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Stearic acid Grade I, = 98.5 capillary GC 57-11-4

Stearic acid Grade I, &#8805;98.5% (capillary GC)

Stearic acid

Hypoxia potentiates palmitate-induced pro-inflammatory activation of primary human macrophages

Solid liquid phase diagrams of binary fatty acid mixtures?Palmitic/stearic with oleic/linoleic/linolenic acid mixture

Construction and comparison of solid liquid phase diagrams of binary sat-sat and unsat-unsat fatty acid mixtures comprising two of palmitic/stearic/oleic/linoleic/linolenic acid

The nematode Caenorhabditis elegans constitutes a leading animal model to study how signaling pathway components function in conserved biological processes. Here, we describe the role of an Axin family member, PRY-1, in lipid metabolism. Axins are scaffolding proteins that play crucial roles in signal transduction pathways by physically interacting with multiple factors and coordinating the assembly of protein complexes. Genome-wide transcriptome profiling of a pry-1 mutant revealed differentially regulated genes that are associated with lipid metabolism such as vitellogenins (yolk lipoproteins), fatty acid desaturases, lipases, and fatty acid transporters. Consistent with these categorizations, we found that pry-1 is crucial for the maintenance of lipid levels. Knockdowns of vit genes in a pry-1 mutant background restored lipid levels, suggesting that vitellogenins contribute to PRY-1 function in lipid metabolic processes. Additionally, lowered expression of desaturases and lipidomic analysis provided evidence that fatty acid synthesis is reduced in pry-1 mutants. Accordingly, an exogenous supply of oleic acid restored depleted lipids in somatic tissues of worms. Overall, our findings demonstrate that PRY-1/Axin signaling is essential for lipid metabolism and involves the regulation of yolk proteins.

PRY-1/Axin signaling regulates lipid metabolism in Caenorhabditis elegans.

The detrimental role of hepatic lipotoxicity has been well-implicated in the pathogenesis of NAFLD. Previously, we reported that inhibiting autophagy aggravated saturated fatty acid (SFA)-induced hepatotoxicity. Insulin, a physiological inhibitor of autophagy, is commonly increased within NAFLD mainly caused by insulin resistance. We therefore hypothesized that insulin augments the sensitivity of hepatocyte to SFA-induced lipotoxicity. The present study was conducted via employing human and mouse hepatocytes, which were exposed to SFAs, insulin, or their combination. Unexpectedly, our results indicated that insulin protected hepatocytes against SFA-induced lipotoxicity, based on the LDH, MTT, and nuclear morphological measurements, and the detection from cleaved-Parp-1 and -caspase-3 expressions. We subsequently clarified that insulin led to a rapid and short-period inhibition of autophagy, which was gradually recovered after 1 h incubation in hepatocytes, and such extent of inhibition was insufficient to aggravate SFA-induced lipotoxicity. The mechanistic study revealed that insulin-induced alleviation of ER stress contributed to its hepatoprotective role. Pre-treating hepatocytes with insulin significantly stimulated phosphorylated-Akt and reversed SFA-induced up-regulation of p53. Chemical inhibition of p53 by pifithrin-α robustly prevented palmitate-induced cell death. The PI3K/Akt pathway blockade by its special antagonist abolished the protective role of insulin against SFA-induced lipotoxicity and p53 up-regulation. Furthermore, we observed that insulin promoted intracellular TG deposits in hepatocytes in the present of palmitate. However, blocking TG accumulation via genetically silencing DGAT-2 did not prevent insulin-protected lipotoxicity. Our study demonstrated that insulin strongly protected against SFA-induced lipotoxicity in hepatocytes mechanistically through alleviating ER stress via a PI3K/Akt/p53 involved pathway but independently from autophagy.

Insulin Protects Hepatic Lipotoxicity by Regulating ER Stress through the PI3K/Akt/p53 Involved Pathway Independently of Autophagy Inhibition.

Saturated fatty acids (SFAs) induce hepatocyte cell death, wherein oxidative stress is mechanistically involved. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master transcriptional regulator of cellular antioxidant defense enzymes. Therefore, Nrf2 activation is regarded as an effective strategy against oxidative stress-triggered cellular damage. In this study, tert-butylhydroquinone (tBHQ), a widely used Nrf2 activator, was initially employed to investigate the potential protective role of Nrf2 activation in SFA-induced hepatoxicity. As expected, SFA-induced hepatocyte cell death was prevented by tBHQ in both AML-12 mouse hepatocytes and HepG2 human hepatoma cells. However, the protective effect of tBHQ is Nrf2-independent, because the siRNA-mediated Nrf2 silencing did not abrogate tBHQ-conferred protection. Alternatively, our results revealed that autophagy activation was critically involved in the protective effect of tBHQ on lipotoxicity. tBHQ induced autophagy activation and autophagy inhibitors abolished tBHQ's protection. The induction of autophagy by tBHQ exposure was demonstrated by the increased accumulation of LC3 puncta, LC3-II conversion, and autophagic flux (LC3-II conversion in the presence of proteolysis inhibitors). Subsequent mechanistic investigation discovered that tBHQ exposure activated AMP-activated protein kinase (AMPK) and siRNA-mediated AMPK gene silencing abolished tBHQ-induced autophagy activation, indicating that AMPK is critically involved in tBHQ-triggered autophagy induction. Furthermore, our study provided evidence that tBHQ-induced autophagy activation is required for its Nrf2-activating property. Collectively, our data uncover a novel mechanism for tBHQ in protecting hepatocytes against SFA-induced lipotoxicity. tBHQ-triggered autophagy induction contributes not only to its hepatoprotective effect, but also to its Nrf2-activating property.

tert-Butylhydroquinone (tBHQ) protects hepatocytes against lipotoxicity via inducing autophagy independently of Nrf2 activation.

Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O2) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate-induced mRNA expression and protein secretion of IL-6 and IL-1β. Although palmitate-induced endoplasmic reticulum stress and nuclear factor κB pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1α and HIF-2α alone or in combination failed to reduce IL-6 and only modestly reduced IL-1β gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1β and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage-mediated inflammation.

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages.

RT-qPCR analysis is a widely used method for the analysis of mRNA expression throughout the field of mesenchymal stromal cell (MSC) research. Comparison between MSC studies, both in vitro and in vivo, are challenging due to the varied methods of RT-qPCR data normalization and analysis. Therefore, this study focuses on putative housekeeping genes for the normalization of RT-qPCR data between heterogeneous commercially available human MSC, compared with more homogeneous populations of MSC such as MIAMI and RS-1 cells. Eight genes including; ACTB, B2M, EF1alpha, GAPDH, RPL13a, YWHAZ, UBC and HPRT1 were tested as possible housekeeping genes based on their expression level and variability. EF1alpha and RPL13a were validated for RT-qPCR analysis of MIAMI cells during expansion in varied oxygen tensions, endothelial differentiation, neural precursor enrichment, and during the comparison with RS-1 cells and commercially available MSC. RPL13a and YWHAZ were validated as normalization genes for the cross-species analysis of MIAMI cells in an animal model of focal ischemia. GAPDH, which is one of the most common housekeeping genes used for the normalization of RT-qPCR data in the field of MSC research, was found to have the highest variability and deemed not suitable for normalization of RT-qPCR data. In order to make comparisons between heterogeneous MSC populations, as well as adult stem cell like MSC which are used in different laboratories throughout the world, it is important to have a standardized, reproducible set of housekeeping genes for RT-qPCR analysis. In this study we demonstrate that EF1alpha, RPL13a and YWHAZ are suitable genes for the RT-qPCR analysis and comparison of several sources of human MSC during in vitro characterization and differentiation as well as in an ex vivo animal model of global cerebral ischemia. This will allow for the comparative RT-qPCR analysis of multiple MSC populations with the goal of future use in animal models of disease as well as tissue repair.

EF1alpha and RPL13a represent normalization genes suitable for RT-qPCR analysis of bone marrow derived mesenchymal stem cells.

Lecithin/sphingomyelin (L/S) ratio, creatinine, percentage of lipid-positive cells, palmitic acid, palmitic acid/stearic acid (P/S) ratio, and total cortisol were analyzed as tests for fetal maturity and fetal pulmonary maturity in 164 samples of amniotic fluid from 121 patients. Fifty samples were taken within 72 hours of delivery. The best tests for fetal maturity (37 weeks) with differential percentages were L/S ratio, palmitic acid, and P/S ratio. In the assessment of fetal pulmonary maturity, we studied an additional 174 samples in which only L/S ratio, creatinine, and lipid-positive cells were analyzed. All tests showed a high predictive value of an immature (positive) result was much less for all six parameters; the three best tests were total cortisol (33%), lipid-positive cells (26%) and L/S ratio (14%).

Amniotic fluid lecithin/sphingomyelin ratio, palmitic acid, palmitic acid/stearic acid ratio, total cortisol, creatinine, and percentage of lipid-positive cells in assessment of fetal maturity and fetal pulmonary maturity: a comparison.

Harnessing of a branched structure is a novel approach in the design of cell-penetrating peptides and it has provided highly efficient transfection reagents for intracellular delivery of nucleic acids. The new stearylated TP10 analogs, NickFects, condense plasmid DNA, splice correcting oligonucleotides and short interfering RNAs into stable nanoparticles with a size of 62-160nm. Such nanoparticles have a negative surface charge (-11 to -18mV) in serum containing medium and enable highly efficient gene expression, splice correction and gene silencing. One of the novel peptides, NickFect51 is capable of transfecting plasmid DNA into a large variety of cell lines, including refractory suspension and primary cells and in several cases exceeds the transfection level of commercially available reagent Lipofectamine™ 2000 without any cytotoxic side effects. Additionally we demonstrate the advantages of NickFect51 in a protein production system, QMCF technology, for expression and production of recombinant proteins in hardly transfectable suspension cells.

New generation of efficient peptide-based vectors, NickFects, for the delivery of nucleic acids.

Breast milk fatty acids may have immunomodulatory properties related to the development of atopic disease. The aim of this study was to assess the impact of the breast milk fatty acid composition on the development of atopic dermatitis (AD) in high-risk infants. Mothers with atopic disease were recruited at the end of gestation. Maternal food records and breast milk samples were collected at the infants' age of one month. Infants were clinically examined and AD diagnosed at one, three, six, and 12 months. Altogether 13 of 34 (38%) infants were diagnosed with AD during the first year of life. Infants developing AD had consumed breast milk with a higher ratio of saturated to polyunsaturated fatty acids and less n-3 fatty acids compared to infants not developing AD. Specifically, breast milk consumed by infants with AD contained more stearic acid, 8.9% of total fatty acids (95% confidence interval 7.9-10.0) in comparison to those without AD, 7.1% (95% CI 6.6-7.7). Breast milk rich in saturated and low in n-3 fatty acids may be a risk factor for atopic dermatitis in the infant.

Breast milk fatty acid composition is associated with development of atopic dermatitis in the infant.

The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A(2) IIA and have potential in liposomal drug delivery targeting tumors. We have synthesized four different retinoid phospholipid prodrugs and shown that they form particles in the liposome size region with average diameters of 94-118 nm. Upon subjection to phospholipase A(2), the lipid prodrugs were hydrolyzed, releasing cytotoxic retinoids and lysolipids. The formulated lipid prodrugs displayed IC(50) values in the range of 3-19 microM toward HT-29 and Colo205 colon cancer cells in the presence of phospholipase A(2), while no significant cell death was observed in the absence of the enzyme.

Liposomal formulation of retinoids designed for enzyme triggered release.

Two Pseudomonas strains, identified as closely related to Pseudomonas tolaasii, were isolated from milk of a farm with frequent false-positive Delvotest results for screening putative antibiotic residues in raw milk executed as part of the regulatory quality programme. Growth at 5 to 7°C of these isolates in milk resulted in high lipolysis and the production of bacterial inhibitors. The two main bacterial inhibitors have a molecular weight of 1168.7 and 1140.7 Da respectively, are heat-tolerant and inhibit Geobacillus stearothermophilus var. calidolactis, the test strain of most of the commercially available microbiological inhibitor tests for screening of antibiotic residues in milk. Furthermore, these bacterial inhibitors show antimicrobial activity against Staphylococcus aureus, Bacillus cereus and B. subtilis and also interfere negatively with yoghurt production. Following their isolation and purification with RP-HPLC, the inhibitors were identified by NMR analysis as cyclic lipodepsipeptides of the viscosin group. Our findings bring to light a new challenge for quality control in the dairy industry. By prolonging the refrigerated storage of raw milk, the keeping quality of milk is influenced by growth and metabolic activities of psychrotrophic bacteria such as pseudomonads. Besides an increased risk of possible spoilage of long shelf-life milk, the production at low temperature of natural bacterial inhibitors may also result in false-positive results for antibiotic residue screening tests based on microbial inhibitor assays thus leading to undue production loss.

Cyclic lipodepsipeptides produced by Pseudomonas spp. naturally present in raw milk induce inhibitory effects on microbiological inhibitor assays for antibiotic residue screening.

Autophagy is a major catabolic process responsible for the delivery of proteins and organelles to the lysosome/vacuole for degradation. Malfunction of this pathway has been implicated in numerous pathological conditions. Different organelles have been found to contribute to the formation of autophagosomes, but the exact mechanism mediating this process remains obscure. Here, we show that lipid droplets (LDs) are important for the regulation of starvation-induced autophagy. Deletion of Dga1 and Lro1 enzymes responsible for triacylglycerol (TAG) synthesis, or of Are1 and Are2 enzymes responsible for the synthesis of steryl esters (STE), results in the inhibition of autophagy. Moreover, we identified the STE hydrolase Yeh1 and the TAG lipase Ayr1 as well as the lipase/hydrolase Ldh1 as essential for autophagy. Finally, we provide evidence that the ER-LD contact-site proteins Ice2 and Ldb16 regulate autophagy. Our study thus highlights the importance of lipid droplet dynamics for the autophagic process under nitrogen starvation.

Lipid droplets and their component triglycerides and steryl esters regulate autophagosome biogenesis.

Transmembrane protein CD36 binds multiple ligands, including oxidized low-density lipoproteins (oxLDLs) and long-chain fatty acids (LCFAs). Our aim was to determine whether LCFAs compete with oxLDLs for binding to CD36. We addressed this issue by examining the inhibitory effect of LCFAs against the binding of Alexa-fluor-labeled oxLDLs (AFL-oxLDL) to a synthetic peptide representing the oxLDL-binding site on CD36 (3S-CD36₁₅₀₋₁₆₈). All of the unsaturated LCFAs tested, inhibited the binding of AFL-oxLDL to 3S-CD36₁₅₀₋₁₆₈, albeit to varying degrees. For instance, the concentrations required for 50% inhibition of binding for oleic, linoleic, and α-linolenic acids were 0.25, 0.97, and 1.2 mM, respectively. None of the saturated LCFAs tested (e.g. stearic acid) exhibited inhibitory effects. These results suggest that at least unsaturated LCFAs can compete with oxLDLs for binding to CD36. The study also provides information on the structural requirements of LCFAs for inhibition of oxLDLs-CD36 binding.

Unsaturated long-chain fatty acids inhibit the binding of oxidized low-density lipoproteins to a model CD36.

Human carotid atherosclerotic plaque is in direct contact with circulatory blood components. Thus, plaque and blood components may affect each other. The current study presents the effects of plaque chloroform:methanol (C:M) extract on the HDL-associated enzyme paraoxnase 1 (PON1). This study is part of our investigation on the mutual effects of the interactions between atherosclerotic lesions and blood components. Recombinant PON1 (rePON1) was incubated with the human carotid plaques C:M extract and PON1 activities were analyzed. Lactonase and paraoxonase activities were elevated due to C:M treatment, by 140 and by 69%, respectively. Analytical chemistry analyses revealed specific phosphatidylcholines (PCs) as the plaque active components. Tryptophan fluorescence quenching assay, together with molecular docking, shows that PON1 activity is enhanced in correlation with the level of PC affinity to PON1. Molecular docking revealed that PCs interact specifically with H2-PON1 α-helix, which together with H1 enzyme α-helix links the protein to the HDL surface. These findings are supported by additional results from the PON1 ∆20 mutant that lack its H1-α-helix. Incubation of this mutant with the plaque C:M extract increased PON1 activity by only 20%, much less than the wild-type PON1 that elevated PON1 activity at the same concentration by as much as 95%. Furthermore, as much as the affinity of the enzyme to the PC was augmented, the ability of PON1 to bind to the HDL particle decreased. Finally, PON1 interaction with PC enhance its uptake into the macrophage cytoplasm. In conclusions, Specific lesion phosphatidylcholines (PCs) present in the human carotid plaque significantly enhance PON1 catalytic activities due to their interaction with the enzyme. Such a lesion׳s PC-PON1 interaction, in turn, competes with HDL PCs and enhances PON1 uptake by macrophage at the expense of PON1 binding to the HDL.

Human carotid plaque phosphatidylcholine specifically interacts with paraoxonase 1, increases its activity, and enhances its uptake by macrophage at the expense of its binding to HDL.

The fatty acid (FA) composition of polysorbate 80 (PS80), a sorbitan oleic acid ester copolymerized with about 20mole of ethylene oxide, is typically characterized by gas chromatography. Here, an alternative method was developed. After saponification with potassium hydroxide the FA fraction was collected with liquid-liquid extraction using methyl-tert-butyl ether. HPLC in combination with a Corona® charged aerosol detector (CAD) was applied for the separation and detection. The method was fully validated in terms of specificity, repeatability, limits of quantification, linearity, range, accuracy and robustness. The characterization of 16 different PS80 batches demonstrated variability regarding their FA composition, with e.g. the amount of oleic acid ranging from 67.8±0.7% to 96.6±1.4%. Furthermore, we identified petroselinic acid, a double-bond positional isomer to oleic acid in all batches, an FA not known to pharmacopoeias at present. In addition, 11-hydroxy-9-octadecenoic acid, an oxidation product of oleic acid was identified. Structure elucidation was performed by means of HPLC-MS/MS. In addition, the method was expanded to the evaluation of the free FAs. Having determined the entire FA composition, the acid value according to EP and USP can be calculated.

Fatty acid composition analysis in polysorbate 80 with high performance liquid chromatography coupled to charged aerosol detection.

The Human Metabolome Database (HMDB, http://www.hmdb.ca) is a richly annotated resource that is designed to address the broad needs of biochemists, clinical chemists, physicians, medical geneticists, nutritionists and members of the metabolomics community. Since its first release in 2007, the HMDB has been used to facilitate the research for nearly 100 published studies in metabolomics, clinical biochemistry and systems biology. The most recent release of HMDB (version 2.0) has been significantly expanded and enhanced over the previous release (version 1.0). In particular, the number of fully annotated metabolite entries has grown from 2180 to more than 6800 (a 300% increase), while the number of metabolites with biofluid or tissue concentration data has grown by a factor of five (from 883 to 4413). Similarly, the number of purified compounds with reference to NMR, LC-MS and GC-MS spectra has more than doubled (from 380 to more than 790 compounds). In addition to this significant expansion in database size, many new database searching tools and new data content has been added or enhanced. These include better algorithms for spectral searching and matching, more powerful chemical substructure searches, faster text searching software, as well as dedicated pathway searching tools and customized, clickable metabolic maps. Changes to the user-interface have also been implemented to accommodate future expansion and to make database navigation much easier. These improvements should make the HMDB much more useful to a much wider community of users.

HMDB: a knowledgebase for the human metabolome.

Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca.

The human serum metabolome.

Fatty acids of the n-3, n-6 and n-9 families are important supplements for cell culture systems. They are important in cell culture systems used to biomanufacture heterologous proteins, such as monoclonal antibodies.

Stearic acid

Grade I, ≥98.5% (capillary GC)

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