Liver X receptor-α activation enhances cholesterol secretion in lactating mammary epithelium.

Liver X receptors (LXRs) are ligand-dependent transcription factors activated by cholesterol metabolites. These receptors induce a suite of target genes required for de novo synthesis of triglycerides and cholesterol transport in many tissues. Two different isoforms, LXRα and LXRß, have been well characterized in liver, adipocytes, macrophages, and intestinal epithelium among others, but their contribution to cholesterol and fatty acid efflux in the lactating mammary epithelium is poorly understood. We hypothesize that LXR regulates lipogenesis during milk fat production in lactation. Global mRNA analysis of mouse mammary epithelial cells (MECs) revealed multiple LXR/RXR targets upregulated sharply early in lactation compared with midpregnancy. LXRα is the primary isoform, and its protein levels increase throughout lactation in MECs. The LXR agonist GW3965 markedly induced several genes involved in cholesterol transport and lipogenesis and enhanced cytoplasmic lipid droplet accumulation in the HC11 MEC cell line. Importantly, in vivo pharmacological activation of LXR increased the milk cholesterol percentage and induced sterol regulatory element-binding protein 1c (Srebp1c) and ATP-binding cassette transporter a7 (Abca7) expression in MECs. Cumulatively, our findings identify LXRα as an important regulator of cholesterol incorporation into the milk through key nodes of de novo lipogenesis, suggesting a potential therapeutic target in women with difficulty initiating lactation.

Virtuous colours for Mary. Identification of lapis lazuli, smalt and cochineal in the Andean colonial image of Our Lady of Copacabana (Bolivia).

The image of Our Lady of Copacabana, a gilded polychrome sculpture carved in maguey wood in 1583, is one of the most important devotions in the Americas. In former research, we have identified the use of gypsum, Armenian bole, cerussite and atacamite in its polychromy. In this study, a red sample taken from the Virgin's tunic and a blue sample extracted from the cloak have been analysed with the aim to identify both pigments and offer insights into the painting technique. Analysis by micro-Raman spectroscopy complemented with scanning electron microscopy-energy dispersive spectroscopy and high-performance liquid chromatography allowed the identification of carmine lake in the red sample. Analysis by micro-Raman spectroscopy of the surface of the blue sample and its cross section showed the presence of smalt-the blue-glass pigment-over a cerussite layer, bathed by a very thin ultramarine layer-from a probable native origin-following a pictorial tradition that would last even until the eighteenth century. This is the first time that lapis lazuli has been scientifically identified in a Spanish American colonial painted layer.This article is part of the themed issue 'Raman spectroscopy in art and archaeology'.

Two Catechol Siderophores, Acinetobactin and Amonabactin, Are Simultaneously Produced by Aeromonas salmonicida subsp. salmonicida Sharing Part of the Biosynthetic Pathway.

The iron uptake mechanisms based on siderophore synthesis used by the fish pathogen Aeromonas salmonicida subsp. salmonicida are still not completely understood, and the precise structure of the siderophore(s) is unknown. The analysis of genome sequences revealed that this bacterium possesses two gene clusters putatively involved in the synthesis of siderophores. One cluster is a candidate to encode the synthesis of acinetobactin, the siderophore of the human pathogen Acinetobacter baumannii, while the second cluster shows high similarity to the genes encoding amonabactin synthesis in Aeromonas hydrophila. Using a combination of genomic analysis, mutagenesis, biological assays, chemical purification, and structural determination procedures, here we demonstrate that most A. salmonicida subsp. salmonicida strains produce simultaneously the two siderophores, acinetobactin and amonabactin. Interestingly, the synthesis of both siderophores relies on a single copy of the genes encoding the synthesis of the catechol moiety (2,3-dihydroxybenzoic acid) and on one encoding a phosphopantetheinyl transferase. These genes are present only in the amonabactin cluster, and a single mutation in any of them abolishes production of both siderophores. We could also demonstrate that some strains, isolated from fish raised in seawater, produce only acinetobactin since they present a deletion in the amonabactin biosynthesis gene amoG. Our study represents the first evidence of simultaneous production of acinetobactin and amonabactin by a bacterial pathogen and reveals the plasticity of bacterial genomes and biosynthetic pathways. The fact that the same siderophore is produced by unrelated pathogens highlights the importance of these systems and their interchangeability between different bacteria.

Synthesis and cytotoxic evaluation of four new 6E-hydroximinosteroids.

Four new 6E-hydroximinosteroids (1, 2a, 3 and 4) have been synthesized from the corresponding ketones, 2ß,3ß-dihydroxy-5α-cholestan-6-one (5), 2α,3α-dihydroxy-5α-cholestan-6-one (6), 2ß,3α-dihydroxy-5α-cholestan-6-one (7) and 2ß,3α-dihydroxy-5α-cholestan-6-one-disulfate (8). The cytotoxic activity of the steroidal oximes was evaluated against two prostate carcinoma cell lines (PC-3 and LNCaP) and compared with that of five polyhydroxylated sulfated analogs (8-12). Oxime 3 and trisulfated analog 11 were the most active compounds with IC50 values of 10.8µM (PC-3) and 7.9µM (LNCaP), respectively.

Pseudocnoside A, a new cytotoxic and antiproliferative triterpene glycoside from the sea cucumber Pseudocnus dubiosus leoninus.

A new triterpene glycoside, pseudocnoside A (1), was isolated from the sea cucumber Pseudocnus dubiosus leoninus. The structure of the new compound was established on the basis of extensive NMR spectroscopic analysis ((1)H and (13)C NMR, (1)H,(1)H-COSY, HMBC, HSQC, TOCSY and NOESY), HR-ESI-MS data and chemical transformations. In addition, the cytotoxicity and antiproliferative activities of 1 and structurally related triterpene glycosides isolated from the sea cucumbers Psolus patagonicus and Hemioedema spectabilis were evaluated against cancer cell lines A-549 and HeLa.

Fatty acid composition of the edible sea cucumber Athyonidium chilensis.

The edible sea cucumber Athyonidium chilensis is a fishery resource of high commercial value in Chile, but no information on its lipid and fatty acid composition has been previously reported. Phospholipids were the major lipid contents of the ethanolic extracts of tubules, internal organs and body wall of A. chilensis. Saturated fatty acids predominated in tubule phospholipids (40.69%), while in internal organs and body wall phospholipids, the monounsaturated fatty acids were in higher amounts (41.99% and 37.94%, respectively). The main polyunsaturated fatty acids in phospholipids were C20 : 2ω-6, arachidonic (C20 : 4ω-6) and eicosapentaenoic (C20 : 5ω-3) acids. These results demonstrate for the first time that A. chilensis is a valuable food for human consumption in terms of fatty acids.

Patagonicosides B and C, two antifungal sulfated triterpene glycosides from the sea cucumber Psolus patagonicus.

Two new triterpene glycosides, patagonicosides B and C (2 and 3, resp.), together with the known patagonicoside A (1), have been isolated from the EtOH extract of the sea cucumber Psolus patagonicus. The structures of the new compounds were established on the basis of extensive NMR spectroscopic analysis ((1)H- and (13)C-NMR, (1)H,(1)H-COSY, HMBC, HSQC, TOCSY, and NOESY), HR-ESI-MS data, and chemical transformations. Compounds 1-3 and their desulfated analogs showed antifungal activities against the phytopathogenic fungus Cladosporium cladosporoides in a dose-dependent fashion.

Antiproliferative, cytotoxic and hemolytic activities of a triterpene glycoside from Psolus patagonicus and its desulfated analog.

BACKGROUND: The major triterpene glycoside of the sea cucumber Psolus patagonicus and its desulfated analog were tested for their antiproliferative, cytotoxic and hemolytic activities, and their effect on NF-kappaB activation. METHODS: The antiproliferative action of glycosides 1 and 2 were determined on 3 tumor cell lines. Their effect on the activation of NF-kappaB was evaluated by indirect immunofluorescence assay staining and the concomitant IkappaBalpha degradation was studied by Western blot. RESULTS: Both compounds were able to suppress the growth of 3 tumor cell lines (Hep3B, MDA-MB231 and A549) and induced the activation of NF-kappaB, a key player linking chronic inflammation and cancer, concomitant with IkappaBalpha degradation in the A549 tumor cell line. Compounds 1 and 2 showed hemolytic activity with half maximal inhibitory concentration (IC(50)) values around 80 microM. CONCLUSIONS: Both glycosides showed low cytotoxic activity in A549 tumor cells in comparison with sea cucumber triterpene glycosides containing a linear tetrasaccharide chain. This could be a result of the uncommon presence of two 12alpha- and 17alpha-hydroxyl groups and a Delta(7) double bond in the aglycone moiety. This aglycone functionalization may be related to their low membranolytic activity. Although glycosides 1 and 2 exert an antiproliferative effect, their mechanisms of action do not involve inhibition of NF-kappaB. Recently, it has been shown that diverse and new mechanisms of action are responsible for the antitumor and cytotoxic activities of marine compounds. Therefore, more extensive studies are needed to establish a mechanism of action and to deduce a clear structure-activity relationship of sea cucumber triterpene glycosides.