y cells. The cell viability of neuroblastoma cells increased when the compounds were added to BV2 cells. SH-SY5Y-TMHT441 cells were used to determine the effect of compounds on tau phosphorylation. Both compounds reduced tau hyperphophorylation by targeting MAPK kinases. Moreover, streptocyclinone B (2) was able to inhibit the activity of β-secretase 1 and decrease the release of reactive oxygen species in BV2 cells stimulated with Aβ. With the same co-culture trans-well system, the treatment of Aβ-stimulated microglia with compound 2 augmented the viability of SH-SY5Y-TMHT441 cells. The results presented in this work provide evidences of the multitarget activities displayed by these new Streptomyces compounds, making them good candidates for further studies in the treatment of ADThe research leading to these results has received funding from the following FEDER cofunded-grants. From Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia, 2017 GRC GI-1682 (ED431C 2017/01). From CDTI and Technological Funds, supported by Ministerio de Economía, Industria y Competitividad, AGL2014-58210-R, AGL2016-78728-R (AEI/FEDER, UE), ISCIII/PI16/01830 and RTC-2016-5507-2, ITC-20161072. From European Union POCTEP 0161-Nanoeaters -1-E-1, Interreg AlertoxNet EAPA-317-2016, H2020 778069-EMERTOX and FP7 PharmaSea (Grant Agreement 312184).S

Phytotoxic effect of bioactive compounds isolated from Myrcia tomentosa (Myrtaceae) leaves.

The aim of this study was to assess the phytotoxic potential of leaves of Myrcia tomentosa, as well as to isolate and identify the main bioactive compounds. The results for the coleoptile and phytotoxicity bioassays indicated the ethyl acetate extract for the phytochemistry study, owing to the high activity and the maintenance of the activity at lower concentrations. This extract was chromatographed and subjected to 1H NMR and 13C NMR. Two major active compounds were isolated from the ethyl acetate extract of leaves of M. tomentosa: avicularin and juglanin. The fractions where these compounds were isolated showed potent inhibition of coleoptile growth. This paper is the first report on the presence of the flavonoids avicularin and juglanin in species of Myrtaceae from Neotropical savanna and provides a basis for future studies on the bioprospecting of M. tomentosa

MDN-0170, a New Napyradiomycin from Streptomyces sp. Strain CA-271078

A new napyradiomycin, MDN-0170 (1), was isolated from the culture broth of the marine-derived actinomycete strain CA-271078, together with three known related compounds identified as 4-dehydro-4a-dechloronapyradiomycin A1 (2), napyradiomycin A1 (3) and 3-chloro-6,8-dihydroxy-8-α-lapachone (4). The structure of the new compound was determined using a combination of spectroscopic techniques, including 1D and 2D NMR and electrospray-time of flight mass spectrometry (ESI-TOF MS). The relative configuration of compound 1, which contains two independent stereoclusters, has been established by molecular modelling in combination with nOe and coupling constant analyses. Biosynthetic arguments also allowed us to propose its absolute stereochemistry. The antimicrobial properties of the compounds isolated were evaluated against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Aspergillus fumigatus, and Candida albicans. The potent bioactivity previously reported for compounds 2 and 3 against methicillin-sensitive S. aureus has been extended to methicillin-resistant strains in this report

Extract of plant material of the genus Crocus L. having high levels of bio-insecticide activity

Las plagas de insectos fitófagos afectan una gran variedad de cultivos y tienen especial relevancia en sistemas agrícolas sostenibles donde los productos de síntesis están restringidos. La presente invención reivindica un extracto alcohólico de material vegetal del género Crocus L. con alta actividad bioinsecticida, que se caracteriza por comprender 3-O-β-D-glucopiranosil-(3R)-hidroxibutanolida, por ser fácilmente obtenible y por estar exento de problemas de toxicidad. La invención también reivindica el procedimiento de obtención del extracto; una composición fitosanitaria que lo comprende; el uso como bioinsecticida del extracto, de la composición fitosanitaria y de compuestos presentes en el extracto que se identifican por primera vez con actividad bioinsecticida; así como un método de control de plagas de insectos.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Fundación Parque Científico y Tecnológico de Albacete, Holland Biodiversity B.V.A1 Solicitud de patente con informe sobre el estado de la técnic

Antileishmanial, antitrypanosomal and cytotoxic screening of ethnopharmacologically selected Peruvian plants

Abstract Extracts (34) from eight plant species of the Peruvian Amazonia currently used in traditional Peruvian medicine, mostly as antileishmanial remedies and also as painkiller, antiseptic, antipyretic, anti-inflamatory, antiflu, astringent, diuretic, antipoison, anticancerous, antiparasitic, insecticidal, or healing agents, have been tested for their antileishmanial, antitrypanosomal, and cytotoxic activity. Plant species were selected based on interviews conducted with residents of rural areas. The different plant parts were dried, powdered, and extracted by maceration with different olvents (hexane, chloroform, and 70% ethanol¿water). These extracts were tested on promastigote forms of Leishmania infantum strain PB75, epimastigote forms of Trypanosoma cruzi strain Y, and the mammalian CHO cell line. Parasite viability and nonspecific cytotoxicity were analyzed by a modified MTT colorimetric assay method. The isolation and identification of pure compounds from selected extracts were performed by column chromatography, gas chromatography mass spectrometry (GC-MS; mixtures), spectroscopic techniques [MS, infrared (IR), ultraviolet (UV)], and mono and two-dimensional 1H and 13C nuclear magnetic resonance (NMR; COSY, HSQC, NOESY) experiments. Chondodendron tomentosum bark and Cedrela odorata were the most active extracts against Leishmania, while C. odorata and Aristoloquia pilosa were the most active against Trypanosoma, followed by Tabebuia serratifolia, Tradescantia zebrina, and Zamia ulei. Six compounds and two mixtures were isolated from Z. ulei [cycasin (1)], T. serratifolia {mixtures 1¿2, and naphthoquinones 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (2) and 2-(1-hydroxyethyl)-4H,9H-naphtho[2,3-b]furan-4,9-dione (3)}, and C. tomentosum [chondrocurine (4); (S, S¿)-12-O-methyl(+)-curine (5); and cycleanine (6)]. Four compounds and the two mixtures exhibited significant activity.Peer Reviewe

Antifeedant, antifungal and nematicidal compounds from the endophyte Stemphylium solani isolated from wormwood

Abstract The continuous search for natural product-based biopesticides from fungi isolated from untapped sources is an effective tool. In this study, we studied a pre-selected fungal endophyte, isolate Aa22, from the medicinal plant Artemisia absinthium, along with the antifungal, insect antifeedant and nematicidal compounds present in the extract. The endophyte Aa22 was identified as Stemphylium solani by molecular analysis. The antifungal activity was tested by broth microdilution against Fusarium solani, F. oxysporum, F. moniliforme and Botrytis cinerea, the insect antifeedant by choice bioassays against Spodoptera littoralis, Myzus persicae and Rhopalosiphum padi and the in vitro mortality against the root-knot nematode Meloiydogyne javanica. The structures of bioactive compounds were determined on the basis of 1D and 2D NMR spectroscopy and mass spectrometry. The ethyl acetate extract obtained from the solid rice fermentation showed mycelial growth inhibition of fungal pathogens (EC50 0.08–0.31 mg/mL), was antifeedant to M. persicae (99%) and nematicidal (68% mortality). A bioguided fractionation led to the isolation of the new compound stempholone A (1), and the known stempholone B (2) and stemphol (3). These compounds exhibited antifeedant (EC50 0.50 mg/mL), antifungal (EC50 0.02–0.43 mg/L) and nematicidal (MLD 0.5 mg/mL) activities. The extract activities can be explained by 3 (antifungal), 1–3 (antifeedant) and 1 (nematicidal). Phytotoxicity tests on Lolium perenne and Lactuca sativa showed that the extract and 1 increased L. sativa root growth (121–130%) and 1 reduced L. perenne growth (48–49%). These results highlight the potential of the endophytic fungi Aa22 as biotechnological source of natural product-based biopesticides

Biocidas naturales de amplio espectro

In the field of agriculture, organisms that are harmful to vegetation are a major problem in relation to the productivity of harvests. The present invention relates to a fermentation product obtained from endophytic fungi of the Stemphylium solani family, which may comprise a novel compound of formula (I) and a second known compound of formula (II), and having biocidal activity simultaneously against more than one category of harmful organisms affecting plants, and which are preferably selected from insect-pests, fungi and nematodes. Both the fermentation product, and the compounds included in the scope of the invention, are used in the preparation of a broad-spectrum biocidal composition. Finally, the invention also includes the process for preparing of the fermentation product and the new compound of formula (I).Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad de La Laguna, The Energy and the Resources InstituteY Modelo de utilida