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The human pathogenic bacterium Pseudomonas aeruginosa produces rhamnolipids, glycolipids with functions for bacterial motility, biofilm formation, and uptake of hydrophobic substrates. Rhamnolipids represent a chemically heterogeneous group of secondary metabolites composed of one or two rhamnose molecules linked to one or mostly two 3-hydroxyfatty acids of various chain lengths. The biosynthetic pathway involves rhamnosyltransferase I encoded by the rhlAB operon, which synthesizes 3-(3-hydroxyalkanoyloxy)alkanoic acids (HAAs) followed by their coupling to one rhamnose moiety. The resulting mono-rhamnolipids are converted to di-rhamnolipids in a third reaction catalyzed by the rhamnosyltransferase II RhlC. However, the mechanism behind the biosynthesis of rhamnolipids containing only a single fatty acid is still unknown. To understand the role of proteins involved in rhamnolipid biosynthesis the heterologous expression of rhl -genes in non-pathogenic Pseudomonas putida KT2440 strains was used in this study to circumvent the complex quorum sensing regulation in P . aeruginosa . Our results reveal that RhlA and RhlB are independently involved in rhamnolipid biosynthesis and not in the form of a RhlAB heterodimer complex as it has been previously postulated. Furthermore, we demonstrate that mono-rhamnolipids provided extracellularly as well as HAAs as their precursors are generally taken up into the cell and are subsequently converted to di-rhamnolipids by P . putida and the native host P . aeruginosa . Finally, our results throw light on the biosynthesis of rhamnolipids containing one fatty acid, which occurs by hydrolyzation of typical rhamnolipids containing two fatty acids, valuable for the production of designer rhamnolipids with desired physicochemical properties.

Rhamnolipids are glycolipidic biosurfactants produced by various bacterial species. They were initially found as exoproducts of the opportunistic pathogen Pseudomonas aeruginosa and described as a mixture of four congeners: α-L-rhamnopyranosyl-α-L-rhamnopyranosyl-β-hydroxydecanoyl-β-hydroxydecanoate (Rha-Rha-C₁₀-C₁₀), α-L-rhamnopyranosyl-α-L-rhamnopyranosyl-β-hydroxydecanoate (Rha-Rha-C₁₀), as well as their mono-rhamnolipid congeners Rha-C₁₀-C₁₀ and Rha-C₁₀. The development of more sensitive analytical techniques has lead to the further discovery of a wide diversity of rhamnolipid congeners and homologues (about 60) that are produced at different concentrations by various Pseudomonas species and by bacteria belonging to other families, classes, or even phyla. For example, various Burkholderia species have been shown to produce rhamnolipids that have longer alkyl chains than those produced by P. aeruginosa. In P. aeruginosa, three genes, carried on two distinct operons, code for the enzymes responsible for the final steps of rhamnolipid synthesis: one operon carries the rhlAB genes and the other rhlC. Genes highly similar to rhlA, rhlB, and rhlC have also been found in various Burkholderia species but grouped within one putative operon, and they have been shown to be required for rhamnolipid production as well. The exact physiological function of these secondary metabolites is still unclear. Most identified activities are derived from the surface activity, wetting ability, detergency, and other amphipathic-related properties of these molecules. Indeed, rhamnolipids promote the uptake and biodegradation of poorly soluble substrates, act as immune modulators and virulence factors, have antimicrobial activities, and are involved in surface motility and in bacterial biofilm development.

Glycolipids are structurally diverse amphiphilic molecules with potential as non-petrochemical-derived bioproducts, including surfactants, emulsifiers, and antioxidants. The different bioactivities associated with this range of glycolipid structures also present opportunities for dietary supplements, cosmetics, and pharmaceuticals. Marine glycolipids are underexplored due to challenges with purification and structural characterisation. Analytical approaches enabling efficient sample purification, isolation, and identification of target glycolipids are crucial to determining the bioactivity and functions of organisms such as shellfish and seaweed. This review summarises advances in analytical methods applicable to marine glycolipids, including extraction and enrichment methods tailored to specific subclasses. Thin-layer chromatography (TLC)-based rapid detection techniques developed for specific subclasses in complex biological samples are discussed, alongside structure identification methods based on liquid chromatography (LC)–electrospray ionisation (ESI)–tandem mass spectrometry (MS/MS). Hydrophilic interaction liquid chromatography (HILIC), reverse-phase liquid chromatography (RPLC), and supercritical fluid chromatography (SFC) coupled with MS detection are reviewed for their application to glycolipids. The application of two-dimensional liquid chromatography (2D-LC) and advanced MS-based approaches that facilitate both the rapid resolution and comprehensive characterisation of molecular species are also reviewed.

Interest in Toll-like receptor (TLR) agonists for cancer treatment has been renewed after promising preliminary clinical data in combination with checkpoint inhibitors. This first-in-human study assessed the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of intravenous GSK1795091, a synthetic TLR4 agonist, in healthy volunteers as a precursor to evaluation in patients with cancer. Healthy participants were randomized (1:3; double-blinded manner) to receive placebo or a single intravenous injection of GSK1795091 at doses of 7–100 ng. The primary objective was to evaluate the safety and tolerability of GSK1795091; secondary and exploratory objectives were to characterize GSK1795091 PK and PD properties. Forty participants received study treatment (10 received placebo and 30 received GSK1795091). Overall, 3 of the 10 participants (30%) who received placebo and 16 of the 30 (53%) who received GSK1795091 experienced ≥1 adverse event (AE). The most common AEs were influenza-like illness, headache, back pain, and increased body temperature. One participant experienced late-occurring AEs (alanine aminotransferase and aspartate aminotransferase increases), considered possibly related to GSK1795091. No serious AEs were reported. GSK1795091 PK properties were characterized by dose proportional increase in exposure. Transient and dose-dependent changes in induced cytokine and chemokine concentrations and immune cell counts were observed 1–4 h after GSK1795091 administration and returned to baseline within 24 h. Intravenously administered GSK1795091 was acceptably tolerated in healthy volunteers, had favorable PK properties, and stimulated immune cell changes in a dose-dependent manner, providing evidence of target engagement and downstream pharmacology. These results supported the design and initiation of a repeat-dose study of intravenous GSK1795091 in combination with other immunotherapies in patients with advanced cancer. ClinicalTrials.gov identifier: NCT02798978. •TLR4 agonist GSK1795091 has an acceptable safety profile in healthy participants•GSK1795091 was characterized by dose proportional increase in exposure•GSK1795091 stimulated transient and dose-dependent cytokine and immune cell changes

Phosphorus supply is a major factor responsible for reduced crop yields. As a result, plants utilize various adaptive mechanisms against phosphorus depletion, including lipid remodelling. Here we report the involvement of a novel plant lipid, glucuronosyldiacylglycerol, against phosphorus depletion. Lipidomic analysis of Arabidopsis plants cultured in phosphorus-depleted conditions revealed inducible accumulation of glucuronosyldiacylglycerol. Investigation using a series of sulfolipid sulfoquinovosyldiacylglycerol synthesis-deficient mutants of Arabidopsis determined that the biosynthesis of glucuronosyldiacylglycerol shares the pathway of sulfoquinovosyldiacylglycerol synthesis in chloroplasts. Under phosphorus-depleted conditions, the Arabidopsis sqd2 mutant, which does not accumulate either sulfoquinovosyldiacylglycerol or glucuronosyldiacylglycerol, was the most severely damaged of three sulfoquinovosyldiacylglycerol-deficient mutants. As glucuronosyldiacylglycerol is still present in the other two mutants, this result indicates that glucuronosyldiacylglycerol has a role in the protection of plants against phosphorus limitation stress. Glucuronosyldiacylglycerol was also found in rice, and its concentration increased significantly following phosphorus limitation, suggesting a shared physiological significance of this novel lipid against phosphorus depletion in plants. Phosphorus supply is one of the major factors responsible for reduced crop yields. Here Okazaki et al. use untargeted lipidomics to elucidate the biosynthetic pathway of a novel plant lipid, glucuronosyldiacylglycerol, which is essential for the protection of plants against phosphorus depletion.

Biosurfactants offer good advantages over synthetic counterparts, including biodegradability, environmentally friendly and low toxicity. This study employed a yeast Meyerozyma guilliermondii MX strain for bioconversion of lignocellulosic xylose and palm oil to valuable glycolipid biosurfactant with desirable properties. The objective was to elucidate metabolic pathways related to production of glycolipids and its functional properties. To enhance de novo glycolipid production, manipulation of responsible enzymatic genes was conducted using media and environmental means in comparison to the industrial glycolipid producer, Candida bombicola . Proteomic profiles of yeast cells grown with or without palm oil uncovered novel key metabolic enzymes, namely fatty acid biosynthetic enzymes, leading to formation of glycolipid precursors. qRT-PCR identified some cluster genes responsible for biosynthesis of desirable glycolipids. Finally, LC-MS-based lipidomics of glycolipid fraction identified 15-(2′- O -β- d -glucopyranosyl-β- d -glucopyranosyloxy)hexadecanoic acid 1′,4″-lactone 6′,6″-diacetate (663.4525 m/z) as a major product. Using co-carbon substrates in the presence of salt and zinc, maximum glycolipid yield was achieved (55.72 g/L) with 55.30% emulsification activity and 10 mg/L of CMCs. Mixed glycolipids demonstrated antibiofilm activity against Candida albicans shown by reduction of metabolic activity. The novel biosurfactant-producing yeast M. guilliermondii MX is a promising cell factory of new antibiofilm glycolipids with potential for industrial-scale up.

Polar lipids constitute an important part of cellular membranes. The mucosal surface of the gastrointestinal tract is a critical barrier between noxious and immunogenic substances in the lumen and the mucosal immune system. We conducted a prospective, double-blinded, randomized, controlled trial in healthy children to evaluate the acceptability, safety, effect on intestinal comfort (constipation), common infectious symptoms (fever, diarrhea, cough), and behavioral regulation of a 4-mo daily intake of 200-mL formula with or without enrichment of the milk fat globule membrane (INPULSE). Data were collected from parental diaries. The primary endpoints for analysis were the number of days with fever, diarrhea, coughing, or constipation. The secondary endpoints were the number of doctor visits, medication intake, number of missed schooldays, acceptability of the test drinks, and safety. The Achenbach System of Empirically Based Assessment, a validated questionnaire to assess behavior, was submitted to parents at the end of the intervention period. Initially 253 children were included, but 71 dropped out (these were subjects with <80% intake or for <90 d). No adverse effects led to the discontinuation. Per-protocol analysis was performed in 97 girls and 85 boys. The group (n = 182) was normally distributed, with a mean age of 4.4 ± 0.9 y. The amount of product taken each day and the acceptability were similar in the intervention and control groups. The number of days with fever (>38.5°C) and the number of short (<3 d) febrile periods were significantly (P < 0.03) decreased in the intervention group (1.7 ± 2.5 vs 2.6 ± 3.1 d) This significant difference in febrile episodes appeared after 6 wk of consecutive intake. Other outcome parameters (diarrhea, constipation, cough, doctor visit, and days of school absence) were similar in the two groups. An analysis of the 169 Achenbach System of Empirically Based Assessment questionnaires (two-tailed t test) showed significant differences in the internal (P < 0.003), external (P < 0.004), and total (P < 0.002) problem scores in favor of the intervention group. Between-subjects effects were highly correlated (internal, P < 0.003; external, P < 0.005; total, P < 0.002, one-way analysis of variance). Regular consumption of formula enriched with a concentrated milk fat membrane (INPULSE) product by preschool children was safe, well tolerated, and, based on per-protocol analysis, is associated with a significant decrease in the number of short febrile episodes and leads to improved behavioral regulation.

Glycosylation—the covalent addition of carbohydrates to proteins—is central to many biological processes. Recent advances in understanding the roles of glycans—for example, in protein folding and immune regulation—have revealed that glycans are also involved in many disease conditions, from cancer to microbial infection. Dalziel et al. (p. 10.1126/science.1235681 ) review the current knowledge of glycans in pathogen invasion, cancer, autoimmunity, and congenital diseases. Glycosylation plays a key role in a wide range of biological processes. Specific modification to a glycan’s structure can directly modulate its biological function. Glycans are not only essential to glycoprotein folding, cellular homeostasis, and immune regulation but are involved in multiple disease conditions. An increased molecular and structural understanding of the mechanistic role that glycans play in these pathological processes has driven the development of therapeutics and illuminated novel targets for drug design. This knowledge has enabled the treatment of metabolic disorders and the development of antivirals and shaped cancer and viral vaccine strategies. Furthermore, an understanding of glycosylation has led to the development of specific drug glycoforms, for example, monoclonal antibodies, with enhanced potency.

Background: Exercise therapy plays an important role in the prevention and treatment of type 2 diabetes (T2DM). The mechanism of exercise therapy in the improvement of glycolipid metabolism of T2DM is very complex and not completely clear. Summary: Exercise training improves the whole body metabolic health in patients with T2DM, leading to an increase in glycolipid uptake and utilization, improved insulin sensitivity, optimized body mass index, and modulated DNA methylation, etc. Recent findings support that some cytokines such as irisin, osteocalcin, and adiponectin are closely related to exercise and metabolic diseases. This study briefly reviews the physiological mechanisms of exercise therapy in diabetes and the potential role of these cytokines in exercise. Key Messages: More high-quality, targeted, randomized controlled studies are needed urgently, from mechanism study to treatment direction, to provide a more theoretical basis for exercise therapy and to explore new therapeutic targets for diabetes.

Glycolipid biosurfactants produced by bacteria and yeasts provide significant opportunities to replace chemical surfactants with sustainable biologically produced alternatives in bulk commercial products such as laundry detergents and surface cleaners. Sophorolipids are already available in sufficient yield to make their use feasible while rhamnolipids and mannosylerythritol lipids require further development. The ability to tailor the biosurfactant produced to the specific needs of the product formulation will be an important future step.