Asymmetric synthesis of the four diastereoisomers of a novel non-steroidal farnesoid X receptor (FXR) agonist: Role of the chirality on the biological activity

An asymmetric synthetic strategy was designed for the preparation of the four possible diastereoisomers of 3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one, a non-steroidal FXR agonist, we recently discovered following a virtual screening approach. The results obtained from an AlphaScreen assay clearly demonstrated that only the isomer endowed with 4R,6S absolute configuration is responsible for the biological activity. A deep investigation of the different putative binding modes adopted by these enantiomerically pure ligands using computational modeling studies confirmed the enantioselectivity of FXR towards this class of molecules.     

Genome Editing by CRISPR/Cas9: A Game Change in the Genetic Manipulation of Protists

Genome editing by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR‐associated gene 9) system has been transformative in biology. Originally discovered as an adaptive prokaryotic immune system, CRISPR/Cas9 has been repurposed for genome editing in a broad range of model organisms, from yeast to mammalian cells. Protist parasites are unicellular organisms producing important human diseases that affect millions of people around the world. For many of these diseases, such as malaria, Chagas disease, leishmaniasis and cryptosporidiosis, there are no effective treatments or vaccines available. The recent adaptation of the CRISPR/Cas9 technology to several protist models will be playing a key role in the functional study of their proteins, in the characterization of their metabolic pathways, and in the understanding of their biology, and will facilitate the search for new chemotherapeutic targets. In this work we review recent studies where the CRISPR/Cas9 system was adapted to protist parasites, particularly to Apicomplexans and trypanosomatids, emphasizing the different molecular strategies used for genome editing of each organism, as well as their advantages. We also discuss the potential usefulness of this technology in the green alga Chlamydomonas reinhardtii.     

Systematic review of Atractus schach (Serpentes: Dipsadidae) species complex from the Guiana Shield with description of three new species

The Guiana Shield harbours one of the best preserved and largest extents of tropical forest on Earth and an immense biodiversity. The herpetofauna of this region remains poorly known. The species-rich snake genus Atractus contains ～140 species, many with complicated taxonomic histories, including A. schach. Examination of specimens in museums and newly collected material from French Guiana has allowed the illustration of hemipenial morphology for the first time and an expanded diagnosis. Concatenated molecular phylogenetic (mitochondrial and nuclear genes) and phenotypic (morphometrics, external and hemipenial morphology) analyses confirm non-monophyly of the A. flammigerus group and indicate that A. schach is a species complex with three new species described here. The geographic distribution of A. schach sensu stricto is restricted to Guiana, Surinam, and French Guiana north of Tumucumaque massif. Populations tentatively assigned to A. schach from the east from French Guiana in the Roura lowlands to Almeirim, and from central Amazonia between the Negro and Trombetas rivers in Brazil are also recognized as new species. Our results suggest that populations from south of the Amazon River are not conspecific with those from the Guiana Shield.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:A7AE40BC-4716-4302-B3BE-1F43600B0A72     

Evaluation of chemokine and cytokine profiles in osteoblast progenitors from umbilical cord blood stem cells by BIO-PLEX technology

We have used cytokine protein array to analyze the secretion of cytokines from an osteoblastic clone derived from human umbilical cord blood mesenchymal stem cells (MSCs) cultured in an osteogenic differentiation medium. The analysis demonstrated the unexpected ability of osteoblast committed cells and their early progenitors to produce significant amounts of a range of soluble immune mediators without in vitro exposure to clinically relevant bacterial pathogens. The cells were expanded and their osteogenic potential analyzed over 45 days of culture was revealed by the expression of osteoblast-specific markers (alkaline phosphatase and Runx2), and by matrix mineralization. Over this culture period, the cells secreted particularly high levels of IL-8, MCP-1 and VEGF, but did not express IL-2, IL-7, IL-17, eotaxin, G-CSF and IFN-gamma. These findings should encourage the use of human umbilical cord blood as a potential stem cells source for bone regeneration.     

Repair of UVB-Damaged Skin by the Antioxidant Sulphated Flavone Glycoside Thalassiolin B Isolated from the Marine Plant Thalassia testudinum Banks ex König

Daily topical application of the aqueous ethanolic extract of the marine sea grass, Thalassia testudinum, on mice skin exposed to UVB radiation resulted in a dose-dependent recovery of the skin macroscopic alterations over a 6-day period. Maximal effect (90%) occurred at a dose of 240 μg/cm², with no additional effects at higher doses. Bioassay-guided fractionation of the plant extract resulted in the isolation of thalassiolin B (1). Topical application of 1 (240 μg/cm²) markedly reduces skin UVB-induced damage. In addition, thalassiolin B scavenged 2,2-diphenyl-2-picrylhydrazyl radical with an EC₅₀ = 100 μg/ml. These results suggest that thalassiolin B is responsible for the skin-regenerating effects of the crude extract of T. testudinum. Erik L. Regalado and María Rodríguez have contributed equally to this work and should be considered as first authors.     

Synthesis,semipreparative HPLC separation,biological evaluation,and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors

The present study reports on synthesis in high yields (70–99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1–45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds.     

Glacial and postglacial sedimentation in the Fryxell basin, Taylor Valley, southern Victoria Land, Antarctica

A 9.14 m long sediment sequence was recovered from Lake Fryxell, Taylor Valley, southern Victoria Land, Antarctica, and investigated for its chronology and sedimentological, mineralogical, and biogeochemical changes. The basal part of the sequence is dominated by coarse clastic matter, i.e., mainly sand. The sediment composition suggests that a lake existed in Fryxell basin during the Middle Weichselian by ca. 48,000 cal. year BP. After a short period of lake-level lowstand ca. 43,000 cal. year BP, lower Taylor Valley became occupied by the proglacial Lake Washburn, which was at least partly supplied by meltwater and sediments from the Ross Ice Sheet that was advanced to the mouth of Taylor Valley. Evaporation of Lake Washburn to lower levels started during the Last Glacial Maximum at ca. 22,000 cal. year BP, long before the Ross Ice Sheet retreated significantly. Lake-level lowering was discontinuous with a series of high and low stands. From ca. 4000 cal. year BP environmental conditions were similar to those of today and lower Fryxell basin was occupied by a small lake. This lake evaporated to a saline or hypersaline pond between ca. 2500 and 1000 cal. year BP and refilled subsequently.     

Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, both in adults and in children. NAFLD is characterized by aberrant lipid storage in hepatocytes (hepatic steatosis) and inflammatory progression to nonalcoholic steatohepatitis. Evidences so far suggest that intrahepatic lipid accumulation does not always derive from obesity. Gut microbiota has been considered as a regulator of energy homeostasis and ectopic fat deposition, suggesting its implications in metabolic diseases. Probiotics are live microbial that alter the enteric microflora and have beneficial effects on human health. Although the molecular mechanisms of probiotics have not been completely elucidated yet, many of their effects have proved to be beneficial in NAFLD, including the modulation of the intestinal microbiota, an antibacterial substance production, an improved epithelial barrier function and a reduced intestinal inflammation. Given the close anatomical and functional correlation between the bowel and the liver, and the immunoregulatory effects elicited by probiotics, the aim of this review is to summarize today's knowledge about probiotics in NAFLD, focusing in particular on their molecular and biochemical mechanisms, as well as highlighting their efficacy as an emerging therapeutic strategy to treat this condition.