Isolation of anticancer and anti-trypanosome secondary metabolites from the endophytic fungus Aspergillus flocculus via bioactivity guided isolation and MS based metabolomics

This study aims to identify bioactive anticancer and anti-trypanosome secondary metabolites from the fermentation culture of Aspergillus flocculus endophyte assisted by modern metabolomics technologies. The endophyte was isolated from the stem of the medicinal plant Markhamia platycalyx and identified using phylogenetics. Principle component analysis was employed to screen for the optimum growth endophyte culturing conditions and revealing that the 30-days rice culture (RC-30d) provided the highest levels of the bioactive agents. To pinpoint for active chemicals in endophyte crude extracts and successive fractions, a new application of molecular interaction network is implemented to correlate the chemical and biological profiles of the anti-trypanosome active fractions to highlight the metabolites mediating for bioactivity prior to purification trials. Multivariate data analysis (MVDA), with the aid of dereplication studies, efficiently annotated the putatively active anticancer molecules. The small-scale RC-30d fungal culture was purified using high-throughput chromatographic techniques to yield compound 1, a novel polyketide molecule though inactive. Whereas, active fractions revealed from the bioactivity guided fractionation of medium scale RC-30d culture were further purified to yield 7 metabolites, 5 of which namely cis-4-hydroxymellein, 5-hydroxymellein, diorcinol, botryoisocoumarin A and mellein, inhibited the growth of chronic myelogenous leukemia cell line K562 at 30 μM. 3-Hydroxymellein and diorcinol exhibited a respective inhibition of 56% and 97% to the sleeping sickness causing parasite Trypanosoma brucei brucei. More interestingly, the anti-trypanosomal activity of A. flocculus extract appeared to be mediated by the synergistic effect of the active steroidal compounds i.e. ergosterol peroxide, ergosterol and campesterol. The isolated structures were elucidated by using 1D, 2D NMR and HR-ESIMS

Metabolomic tools to assess the chemistry and bioactivity of endophytic aspergillus strain

Endophytic fungi associated with medicinal plants are a potential source of novel chemistry and biology that may find applications as pharmaceutical and agrochemical drugs. In this study, a combination of metabolomics and bioactivity-guided approaches were employed to isolate anticancer secondary metabolites from an endophytic Aspergillus aculeatus. The endophyte was isolated from the Egyptian medicinal plant Terminalia laxiflora and identified using molecular biological methods. Metabolomics and dereplication studies were accomplished by utilizing the MZmine software coupled with the universal Dictionary of Natural Products database. Metabolic profiling, with aid of multivariate data analysis, was performed at different stages of the growth curve to choose the optimised method suitable for up-scaling. The optimised culture method yielded a crude extract abundant with biologically-active secondary metabolites. Crude extracts were fractionated using different high-throughput chromatographic techniques. Purified compounds were identified by HRESI-MS, 1D and 2D-NMR. This study introduced a new method of dereplication utilising both high-resolution mass spectrometry and NMR spectroscopy. The metabolites were putatively identified by applying a chemotaxonomic filter. We also present a short review on the diverse chemistry of terrestrial endophytic strains of Aspergillus, which has become a part of our dereplication work and this will be of wide interest to those working in this field. This article is protected by copyright. All rights reserved

Testing theories of post-error slowing

People tend to slow down after they make an error. This phenomenon, generally referred to as post-error slowing, has been hypothesized to reflect perceptual distraction, time wasted on irrelevant processes, an a priori bias against the response made in error, increased variability in a priori bias, or an increase in response caution. Although the response caution interpretation has dominated the empirical literature, little research has attempted to test this interpretation in the context of a formal process model. Here, we used the drift diffusion model to isolate and identify the psychological processes responsible for post-error slowing. In a very large lexical decision data set, we found that post-error slowing was associated with an increase in response caution and—to a lesser extent—a change in response bias. In the present data set, we found no evidence that post-error slowing is caused by perceptual distraction or time wasted on irrelevant processes. These results support a response-monitoring account of post-error slowing

Epigenetics Offer New Horizons for Colorectal Cancer Prevention

In recent years, colorectal cancer (CRC) incidence has been increasing to become a major cause of morbidity and mortality worldwide from cancers, with high rates in westernized societies and increasing rates in developing countries. Epigenetic modifications including changes in DNA methylation, histone modifications, and non-coding RNAs play a critical role in carcinogenesis. Epidemiological data suggest that, in comparison to other cancers, these alterations are particularly common within the gastrointestinal tract. To explain these observations, environmental factors and especially diet were suggested to both prevent and induce CRC. Epigenetic alterations are, in contrast to genetic modifications, potentially reversible, making the use of dietary agents a promising approach in CRC for the development of chemopreventive strategies targeting epigenetic mechanisms. This review focuses on CRC-related epigenetic alterations as a rationale for various levels of prevention strategies and their potential modulation by natural dietary compounds

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Temporal and spatial analysis of the 2014-2015 Ebola virus outbreak in West Africa

West Africa is currently witnessing the most extensive Ebola virus (EBOV) outbreak so far recorded. Until now, there have been 27,013 reported cases and 11,134 deaths. The origin of the virus is thought to have been a zoonotic transmission from a bat to a two-year-old boy in December 2013 (ref. 2). From this index case the virus was spread by human-to-human contact throughout Guinea, Sierra Leone and Liberia. However, the origin of the particular virus in each country and time of transmission is not known and currently relies on epidemiological analysis, which may be unreliable owing to the difficulties of obtaining patient information. Here we trace the genetic evolution of EBOV in the current outbreak that has resulted in multiple lineages. Deep sequencing of 179 patient samples processed by the European Mobile Laboratory, the first diagnostics unit to be deployed to the epicentre of the outbreak in Guinea, reveals an epidemiological and evolutionary history of the epidemic from March 2014 to January 2015. Analysis of EBOV genome evolution has also benefited from a similar sequencing effort of patient samples from Sierra Leone. Our results confirm that the EBOV from Guinea moved into Sierra Leone, most likely in April or early May. The viruses of the Guinea/Sierra Leone lineage mixed around June/July 2014. Viral sequences covering August, September and October 2014 indicate that this lineage evolved independently within Guinea. These data can be used in conjunction with epidemiological information to test retrospectively the effectiveness of control measures, and provides an unprecedented window into the evolution of an ongoing viral haemorrhagic fever outbreak.status: publishe

Phytochemical Screening and Antioxidant and Cytotoxic Effects of Acacia macrostachya

Acacia macrostachya is used in Burkina Faso folk medicine for the treatment of inflammation and cancer. The purpose of this study was to evaluate the antioxidant and cytotoxic effects of this plant. The cytotoxic effects of root (dichloromethane B1 and methanol B2) and stem (dichloromethane B3 and methanol B4) bark extracts of A. macrostachya were assessed on chronic K562 and acute U937 myeloid leukemia cancer cells using trypan blue, Hoechst, and MitoTracker Red staining methods. The antioxidant content of extracts was evaluated using DPPH (2,2-diphenyl-1-picryl-hydrazyl) and FRAP (ferric reducing antioxidant power) methods. The root bark extracts B1 and B2 of A. macrostachya demonstrated higher cytotoxicity with IC50 values in a low µg/mL range on both U937 and K562 cells, while the stem bark B4 extract selectively affected U937 cells. Overall, healthy proliferating peripheral blood mononuclear cells (pPBMCs) were not or barely impacted in the range of concentrations cytotoxic to cancer cells. In addition, A. macrostachya exhibited significant antioxidant content with 646.06 and 428.08 µg ET/mg of extract for the B4 and B2 extracts, respectively. Phytochemical screening showed the presence of flavonoids, tannins, alkaloids, and terpenoids/steroids. The results of this study highlight the interest of A. macrostachya extracts for the isolation of anticancer molecules

Tanzawaic acids isolated from a marine-derived fungus of the genus Penicillium with cytotoxic activities

Tanzawaic acids M (1), N (2), O (3) and P (4) and the known tanzawaic acids B (5) and E (6), have been isolated from an extract of a cultured marine-derived fungus (strain CF07370) identified as a member of the genus Penicillium. The structures of 1–4 were determined based on spectroscopic evidence. The antimicrobial and cytotoxic activities of compounds 1–6 were evaluated.This work was supported by the Ministerio de Ciencia e Innovación SAF2009–0839. F. C. acknowledges financial support from Programa JAE-Pre (CSIC). ARDM acknowledges funding from the IMBRAIN project (FP7-REGPOT-2012-CT2012–31637-IMBRAIN). CC is supported by a “Waxweiler grant for cancer prevention research” from the Action Lions “Vaincre le Cancer”, Luxembourg. This work was supported by Télévie Luxembourg, the “Recherche Cancer et Sang” foundation and “Recherches Scientifiques Luxembourg” association. The authors thank the “Een Häerz fir Kriibskrank Kanner” association and the Action Lions “Vaincre le Cancer” for generous support. MD is supported by the National Research Foundation (NRF) by the MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) grant, [grant number 2012–0001184].Peer Reviewe