Diphytanyl glycerol ether distributions in sediments of the Orca Basin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pease, T.K.; VanVleet, E.S.; Barre, J.S.

1992-09-01

Archaebacterially produced diphytanyl glycerol ether (DPGE) was examined in core sediments from the Orca Basin, an anoxic hypersaline basin in the northwestern Gulf of Mexico, to observe its spatial variability and potential origin. A differential extraction protocol was employed to quantify the isopranyl glycerol ethers associated with unbound, intermediate-bound, and kerogen-bound lipid fractions. Archaebacterial lipids were evident at all depths for the unbound and intermediate-bound fractions. Concentrations of DPGE ranged from 0.51 to 2.91 [mu]g/g dry sediment at the surface and showed secondary maxima deeper in basin sediments. Intermediate-bound DPGE concentrations exhibited an inverse relationship to unbound DPGE concentrations. Kerogen-boundmore » DPGE concentrations were normally below detection limits. Earlier studies describing the general homogeneity of lipid components within the overlying brine and at the brine/seawater interface suggest that the large-scale sedimentary DPGE variations observed in this study result from spatial and temporal variations in in-situ production by methanogenic or extremely halophilic archaebacteria.« less

Composition of Hydrothermal Vent Microbial Communities as Revealed by Analyses of Signature Lipids, Stable Carbon Isotopes and Aquificales Cultures

NASA Technical Reports Server (NTRS)

Jahnke, Linda L.; Eder, Wolfgang; Huber, Robert; Hinrichs, Kai-Uwe; Hayes, John M.; Cady, Sherry L.; DesMarais, David J.; Hope, Janet M.; Summons, Roger E.

2001-01-01

Extremely thermophilic microbial communities associated with the siliceous vent walls and outflow channel of Octopus Spring, Yellowstone National Park, have been examined for lipid biomarker and carbon isotopic signatures. These data were compared with that obtained from representatives of three Aquificales genera. Thermocrinis ruber, Thermocrinis sp. HI, Hydrogenobacter thermophilus, Aquifex pyrophilus and Aquifex aeolicus all contained phospholipids composed not only of the usual ester-linked fatty acids, but also ether-linked alkyl moieties. The fatty acids of all cultured organisms were dominated by very distinct pattern of n-C-20:1 and cy-C-21 compounds. The alkyl glycerol ethers were present primarily as C-18:0 monoethers with the exception of the Aquifex spp. in which dialkyl glycerol ethers with a boarder carbon-number distribution were also present. These Aquificales biomarker lipids were the major constituents in the lipid extracts of the Octopus Spring microbial samples. Two natural samples, a microbial biofilm growing in association with deposition of amorphous silica on the vent walls at 92 C, and the well-known "pink-streamer community" (PSC), siliceous filaments of a microbial consortia growing in the outflow channel at 87 C were analyzed. Both the biofilm and PSC samples contained mono- and dialkyl glycerol ethers with a prevalence of C-18 and C-20 alkyls. Phospholipid fatty acids were comprised of both the characteristic. Additional information is contained in the original extended abstract.

Concentrations and distributions of polybrominated diphenyl ethers and novel brominated flame retardants in tree bark and human hair from Yunnan Province, China.

PubMed

Yuan, Haodong; Jin, Jun; Bai, Yao; Li, Qiuxu; Wang, Ying; Hu, Jicheng

2016-07-01

The concentrations and distributions of polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs) in tree bark and hair samples from the same area in Yunnan Province, China, were determined. The total PBDE and NBFR concentrations in the tree bark samples were 3.8 ng/g lipid weight to 91 ng/g lipid weight and 0.23 ng/g lipid weight to 5.0 ng/g lipid weight, respectively. The total PBDE and NBFR concentrations in the hair samples were 2.1 ng/g dry weight to 14 ng/g dry weight and 0.083 ng/g dry weight to 0.29 ng/g dry weight, respectively. Decabromodiphenyl ether had similar distributions in the tree bark and hair samples, but other PBDE congeners and NBFRs had different distributions in the tree bark and hair samples. External exposure was found to be mainly responsible for the total PBDE and pentabromotoluene concentrations in hair, but both external and internal exposure were responsible for the pentabromophenyl and hexabromobenzene concentrations in hair. Copyright © 2016 Elsevier Ltd. All rights reserved.

Amphiphilic lipid derivatives of 3'-hydroxyurea-deoxythymidine: preparation, properties, molecular self-assembly, simulation and in vitro anticancer activity.

PubMed

Li, Miao; Qi, Shuo; Jin, Yiguang; Yao, Weishang; Zhang, Sa; Zhao, Jingyu

2014-11-01

Lipid derivatives of nucleoside analogs and their nanoassemblies have become the research hotspot due to their unique function in cancer therapy. Six lipid derivatives of 3'-hydroxyurea-deoxythymidine were prepared with zidovudine as the raw material. The 5'-substituted lipid chains in the derivatives were from the various fatty acids including octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid and octadecanoic acid corresponding to the derivatives OHT, DHT, DDHT, TDHT, HDHT and ODHT. The amphiphilic derivatives formed Langmuir monolayers at the air/water interface with different surface pressure-molecular area isotherms depending on the length of lipid chains. The nanoassemblies of OHT, DHT, DDHT, TDHT and HDHT and the nanoscale precipitates of ODHT were obtained after we injected their tetrahydrofuran solutions doped with hydrophilic long chained polymers into water. Electron microscopy showed that the morphology of nanoassemblies may be vesicles or nanotubes depending on the length of lipid chains. The shorter the lipid chains were, the softer the nanoassemblies. Computer simulation supported the experimental results. The nanoassemblies and the nanoscale precipitates showed much higher anticancer effects on SW620 cells than the parent drug hydroxyurea. The nanostructures of the derivatives are promising anticancer nanomedicines. Copyright © 2014 Elsevier B.V. All rights reserved.

Extraction and Analysis of Food Lipids

USDA-ARS?s Scientific Manuscript database

Along with proteins and carbohydrates, lipids are one of the main components of foods. Lipids are often defined as a group of biomolecules that are insoluble in water and soluble in organic solvents such as hexane, diethyl ether or chloroform. Modern methods for the extraction and analysis of lipi...

Lipid oxidation by hypochlorous acid: chlorinated lipids in atherosclerosis and myocardial ischemia

PubMed Central

Ford, David A

2011-01-01

Leukocytes, containing myeloperoxidase (MPO), produce the reactive chlorinating species, HOCl, and they have important roles in the pathophysiology of cardiovascular disease. Leukocyte-derived HOCl can target primary amines, alkenes and vinyl ethers of lipids, resulting in chlorinated products. Plasmalogens are vinyl ether-containing phospholipids that are abundant in tissues of the cardiovascular system. The HOCl oxidation products derived from plasmalogens are α-chlorofatty aldehyde and unsaturated molecular species of lysophosphatidylcholine. α-chlorofatty aldehyde is the precursor of both α-chlorofatty alcohol and α-chlorofatty acid. Both α-chlorofatty aldehyde and α-chlorofatty acid accumulate in activated neutrophils and have disparate chemotactic properties. In addition, α-chlorofatty aldehyde increases in activated monocytes, human atherosclerotic lesions and rat infarcted myocardium. This article addresses the pathways for the synthesis of these lipids and their biological targets. PMID:21339854

Multiple QSAR models, pharmacophore pattern and molecular docking analysis for anticancer activity of α, β-unsaturated carbonyl-based compounds, oxime and oxime ether analogues

NASA Astrophysics Data System (ADS)

Masand, Vijay H.; El-Sayed, Nahed N. E.; Bambole, Mukesh U.; Quazi, Syed A.

2018-04-01

Multiple discrete quantitative structure-activity relationships (QSARs) models were constructed for the anticancer activity of α, β-unsaturated carbonyl-based compounds, oxime and oxime ether analogues with a variety of substituents like sbnd Br, sbnd OH, -OMe, etc. at different positions. A big pool of descriptors was considered for QSAR model building. Genetic algorithm (GA), available in QSARINS-Chem, was executed to choose optimum number and set of descriptors to create the multi-linear regression equations for a dataset of sixty-nine compounds. The newly developed five parametric models were subjected to exhaustive internal and external validation along with Y-scrambling using QSARINS-Chem, according to the OECD principles for QSAR model validation. The models were built using easily interpretable descriptors and accepted after confirming statistically robustness with high external predictive ability. The five parametric models were found to have R2 = 0.80 to 0.86, R2ex = 0.75 to 0.84, and CCCex = 0.85 to 0.90. The models indicate that frequency of nitrogen and oxygen atoms separated by five bonds from each other and internal electronic environment of the molecule have correlation with the anticancer activity.

Lipid Biomarkers for Methanogens in Hypersaline Cyanobacterial Mats for Guerrero Negro, Baja California Sur

NASA Technical Reports Server (NTRS)

Jahnke, Linda L.; Embaye, Tsegereda; Summons, Roger E.; Fonda, Mark (Technical Monitor)

2002-01-01

Analyses of sediments from the vicinity of active methane seeps have uncovered a particular suite of lipid biomarker patterns that characterize methane consuming archaea and their syntrophic, sulfate reducing partners. These isoprenoid biomarkers, largely identified by their anomalously light carbon isotopic signatures, have been a topic of intense research activity and are recorded in numerous methane-rich environments from Holocene to Cenozoic. This phenomenon has implications for depleted kerogens at 2.7 Ga on early Earth (Hinrichs 2002). In contrast, the lipid biosignatures of methane producing archaea are not readily identified through distinct isotopic labels and have received comparably little attention in analyses of archaea in environmental samples. Indeed, environmental analyses generally detect only free archaeal lipids, not the intact, polar molecules found in the membrane of living organisms. As part of the Ames NAI, the 'Early Microbial Ecosystem Research Group' (EMERG) is working to understand microbial processes in the hypersaline cyanobacterial mats growing in the salt evaporation ponds of the Exportadora de Sal at Guerrero Negro, Baja California Sur, Mexico. The aim of this study was to develop methods by which we could identify the organisms responsible for methane generation in this environment. While the ester-bound fatty acids, hopanoids and wax esters provide a means to identify most of the bacterial components of these mats, the archaea which Ere evidently present through genomic assays and the fact of intense methane production (Hoehler et al. 200l), have not been identified through their corresponding lipid signatures. Archaeal core lipids present a number of analytical challenges. The core lipids of methanogens comprise C20, C40 and sometimes C25 isoprenoid chains, linked through ether bonds to glycerol. As well as archaeal (C20), sn-2- and sn-3-hydroxyarchaeol are associated particularly with methylotrophic methanogens. Recently, we have also identified a dihydroxyarchaeol in a hyperthermophilic methanogen (Summons et al. 2002). Additional structural diversity is encoded into the polar head groups that are attached to the glycerol ether cores. The C20 core lipids are readily analyzed by GC-MS as their volatile trimethylsilyl derivatives while compounds with intact polar head groups can only be detected using LC-MS approaches. Our approach was to utilize the alternative of an ether cleavage reagent (BBr3 vs. HI) and a hydride reducing agent to convert all ether lipids to hydrocarbon in order to provide a vertical profile of quantitative information that might be matched to methane fluxes. We have found that while conventional acid hydrolysis and HI treatment will destroy hydroxyarchaeols, molecular information remains intact through use of BBr3 for ether cleavage. This method revealed the presence of traces of biphytane and various ether alkyls associated with some sulfate reducing bacteria within the mat structure. An interesting, and potentially valuable, byproduct of the method utilizing HI was the identification of abundant homohopanoids after superhydride reduction. Evidently present as sulfur-bound diagenetic products these hopanoids are likely cyanobacterial biomarkers in the early stages of diagenetic preservation.

Combination of Oxaliplatin and Vit.E-TPGS in Lipid Nanosystem for Enhanced Therapeutic Efficacy in Colon Cancers.

PubMed

Wang, Yanlei; Zhang, Xiang; Zhang, Wenqiang; Dong, Hao; Zhang, Wenjie; Mao, Jiajia; Dai, Yong

2018-01-08

The main aim of present study was to prepare the oxaliplatin (OXL)-loaded D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS)-based lipid nanoparticles to enhance the anticancer effect in colon cancer cells. The nanoparticles were nanosized and spherical shaped and exhibited controlled release kinetics. Flow cytometer and confocal laser scanning microscopy (CLSM) showed a remarkable uptake of nanoparticles in cancer cells in a time-dependent manner. The presence of TPGS remarkably increased the anticancer effect of OXL in HT-29 colon cancer cells. The IC50 value of free OXL was 4.25 μg/ml whereas IC50 value of OXL-loaded TPGS-based lipid nanoparticles (OXL/TLNP) was 1.12 μg/ml. The 3-fold lower IC50 value of OXL/TLNP indicates the superior anticancer effect of nanoparticle-based OXL. Consistently, OXL/TLNP induced a remarkable apoptosis of cancer cells. Approximately, ~52% of cells were in early apoptosis phase and ~13% of cells were in late apoptosis phase indicating the potent anticancer effect of the formulations. The findings from this study provide novel insights into the use of TPGS and lipid nanoparticle together for the better antitumor effect in colon cancers. Future studies will involve the detailed in vitro and in vivo studies on clinically relevant animals.

Anandamide and analogous endocannabinoids: a lipid self-assembly study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sagnella, Sharon M.; Conn, Charlotte E.; Krodkiewska, Irena

Anandamide, the endogenous agonist of the cannabinoid receptors, has been widely studied for its interesting biological and medicinal properties and is recognized as a highly significant lipid signaling molecule within the nervous system. Few studies have, however, examined the effect of the physical conformation of anandamide on its function. The study presented herein has focused on characterizing the self-assembly behaviour of anandamide and four other endocannabinoid analogues of anandamide, viz., 2-arachidonyl glycerol, arachidonyl dopamine, 2-arachidonyl glycerol ether (noladin ether), and o-arachidonyl ethanolamide (virodhamine). Molecular modeling of the five endocannabinoid lipids indicates that the highly unsaturated arachidonyl chain has a preferencemore » for a U or J shaped conformation. Thermal phase studies of the neat amphiphiles showed that a glass transition was observed for all of the endocannabinoids at {approx} -110 C with the exception of anandamide, with a second glass transition occurring for 2-arachidonyl glycerol, 2-arachidonyl glycerol ether, and virodhamine (-86 C, -95 C, -46 C respectively). Both anandamide and arachidonyl dopamine displayed a crystal-isotropic melting point (-4.8 and -20.4 C respectively), while a liquid crystal-isotropic melting transition was seen for 2-arachidonyl glycerol (-40.7 C) and 2-arachidonyl glycerol ether (-71.2 C). No additional transitions were observed for virodhamine. Small angle X-ray scattering and cross polarized optical microscopy studies as a function of temperature indicated that in the presence of excess water, both 2-arachidonyl glycerol and anandamide form co-existing Q{sub II}{sup G} (gyroid) and Q{sub II}{sup D} (diamond) bicontinuous cubic phases from 0 C to 20 C, which are kinetically stable over a period of weeks but may not represent true thermodynamic equilibrium. Similarly, 2-arachidonyl glycerol ether acquired an inverse hexagonal (HII) phase in excess water from 0 C to 40 C, while virodhamine and arachidonyl dopamine exist as an isotropic L{sub 2} phase, even at very low temperatures. Due to their preferential conformation and lipid self-assembly behaviour, all five endocannabinoids constitute high curvature lipids that can impart membrane stress within a cell membrane which has been linked to a number of membrane and membrane protein associated processes.« less

Archaeal lipids in oral delivery of therapeutic peptides.

PubMed

Jacobsen, Ann-Christin; Jensen, Sara M; Fricker, Gert; Brandl, Martin; Treusch, Alexander H

2017-10-15

Archaea contain membrane lipids that differ from those found in the other domains of life (Eukarya and Bacteria). These lipids consist of isoprenoid chains attached via ether bonds to the glycerol carbons at the sn-2,3 positions. Two types of ether lipids are known, polar diether lipids and bipolar tetraether lipids. The inherent chemical stability and unique membrane-spanning characteristics of tetraether lipids render them interesting for oral drug delivery purposes. Archaeal lipids form liposomes spontaneously (archaeosomes) and may be incorporated in conventional liposomes (mixed vesicles). Both types of liposomes are promising to protect their drug cargo, such as therapeutic peptides, against the acidic environment of the stomach and proteolytic degradation in the intestine. They appear to withstand lipolytic enzymes and bile salts and may thus deliver orally administered therapeutic peptides to distant sections of the intestine or to the colon, where they may be absorbed, eventually by the help of absorption enhancers. Archaeal lipids and their semisynthetic derivatives may thus serve as biological source for the next generation oral drug delivery systems. The aim of this review is to present a systematic overview over existing literature on archaea carrying diether and tetraether lipids, lipid diversity, means of lipid extraction and purification, preparation and in vitro stability studies of archaeal lipid-based liposomal drug carriers and in vivo proof-of concepts studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Radiolabeled cholesteryl ethers: A need to analyze for biological stability before use.

PubMed

Manual Kollareth, Denny Joseph; Chang, Chuchun L; Hansen, Inge H; Deckelbaum, Richard J

2018-03-01

Radiolabeled cholesteryl ethers are widely used as non-metabolizable tracers for lipoproteins and lipid emulsions in a variety of in vitro and in vivo experiments. Since cholesteryl ethers do not leave cells after uptake and are not hydrolyzed by mammalian cellular enzymes, these compounds can act as markers for cumulative cell uptakes of labeled particles. We have employed [ 3 H]cholesteryl oleoyl ether to study the uptake and distribution of triglyceride-rich emulsion particles on animal models. However, questionable unexpected results compelled us to analyze the stability of these ethers. We tested the stability of two commercially available radiolabeled cholesteryl ethers - [ 3 H]cholesteryl oleoyl ether and [ 3 H]cholesteryl hexadecyl ether from different suppliers, employing in vitro , in vivo and chemical model systems. Our results show that, among the two cholesteryl ethers tested, one ether was hydrolyzed to free cholesterol in vitro , in vivo and chemically under alkaline hydrolyzing agent. Free cholesterol, unlike cholesteryl ether, can then re-enter the circulation leading to confounding results. The other ether was not hydrolyzed to free cholesterol and remained as a stable ether. Hence, radiolabeled cholesteryl ethers should be analyzed for biological stability before utilizing them for in vitro or in vivo experiments.

Triacylglycerol estolides, a new class of mammalian lipids, in the paracloacal gland of the brushtail possum (Trichosurus vulpecula).

PubMed

McLean, Stuart; Davies, Noel W; Nichols, David S; Mcleod, Bernie J

2015-06-01

The paracloacal glands are the most prevalent scent glands in marsupials, and previous investigation of their secretions in the brushtail possum (Trichosurus vulpecula) has identified many odorous compounds together with large amounts of neutral lipids. We have examined the lipids by LC-MS, generating ammonium adducts of acylglycerols by electrospray ionisation. Chromatograms showed a complex mixture of coeluting acylglycerols, with m/z from about 404 to 1048. Plots of single [M + NH4](+) ions showed three groups of lipids clearly separated by retention time. MS-MS enabled triacylglycerols and diacylglycerol ethers to be identified from neutral losses and formation of diacylglycerols and other product ions. The earliest-eluting lipids were found to be triacylglycerol estolides, in which a fourth fatty acid forms an ester link with a hydroxy fatty acid attached to the glycerol chain. This is the first report of triacylglycerol estolides in animals. They form a complex mixture with the triacylglycerols and diacylglycerol ethers of lipids with short- and long-chain fatty acids with varying degrees of unsaturation. This complexity suggests a functional role, possibly in social communication.

Lipids and buoyancy in Southern ocean pteropods.

PubMed

Phleger, C F; Nichols, P D; Virtue, P

1997-10-01

The lipids of Clione limacina, a Southern Ocean pteropod (order Gymnosomata), contain 28% diacylglyceryl ether (DAGE) (as percentage of total lipid) whereas the pteropod Limacina helicina (order Thecosomata) lacks DAGE. The alkyl glyceryl ether diols (1-O-alkyl glycerols, GE) of Clione DAGE are dominated by 16:0 (60%) and 15:0 (21%), in contrast with deep-sea shark liver DAGE, which is dominated by 18:1 GE. The fatty acid profiles of Clione and Limacina are similar (28-32% polyunsaturated, 26-34% monounsaturated) as are the sterols, which include 24-methylenecholesterol, transdehydrocholesterol, cholesterol, and desmosterol. This finding probably reflects the fact that Limacina is the major food source for Clione. Spongiobranchaea australis, another Southern Ocean pteropod (order Gymnosomata), has 0.9-1.7% DAGE, but has less lipid (3.3-4.8 mg/g lipid, wet weight) than Clione (50.8 mg/g lipid, wet weight). We propose a buoyancy role for DAGE in Clione since Limacina has bubbles for flotation which Clione lack; DAGE provides 23% more uplift than triacylglycerol at a concentration of 1.025 g/mL seawater.

Unimolecular Micelles of Amphiphilic Cyclodextrin-Core Star-Like Copolymers with Covalent pH-Responsive Linkage of Anticancer Prodrugs.

PubMed

Jia, Tao; Huang, Shuo; Yang, Cangjie; Wang, Mingfeng

2017-08-07

Multifunctional stable and stimuli-responsive drug delivery systems are important for efficient cancer treatment due to their advantages such as enhanced cancer-targeting efficiency, improved pharmacokinetics, minimized drug leaching, and reduced undesirable side effects. Here we report a robust and pH-responsive anticancer drug delivery system based on unimolecular micelles of star-like amphiphilic copolymers. The polymers (denoted as CPOFs) were facilely synthesized via one-step atom transfer radical polymerization of functionalizable benzoaldehyde and hydrophilic poly[(oligo ethylene glycol) methyl ether methacrylate] as comonomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl]-β-cyclodextrin as the initiator. Doxorubicin (DOX) as an anticancer drug was covalently linked to the benzoaldehyde groups of CPOFs through pH-sensitive Schiff-base bonds. The DOX-conjugated polymers, denoted as CPOF-DOX, formed robust unimolecular micelles with an average diameter of 18 nm in aqueous media. More importantly, these unimolecular micelles showed higher drug loading capacity and more controllable drug release characteristics, compared to our previous unimolecular micelles of β-cyclodextrin-poly(lactic acid)-b-poly[(oligo ethylene glycol) methyl ether methacrylates] that physically encapsulated DOX via hydrophobic interaction. Moreover, the CPOF-DOX unimolecular micelles could be internalized by human cervical cancer HeLa cells in a stepwise way and showed less cytotoxicity compared to carrier-free DOX. We foresee that CPOF-DOX would provide a promising robust and controllable anticancer drug delivery system for future animal study and clinical trials for cancer treatment.

Synthesis of neutral ether lipid monoalkyl-diacylglycerol by lipid acyltransferases[S

PubMed Central

Ma, Zhengping; Onorato, Joelle M.; Chen, Luping; Nelson, David W.; Yen, Chi-Liang Eric; Cheng, Dong

2017-01-01

In mammals, ether lipids exert a wide spectrum of signaling and structural functions, such as stimulation of immune responses, anti-tumor activities, and enhancement of sperm functions. Abnormal accumulation of monoalkyl-diacylglycerol (MADAG) was found in Wolman’s disease, a human genetic disorder defined by a deficiency in lysosomal acid lipase. In the current study, we found that among the nine recombinant human lipid acyltransferases examined, acyl-CoA:diacylglycerol acyltransferase (DGAT)1, DGAT2, acyl-CoA:monoacylglycerol acyltransferase (MGAT)2, MGAT3, acyl-CoA:wax-alcohol acyltransferase 2/MFAT, and DGAT candidate 3 were able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG). These enzymes demonstrated different enzymatic turnover rates and relative efficiencies for the first and second acylation steps leading to the synthesis of MAMAG and MADAG, respectively. They also exhibited different degrees of substrate preference when presented with 1-monooleoylglycerol versus 1-MAkG. In CHO-K1 cells, treatment with DGAT1 selective inhibitor, XP-620, completely blocked the synthesis of MADAG, indicating that DGAT1 is the predominant enzyme responsible for the intracellular synthesis of MADAG in this model system. The levels of MADAG in the adrenal gland of DGAT1 KO mice were reduced as compared with those of the WT mice, suggesting that DGAT1 is a major enzyme for the synthesis of MADAG in this tissue. Our findings indicate that several of these lipid acyltransferases may be able to synthesize neutral ether lipids in mammals. PMID:28420705

Tissue-selective alteration of ethanolamine plasmalogen metabolism in dedifferentiated colon mucosa.

PubMed

Lopez, Daniel H; Bestard-Escalas, Joan; Garate, Jone; Maimó-Barceló, Albert; Fernández, Roberto; Reigada, Rebeca; Khorrami, Sam; Ginard, Daniel; Okazaki, Toshiro; Fernández, José A; Barceló-Coblijn, Gwendolyn

2018-08-01

Human colon lipid analysis by imaging mass spectrometry (IMS) demonstrates that the lipid fingerprint is highly sensitive to a cell's pathophysiological state. Along the colon crypt axis, and concomitant to the differentiation process, certain lipid species tightly linked to signaling (phosphatidylinositols and arachidonic acid (AA)-containing diacylglycerophospholipids), change following a rather simple mathematical expression. We extend here our observations to ethanolamine plasmalogens (PlsEtn), a unique type of glycerophospholipid presenting a vinyl ether linkage at sn-1 position. PlsEtn distribution was studied in healthy, adenomatous, and carcinomatous colon mucosa sections by IMS. In epithelium, 75% of PlsEtn changed in a highly regular manner along the crypt axis, in clear contrast with diacyl species (67% of which remained constant). Consistently, AA-containing PlsEtn species were more abundant at the base, where stem cells reside, and decreased while ascending the crypt. In turn, mono-/diunsaturated species experienced the opposite change. These gradients were accompanied by a gradual expression of ether lipid synthesis enzymes. In lamina propria, 90% of stromal PlsEtn remained unchanged despite the high content of AA and the gradient in AA-containing diacylglycerophospholipids. Finally, both lipid and protein gradients were severely affected in polyps and carcinoma. These results link PlsEtn species regulation to cell differentiation for the first time and confirm that diacyl and ether species are differently regulated. Furthermore, they reaffirm the observations on cell lipid fingerprint image sensitivity to predict cell pathophysiological status, reinforcing the translational impact both lipidome and IMS might have in clinical research. Copyright © 2018 Elsevier B.V. All rights reserved.

Polybrominated diphenyl ethers (PBDEs) levels in blood samples from children living in the metropolitan area of Guadalajara, Jalisco, Mexico.

PubMed

Orta-García, Sandra T; Ochoa-Martínez, Ángeles C; Varela-Silva, José A; Pérez-Maldonado, Iván N

2018-02-01

The aim of this study was to perform a polybrominated diphenyl ethers (PBDEs) exposure assessment using blood samples collected from children living in the metropolitan area of Guadalajara, Jalisco, Mexico (GDL). Five congeners of PBDEs were analyzed using a gas chromatography/mass spectrometry technique. The blood concentrations of total PBDEs ranged from 5.50 to 169 ng/g lipid (42.0 ± 18.0 ng/g lipid; mean ± standard deviation). Regarding BDE congeners, the main congener (highest blood levels) was BDE99 (14.5 ± 5.50 ng/g lipid), followed by BDE100 (9.80 ± 3.40 ng/g lipid) and BDE154 (9.80 ± 5.90 ng/g lipid), and finally BDE153 (5.80 ± 2.30 ng/g lipid) and BDE47 (2.20 ± 1.20 ng/g lipid). In conclusion, blood PBDEs concentrations of concern were detected in this study, as blood levels were similar to the ones found in North America (the highest worldwide).

Biomedical potentials of crown ethers: prospective antitumor agents.

PubMed

Kralj, Marijeta; Tusek-Bozić, Ljerka; Frkanec, Leo

2008-10-01

Crown ethers are of enormous interest and importance in chemistry, biochemistry, materials science, catalysis, separation, transport and encapsulated processes, as well as in the design and synthesis of various synthetic systems with specific properties, diverse capabilities, and programmable functions. Classical crown ethers are macrocyclic polyethers that contain 3-20 oxygen atoms separated from each other by two or more carbon atoms. They are exceptionally versatile in selectively binding a range of metal ions and a variety of organic neutral and ionic species. Crown ethers are currently being studied and used in a variety of applications beyond their traditional place in chemistry. This review presents additional applications and the ever-increasing biomedical potentials of these intriguing compounds, with particular emphasis on the prospects of their relevance as anticancer agents. We believe that further research in this direction should be encouraged, as crown compounds could either induce toxicities that are different from those of conventional antitumor drugs, or complement drugs in current use, thereby providing a valuable adjunct to therapy.

Mode of Action Studies on Nitrodiphenyl Ether Herbicides

PubMed Central

Bowyer, John R.; Smith, Beverly J.; Camilleri, Patrick; Lee, Susan A.

1987-01-01

5-[2-Chloro-4-(trifluoromethyl)phenoxy]-2-nitroacetophenone oxime-o-(acetic acid, methyl ester) (DPEI), is a potent nitrodiphenyl ether herbicide which causes rapid leaf wilting, membrane lipid peroxidation, and chlorophyll destruction in a process which is both light- and O2-dependent. These effects resemble those of other nitrodiphenyl ether herbicides. Unlike paraquat, the herbicidal effects of DPEI are only slightly reduced by pretreatment with the photosynthetic electron transport inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethylurea. DPEI is a weak inhibitor of photosynthetic electron transport (I50 15 micromolar for water to paraquat) in vitro, with at least one site of action at the cytochrome b6f complex. Ultrastructural studies and measurements of ethane formation resulting from lipid peroxidation indicate that mutants of barley lacking photosystem I (PSI) (viridis-zb63) or photosystem II (viridis-zd69) are resistant to paraquat but susceptible to DPEI. The results indicate that electron transfer through both photosystems is not essential for the toxic effects of nitrodiphenyl ether herbicides. Furthermore, the results show that neither cyclic electron transport around PSI, nor the diversion of electrons from PSI to O2 when NADPH consumption is blocked are essential for the phytotoxicity of nitrodiphenyl ether herbicides. Images Fig. 2 Fig. 3 Fig. 4 PMID:16665297

Poly(vinyl methyl ether/maleic anhydride)-Doped PEG-PLA Nanoparticles for Oral Paclitaxel Delivery To Improve Bioadhesive Efficiency.

PubMed

Wang, Qian; Li, Chan; Ren, Tianyang; Chen, Shizhu; Ye, Xiaoxia; Guo, Hongbo; He, Haibing; Zhang, Yu; Yin, Tian; Liang, Xing-Jie; Tang, Xing

2017-10-02

Bioadhesive nanoparticles based on poly(vinyl methyl ether/maleic anhydride) (PVMMA) and poly(ethylene glycol) methyl ether-b-poly(d,l-lactic acid) (mPEG-b-PLA) were produced by the emulsification solvent evaporation method. Paclitaxel was utilized as the model drug, with an encapsulation efficiency of up to 90.2 ± 4.0%. The nanoparticles were uniform and spherical in shape and exhibited a sustained drug release compared with Taxol. m-NPs also exhibited favorable bioadhesive efficiency at the same time. Coumarin 6 or DiR-loaded nanoparticles with/without PVMMA (C6-m-NPs/DiR-m-NPs or C6-p-NPs/DiR-p-NPs) were used for cellular uptake and intestinal adhesion experiments, respectively. C6-m-NPs were shown to enhance cellular uptake, and caveolae/lipid raft mediated endocytosis was the primary route for the uptake of the nanoparticles. Favorable bioadhesive efficiency led to prolonged retention in the intestine reflected by the fluorescence in isolated intestines ex vivo. In a ligated intestinal loops model, C6-m-NPs showed a clear advantage for transporting NPs across the mucus layer over C6-p-NPs and free C6. The apparent permeability coefficient (Papp) of PTX-m-NPs through Caco-2/HT29 monolayers was 1.3- and 1.6-fold higher than PTX-p-NPs and Taxol, respectively, which was consistent with the AUC 0-t of different PTX formulations after oral administration in rats. PTX-m-NPs also exhibited a more effective anticancer efficacy, with an IC 50 of 0.2 ± 1.4 μg/mL for A549 cell lines, further demonstrating the advantage of bioadhesive nanoparticles. The bioadhesive nanoparticles m-NPs demonstrated both mucus permeation and epithelial absorption, and thus, this bioadhesive drug delivery system has the potential to improve the bioavailability of drugs that are insoluble in the gastrointestinal environment.

Digestibility of energy and lipids and oxidative stress in nursery pigs fed commercially available lipids

USDA-ARS?s Scientific Manuscript database

An experiment was conducted to evaluate the impact of lipid source on GE and ether extract (EE) digestibility, oxidative stress, and gut integrity in nursery pigs fed diets containing 10% of soybean oil (SO), choice white grease (CWG), palm oil (PO), or 2 different distillers corn oils (DCO-1 and DC...

[Participation of final products of lipid peroxidation in the anticancer mechanism of ionizing radiation and radiomimetic cytostatics].

PubMed

Przybyszewski, W M

2001-01-01

This review reports the evidence for the participation of final products of lipid peroxidation in the anticancer mechanism of ionising radiation and radiomimetic cytostatics. Processes of lipid peroxidation occur endogenously in response to oxidative stress and great diversity of reactive metabolites is formed. However, direct observation of radical reaction in pathophysiology of cells, tissues and organs is limited technically. Most investigations focused on the indirect assessment of their final products, aldehydes. The peroxidative breakdown of polyunsaturated fatty acids is believed to be involved in the regulation of cell division, and antitumor effect through biochemical and genetic processes.

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs.

PubMed

Murray, Michael; Hraiki, Adam; Bebawy, Mary; Pazderka, Curtis; Rawling, Tristan

2015-06-01

Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

In vitro anticancer evaluation of 5-fluorouracil lipid nanoparticles using B16F10 melanoma cell lines

NASA Astrophysics Data System (ADS)

Shenoy, Vikram S.; Gude, Rajiv P.; Murthy, Rayasa S. Ramachandra

2013-05-01

The present study is aimed to investigate the formulation and in vitro anticancer activities of solid lipid nanoparticles (SLNs) of 5-fluorouracil (5-FU) prepared using glyceryl monostearate (GMS) and cetyl palmitate (CP) by hot homogenization method. The lipids were selected based on the partition coefficient of 5-FU in lipids. The lipid nanoparticles were optimized for process and formulation parameters. The optimized nanoparticles were characterized for their zeta potential, morphology, release kinetics, and anticancer activity. Higher entrapments were achieved using a combination of emulsifiers. The zeta potential of the optimized CP and GMS SLN formulation were -8.26 and -9.35 mV, respectively. Both the optimized formulations were spherical. The in vitro release studies of SLNs of both the lipid carriers followed Peppas-Korsenmeyer equation when carried out at pH 3.5 and 7.4. The chemosensitivity assay carried out in B16F10 cell lines revealed that CP SLNs had better cytotoxicity than 5-FU solution and GMS SLNs at 48 h of incubation. Subtoxic concentration of 5-FU-loaded CP SLNs (0.12 μg/mL) possessed comparable antimigrational activity, colony inhibition activity, and cytopathic as that of 5-FU solution effects. The results indicated that encapsulating 5-FU in CP would be a promising delivery system for delivering 5-FU.

Extraction and characterization of seed oil from naturally-grown Chinese tallow trees

Treesearch

Xiao-Qin Yang; Hui Pan; Tao Zeng; Todd F. Shupe; Chung-Yun Hse

2013-01-01

Seeds were collected from locally and naturally grown Chinese tallow trees (CTT) and characterized for general physical and chemical properties and fatty acid composition of the lipids. The effects of four different solvents (petroleum ether, hexane, diethyl ether, and 95 % ethanol) and two extraction methods (supercritical carbon dioxide (SC-CO2) and conventional...

Biomonitoring Breast Milk Polybrominated Diphenyl Ethers as a Function of Environment, Dietary Intake, and Demographics in New Hampshire

USDA-ARS?s Scientific Manuscript database

Breast milk is a valuable biological specimen for biomonitoring lipid-soluble polybrominated diphenyl ethers (PBDEs). The purpose of this study was to determine the levels of PBDEs in breast milk from New Hampshire and to examine potential relationships between PBDE levels in breast milk and stage o...

Aluminum–phthalocyanine chloride associated to poly(methyl vinyl ether-co-maleic anhydride) nanoparticles as a new third-generation photosensitizer for anticancer photodynamic therapy

PubMed Central

Muehlmann, Luis Alexandre; Ma, Beatriz Chiyin; Longo, João Paulo Figueiró; Almeida Santos, Maria de Fátima Menezes; Azevedo, Ricardo Bentes

2014-01-01

Photodynamic therapy is generally considered to be safer than conventional anticancer therapies, and it is effective against different kinds of cancer. However, its clinical application has been significantly limited by the hydrophobicity of photosensitizers. In this work, a system composed of the hydrophobic photosensitizer aluminum–phthalocyanine chloride (AlPc) associated with water dispersible poly(methyl vinyl ether-co-maleic anhydride) nanoparticles is described. AlPc was associated with nanoparticles produced by a method of solvent displacement. This system was analyzed for its physicochemical characteristics, and for its photodynamic activity in vitro in cancerous (murine mammary carcinoma cell lineage 4T1, and human mammary adenocarcinoma cells MCF-7) and noncancerous (murine fibroblast cell lineage NIH/3T3, and human mammary epithelial cell lineage MCF-10A) cell lines. Cell viability and the elicited mechanisms of cell death were evaluated after the application of photodynamic therapy. This system showed improved photophysical and photochemical properties in aqueous media in comparison to the free photosensitizer, and it was effective against cancerous cells in vitro. PMID:24634582

Cytotoxic and potential anticancer constituents from the stems of Schisandra pubescens.

PubMed

Lu, Yan; Li, Yu-Quan; Liu, Yi-Nan; Lee, Kuo-Hsiung; Chen, Dao-Feng

2013-09-01

The diethyl ether extract of the stems of Schisandra pubescens Hemsl. et Wils. (Schisandraceae) was found to exhibit cytotoxic activity in vitro. However, investigations of the bioactive constituents of this plant have been very limited. Elucidation of the cytotoxic constituents of S. pubescens was performed. Repeated silica gel column chromatography and preparative TLC were used for the chemical investigation of the diethyl ether extract of S. pubescens stems. All isolates were evaluated for their in vitro cytotoxicity against A549, PC-3, KB and KBvin human cancer cell lines. Nine known compounds were obtained, including four lignans, epischisandrone (1), tigloylgomisin P (2), cagayanone (3) and (-)-gomisin L₂ (4), together with five triterpenoids, micranoic acid B (5), lancifodilactone H (6), coccinic acid (7), schisanlactone B (8) and anwuweizonic acid (9). Compounds 2-6 and 8 showed moderate to marginal cytotoxicity, with GI₅₀ values of 11.83-35.65 μM. The isolation of 1-9 from S. pubescens and the cytotoxicities of 3-6 are first reported. Compounds 2-6 and 8 could be the active principles responsible for the anticancer effects of S. pubescens.

Interaction of plasmalogens and their diacyl analogs with singlet oxygen in selected model systems

PubMed Central

Broniec, Agnieszka; Klosinski, Radoslaw; Pawlak, Anna; Wrona-Krol, Marta; Thompson, David; Sarna, Tadeusz

2011-01-01

Plasmalogens (Plg) are phospholipids containing vinyl ether linkage at the sn-1 position of the glycerophospholipid backbone. In spite of being quite abundant in humans, the biological role of plasmalogens remains speculative. It has been postulated that plasmalogens are physiological antioxidants with the vinyl ether functionality serving as sacrificial trap for free radicals and singlet oxygen. However, no quantitative data on the efficiency of plasmalogens to scavenge these reactive species are available. In this study, rate constants of quenching of singlet oxygen, generated by photosensitized energy transfer, by several plasmalogens and, for comparison, by their diacyl analogs, were determined by time-resolved detection of phosphorescence at 1270 nm. Relative rates of the interaction of singlet oxygen, with plasmalogens and other lipids in solution and liposomal membranes were measured by electron paramagnetic resonance oximetry and product analysis, employing HPLC-EC detection of cholesterol hydroperoxides and iodometric assay of lipid hydroperoxides. Results show that singlet oxygen interacts with plasmalogens significantly faster than with the other lipids, with he corresponding rate constants being by one-two orders of magnitude greater. The quenching of singlet oxygen by plasmalogens is mostly reactive in nature and results from its preferential interaction with the vinyl ether bond. The data suggest that plasmalogens could protect unsaturated membrane lipids against oxidation induced by singlet oxygen, providing that the oxidation products are not excessively cytotoxic. PMID:21236336

Identification and Characterization of Heptaprenylglyceryl Phosphate Processing Enzymes in Bacillus subtilis.

PubMed

Linde, Mona; Peterhoff, David; Sterner, Reinhard; Babinger, Patrick

2016-07-08

In Archaea, ether lipids play an essential role as the main building blocks of the cellular membrane. Recently, ether lipids have also been discovered in the domain of Bacteria, and the key enzymes that catalyze their synthesis, glycerol-1-phosphate dehydrogenase and heptaprenylglyceryl phosphate synthase, have been described. In Bacillales, heptaprenylglyceryl phosphate does not become linked to a second polyprenyl moiety like ether lipids in Archaea but is dephosphorylated and acetylated. Here, we report on the enzymes that catalyze these reactions. We enriched the phosphatase activity from a B. subtilis cell extract and suppose that dephosphorylation is catalyzed by the phosphatase PhoB or by any other phosphatase in an unspecific manner. By screening a B. subtilis knock-out library for deficiency in acetylation, the yvoF gene product was identified to be the acetyltransferase. The acetyl-CoA-dependent enzyme YvoF is a close relative of maltose O-acetyltransferase (MAT). Its catalytic properties were analyzed and compared with MAT. YvoF and MAT partially overlap in substrate and product range in vitro, but MAT is not able to complement the yvoF knock-out in vivo. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Mode of Action Studies on Nitrodiphenyl Ether Herbicides 1

PubMed Central

Bowyer, John R.; Hallahan, Beverly J.; Camilleri, Patrick; Howard, Joy

1989-01-01

The nitrodiphenyl ether herbicide 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitroacetophenone oxime-o-(acetic acid, methyl ester) (DPEI) induces light- and O2-dependent lipid peroxidation and chlorophyll (Chl) bleaching in the green alga Scenedesmus obliquus. Under conditions of O2-limitation, these effects are diminished by prometyne and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), both inhibitors of photosynthetic electron transport. Mutants in which photosynthetic electron transport is blocked are also resistant to DPEI under conditions of O2-limitation. Light- and O2-dependent lipid peroxidation and Chl bleaching are also induced by 5-[2-chloro-4-(trifluoromethyl)phenoxy]-3-methoxyphthalide (DPEII), a diphenyl ether whose redox properties preclude reduction by photosystem I. However, these effects of DPEII are also inhibited by DCMU. Under conditions of high aeration, DCMU does not protect Scenedesmus cells from Chl bleaching induced by DPEI, but does protect against paraquat. DPEI, but not paraquat, induces tetrapyrrole formation in treated cells in the dark. This is also observed in a mutant lacking photosystem I but is suppressed under conditions likely to lead to O2 limitation. Our results indicate that, in contrast to paraquat, the role of photosynthetic electron transport in diphenyl ether toxicity in Scenedesmus is not to reduce the herbicide to a radical species which initiates lipid peroxidation. Its role is probably to maintain a sufficiently high O2 concentration, through water-splitting, in the algal suspension. PMID:16666600

A robust and efficient method for the extraction of plant extracellular surface lipids as applied to the analysis of silks and seedling leaves of maize

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loneman, Derek M.; Peddicord, Layton; Al-Rashid, Amani

Aerial plant organs possess a diverse array of extracellular surface lipids, including both non-polar and amphipathic constituents that collectively provide a primary line of defense against environmental stressors. Extracellular surface lipids on the stigmatic silks of maize are composed primarily of saturated and unsaturated linear hydrocarbons, as well as fatty acids, and aldehydes. To efficiently extract lipids of differing polarities from maize silks, five solvent systems (hexanes; hexanes:diethyl ether (95:5); hexanes:diethyl ether (90:10); chloroform:hexanes (1:1) and chloroform) were tested by immersing fresh silks in solvent for different extraction times. Surface lipid recovery and the relative composition of individual constituents weremore » impacted to varying degrees depending on solvent choice and duration of extraction. Analyses were performed using both silks and leaves to demonstrate the utility of the solvent- and time-optimized protocol in comparison to extraction with the commonly used chloroform solvent. Overall, the preferred solvent system was identified as hexanes:diethyl ether (90:10), based on its effectiveness in extracting surface hydrocarbons and fatty acids as well as its reduced propensity to extract presumed internal fatty acids. Metabolite profiling of wildtype and glossy1 seedlings, which are impaired in surface lipid biosynthesis, demonstrated the ability of the preferred solvent to extract extracellular surface lipids rich in amphipathic compounds (aldehydes and alcohols). In addition to the expected deficiencies in dotriacontanal and dotriacontan-1-ol for gl1 seedlings, an unexpected increase in fatty acid recovery was observed in gl1 seedlings extracted in chloroform, suggesting that chloro-form extracts lipids from internal tissues of gl1 seedlings. This highlights the importance of extraction method when evaluating mutants that have altered cuticular lipid compositions. Lastly, metabolite profiling of silks from maize inbreds B73 and Mo17, exposed to different environments and harvested at different ages, revealed differences in hydrocarbon and fatty acid composition, demonstrating the dynamic nature of surface lipid accumulation on silks.« less

A robust and efficient method for the extraction of plant extracellular surface lipids as applied to the analysis of silks and seedling leaves of maize

DOE PAGES

Loneman, Derek M.; Peddicord, Layton; Al-Rashid, Amani; ...

2017-07-11

Aerial plant organs possess a diverse array of extracellular surface lipids, including both non-polar and amphipathic constituents that collectively provide a primary line of defense against environmental stressors. Extracellular surface lipids on the stigmatic silks of maize are composed primarily of saturated and unsaturated linear hydrocarbons, as well as fatty acids, and aldehydes. To efficiently extract lipids of differing polarities from maize silks, five solvent systems (hexanes; hexanes:diethyl ether (95:5); hexanes:diethyl ether (90:10); chloroform:hexanes (1:1) and chloroform) were tested by immersing fresh silks in solvent for different extraction times. Surface lipid recovery and the relative composition of individual constituents weremore » impacted to varying degrees depending on solvent choice and duration of extraction. Analyses were performed using both silks and leaves to demonstrate the utility of the solvent- and time-optimized protocol in comparison to extraction with the commonly used chloroform solvent. Overall, the preferred solvent system was identified as hexanes:diethyl ether (90:10), based on its effectiveness in extracting surface hydrocarbons and fatty acids as well as its reduced propensity to extract presumed internal fatty acids. Metabolite profiling of wildtype and glossy1 seedlings, which are impaired in surface lipid biosynthesis, demonstrated the ability of the preferred solvent to extract extracellular surface lipids rich in amphipathic compounds (aldehydes and alcohols). In addition to the expected deficiencies in dotriacontanal and dotriacontan-1-ol for gl1 seedlings, an unexpected increase in fatty acid recovery was observed in gl1 seedlings extracted in chloroform, suggesting that chloro-form extracts lipids from internal tissues of gl1 seedlings. This highlights the importance of extraction method when evaluating mutants that have altered cuticular lipid compositions. Lastly, metabolite profiling of silks from maize inbreds B73 and Mo17, exposed to different environments and harvested at different ages, revealed differences in hydrocarbon and fatty acid composition, demonstrating the dynamic nature of surface lipid accumulation on silks.« less

The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk.

PubMed

Knowles, E E M; Huynh, K; Meikle, P J; Göring, H H H; Olvera, R L; Mathias, S R; Duggirala, R; Almasy, L; Blangero, J; Curran, J E; Glahn, D C

2017-06-01

The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated. In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range=3-80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD. We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Interactions of the anticancer drug tamoxifen with lipid membranes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khadka, Nawal K.; Cheng, Xiaolin; Ho, Chian Sing

Interactions of the hydrophobic anticancer drug tamoxifen (TAM) with lipid model membranes were studied using calcein-encapsulated vesicle leakage, attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, small-angle neutron scattering (SANS), atomic force microscopy (AFM) based force spectroscopy, and all-atom molecular dynamics (MD) simulations. The addition of TAM enhances membrane permeability, inducing calcein to translocate from the interior to the exterior of lipid vesicles. A large decrease in the FTIR absorption band’s magnitude was observed in the hydrocarbon chain region, suggesting suppressed bond vibrational dynamics. Bilayer thickening was determined from SANS data. Force spectroscopy measurements indicate that the lipid bilayer areamore » compressibility modulus KA is increased by a large amount after the incorporation of TAM. MD simulations show that TAM decreases the lipid area and increases chain order parameters. Moreover, orientational and positional analyses show that TAM exhibits a highly dynamic conformation within the lipid bilayer. Lastly, our detailed experimental and computational studies of TAM interacting with model lipid membranes shed new light on membrane modulation by TAM.« less

Interactions of the anticancer drug tamoxifen with lipid membranes

DOE PAGES

Khadka, Nawal K.; Cheng, Xiaolin; Ho, Chian Sing; ...

2015-05-19

Interactions of the hydrophobic anticancer drug tamoxifen (TAM) with lipid model membranes were studied using calcein-encapsulated vesicle leakage, attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, small-angle neutron scattering (SANS), atomic force microscopy (AFM) based force spectroscopy, and all-atom molecular dynamics (MD) simulations. The addition of TAM enhances membrane permeability, inducing calcein to translocate from the interior to the exterior of lipid vesicles. A large decrease in the FTIR absorption band’s magnitude was observed in the hydrocarbon chain region, suggesting suppressed bond vibrational dynamics. Bilayer thickening was determined from SANS data. Force spectroscopy measurements indicate that the lipid bilayer areamore » compressibility modulus KA is increased by a large amount after the incorporation of TAM. MD simulations show that TAM decreases the lipid area and increases chain order parameters. Moreover, orientational and positional analyses show that TAM exhibits a highly dynamic conformation within the lipid bilayer. Lastly, our detailed experimental and computational studies of TAM interacting with model lipid membranes shed new light on membrane modulation by TAM.« less

Neutral sphingomyelinase 2 modulates cytotoxic effects of protopanaxadiol on different human cancer cells

PubMed Central

2013-01-01

Background Some of ginsenosides, root extracts from Panax ginseng, exert cytotoxicity against cancer cells through disruption of membrane subdomains called lipid rafts. Protopanaxadiol (PPD) exhibits the highest cytotoxic effect among 8 ginsenosides which we evaluated for anti-cancer activity. We investigated if PPD disrupts lipid rafts in its cytotoxic effects and also the possible mechanisms. Methods Eight ginsenosides were evaluated using different cancer cells and cell viability assays. The potent ginsenoside, PPD was investigated for its roles in lipid raft disruption and downstream pathways to apoptosis of cancer cells. Anti-cancer effects of PPD was also investigated in vivo using mouse xenograft model. Results PPD consistently exerts its potent cytotoxicity in 2 cell survival assays using 5 different cancer cell lines. PPD disrupts lipid rafts in different ways from methyl-β-cyclodextrin (MβCD) depleting cholesterol out of the subdomains, since lipid raft proteins were differentially modulated by the saponin. During disruption of lipid rafts, PPD activated neutral sphingomyelinase 2 (nSMase 2) hydrolyzing membrane sphingomyelins into pro-apoptotic intracellular ceramides. Furthermore, PPD demonstrated its anti-cancer activities against K562 tumor cells in mouse xenograft model, confirming its potential as an adjunct or chemotherapeutic agent by itself in vivo. Conclusions This study demonstrates that neutral sphingomyelinase 2 is responsible for the cytotoxicity of PPD through production of apoptotic ceramides from membrane sphingomyelins. Thus neutral sphingomyelinase 2 and its relevant mechanisms may potentially be employed in cancer chemotherapies. PMID:23889969

Cholesterol-based cationic lipids for gene delivery: contribution of molecular structure factors to physico-chemical and biological properties.

PubMed

Sheng, Ruilong; Luo, Ting; Li, Hui; Sun, Jingjing; Wang, Zhao; Cao, Amin

2014-04-01

In this work, we prepared a series of cholesterol-based cationic (Cho-cat) lipids bearing cholesterol hydrophobe, natural amino acid headgroups (lysine/histidine) and linkage (carbonate ester/ether) bonds. In which, the natural amino acid headgroups made dominant contribution to their physico-chemical and biological properties. Among the lipids, the l-lysine headgroup bearing lipids (Cho-es/et-Lys) showed higher pDNA binding affinity and were able to form larger sized and higher surface charged lipoplexes than that of l-histidine headgroup bearing lipids (Cho-es/et-His), they also demonstrated higher transfection efficacy and higher membrane disruption capacities than that of their l-histidine headgroup bearing counterparts. However, compared to the contributions of the headgroups, the (carbonate ester/ether) linkage bonds showed much less affects. Besides, it could be noted that, Cho-es/et-Lys lipids exhibited very high luciferase gene transfection efficiency that almost reached the transfection level of "gold standard" bPEI-25k, made them potential transfection reagents for practical application. Moreover, the results facilitated the understanding for the structure-activity relationship of the cholesterol-based cationic lipids, and also paved a simple and efficient way for achieving high transfection efficiency by modification of suitable headgroups on lipid gene carriers. Copyright © 2014 Elsevier B.V. All rights reserved.

Quercetin-3-methyl ether inhibits lapatinib-sensitive and -resistant breast cancer cell growth by inducing G2/M arrest and apoptosis

PubMed Central

Li, Jixia; Zhu, Feng; Lubet, Ronald A.; De Luca, Antonella; Grubbs, Clinton; Ericson, Marna E.; D’Alessio, Amelia; Normano, Nicola; Dong, Zigang; Bode, Ann M.

2012-01-01

Lapatinib, an oral, small-molecule, reversible inhibitor of both EGFR and HER2, is highly active in HER2 positive breast cancer as a single agent and in combination with other therapeutics. However, resistance against lapatinib is an unresolved problem in clinical oncology. Recently, interest in the use of natural compounds to prevent or treat cancers has gained increasing interest because of presumed low toxicity. Quercetin-3-methyl ether, a naturally occurring compound present in various plants, has potent anticancer activity. Here, we found that quercetin-3-methyl ether caused in a significant growth inhibition of lapatinib-sensitive and -resistant breast cancer cells. Western blot data showed that quercetin-3-methyl ether had no effect on Akt or ERKs signaling in resistant cells. However, quercetin-3-methyl ether caused a pronounced G2/M block mainly through the Chk1-Cdc25c-cyclin B1/Cdk1 pathway in lapatinib-sensitive and -resistant cells. In contrast, lapatinib produced an accumulation of cells in the G1 phase mediated through cyclin D1, but only in lapatinib-sensitive cells. Moreover, quercetin-3-methyl ether induced significant apoptosis, accompanied with increased levels of cleaved caspase 3, caspase 7 and poly (ADP-ribose) polymerase (PARP) in both cell lines. Overall, these results suggested that quercetin-3-methyl ether might be a novel and promising therapeutic agent in lapatinib-sensitive or -resistant breast cancer patients. PMID:22086611

Simple and fast analysis of tetrabromobisphenol A, hexabromocyclododecane isomers, and polybrominated diphenyl ethers in serum using solid-phase extraction or QuEChERS extraction followed by tandem mass spectrometry coupled to HPLC and GC.

PubMed

Li, Jian; Chen, Tian; Wang, Yuwei; Shi, Zhixiong; Zhou, Xianqing; Sun, Zhiwei; Wang, Dejun; Wu, Yongning

2017-02-01

Two simplified sample preparation procedures for simultaneous extraction and clean-up of tetrabromobisphenol A, α-, β-, and γ-hexabromocyclododecane and polybrominated diphenyl ethers in human serum were developed and validated. The first procedure was based on solid-phase extraction. Sample extraction, purification, and lipid removal were carried out directly on an Oasis HLB cartridge. The second procedure was a quick, easy, cheap, effective, rugged, and safe-based approach using octadecyl-modified silica particles as a sorbent. After sample extraction and cleanup, tetrabromobisphenol A/hexabromocyclododecane was separated from polybrominated diphenyl ethers by using a Si-based cartridge. Tetrabromobisphenol A and hexabromocyclododecane were then detected by high-performance liquid chromatography coupled to tandem mass spectrometry, while polybrominated diphenyl ethers were detected by gas chromatography coupled to tandem mass spectrometry. The results of the spike recovery test using fetal bovine serum showed that the average recoveries of the analytes ranged from 87.3 to 115.3% with relative standard deviations equal to or lower than 13.4 %. Limits of detection of the analytes were in the range of 0.4-19 pg/mL except for decabromodiphenyl ether. The developed method was successfully applied to routine analysis of human serum samples from occupational workers and the general population. Extremely high serum polybrominated diphenyl ethers levels up to 3.32 × 10 4 ng/g lipid weight were found in occupational workers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

LC-MS-Based Lipidomics and Automated Identification of Lipids Using the LipidBlast In-Silico MS/MS Library.

PubMed

Cajka, Tomas; Fiehn, Oliver

2017-01-01

This protocol describes the analysis, specifically the identification, of blood plasma lipids. Plasma lipids are extracted using methyl tert-butyl ether (MTBE), methanol, and water followed by separation and data acquisition of isolated lipids using reversed-phase liquid chromatography coupled to quadrupole/time-of-flight mass spectrometry (RPLC-QTOFMS) operated in MS/MS mode. For lipid identification, acquired MS/MS spectra are converted to the mascot generic format (MGF) followed by library search using the in-silico MS/MS library LipidBlast. Using this approach, lipid classes, carbon-chain lengths, and degree of unsaturation of fatty-acid components are annotated.

A Critical Review of Lipid-based Nanoparticles for Taxane Delivery

PubMed Central

Feng, Lan; Mumper, Russell J.

2012-01-01

Nano-based delivery systems have attracted a great deal of attention in the past two decades as a strategy to overcome the low therapeutic index of conventional anticancer drugs and delivery barriers in solid tumors. Myriads of preclinical studies have been focused on developing nano-based formulations to effectively deliver taxanes, one of the most important and most prescribed anticancer drug types in the clinic. Given the hydrophobic property of taxanes, lipid-based NPs, serve as a viable alternative delivery system. This critical review will provide an overview and perspective of the advancement of lipid-based nanoparticles for taxane delivery. Currently available formulations of taxanes and their drawbacks as well as criteria for idea taxane delivery system will be discussed. PMID:22796606

The cellular lipids of Romboutsia.

PubMed

Guan, Ziqiang; Chen, Lingli; Gerritsen, Jacoline; Smidt, Hauke; Goldfine, Howard

2016-09-01

We have examined the lipids of three isolates, Romboutsia lituseburensis, Romboutsia ilealis, and Romboutsia sp. strain FRIFI, of the newly described genus Romboutsia by two-dimensional thin-layer chromatography (2D-TLC) and by liquid chromatography/mass spectrometry (LC/MS). We have found three phospholipids, phosphatidylglycerol (PG), cardiolipin and phosphatidic acid in all three species. A fourth phospholipid, lysyl-PG, was found in R. lituseburensis and strain FRIFI. Polyprenyl-phosphates were identified in the lipid extracts of all three species. Three glycolipids, mono-, di- and tri-hexosyldiacylglycerol, were common to all three species. An additional glycolipid, tetrahexosyl-diacylglycerol was identified in strain FRIFI. Acylated trihexosyldiacylglycerol and acyl-tetrahexosydiacylglycerol were also found in R. ilealis and strain FRIFI. Remarkably, no alk-1-enyl ether lipids (plasmalogens) were present in Romboutsia as distinct from bacteria of the related genus Clostridium in which these ether lipids are common. We have compared the lipidome of Romboutsia with that recently described for Clostridium difficile, which has plasmalogens, no lysyl-PG, and no tetrahexosyl-diacylglycerol. According to 16S rRNA gene sequencing, Romboutsia spp. and C. difficile are closely related (>95% sequence identity). Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of aging on serum levels of lipid molecular species as determined by lipidomics analysis in Japanese men and women.

PubMed

Kawanishi, Noriaki; Kato, Yuki; Yokozeki, Kyosuke; Sawada, Shuji; Sakurai, Ryota; Fujiwara, Yoshinori; Shinkai, Shoji; Goda, Nobuhito; Suzuki, Katsuhiko

2018-06-06

Aging is known to be associated with increased risk of lipid disorders related to the development of type 2 diabetes. Recent evidence revealed that change of lipid molecule species in blood is associated with the risk of type 2 diabetes. However, changes in lipid molecular species induced by aging are still unknown. We assessed the effects of age on the serum levels of lipid molecular species as determined by lipidomics analysis. Serum samples were collected from ten elderly men (71.7 ± 0.5 years old) and women (70.2 ± 1.0 years old), ten young men (23.9 ± 0.4 years old), and women (23.9 ± 0.7 years old). Serum levels of lipid molecular species were determined by liquid chromatography mass spectrometry-based lipidomics analysis. Our mass spectrometry analysis revealed increases in the levels of multiple triacylglycerol molecular species in the serum of elderly men and women. Moreover, serum levels of total ester-linked phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased by aging. In contrast, serum levels of specific ether-linked PC and PE molecular species were lower in elderly individuals than in young individuals. Our finding indicates that specific lipid molecular species, such as ether- and ester- linked phospholipids, may be selectively altered by aging.

Pharmacokinetic studies and anticancer activity of curcumin-loaded nanostructured lipid carriers.

PubMed

Wang, Fengling; Chen, Jin; Dai, Wenting; He, Zhengmin; Zhai, Dandan; Chen, Weidong

2017-09-01

In order to investigate the potential of nanostructured lipid carriers for efficient and targeted delivery of curcumin, the pharmacokinetic parameters of curcumin-loaded nanostructured lipid carriers (Cur-NLC) were evaluated in rats after a single intraperitoneal dose of Cur-NLC. In addition, the anticancer activity of Cur-NLC against human lung adenocarcinoma A549 cells was verified by a cellular uptake study, and a cytotoxicity and apoptosis assay. Bioavailability of Cur-NLC was better than that of native curcumin (p > 0.01), as seen from the area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), mean residence time (MRT) and total plasma clearance (CLz/F). Cur-NLC has a more obvious lung-targeting property in comparison with native curcumin. Cur-NLC showed higher anticancer activity in vitro against A549 cells than native curcumin (IC50 value of 5.66 vs. 9.81 mg L-1, respectively). Meanwhile, Cur-NLC treated A549 cells showed a higher apoptosis rate compared to that of native curcumin. These results indicate that NLC is a promising system for the delivery of curcumin in the treatment of lung adenocarcinoma.

Development of octreotide-conjugated polymeric prodrug of bufalin for targeted delivery to somatostatin receptor 2 overexpressing breast cancer in vitro and in vivo

PubMed Central

Liu, Tao; Jia, Tingting; Yuan, Xia; Liu, Cheng; Sun, Jian; Ni, Zhenhua; Xu, Jian; Wang, Xuhui; Yuan, Yi

2016-01-01

Background Development of polymeric prodrugs of small molecular anticancer drugs has become one of the most promising strategies to overcome the intrinsic shortcomings of small molecular anticancer drugs and improve their anticancer performance. Materials and methods In the current work, we fabricated a novel octreotide (Oct)-modified esterase-sensitive tumor-targeting polymeric prodrug of bufalin (BUF) and explored its anticancer performance against somatostatin receptor 2 overexpressing breast cancer. Results The obtained tumor-targeting polymeric prodrug of BUF, P(oligo[ethylene glycol] monomethyl ether methacrylate [OEGMA]-co-BUF-co-Oct), showed a nanosize dimension and controlled drug release features in the presence of esterase. It was demonstrated by in vitro experiment that P(OEGMA-co-BUF-co-Oct) showed enhanced cytotoxicity, cellular uptake, and apoptosis in comparison with those of free BUF. In vivo experiment further revealed the improved accumulation of drugs in tumor tissues and enhanced anticancer performance of P(OEGMA-co-BUF-co-Oct). Conclusion Taken together, this study indicated that polymeric prodrug of BUF holds promising potential toward the treatment of somatostatin receptor 2 overexpressing breast cancer. PMID:27284243

Effects of Ether vs. Ester Linkage on Lipid Bilayer Structure and Water Permeability

PubMed Central

Guler, S. Deren; Ghosh, D. Dipon; Pan, Jianjun; Matthai, John C.; Zeidel, Mark L.; Nagle, John F.; Tristram-Nagle, Stephanie

2009-01-01

The structure and water permeability of bilayers composed of the ether linked lipid, dihexadecylphosphatidylcholine (DHPC), were studied and compared with the ester linked lipid, dipalmitoylphosphaditdylcholine (DPPC). Wide angle x-ray scattering on oriented bilayers in the fluid phase indicate that the area per lipid A is slightly larger for DHPC than for DPPC. Low angle x-ray scattering yields A=65.1Å2 for DHPC at 48°C. LAXS data provide the bending modulus, KC=4.2×10−13erg, and the Hamaker parameter H=7.2×10−14erg for the van der Waals attractive interaction between neighboring bilayers. For the low temperature phases with ordered hydrocarbon chains, we confirm the transition from a tilted Lß’ gel phase to an untilted, interdigitated LßI phase as the sample hydrates at 20°C. Our measurement of water permeability, Pf=0.022 cm/s at 48 °C for fluid phase DHPC is slightly smaller than that of DPPC, (Pf=0.027 cm/s) at 50 °C, consistent with our triple slab theory of permeability. PMID:19416724

Modulation of butyrate anticancer activity by solid lipid nanoparticle delivery: an in vitro investigation on human breast cancer and leukemia cell lines.

PubMed

Foglietta, Federica; Serpe, Loredana; Canaparo, Roberto; Vivenza, Nicoletta; Riccio, Giovanna; Imbalzano, Erica; Gasco, Paolo; Zara, Gian Paolo

2014-01-01

Histone modification has emerged as a promising approach to cancer therapy. The short-chain fatty acid, butyric acid, a histone deacetylase (HD) inhibitor, has shown anticancer activity. Butyrate transcriptional activation is indeed able to withdraw cancer cells from the cell cycle, leading to programmed cell death. Since butyrate's clinical use is hampered by unfavorable pharmacokinetic and pharmacodynamic properties, delivery systems, such as solid lipid nanoparticles (SLN), have been developed to overcome these constraints. In order to outline the influence of butyrate delivery on its anticancer activity, the effects of butyrate as a free (sodium butyrate, NB) or nanoparticle (cholesteryl butyrate solid lipid nanoparticles, CBSLN) formulation on the growth of different human cancer cell lines, such as the promyelocytic leukemia, HL-60, and the breast cancer, MCF-7 was investigated. A detailed investigation into the mechanism of the induced cytotoxicity was also carried out, with a special focus on the modulation of HD and cyclin-dependent kinase (CDK) mRNA gene expression by real time PCR analysis. In HL-60 cells, CBSLN induced a higher and prolonged expression level of the butyrate target genes at lower concentrations than NB. This led to a significant decrease in cell proliferation, along with considerable apoptosis, cell cycle block in the G0/G1 phase, significant inhibition of total HD activity and overexpression of the p21 protein. Conversely, in MCF-7 cells, CBSLN did not enhance the level of expression of the butyrate target genes, leading to the same anticancer activity as that of NB. Solid lipid nanoparticles were able to improve butyrate anticancer activity in HL-60, but not in MCF-7 cells. This is consistent with difference in properties of the cells under study, such as expression of the TP53 tumor suppressor, or the transporter for short-chain fatty acids, SLC5A8.

Nanostructured Lipid Carriers as Multifunctional Nanomedicine Platform for Pulmonary Co-Delivery of Anticancer Drugs and siRNA

PubMed Central

Taratula, Oleh; Kuzmov, Andriy; Shah, Milin; Garbuzenko, Olga B.; Minko, Tamara

2013-01-01

We developed, synthesized, and tested a multifunctional nanostructured lipid nanocarrier-based system (NLCS) for efficient delivery of an anticancer drug and siRNA directly into the lungs by inhalation. The system contains: (1) nanostructured lipid carriers (NLC); (2) anticancer drug (doxorubicin or paclitaxel); (3) siRNA targeted to MRP1 mRNA as a suppressor of pump drug resistance; (4) siRNA targeted to BCL2 mRNA as a suppressor of nonpump cellular resistance and (5) a modified synthetic analog of luteinizing hormone-releasing hormone (LHRH) as a targeting moiety specific to the receptors that are overexpressed in the plasma membrane of lung cancer cells. The NLCS was tested in vitro using human lung cancer cells and in vivo utilizing mouse orthotopic model of human lung cancer. After inhalation, the proposed NLCS effectively delivered its payload into lung cancer cells leaving healthy lung tissues intact and also significantly decreasing the exposure of healthy organs when compared with intravenous injection. The NLCS showed enhanced antitumor activity when compared with intravenous treatment. The data obtained demonstrated high efficiency of proposed NLCS for tumor-targeted local delivery by inhalation of anticancer drugs and mixture of siRNAs specifically to lung cancer cells and, as a result, efficient suppression of tumor growth and prevention of adverse side effects on healthy organs. PMID:23648833

Evaluation of phenolic composition, antioxidant, anti-inflammatory and anticancer activities of Polygonatum verticillatum (L.).

PubMed

Kumar Singh, Sandeep; Patra, Arjun

2018-04-18

Polygonatum verticillatum (L.) All. (Ruscaceae), one of the Ashtawarga plants, is widely used for treatment of various ailments. The present study was undertaken to determine the phenolic composition, antioxidant, anti-inflammatory and anticancer activities of several extracts (petroleum ether, dichloromethane, chloroform, ethanol, and aqueous) from the rhizomes of the plant. Coarsely powdered dry rhizome was successively extracted with different solvents of increasing polarity (petroleum ether, dichloromethane, chloroform, ethanol and water). The phenolic compositions, in terms of total phenolic content (TPC), total flavonoid content (TFC) and total condensed tannin content (TTC), were evaluated with the Folin-Ciocalteu assay, aluminum chloride colorimetric assay and vanillin spectrophotometric assay, respectively. Total antioxidant capacity, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assays were used to assess the antioxidant potential of each extract. A protein denaturation model and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay were used to evaluate in vitro anti-inflammatory and anticancer activities, respectively. Gas chromatography-mass spectrometry (GC/MS) analysis was carried out to demonstrate various phytoconstituents in each extract. Correlation studies were also performed between phenolic composition (TPC, TFC and TTC) and different biological activities. Ethanol extract showed maximum TPC (0.126 mg/g, gallic acid equivalent in dry sample), TFC (0.094 mg/g, rutin equivalent in dry sample) and TTC (29.32 mg/g, catechin equivalent in dry sample), as well as antioxidant and anti-inflammatory properties. Chloroform extract exhibited the strongest cytotoxicity against the human breast cancer cell line, MCF-7. GC/MS analysis revealed the presence of 90 different phytoconstituents among the extracts. Antioxidant and anti-inflammatory activities had a positive correlation with TPC, TFC and TTC. However, the anticancer activity showed a negative correlation with TPC, TFC and TTC. From the present study, it can be concluded that P. verticillatum possessed remarkable antioxidant, anti-inflammatory, and anticancer activities, which could be due to different secondary metabolites of the plant. Phenolic compounds are likely responsible for antioxidant and anti-inflammatory activities. However, flavonoids and other compounds might contribute to the anticancer potential of the plant. Copyright © 2018 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.

Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nomura, Daniel K.; Fujioka, Kazutoshi; Issa, Roger S.

2008-04-01

Serine hydrolase KIAA1363 is an acetyl monoalkylglycerol ether (AcMAGE) hydrolase involved in tumor cell invasiveness. It is also an organophosphate (OP) insecticide-detoxifying enzyme. The key to understanding these dual properties was the use of KIAA1363 +/+ (wildtype) and -/- (gene deficient) mice to define the role of this enzyme in brain and other tissues and its effectiveness in vivo in reducing OP toxicity. KIAA1363 was the primary AcMAGE hydrolase in brain, lung, heart and kidney and was highly sensitive to inactivation by chlorpyrifos oxon (CPO) (IC{sub 50} 2 nM) [the bioactivated metabolite of the major insecticide chlorpyrifos (CPF)]. Although theremore » was no difference in hydrolysis product monoalkylglycerol ether (MAGE) levels in +/+ and -/- mouse brains in vivo, isopropyl dodecylfluorophosphonate (30 mg/kg) and CPF (100 mg/kg) resulted in 23-51% decrease in brain MAGE levels consistent with inhibition of AcMAGE hydrolase activity. On incubating +/+ and -/- brain membranes with AcMAGE and cytidine-5'-diphosphocholine, the absence of KIAA1363 activity dramatically increased de novo formation of platelet-activating factor (PAF) and lyso-PAF, signifying that metabolically-stabilized AcMAGE can be converted to this bioactive lipid in brain. On considering detoxification, KIAA1363 -/- mice were significantly more sensitive than +/+ mice to ip-administered CPF (100 mg/kg) and parathion (10 mg/kg) with increased tremoring and mortality that correlated for CPF with greater brain acetylcholinesterase inhibition. Docking AcMAGE and CPO in a KIAA1363 active site model showed similar positioning of their acetyl and trichloropyridinyl moieties, respectively. This study establishes the relevance of KIAA1363 in ether lipid metabolism and OP detoxification.« less

Modification of the plasma clearance and liver uptake of steroid ester-conjugated oligodeoxynucleotides by association with (lactosylated) low-density lipoprotein.

PubMed

Rump, E T; de Vrueh, R L; Manoharan, M; Waarlo, I H; van Veghel, R; Biessen, E A; van Berkel, T J; Bijsterbosch, M K

2000-06-01

Low-density lipoprotein (LDL) has been proposed as carrier for the selective delivery of anticancer drugs to tumor cells. We reported earlier the association of several lipidic steroid-conjugated anticancer oligodeoxynucleotides (ODNs) with LDL. In the present study, we determined the stability of these complexes. When the complexes were incubated with a mixture of high-density lipoprotein and albumin, or with rat plasma, the oleoyl steroid-conjugated ODNs appeared to be more stably associated with LDL than the cholesteryl-conjugated ODN. Intravenously injected free lipid-ODNs were very rapidly cleared from the circulation of rats. The area under the curve (AUC) of the lipid-ODNs in plasma was <0.4 microg x min/mL. After complexation with LDL, plasma clearance of the lipid-ODNs was delayed. This was most evident for ODN-5, the ODN conjugated with the oleoyl ester of lithocholic acid (AUC = 6.82 +/- 1.34 microg x min/mL). The AUC of ODN-4, a cholesteryl-conjugated ODN, was 1.49 +/- 0.37 microg x min/mL. In addition, the liver uptake of the LDL-complexed lipid-ODNs was reduced. The lipid-ODNs were also administered as a complex with lactosylated LDL, a modified LDL particle that is selectively taken up by the liver. A high proportion of ODN-5 was transported to the liver along with lactosylated LDL (69.1 +/- 8.1% of the dose at 15 min after injection), whereas much less ODN-4 was transported (36.6 +/- 0.1% of the dose at 15 min after injection). We conclude that the oleoyl ester of lithocholic acid is a more potent lipid anchor than the other steroid lipid anchors. Because of the stable association, the oleoyl ester of lithocholic acid is an interesting candidate for tumor targeting of anticancer ODNs with lipoproteins.

“Click” Synthesis of Dextran Macrostructures for Combinatorial-Designed Self-Assembled Nanoparticles Encapsulating Diverse Anticancer Therapeutics

PubMed Central

Abeylath, Sampath C.; Amiji, Mansoor

2011-01-01

With the non-specific toxicity of anticancer drugs to healthy tissues upon systemic administration, formulations capable of enhanced selectivity in delivery to the tumor mass and cells are highly desirable. Based on the diversity of the drug payloads, we have investigated a combinatorial-designed strategy where the nano-sized formulations are tailored based on the physicochemical properties of the drug and the delivery needs. Individually functionalized C2 to C12 lipid-, thiol-, and poly(ethylene glycol) (PEG)-modified dextran derivatives were synthesized via “click” chemistry from O-pentynyl dextran and relevant azides. These functionalized dextrans in combination with anticancer drugs form nanoparticles by self-assembling in aqueous medium having PEG surface functionalization and intermolecular disulfide bonds. Using anticancer drugs with logP values ranging from −0.5 to 3.0, the optimized nanoparticles formulations were evaluated for preliminary cellular delivery and cytotoxic effects in SKOV3 human ovarian adenocarcinoma cells. The results show that with the appropriate selection of lipid-modified dextran, one can effectively tailor the self-assembled nano-formulation for intended therapeutic payload. PMID:21978947

Lipid Biomarkers for a Hypersaline Microbial Mat Community

NASA Technical Reports Server (NTRS)

Jahnke, Linda; Orphan, Victoria; Embaye, Tsegereda; Turk, Kendra; Kubo, Mike; Summons, Roger

2004-01-01

The use of lipid biomarkers and their carbon isotopic compositions are valuable tools for establishing links to ancient microbial ecosystems. Various lipids associated with specific microbial groups can serve as biomarkers for establishing organism source and function in contemporary microbial ecosystems (membrane lipids), and by analogy, potential relevance to ancient organic-rich sedimentary rocks (geolipids). As witnessed by the stromatolite record, benthic microbial mats grew in shallow water lagoonal environments. Our recent work has focused on lipid biomarker analysis of a potential analogue for such ancient mats growing in a set of hypersaline evaporation ponds at Guerrero Negro, Baja California Sur, Mexico. The aerobic, surface layer of this mat (0 to 1 mm) contained a variety of ester-bound fatty acids (FA) representing a diverse bacterial population including cyanobacteria, sulphate reducers (SRB) and heterotrophs. Biomarkers for microeukaryotes detected in this layer included sterols, C-20 polyunsaturated FA and a highly branched isoprenoid, diagnostic for diatoms. Cyanobacteria were also indicated by the presence of a diagnostic set of mid-chain methylalkanes. C-28, to C-34 wax esters (WXE) present in relatively small amounts in the upper 3 mm of the mat are considered biomarkers for green non-sulphur bacteria. Ether-bound isoprenoids were also identified although in considerably lower abundance than ester-bound FA (approx. 1:l0). These complex ether lipids included archatol, hydroxyarchaeol and a C-40 tetraether, all in small amounts. After ether cleavage with boron tribromide, the major recovered isoprenyl was a C-30:1. This C(sub 30;1) yelded squalane after hydrogenation, a known geobiomarker for hypersaline environments in ancient oils and sediments. In this mat, it represents the dominant Archaeal population. The carbon isotopic composition of biomarker lipids were generally depleted relative to the bulk organic material (delta C-13 TOC -10%). Most depleted were the cyanobacterial methylalkanes at -27% with FA such as the SRB biomarker, 10- methyl C-I6, somewhat heavier at -16%, and WXE at -17%. The C-30:1 isoprenyl was most enriched with delta C-13 in the -7 to -11% range, much too heavy to represent the methanogen population responsible for mat methane values measured at -60%.

The effect of dietary protein and lipid source on dorsal fin erosion in rainbow trout, Oncorhynchus mykiss

USGS Publications Warehouse

Barrows, F.T.; Lellis, W.A.

1999-01-01

A study was conducted to determine the effect of dietary protein and lipid source on dorsal fin erosion in rainbow trout. Seven diets were each fed to four replicate lots of 300 first-feeding fry cultured in 75 1 aluminum troughs for 8 weeks. Two basal diets were manufactured with approximately equal nutrient content, one using krill and squid meals and the other anchovy meal as the primary protein-containing ingredients. The meals used to manufacture the diets were separated into two fractions: lipid (ether-extractable); and protein/ash (non-ether-extractable) using a large soxhlet. The fractions were then recombined to create two additional diets; one containing anchovy protein/ash with krill/squid lipid, the other krill/squid protein/ash with fish lipid. A fifth diet recombined krill/squid protein/ash with krill/squid lipid to evaluate effects of the extraction process. Two additional treatments included a diet with a portion of the krill meal replaced by poultry by-product meal, and the basal anchovy meal diet supplemented with sodium, magnesium, and copper. Fish consuming diets containing anchovy meal as the primary protein source gained more weight (P < 0.05) than fish consuming krill/squid meal-based diets. Dorsal fin index (DFI, measured as mean dorsal fin height x 100/total fish length) was greater (P < 0.05) for fish consuming diets containing krill/squid meal protein/ash fraction (DFI = 9.9%-10.0%) than for fish consuming diets containing anchovy meal protein/ash fraction (DFI = 4.9%-5.3%), regardless of lipid source. Supplementation of the anchovy meal diet with sodium, magnesium, and copper improved (P < 0.05) DFI by approximately 20%, but not to the level supported by the krill/squid meal protein/ash fraction diets. The cost of the krill meal diet was reduced by inclusion of poultry by-product meal without affecting dorsal fin condition. These data indicate that the dietary agent contributing to dorsal fin erosion in rainbow trout is not present in the ether-extractable fraction of the diet, but rather in the protein or mineral fraction.

Hansen solubility parameters (HSP) for prescreening formulation of solid lipid nanoparticles (SLN): in vitro testing of curcumin-loaded SLN in MCF-7 and BT-474 cell lines.

PubMed

Doktorovova, Slavomira; Souto, Eliana B; Silva, Amélia M

2018-01-01

Curcumin, a phenolic compound from turmeric rhizome (Curcuma longa), has many interesting pharmacological effects, but shows very low aqueous solubility. Consequently, several drug delivery systems based on polymeric and lipid raw materials have been proposed to increase its bioavailability. Solid lipid nanoparticles (SLN), consisting of solid lipid matrix and a surfactant layer can load poorly water-soluble drugs, such as curcumin, deliver them at defined rates and enhance their intracellular uptake. In the present work, we demonstrate that, despite the drug's affinity to lipids frequently used in SLN production, the curcumin amount loaded in most SLN formulations may be too low to exhibit anticancer properties. The predictive curcumin solubility in solid lipids has been thoroughly analyzed by Hansen solubility parameters, in parallel with the lipid-screening solubility tests for a range of selected lipids. We identified the most suitable lipid materials for curcumin-loaded SLN, producing physicochemically stable particles with high encapsulation efficiency (>90%). Loading capacity of curcumin in SLN allowed preventing the cellular damage caused by cationic SLN on MCF-7 and BT-474 cells but was not sufficient to exhibit drug's anticancer properties. But curcumin-loaded SLN exhibited antioxidant properties, substantiating the conclusions that curcumin's effect in cancer cells is highly dose dependent.

Coarse Graining to Investigate Membrane Induced Peptide Folding of Anticancer Peptides

NASA Astrophysics Data System (ADS)

Ganesan, Sai; Xu, Hongcheng; Matysiak, Silvina

Information about membrane induced peptide folding mechanisms using all-atom molecular dynamics simulations is a challenge due to time and length scale issues.We recently developed a low resolution Water Explicit Polarizable PROtein coarse-grained Model by adding oppositely charged dummy particles inside protein backbone beads.These two dummy particles represent a fluctuating dipole,thus introducing structural polarization into the coarse-grained model.With this model,we were able to achieve significant α- β secondary structure content de novo,without any added bias.We extended the model to zwitterionic and anionic lipids,by adding oppositely charged dummy particles inside polar beads, to capture the ability of the head group region to form hydrogen bonds.We use zwitterionic POPC and anionic POPS as our model lipids, and a cationic anticancer peptide,SVS1,as our model peptide.We have characterized the driving forces for SVS1 folding on lipid bilayers with varying anionic and zwitterionic lipid compositions.Based on our results, dipolar interactions between peptide backbone and lipid head groups contribute to stabilize folded conformations.Cooperativity in folding is induced by both intra peptide and membrane-peptide interaction.

A simple method to identify ether lipids in spermatozoa samples by MALDI-TOF mass spectrometry.

PubMed

Nimptsch, Ariane; Fuchs, Beate; Süß, Rosmarie; Zschörnig, Kristin; Jakop, Ulrike; Göritz, Frank; Schiller, Jürgen; Müller, Karin

2013-08-01

Plasmalogens (alkenylacyl glycerophospholipids) are important lipid constituents of many tissues and cells (e.g., selected spermatozoa). Since the molecular weights of plasmalogens overlap with that of diacyl- or alkyl acyl lipids, sophisticated mass spectrometry (MS; including MS/MS) analysis is normally used for the unequivocal identification of plasmalogens. We will show here that a simple matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (without MS/MS capability) in combination with acidic hydrolysis and subsequent derivatization with 2,4-dinitrophenylhydrazine (DNPH) and/or digestion with phospholipase A2 (PLA2) is sufficient to determine the contributions of ether lipids in spermatozoa extracts. As neither diacyl nor alkylacyl lipids are sensitive to acids and do not react with DNPH, the comparison of the mass spectra before and after treatment with acids and/or DNPH addition readily provides unequivocal information about the plasmalogen content. Additionally, the released aldehydes are readily converted into the 2,4-dinitrophenylhydrazones and can be easily identified in the corresponding negative ion mass spectra. Finally, PLA2 digestion is very useful in confirming the presence of plasmalogens. The suggested method was validated by analyzing roe deer, bovine, boar, and domestic cat spermatozoa extracts and comparing the results with isolated phospholipids.

Miscibility and interactions of animal and plant sterols with choline plasmalogen in binary and multicomponent model systems.

PubMed

Hąc-Wydro, Katarzyna; Luty, Katarzyna

2014-04-01

In this work miscibility and interactions of sterols with choline plasmalogen (PC-plasm) in Langmuir monolayers were studied. Moreover, the properties of cholesterol/phosphatidylcholine/plasmalogen mixtures of different PC-plasm concentration were investigated. The foregoing systems were treated as a model of cancer cell membranes, which are of higher plasmalogen level than normal cells. Finally, the influence of β-sitosterol and stigmasterol (phytosterols differing in anticancer potency) on these mixtures was verified. The properties of monolayers were analyzed based on the parameters derived from the surface pressure-area isotherms and images taken with Brewster Angle Microscope. It was found that at 30% of sterol in sterol/plasmalogen monolayer the lipids are immiscible and 3D crystallites are formed within the film. Cholesterol molecules mix favorably with PC-plasm at Xchol ≥ 0.5, while the investigated phytosterols only at their prevailing proportion in binary system. The increase of choline plasmalogen in cholesterol/phosphatidylcholine monolayer causes destabilization of the system. Moreover, the incorporation of phytosterols into cholesterol/phosphatidylcholine+PC-plasm mixtures disturbed membrane morphology and this effect was stronger for β-sitosterol as compared to stigmasterol. It was concluded that the presence of vinyl ether bond at sn-1 position in PC-plasm molecule strongly affects miscibility of choline plasmalogen with sterols. The comparison of the collected data with those reported in literature allowed one to conclude that miscibility and interactions of sterols with PC-plasm are less favorable than those with phosphatidylcholine. It was also suggested that overexpression of plasmalogens in cancer cell membranes may be a factor differentiating sensitivity of cells to anticancer effect of phytosterols. Copyright © 2014 Elsevier B.V. All rights reserved.

Trilysinoyl oleylamide-based cationic liposomes for systemic co-delivery of siRNA and an anticancer drug.

PubMed

Shim, Gayong; Han, Su-Eun; Yu, Yong-Hee; Lee, Sangbin; Lee, Han Young; Kim, Kwangmeyung; Kwon, Ick Chan; Park, Tae Gwan; Kim, Young Bong; Choi, Yong Seok; Kim, Chan-Wha; Oh, Yu-Kyoung

2011-10-10

Oligolysine-based cationic lipid derivatives were synthesized for delivery of siRNA, and formulated into cationic liposomes. Among various oligolysine-based lipid derivatives differing in lysine residue number and lipid moiety, trilysinoyl oleylamide (TLO)-based liposomes (TLOL) showed the highest delivery efficiency combined with minimal cytotoxicity. Delivery of siRNA using TLOL silenced target genes both in vitro and in vivo. In green fluorescent protein (GFP)-expressing tumor tissue, a significant reduction of fluorescence was observed after intratumoral administration of siGFP using TLOL compared with control siGL2. Intravenous administration of siMcl1 employing pegylated TLOL (pTLOL) reduced the expression of human Mcl1 protein in KB-xenografted tumor tissue. Despite the reduction in target protein Mcl1 expression following such systemic delivery, tumor growth was only slightly reduced compared to a siGL2-treated control group. To potentiate the anticancer activity of siMcl1, the anticancer drug suberoylanilide hydroxamic acid (SAHA) was additionally encapsulated in pTLOL. After intravenous administration of siMcl1 using SAHA-loaded pTLOL (pSTLOL), a significant reduction in tumor growth was observed compared to that seen in animals treated with free SAHA or siGL2 complexed with pSTLOL. The results indicate that pTLOL could be further developed as a systemic delivery system for synergistic anticancer siRNA and a drug. Copyright © 2010 Elsevier B.V. All rights reserved.

Enhanced bioavailability of tripterine through lipid nanoparticles using broccoli-derived lipids as a carrier material.

PubMed

Li, Wan; Zhang, Tianpeng; Ye, Yanghuan; Zhang, Xingwang; Wu, Baojian

2015-11-30

Chemotherapy via the oral route remains a considerable challenge due to poor water-solubility and permeability of anticancer agents. This study aimed to construct lipid nanoparticles using broccoli-derived lipids for oral delivery of tripterine (Tri), a natural anticancer candidate, and to enhance its oral bioavailability. Tri-loaded broccoli lipid nanoparticles (Tri-BLNs) were prepared by a solvent-diffusion method. The resulting Tri-BLNs were 75±10 nm in particle size with entrapment efficiency over 98%. In vitro release study indicated that Tri was almost not released from Tri-BLNs (<2%), whereas the lipolytic experiment showed that Tri-BLNs possessed a relatively strong anti-enzymatic degradation ability to Tri-CLNs (Tri-loaded common lipid nanoparticles). In situ single-pass intestinal perfusion manifested that the effective permeability of Tri-BLNs were significantly higher than that of Tri-CLNs. Further, Tri-BLNs exhibited more efficient cellular uptake in MDCK-II cells as evidenced by flow cytometry and confocal microscopy. The relative bioavailability of Tri-BLNs and Tri-CLNs was 494.13% and 281.95% compared with Tri suspensions, respectively. Depending on the ability in enhancement of biomembrane permeability, broccoli-derived lipids as an alternative source should be useful to construct lipid nanoparticles for bettering oral delivery of drugs with low bioavailability. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization of E 471 food emulsifiers by high-performance thin-layer chromatography-fluorescence detection.

PubMed

Oellig, Claudia; Brändle, Klara; Schwack, Wolfgang

2018-07-13

Mono- and diacylglycerol (MAG and DAG) emulsifiers, also known as food additive E 471, are widely used to adjust techno-functional properties in various foods. Besides MAGs and DAGs, E 471 emulsifiers additionally comprise different amounts of triacylglycerols (TAGs) and free fatty acids (FFAs). MAGs, DAGs, TAGs and FFAs are generally determined by high-performance liquid chromatography (HPLC) or gas chromatography (GC) coupled to mass selective detection, analyzing the individual representatives of the lipid classes. In this work we present a rapid and sensitive method for the determination of MAGs, DAGs, TAGs and FFAs in E 471 emulsifiers by high-performance thin-layer chromatography with fluorescence detection (HPTLC-FLD), including a response factor system for quantitation. Samples were simply dissolved and diluted with t-butyl methyl ether before a two-fold development was performed on primuline pre-impregnated LiChrospher silica gel plates with diethyl ether and n-pentane/n-hexane/diethyl ether (52:20:28, v/v/v) as the mobile phases to 18 and 75 mm, respectively. For quantitation, the plate was scanned in the fluorescence mode at UV 366/>400 nm, when the cumulative signal for each lipid class was used. Calibration was done with 1,2-distearin and amounts of lipid classes were calculated with response factors and expressed as monostearin, distearin, tristearin and stearic acid. Limits of detection and quantitation were 1 and 4 ng/zone, respectively, for 1,2-distearin. Thus, the HPTLC-FLD approach represents a simple, rapid and convenient screening alternative to HPLC and GC analysis of the individual compounds. Visual detection additionally enables an easy characterization and the direct comparison of emulsifiers through the lipid class pattern, when utilized as a fingerprint. Copyright © 2018 Elsevier B.V. All rights reserved.

Solid-phase extraction clean-up of ciguatoxin-contaminated coral fish extracts for use in the mouse bioassay.

PubMed

Wong, Chun Kwan; Hung, Patricia; Lee, Kellie L H; Kam, Kai Man

2009-02-01

Florisil solid-phase extraction (SPE) cartridges were used for purifying ciguatoxin (CTX)-contaminated coral fish extracts, with the aim of removing extracted lipid but retaining optimal level of CTXs in the purified fractions. The CTX-containing fraction (target fraction) in fish ether extract was isolated and purified by eluting through a commercially available Florisil cartridge with hexane-acetone-methanol solvent mixtures of increasing polarity (hexane-acetone (4:1, v/v) < acetone-methanol (7:3, v/v) < 100% methanol). Application of Florisil SPE using acetone-methanol (7:3, v/v) condition facilitated the separation of 4.2 +/- 0.4 mg (mean +/- standard error of the mean (SEM)) of purified target fraction from 20 mg ether extract with good retention of CTXs. The mouse bioassay was used to demonstrate that the average CTX recovery of the target fraction from CTX-spiked samples was 75.8% +/- 3.3%, which was significantly increased by 96.7% +/- 15% when compared with CTX recovery from ether extracts (44.8% +/- 5.2%) without performing SPE purification. Over 70% of non-target lipids were removed in which no CTX toxicity was found. Moreover, the target fractions of both CTX-spiked and naturally CTX-contaminated samples gave more prominent toxic responses of hypothermia and/or induced more rapid death of the mice. The use of acetone-methanol (7:3, v/v) condition in the elution could significantly improve overall recovery of CTXs, while minimizing the possible interferences of lipid matrix from co-extractants on mice.

Functionalized nanoparticles for AMF-induced gene and drug delivery

NASA Astrophysics Data System (ADS)

Biswas, Souvik

The properties and broad applications of nano-magnetic colloids have generated much interest in recent years. Specially, Fe3O4 nanoparticles have attracted a great deal of attention since their magnetic properties can be used for hyperthermia treatment or drug targeting. For example, enhanced levels of intracellular gene delivery can be achieved using Fe3O4 nano-vectors in the presence of an external magnetic field, a process known as 'magnetofection'. The low cytotoxicity, tunable particle size, ease of surface functionalization, and ability to generate thermal energy using an external alternating magnetic field (AMF) are properties have propelled Fe3O4 research to the forefront of nanoparticle research. The strategy of nanoparticle-mediated, AMF-induced heat generation has been used to effect intracellular hyperthermia. One application of this 'magnetic hyperthermia' is heat activated local delivery of a therapeutic effector (e.g.; drug or polynucleotide). This thesis describes the development of a magnetic nano-vector for AMF-induced, heat-activated pDNA and small molecule delivery. The use of heat-inducible vectors, such as heat shock protein ( hsp) genes, is a promising mode of gene therapy that would restrict gene expression to a local region by focusing a heat stimulus only at a target region. We thus aimed to design an Fe3O4 nanoparticle-mediated gene transfer vehicle for AMF-induced localized gene expression. We opted to use 'click' oximation techniques to assemble the magnetic gene transfer vector. Chapter 2 describes the synthesis, characterization, and transfection studies of the oxime ether lipid-based nano-magnetic vectors MLP and dMLP. The synthesis and characterization of a novel series of quaternary ammonium aminooxy reagents (2.1--2.4) is described. These cationic aminooxy compounds were loaded onto nanoparticles for ligation with carbonyl groups and also to impart a net positive charge on the nanoparticle surface. Our studies indicated that the non-toxic magnetoplexes (magnetic nanoparticle + pDNA complex) derived from dMLP deliver pDNA into mammalian cells even without external magnetic assistance. To date, dMLP is the only polymer-free magnetic gene delivery system that can deliver pDNA without any magnetic assistance. Chapter 3 of this thesis outlines the synthesis and characterization of other oxime ether lipids and details studies using derived-lipoplexes. These lipids were evaluated in pDNA and siRNA transfection studies in various mammalian cell lines. This work constitutes the first use of an oxime ether as the linking domain in cationic transfection lipids. These biocompatible oxime ether lipids can be readily assembled by click chemistry through ligation of hydrophobic aldehydes with quaternary ammonium aminooxy salts. Our studies showed that the oxime ether lipids transfected pDNA and siRNA efficiently in MCF-7, H 1792, and in PAR C10 cells comparable to and in some cases better than commercial transfection lipids. Chapter 4 describes the design and characterization of a nano-magnetic delivery system for AMF-induced drug (doxorubicin) release. In efforts to develop a magnetic formulation free from thermosensitive materials, such as hydrogels, we synthesized three nanoparticle-based doxorubicin formulations using charge interactions as the key associative force. To do so, we synthesized and characterized a novel cationic oxime ether conjugate at C-13 of doxorubicin. Our investigation indicated that the positive charge of the oxime ether drug conjugate tended to bind better to the negatively charged nanoparticle than did the other formulations prepared in stepwise manner. Our findings show that the nano-magnetic formulations remained essestially inactive at body temperature (37.5 °C) and released a majority of the cargo only when exposed to an external AMF. Our designed magnetic drug delivery platform is the first example of an AMF-inducible system that does not depend on the inclusion of thermosensitive materials. Finally, we have developed a bioanalytical application of the highly chemoselective oximation chemistry using aminooxy reagent 2.1. Chapter 5 describes a silica microchip containing micropillars coated with cationic aminooxy reagent 2.1. The microchip captures gaseous ketones and aldehydes from exhaled human breath. A brief description of microchip fabricated breath analyzer and breath analysis is described in Chapter 5. Our studies showed that the acetone capture efficiency of the aminooxy-loaded microchip was 98%.

Targeted Delivery of Drugs to Brain Tumors (LBNL Summer Lecture Series)

ScienceCinema

Forte, Trudy [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Children’s Hospital Oakland Research Inst. (CHORI), Oakland, CA (United States)

2017-12-15

Summer Lecture Series 2007: Trudy Forte of Berkeley Lab's Life Sciences Division will discuss her work developing nano-sized low-density lipoprotein (LDL) particles that can be used as a safe and effective means of delivering anticancer drugs to brain tumors, particularly glioblastoma multiforme. This is the most common malignant brain tumor in adults and one of the deadliest forms of cancer. Her research team found that the synthetic LDL particles can target and kill such tumors cells in vitro. The nanoparticles are composed of a lipid core surrounded by a peptide. The peptide contains an amino acid sequence that recognizes the LDL receptor, and the lipid core has the ability to accumulate anti-cancer drugs.

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come

PubMed Central

Yingchoncharoen, Phatsapong; Kalinowski, Danuta S.

2016-01-01

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles. PMID:27363439

A multifunctional lipid nanoparticle for co-delivery of paclitaxel and curcumin for targeted delivery and enhanced cytotoxicity in multidrug resistant breast cancer cells

PubMed Central

Baek, Jong-Suep; Cho, Cheong-Weon

2017-01-01

The objective of the work was to develop a multifunctional nanomedicine based on a folate-conjugated lipid nanoparticles loaded with paclitaxel and curcumin. The novel system combines therapeutic advantageous of efficient targeted delivery via folate and timed-release of curcumin and paclitaxel via 2-hydroxypropyl-ß-cyclodextrin, thereby overcoming multidrug resistance in breast cancer cells (MCF-7/ADR). The faster release of curcumin from the folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles enables sufficient p-glycoprotein inhibition, which allows increased cellular uptake and cytotoxicity of paclitaxel. In western blot assay, curcumin can efficiently inhibit the expression of p-glycoprotein, conformed the enhancement of cytotoxicity by paclitaxel. Furthermore, folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles exhibited increased uptake of paclitaxel and curcumin into MCF-7/ADR cells through the folate receptor-mediated internalization. Taken together, these results indicate that folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles enables the enhanced, folate-targeted delivery of multiple anticancer drugs by inhibiting the multi-drug resistance efficiently, which may also serve as a useful nano-system for co-delivery of other anticancer drugs. PMID:28423731

Role of the catechol group in the antioxidant and neuroprotective effects of virgin olive oil components in rat brain.

PubMed

De La Cruz, J P; Ruiz-Moreno, M I; Guerrero, A; López-Villodres, J A; Reyes, J J; Espartero, J L; Labajos, M T; González-Correa, J A

2015-05-01

The aim of the present study was to determine the role of the catechol group in the antioxidant and neuroprotective effects of minor components of virgin olive oil in rat brain tissue. Hydroxytyrosol ethyl ether (HT, 2 OH), tyrosol ethyl ether (Ty, 1 OH) and 3,4-di-ortho-methylidene-hydroxytyrosol ethyl ether (MET, no OH) were compared. Oxidative stress was induced with ferrous salts (lipid peroxidation induction), diethylmaleate (depletion of glutathione) and hypoxia-reoxygenation in brain slices. Lipid peroxidation was inhibited in direct proportion to the number of OH groups: HT>Ty>MET. Exposure to HT led to partial recovery of the glutathione system after chemical inhibition or hypoxia-reoxygenation. All three compounds inhibited cell death in hypoxia-reoxygenation experiments (HT≥Ty>MET). Peroxynitrite formation (3-nitrotyrosine) and inflammatory mediators (prostaglandin E2 and interleukin 1ß) were inhibited by all three compounds. In conclusion, the presence of OH groups in the molecule of these phenolic compounds from virgin olive oil is a determinant factor in their antioxidant effect in brain tissue, but this antioxidant effect is not the only explanation for their neuroprotective effect. Copyright © 2015. Published by Elsevier Inc.

Ultrasound extraction and thin layer chromatography-flame ionization detection analysis of the lipid fraction in marine mucilage samples.

PubMed

Mecozzi, M; Amici, M; Romanelli, G; Pietrantonio, E; Deluca, A

2002-07-19

This paper reports an analytical procedure based on ultrasound to extract lipids in marine mucilage samples. The experimental conditions of the ultrasound procedure (solvent and time) were identified by a FT-IR study performed on different standard samples of lipids and of a standard humic sample, before and after the sonication treatment. This study showed that diethyl ether was a more suitable solvent than methanol for the ultrasonic extraction of lipids from environmental samples because it allowed to minimize the possible oxidative modifications of lipids due to the acoustic cavitation phenomena. The optimized conditions were applied to the extraction of total lipid amount in marine mucilage samples and TLC-flame ionization detection analysis was used to identify the relevant lipid sub-fractions present in samples.

Oxime Ether Lipids as Transfection Agents: Assembly and Complexation with siRNA.

PubMed

Puri, Anu; Zampino, Serena; Viard, Mathias; Shapiro, Bruce A

2017-01-01

RNAi-based therapeutic approaches to combat cancer and other diseases are currently an area of great interest. However, practical applications of this approach rely on optimal tools to carry and deliver siRNA to the desired site. Oxime ether lipids (OELs) are a class of molecules among other various carriers being examined for siRNA delivery. OELs, relatively new candidates, belong to a class of non-glycerol based lipids and have begun to claim their place as an siRNA delivery carrier in the field of RNAi therapy. Chemical synthesis steps of OELs are considered relatively simple with the ability to modify the functionalities as desired. OEL-siRNA complexes can be assembled in the presence of serum-containing buffers (or cell culture media) and recent data from our and other groups have demonstrated that OELs are viable carriers for siRNA delivery in the cell culture systems. In this chapter, we provide the details of experimental protocols routinely used in our laboratory to examine OEL-siRNA complexes including their assembly, stability, and transfection efficiencies.

Targeted co-delivery of Beclin 1 siRNA and FTY720 to hepatocellular carcinoma by calcium phosphate nanoparticles for enhanced anticancer efficacy.

PubMed

Wu, Jun-Yi; Wang, Zhong-Xia; Zhang, Guang; Lu, Xian; Qiang, Guang-Hui; Hu, Wei; Ji, An-Lai; Wu, Jun-Hua; Jiang, Chun-Ping

2018-01-01

FTY720, known as fingolimod, is a new immunosuppressive agent with effective anticancer properties. Although it was recently confirmed that FTY720 inhibits cancer cell proliferation, FTY720 can also induce protective autophagy and reduce cytotoxicity. Blocking autophagy with Beclin 1 siRNA after treatment with FTY720 promotes apoptosis. The objective of this study was to enhance the anticancer effect of FTY720 in hepatocellular carcinoma (HCC) by targeted co-delivery of FTY720 and Beclin 1 siRNA using calcium phosphate (CaP) nanoparticles (NPs). First, the siRNA was encapsulated within the CaP core. To form an asymmetric lipid bilayer structure, we then used an anionic lipid for the inner leaflet and a cationic lipid for the outer leaflet; after removing chloroform by rotary evaporation, these lipids were dispersed in a saline solution with FTY720. The NPs were analyzed by transmission electron microscopy, dynamic light scattering and ultraviolet-visible spectrophotometry. Cancer cell viability and cell death were analyzed by MTT assays, fluorescence-activated cell sorting analysis and Western blotting. In addition, the in vivo effects of the NPs were investigated using an athymic nude mouse subcutaneous transplantation tumor model. When the CaP NPs, called LCP-II NPs, were loaded with FTY720 and siRNA, they exhibited the expected size and were internalized by cells. These NPs were stable in systemic circulation. Furthermore, co-delivery of FTY720 and Beclin 1 siRNA significantly increased cytotoxicity in vitro and in vivo compared with that caused by treatment with the free drug alone. The CaP NP system can be further developed for co-delivery of FTY720 and Beclin 1 siRNA to treat HCC, enhancing the anticancer efficacy of FTY720. Our findings provide a new insight into HCC treatment with co-delivered small molecules and siRNA, and these results can be readily translated into cancer clinical trials.

Influence of north climatic conditions on the peat lipids composition

NASA Astrophysics Data System (ADS)

Serebrennikova, O. V.; Strelnikova, E. B.; Duchko, M. A.; Preis, Yu I.

2018-03-01

The paper studies the composition of lipid organic compounds of peat from the northern regions of the Russian Federation. Peat was sampled in the northern taiga, forest-tundra and tundra zones, characterized by various hydrothermal conditions and vegetation cover. n-Alkanes, fatty acids and their ethers, aldehydes, ketones, alcohols, tocopherols, squalene, bi-, tri- and pentacyclic terpenoids, as well as steroids were identified in peat lipids by gas chromatography-mass spectrometry. The dependences of the total content of lipids and the majority of the investigated compounds classes on the ambient temperature and vegetation, as well as the correlation between the composition of n-alkanes and humidity were revealed.

Evaluation of different solvent mixtures in esterifiable lipids extraction from microalgae Botryococcus braunii for biodiesel production.

PubMed

Hidalgo, Pamela; Ciudad, Gustavo; Navia, Rodrigo

2016-02-01

Non-polar and polar solvents as well as their mixtures were tested for the extraction of microalgae lipids and thus, to evaluate their effect on total and esterifiable lipids extraction yields with potential to be converted to biodiesel. The obtained results show an increase in lipids and esterifiable lipids extraction yields when non-polar and polar solvent mixtures were used. The higher esterifiable lipids extraction yield was 19.2%wt (based on dry biomass) using a chloroform-methanol mixture (75%v/v of methanol), corresponding to a 98.9%wt esterifiable lipids extraction. In addition, esterifiable lipids extraction yield of 18.9%wt (based on dry biomass) was obtained when a petroleum ether-methanol mixture (75%v/v of methanol) was used, corresponding to a 96.9%wt esterifiable lipids extraction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Polybrominated diphenyl ethers (PBDEs) and organochlorines in small cetaceans from Hong Kong waters: levels, profiles and distribution.

PubMed

Ramu, Karri; Kajiwara, Natsuko; Tanabe, Shinsuke; Lam, Paul K S; Jefferson, Thomas A

2005-01-01

Polybrominated diphenyl ethers (PBDEs) and organochlorine compounds (OCs) were determined in the blubber, liver and kidney of Indo-Pacific humpback dolphins (Sousa chinensis) and finless porpoises (Neophocaena phocaenoides) stranded in Hong Kong coastal waters during 1995-2001. Among the organohalogen compounds analyzed, DDTs were the most dominant contaminants with concentrations ranging from 9.9 to 470 microg/g lipid wt. PBDEs in Hong Kong cetaceans, which are reported for the first time, were detected in all the samples with values ranging from 0.23 to 6.0 microg/g lipid wt., with a predominance of BDE-47. Results from this study suggest PBDEs should be classified as priority pollutants in Asia. Higher concentrations were found in humpback dolphins than in finless porpoises, and this was attributed mainly to differences in habitat. Elevated residues of PCBs and DDTs in some cetaceans suggest these species may be at risk.

Brine shrimp lethality assay of Bacopa monnieri.

PubMed

D'Souza, Prashanth; Deepak, Mundkinajeddu; Rani, Padmaja; Kadamboor, Sandhya; Mathew, Anjana; Chandrashekar, Arun P; Agarwal, Amit

2002-03-01

Successive petroleum ether, chloroform, ethanol and water extracts, a saponin rich fraction (SRF) and bacoside A isolated from Bacopa monnieri were tested for brine shrimp lethality. Successive ethanol extracts and SRF showed potent activity. Bacoside A showed the maximum activity with a LC(50) of 38.3 microg/mL. The results confirmed the previous reports of an anticancer effect of Bacopa monnieri and suggest bacoside A as the active constituent. Copyright 2002 John Wiley & Sons, Ltd.

Drug Uptake, Lipid Rafts, and Vesicle Trafficking Modulate Resistance to an Anticancer Lysophosphatidylcholine Analogue in Yeast*

PubMed Central

Cuesta-Marbán, Álvaro; Botet, Javier; Czyz, Ola; Cacharro, Luis M.; Gajate, Consuelo; Hornillos, Valentín; Delgado, Javier; Zhang, Hui; Amat-Guerri, Francisco; Acuña, A. Ulises; McMaster, Christopher R.; Revuelta, José Luis; Zaremberg, Vanina; Mollinedo, Faustino

2013-01-01

The ether-phospholipid edelfosine, a prototype antitumor lipid (ATL), kills yeast cells and selectively kills several cancer cell types. To gain insight into its mechanism of action, we performed chemogenomic screens in the Saccharomyces cerevisiae gene-deletion strain collection, identifying edelfosine-resistant mutants. LEM3, AGP2, and DOC1 genes were required for drug uptake. Edelfosine displaced the essential proton pump Pma1p from rafts, inducing its internalization into the vacuole. Additional ATLs, including miltefosine and perifosine, also displaced Pma1p from rafts to the vacuole, suggesting that this process is a major hallmark of ATL cytotoxicity in yeast. Radioactive and synthetic fluorescent edelfosine analogues accumulated in yeast plasma membrane rafts and subsequently the endoplasmic reticulum. Although both edelfosine and Pma1p were initially located at membrane rafts, internalization of the drug toward endoplasmic reticulum and Pma1p to the vacuole followed different routes. Drug internalization was not dependent on endocytosis and was not critical for yeast cytotoxicity. However, mutants affecting endocytosis, vesicle sorting, or trafficking to the vacuole, including the retromer and ESCRT complexes, prevented Pma1p internalization and were edelfosine-resistant. Our data suggest that edelfosine-induced cytotoxicity involves raft reorganization and retromer- and ESCRT-mediated vesicular transport and degradation of essential raft proteins leading to cell death. Cytotoxicity of ATLs is mainly dependent on the changes they induce in plasma membrane raft-located proteins that lead to their internalization and subsequent degradation. Edelfosine toxicity can be circumvented by inactivating genes that then result in the recycling of internalized cell-surface proteins back to the plasma membrane. PMID:23335509

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come.

PubMed

Yingchoncharoen, Phatsapong; Kalinowski, Danuta S; Richardson, Des R

2016-07-01

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short half-lives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipid-based nanoparticles. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids.

PubMed

Louie, Sharon M; Roberts, Lindsay S; Mulvihill, Melinda M; Luo, Kunxin; Nomura, Daniel K

2013-10-01

De novo lipogenesis is considered the primary source of fatty acids for lipid synthesis in cancer cells, even in the presence of exogenous fatty acids. Here, we have used an isotopic fatty acid labeling strategy coupled with metabolomic profiling platforms to comprehensively map palmitic acid incorporation into complex lipids in cancer cells. We show that cancer cells and tumors robustly incorporate and remodel exogenous palmitate into structural and oncogenic glycerophospholipids, sphingolipids, and ether lipids. We also find that fatty acid incorporation into oxidative pathways is reduced in aggressive human cancer cells, and instead shunted into pathways for generating structural and signaling lipids. Our results demonstrate that cancer cells do not solely rely on de novo lipogenesis, but also utilize exogenous fatty acids for generating lipids required for proliferation and protumorigenic lipid signaling. This article is part of a special issue entitled Lipid Metabolism in Cancer. © 2013.

Determination of the Relative Efficacy of Eicosapentaenoic Acid and Docosahexaenoic Acid for Anti-Cancer Effects in Human Breast Cancer Models

PubMed Central

Mazurak, Vera C.; Damaraju, Sambasivarao

2017-01-01

Epidemiological studies have associated high fish oil consumption with decreased risk of breast cancer (BC). n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish and fish oils exert anti-cancer effects. However, few studies have examined the relative efficacy of EPA and DHA alone and in mixtures on BC subtypes. This was the objective of the present review, as this research is a necessity for the translation of findings to human health and disease. The literature suggests that DHA has a greater anti-cancer effect in triple negative BC (TNBC). In estrogen positive (ER+) BC, DHA has a greater effect on cell viability, while both fatty acids have similar effects on apoptosis and proliferation. These effects are associated with preferential uptake of DHA into TNBC lipid rafts and EPA in ER+ BC. EPA:DHA mixtures have anti-cancer activity; however, the ratio of EPA:DHA does not predict the relative incorporation of these two fatty acids into membrane lipids as EPA appears to be preferentially incorporated. In summary, DHA and EPA should be considered separately in the context of BC prevention. The elucidation of optimal EPA:DHA ratios will be important for designing targeted n-3 LCPUFA treatments. PMID:29207553

Determination of ether extract digestibility and energy content of specialty lipids with different fatty acid and free fatty acid content, and the effect of lecithin, for nursery pigs

USDA-ARS?s Scientific Manuscript database

Various specialty lipids are commercially available and used in nursery pig diets, but may have FA profiles and FFA content that affect their caloric value. In each of 2 experiments, 54 barrows (28-d of age) were fed a common diet for 7-d, allotted to dietary treatments and fed their respective expe...

Marine Microalgae with Anti-Cancer Properties.

PubMed

Martínez Andrade, Kevin A; Lauritano, Chiara; Romano, Giovanna; Ianora, Adrianna

2018-05-15

Cancer is the leading cause of death globally and finding new therapeutic agents for cancer treatment remains a major challenge in the pursuit for a cure. This paper presents an overview on microalgae with anti-cancer activities. Microalgae are eukaryotic unicellular plants that contribute up to 40% of global primary productivity. They are excellent sources of pigments, lipids, carotenoids, omega-3 fatty acids, polysaccharides, vitamins and other fine chemicals, and there is an increasing demand for their use as nutraceuticals and food supplements. Some microalgae are also reported as having anti-cancer activity. In this review, we report the microalgal species that have shown anti-cancer properties, the cancer cell lines affected by algae and the concentrations of compounds/extracts tested to induce arrest of cell growth. We also report the mediums used for growing microalgae that showed anti-cancer activity and compare the bioactivity of these microalgae with marine anticancer drugs already on the market and in phase III clinical trials. Finally, we discuss why some microalgae can be promising sources of anti-cancer compounds for future development.

Signature Lipids and Stable Carbon Isotope Analyses of Octopus Spring Hyperthermophilic Communities Compared with Those of Aquificales Representatives

PubMed Central

Jahnke, Linda L.; Eder, Wolfgang; Huber, Robert; Hope, Janet M.; Hinrichs, Kai-Uwe; Hayes, John M.; Des Marais, David J.; Cady, Sherry L.; Summons, Roger E.

2001-01-01

The molecular and isotopic compositions of lipid biomarkers of cultured Aquificales genera have been used to study the community and trophic structure of the hyperthermophilic pink streamers and vent biofilm from Octopus Spring. Thermocrinis ruber, Thermocrinis sp. strain HI 11/12, Hydrogenobacter thermophilus TK-6, Aquifex pyrophilus, and Aquifex aeolicus all contained glycerol-ether phospholipids as well as acyl glycerides. The n-C20:1 and cy-C21 fatty acids dominated all of the Aquificales, while the alkyl glycerol ethers were mainly C18:0. These Aquificales biomarkers were major constituents of the lipid extracts of two Octopus Spring samples, a biofilm associated with the siliceous vent walls, and the well-known pink streamer community (PSC). Both the biofilm and the PSC contained mono- and dialkyl glycerol ethers in which C18 and C20 alkyl groups were prevalent. Phospholipid fatty acids included both the Aquificales n-C20:1 and cy-C21, plus a series of iso-branched fatty acids (i-C15:0 to i-C21:0), indicating an additional bacterial component. Biomass and lipids from the PSC were depleted in 13C relative to source water CO2 by 10.9 and 17.2‰, respectively. The C20–21 fatty acids of the PSC were less depleted than the iso-branched fatty acids, 18.4 and 22.6‰, respectively. The biomass of T. ruber grown on CO2 was depleted in 13C by only 3.3‰ relative to C source. In contrast, biomass was depleted by 19.7‰ when formate was the C source. Independent of carbon source, T. ruber lipids were heavier than biomass (+1.3‰). The depletion in the C20–21 fatty acids from the PSC indicates that Thermocrinis biomass must be similarly depleted and too light to be explained by growth on CO2. Accordingly, Thermocrinis in the PSC is likely to have utilized formate, presumably generated in the spring source region. PMID:11679343

Signature lipids and stable carbon isotope analyses of Octopus Spring hyperthermophilic communities compared with those of Aquificales representatives

NASA Technical Reports Server (NTRS)

Jahnke, L. L.; Eder, W.; Huber, R.; Hope, J. M.; Hinrichs, K. U.; Hayes, J. M.; Des Marais, D. J.; Cady, S. L.; Summons, R. E.

2001-01-01

The molecular and isotopic compositions of lipid biomarkers of cultured Aquificales genera have been used to study the community and trophic structure of the hyperthermophilic pink streamers and vent biofilm from Octopus Spring. Thermocrinis ruber, Thermocrinis sp. strain HI 11/12, Hydrogenobacter thermophilus TK-6, Aquifex pyrophilus, and Aquifex aeolicus all contained glycerol-ether phospholipids as well as acyl glycerides. The n-C(20:1) and cy-C(21) fatty acids dominated all of the Aquificales, while the alkyl glycerol ethers were mainly C(18:0). These Aquificales biomarkers were major constituents of the lipid extracts of two Octopus Spring samples, a biofilm associated with the siliceous vent walls, and the well-known pink streamer community (PSC). Both the biofilm and the PSC contained mono- and dialkyl glycerol ethers in which C(18) and C(20) alkyl groups were prevalent. Phospholipid fatty acids included both the Aquificales n-C(20:1) and cy-C(21), plus a series of iso-branched fatty acids (i-C(15:0) to i-C(21:0)), indicating an additional bacterial component. Biomass and lipids from the PSC were depleted in (13)C relative to source water CO(2) by 10.9 and 17.2 per thousand, respectively. The C(20-21) fatty acids of the PSC were less depleted than the iso-branched fatty acids, 18.4 and 22.6 per thousand, respectively. The biomass of T. ruber grown on CO(2) was depleted in (13)C by only 3.3 per thousand relative to C source. In contrast, biomass was depleted by 19.7 per thousand when formate was the C source. Independent of carbon source, T. ruber lipids were heavier than biomass (+1.3 per thousand). The depletion in the C(20-21) fatty acids from the PSC indicates that Thermocrinis biomass must be similarly depleted and too light to be explained by growth on CO(2). Accordingly, Thermocrinis in the PSC is likely to have utilized formate, presumably generated in the spring source region.

The augmented anticancer potential of AP9-cd loaded solid lipid nanoparticles in human leukemia Molt-4 cells and experimental tumor.

PubMed

Bhushan, Shashi; Kakkar, Vandita; Pal, Harish Chandra; Mondhe, D M; Kaur, Indu Pal

2016-01-25

AP9-cd, a novel lignan composition from Cedrus deodara has significant anticancer potential, and to further enhance its activity, it was lucratively encumbered into solid lipid nanoparticles (SLNs). These nanoparticles were formulated by micro-emulsion technique with 70% drug trap competence. AP9-cd-SLNs were regular, solid, globular particles in the range of 100-200 nm, which were confirmed by electron microscopic studies. Moreover, AP9-cd-SLNs were found to be stable for up to six months in terms of color, particle size, zeta potential, drug content and entrapment. AP9-cd-SLNs have 30-50% higher cytotoxic and apoptotic potential than the AP9-cd alone. The augmented anticancer potential of AP9-cd-SLNs was observed in cytotoxic IC50 value, apoptosis signaling cascade and in Ehrlich ascites tumor (EAT) model. AP9-cd-SLNs induce apoptosis in Molt-4 cells via both intrinsic and extrinsic pathway. Moreover, the dummy nanoparticles (SLNs without AP9-cd) did not have any cytotoxic effect in cancer as well as in normal cells. Consequently, SLNs of AP9-cd significantly augment the apoptotic and antitumor potential of AP9-cd. The present study provides a podium for ornamental the remedial latent via novel delivery systems like solid lipid nanoparticles. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Leishmania dihydroxyacetonephosphate acyltransferase LmDAT is important for ether lipid biosynthesis but not for the integrity of detergent resistant membranes.

PubMed

Zufferey, Rachel; Al-Ani, Gada K; Dunlap, Kara

2009-12-01

Glycerolipid biosynthesis in Leishmania initiates with the acylation of glycerol-3-phosphate by a single glycerol-3-phosphate acyltransferase, LmGAT, or of dihydroxyacetonephosphate by a dihydroxyacetonephosphate acyltransferase, LmDAT. We previously reported that acylation of the precursor dihydroxyacetonephosphate rather than glycerol-3-phosphate is the physiologically relevant pathway for Leishmania parasites. We demonstrated that LmDAT is important for normal growth, survival during the stationary phase, and for virulence. Here, we assessed the role of LmDAT in glycerolipid metabolism and metacyclogenesis. LmDAT was found to be implicated in the biosynthesis of ether glycerolipids, including the ether lipid derived virulence factor lipophosphoglycan and glycosylphosphatidylinositol-anchored proteins. The null mutant produced longer lipophosphoglycan molecules that were not released in the medium, and augmented levels of glycosylphosphatidylinositol-anchored proteins. In addition, the integrity of detergent resistant membranes was not affected by the absence of the LmDAT gene. Further, our genetic analyses strongly suggest that LmDAT was synthetic lethal with the glycerol-3-phosphate acyltransferase encoding gene LmGAT, implying that Leishmania expresses only two acyltransferases that initiate the biosynthesis of its cellular glycerolipids. Last, despite the fact that LmDAT is important for virulence the null mutant still exhibited the typical characteristics of metacyclics.

Structure transition in lipids and nucleic acids of tumor cells under anticancer drugs applications

NASA Astrophysics Data System (ADS)

Dovbeshko, G. I.; Repnytska, O. P.; Tryndiak, V. P.; Todor, I. N.

2003-12-01

Interaction of DNA and phospholipids from Carcinoma Guerina resistant and sensitive cells of Wistar line rats with anti-cancer drugs - cis-platin and doxorubicin (DOX) have been studied in vivo and in vitro experiments. Surface enhanced infrared absorption (SEIRA) spectroscopy was applied for registration of conformational changes in DNA and lipids induced by anti-cancer drugs. It has been shown in vivo experiment that doxorubicin influences less structural disordering of the membrane than cis-platin. Cis-platin creates irreversible complex with memebrane phospholipids, strongly interacting with phosophates and carbohydrate chains. Doxorubicin influences the ordering of carbohydrate chains and does not strongly influence phosphate heads. This change seems to be partially reversible. In contrast, in vivo experiment the doxorubicin strongly influences the DNA structure, leading to DNA stabilization and formation of new H-bonds in DNA-doxorubicin complex. We have not registered the interaction of DNA with cis-platin in vivo experiment. Experiment in vitro for cis-platin incubation with phospholipids from cancer cells during 0.5 hour at 37°C has not shown those drastic structural peculiarities that it was observed in vivo experiments.

Synthesis, anticancer activity, and iron affinity of the Actinoplanes metabolite 7,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione.

PubMed

Breyer, Sandra; Effenberger-Neidnicht, Katharina; Knauer, Sebastian; Schobert, Rainer

2011-02-01

The first synthesis of 7,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione (1), an isofuranonaphthoquinone produced by an Actinoplanes strain is described. Lactone ring opening of 6-methylfuro[3,4-c]furan-1(3H)-one (4) with ortho-lithiated veratrole (3), oxidation of product alcohol 5, and Friedel-Crafts acylation of the resulting aroylcarboxylic acid 7 afforded the mono methyl ether 2 of the target compound. The latter was obtained by demethylation of 2 with BBr(3) in 14% overall yield. While mono ether 2 was distinctly more cytotoxic than catechol 1 against a panel of five cancer cell lines, only the latter showed a siderophore-like binding affinity for Fe(III) with a complex dissociation constant K(D) of approximately 10(-29) M(3) (pM = 25.9). Copyright © 2010 Elsevier Ltd. All rights reserved.

Lipid Raft: A Floating Island Of Death or Survival

PubMed Central

George, Kimberly S.; Wu, Shiyong

2012-01-01

Lipid rafts are microdomains of the plasma membrane enriched in cholesterol and sphingolipids, and play an important role in the initiation of many pharmacological agent-induced signaling pathways and toxicological effects. The structure of lipid rafts is dynamic, resulting in an ever-changing content of both lipids and proteins. Cholesterol, as a major component of lipid rafts, is critical for the formation and configuration of lipid rafts microdomains, which provide signaling platforms capable of activating both pro-apoptotic and anti-apoptotic signaling pathways. A change of cholesterol level can result in lipid rafts disruption and activate or deactivate raft-associated proteins, such as death receptor proteins, protein kinases, and calcium channels. Several anti-cancer drugs are able to suppress growth and induce apoptosis of tumor cells through alteration of lipid raft contents via disrupting lipid raft integrity. PMID:22289360

Cultivation, characterization, and properties of Chlorella vulgaris microalgae with different lipid contents and effect on fast pyrolysis oil composition.

PubMed

Adamakis, Ioannis-Dimosthenis; Lazaridis, Polykarpos A; Terzopoulou, Evangelia; Torofias, Stylianos; Valari, Maria; Kalaitzi, Photeini; Rousonikolos, Vasilis; Gkoutzikostas, Dimitris; Zouboulis, Anastasios; Zalidis, Georgios; Triantafyllidis, Konstantinos S

2018-06-01

A systematic study of the effect of nitrogen levels in the cultivation medium of Chlorella vulgaris microalgae grown in photobioreactor (PBR) on biomass productivity, biochemical and elemental composition, fatty acid profile, heating value (HHV), and composition of the algae-derived fast pyrolysis (bio-oil) is presented in this work. A relatively high biomass productivity and cell concentration (1.5 g of dry biomass per liter of cultivation medium and 120 × 10 6 cells/ml, respectively) were achieved after 30 h of cultivation under N-rich medium. On the other hand, the highest lipid content (ca. 36 wt.% on dry biomass) was obtained under N-depletion cultivation conditions. The medium and low N levels favored also the increased concentration of the saturated and mono-unsaturated C16:0 and C18:1(n-9) fatty acids (FA) in the lipid/oil fraction, thus providing a raw lipid feedstock that can be more efficiently converted to high-quality biodiesel or green diesel (via hydrotreatment). In terms of overall lipid productivity, taking in consideration both the biomass concentration in the medium and the content of lipids on dry biomass, the most effective system was the N-rich one. The thermal (non-catalytic) pyrolysis of Chlorella vulgaris microalgae produced a highly complex bio-oil composition, including fatty acids, phenolics, ethers, ketones, etc., as well as aromatics, alkanes, and nitrogen compounds (pyrroles and amides), originating from the lipid, protein, and carbohydrate fractions of the microalgae. However, the catalytic fast pyrolysis using a highly acidic ZSM-5 zeolite, afforded a bio-oil enriched in mono-aromatics (BTX), reducing at the same time significantly oxygenated compounds such as phenolics, acids, ethers, and ketones. These effects were even more pronounced in the catalytic fast pyrolysis of Chlorella vulgaris residual biomass (after extraction of lipids), thus showing for the first time the potential of transforming this low value by-product towards high added value platform chemicals.

Linking Archaeal Molecular Diversity and Lipid Biomarker Composition in a Hypersaline Microbial Mat Community

NASA Technical Reports Server (NTRS)

Jahnke, Linda; Orphan, Victoria; Turk, Kendra; Embaye, Tsegereda; Kubo, Mike; Summons, Roger

2005-01-01

Lipid biomarkers for discrete microbial groups are a valuable tool for establishing links to ancient microbial ecosystems. Lipid biomarkers can establish organism source and function in contemporary microbial ecosystems (membrane lipids) and by analogy, potential relevance to the fossilized carbon skeletons (geolipids) extracted from ancient sedimentary rock. The Mars Exploration Rovers have provided clear evidence for an early wet Mars and the presence of hypersaline evaporitic basins. Ongoing work on an early Earth analog, the hypersaline benthic mats in Guerrero Negro, Baja California Sur, may provide clues to what may have evolved and flourished on an early wet Mars, if only for a short period. Cyanobacterial mats are a pertinent early Earth analog for consideration of evolutionary and microbial processes within the aerobic photosynthetic and adjacent anoxic layers. Fluctuations in physio-chemical parameters associated with spatial and temporal scales are expressed through vast microbial metabolic diversity. Our recent work hopes to establish the dynamic of archaeal diversity, particularly as it relates to methane production in this high sulfate environment, through the use of lipid biomarker and phylogenetic analyses. Archaeal 16s rRNA and mcrA gene assemblages, demonstrated distinct spatial separation over the 130 mm core of at least three distinct genera within the order Methanosarcinales, as well as an abundance of uncultured members of the Thermoplasmales and Crenarchaeota. Ether-bound lipid analysis identified abundant 0-alkyl and 0-isopranyl chains throughout the core, and the presence of sn-2 hydroxyarchaeol, a biomarker for methylotrophic methanogens. A unique ether isoprenoid chain, a C30:1 , possibly related to the geolipid squalane, a paleobiomarker associated with hypersaline environments, was most abundant within the oxic-anoxic transition zone.

Polybrominated diphenyl ethers and indicator polychlorinated biphenyls in human milk from China under the Stockholm Convention.

PubMed

Zhang, Lei; Yin, Shuaixing; Zhao, Yunfeng; Shi, Zhixiong; Li, Jingguang; Wu, Yongning

2017-12-01

Seven congeners of polybrominated diphenyl ethers (PBDEs) (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153,BDE-154 and BDE-183) and six indicator polychlorinated biphenyls (PCBs) (PCB-28, PCB-52, PCB-101, PCB-138, PCB-153 and PCB-180) were measured in 32 regional pooled human milk samples originating from 1760 volunteering primiparous mothers to evaluate the current human body burden of general population and the temporal trend in China. Individual human milk samples were collected following a WHO-designed procedure. This work is one of parts of the evaluation of effectiveness of Stockholm Convention performance. The concentration of ∑ 7 PBDEs ranged from 0.3 ng g -1 lipid to 4.0 ng g -1 lipid with a mean of 1.5 ng g -1 lipid. The concentration of ∑ 6 PCBs ranged from 2.3 ng g -1 lipid to 19.0 ng g -1 lipid with a mean of 6.6 ng g -1 lipid. By comparing with background determination in 2007, there was no significance for ∑ 7 PBDEs. However, BDE-47, BDE-99, and BDE-100 significantly decreased with an average of 45%, 48%, and 46%, respectively, from 2007 to 2011, and an increase of BDE-183 was founded in most regions. For ∑ 6 PCBs, there was a significant decline with an average reduction of 41% from 2007 to 2011. These results indicate the effectiveness of reduction and elimination of POPs in China. Future national human milk biomonitoring is worthy to be done to further evaluate the time trend and effectiveness of the Convention performance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Diacyl, alkenyl, and alkyl ether phospholipids in ejaculated, in utero-, and in vitro-incubated porcine spermatozoa.

PubMed

Evans, R W; Weaver, D E; Clegg, E D

1980-02-01

The phospholipids of porcine spermatozoa were analyzed by a hydrolytic procedure directly after ejaculation, and after incubation for 120 min in vitro or in ligated uterine segments of females with induced estrus. Total phospholipid content of ejaculated sperm was 65.7 micro g lipid P per 10(9) sperm, of which 41% was alkyl ether and 23% was alkenyl ether glycerophospholipid. All of the ether phospholipids were choline and ethanolamine glycerophospholipids. In order of decreasing amount (% of total phospholipid), the phospholipids were choline and ethanolamine glycerophospholipids (49.9 and 28.2), sphingolipid (10.6), cardiolipin (5.5), phosphatidylinositol (2.3), phosphatidic acid (1.5), phosphatidylserine (1.2), and phosphatidylglycerol (0.8). Phosphorus-containing sphingolipid separated into two components during thin-layer chromatography. Sphingosine was the only long-chain base identified in either band. Major fatty acids in the band with lower R(f) were 16:0 (56%), 20:0 (23%), and 18:0 (11%) plus smaller amounts of 14:0, 18:1, and 22:0, while those in the band with higher R(f) were 14:0 (30%), 16:0 (45%), and 18:1 (12%) plus smaller amounts of 18:0, 20:0, and 22:0. Choline was the only water-soluble base present in the lower R(f) sphingomyelin while ethanolamine was prevalent in the higher R(f) component. Incubation of washed spermatozoa in Ca(2+)-free Ringer-fructose at 37 degrees C for 2 hr produced no significant change in the level of any of the phospholipids. Incubation of washed sperm in the uterus for 2 hr, in the presence of oviductal secretions, produced an increase in phosphatidylcholine from 7.2 to 10.2 micro g lipid P per 10(9) sperm.-Evans, R. W., D. E. Weaver, and E. D. Clegg. Diacyl, alkenyl, and alkyl ether phospholipids in ejaculated, in utero-, and in vitro-incubated porcine spermatozoa.

The influence of water mixtures on the dermal absorption of glycol ethers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Traynor, Matthew J.; Wilkinson, Simon C.; Williams, Faith M.

2007-01-15

Glycol ethers are solvents widely used alone and as mixtures in industrial and household products. Some glycol ethers have been shown to have a range of toxic effects in humans following absorption and metabolism to their aldehyde and acid metabolites. This study assessed the influence of water mixtures on the dermal absorption of butoxyethanol and ethoxyethanol in vitro through human skin. Butoxyethanol penetrated human skin up to sixfold more rapidly from aqueous solution (50%, 450 mg/ml) than from the neat solvent. Similarly penetration of ethoxyethanol was increased threefold in the presence of water (50%, 697 mg/ml). There was a correspondingmore » increase in apparent permeability coefficient as the glycol ether concentration in water decreased. The maximum penetration rate of water also increased in the presence of both glycol ethers. Absorption through a synthetic membrane obeyed Fick's Law and absorption through rat skin showed a similar profile to human skin but with a lesser effect. The mechanisms for this phenomenon involves disruption of the stratum corneum lipid bilayer by desiccation by neat glycol ether micelles, hydration with water mixtures and the physicochemical properties of the glycol ether-water mixtures. Full elucidation of the profile of absorption of glycol ethers from mixtures is required for risk assessment of dermal exposure. This work supports the view that risk assessments for dermal contact scenarios should ideally be based on absorption data obtained for the relevant formulation or mixture and exposure scenario and that absorption derived from permeability coefficients may be inappropriate for water-miscible solvents.« less

Radioiodinated cholesteryl ester analogs as residualizing tracers of lipoproteins disposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeForge, L.E.

1989-01-01

Due to the importance of low density lipoprotein (LDL) in lipid metabolism and atherosclerosis, efforts were made to incorporate {sup 125}I-cholesteryl iopanoate ({sup 125}I-CI), a residualizing cholesteryl ester (CE) analog, into the lipid core of LDL. This preparation is potentially useful as a scintigraphically detectable tracer of LDL uptake into atheroma and tissues such as the adrenal and liver. Initial studies using a cholesterol-fed rabbit model of atherosclerosis validated the use of {sup 125}I-CI as a tracer of CE deposition. However, scintigraphy revealed considerable nonspecific {sup 125}I-CI uptake due to tissue cholesterol loading. An alternative animal model was the guineamore » pig, which responds moderately to cholesterol feeding and carries the plasma cholesterol predominantly as LDL. Dietary fat and cholesterol, coupled with chronic aortic injury caused by an indwelling catheter, resulted in lipid containing, smooth muscle cell proliferative lesions in many animals. However, further studies are necessary to fully characterize this model. In additional studies, in vitro methods for incorporating {sup 125}I-CI into LDL were examined. These included a reconstitution procedure described by Krieger et al. and a procedure involving incubation of detergent (Tween 20)-solubilized {sup 125}I-CI with plasma. Although both LDL preparations were taken up normally by cultured fibroblasts, the plasma clearance rate of reconstituted LDL was markedly abnormal in guinea pigs. In contrast, LDL labeled by the detergent method cleared from the plasma identically to a radioiodinated LDL control. Therefore, this latter procedure was also used to incorporate two novel radioiodinated cholesteryl ether analogs {sup 125}I-CI cholesteryl m-iodobenzyl ether ({sup 125}I-CIDE) and {sup 125}I-cholesteryl 12-(miodophenyl)dodecyl ether ({sup 125}I-CIDE) into LDL.« less

Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells.

PubMed

Alawin, Osama A; Ahmed, Rayan A; Ibrahim, Baher A; Briski, Karen P; Sylvester, Paul W

2016-01-01

A large percentage of human breast cancers are characterized by excessive or aberrant HER2 activity. Lipid rafts are specialized microdomains within the plasma membrane that are required for HER2 activation and signal transduction. Since the anticancer activity of γ-tocotrienol is associated with suppression in HER2 signaling, studies were conducted to examine the effects of γ-tocotrienol on HER2 activation within the lipid raft microdomain in HER2-positive SKBR3 and BT474 human breast cancer cells. Treatment with 0-5μM γ-tocotrienol induced a significant dose-dependent inhibition in cancer cell growth after a 5-day culture period, and these growth inhibitory effects were associated with a reduction in HER2 dimerization and phosphorylation (activation). Phosphorylated HER2 was found to be primarily located in the lipid raft microdomain of the plasma membrane in vehicle-treated control groups, whereas γ-tocotrienol treatment significantly inhibited this effect. Assay of plasma membrane subcellular fractions showed that γ-tocotrienol also accumulates exclusively within the lipid raft microdomain. Hydroxypropyl-β-cyclodextrin (HPβCD) is an agent that disrupts lipid raft integrity. Acute exposure to 3mM HPβCD alone had no effect, whereas an acute 24-h exposure to 20μM γ-tocotrienol alone significantly decreased SKBR3 and BT474 cell viability. However, combined treatment with these agents greatly reduced γ-tocotrienol accumulation in the lipid raft microdomain and cytotoxicity. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are associated with its accumulation in the lipid raft microdomain and subsequent interference with HER2 dimerization and activation in SKBR3 and BT474 human breast cancer cells. Copyright © 2015 Elsevier Inc. All rights reserved.

The effect of virtual cross linking on the oxidative stability and lipid uptake of aliphatic poly(urethane urea).

PubMed

Thomas, Vinoy; Jayabalan, Muthu

2002-01-01

In vitro oxidative degradation and lipid sorption of aliphatic, low elastic modulus and virtually cross-linked poly(urethane urea)s based on 4,4' methylene bis(cyclohexyl isocyanate), hydroxy terminated poly butadiene and hexamethylene diamine were evaluated. The aged samples revealed no weight loss in the oxidation medium. The IR spectral analyses revealed the stability of unsaturated double bonds at 964 cm(-1) (characteristic for polybutadiene soft segment) with no change in peak intensity. The poly(tetramethylene glycol) (PTMG)-added poly(ether urethane urea) polymer also revealed no disappearance of IR peaks for ether and unsaturated double bonds in samples aged in vitro oxidation medium. All the polymers have shown increase in weight due to lipid up take in lipid-rich medium (palm oil) but it was rather low in Dulbecco's modified eagle medium (DMEM) cholesterol. The slight change in mechanical properties of the present polymers in oxidation and DMEM is due to the rearrangement of molecular structure with virtual cross links of hydrogen bonding (physical cross linking) without degradation and plasticization effect of lipid. The influence of these media on the rearrangement of virtual cross links has been observed. Higher the virtual cross-link density, lesser is the loss of tensile properties of poly(urethane urea)s in the oxidation medium and vice versa. On the other hand, higher the virtual cross-link density of poly(urethane urea), higher is the loss of ultimate tensile strength and stress at 100% strain and vice versa in DMEM medium.

Synthesis and validation of novel cholesterol-based fluorescent lipids designed to observe the cellular trafficking of cationic liposomes.

PubMed

Kim, Bieong-Kil; Seu, Young-Bae; Choi, Jong-Soo; Park, Jong-Won; Doh, Kyung-Oh

2015-09-15

Cholesterol-based fluorescent lipids with ether linker were synthesized using NBD (Chol-E-NBD) or Rhodamine B (Chol-E-Rh), and the usefulnesses as fluorescent probes for tracing cholesterol-based liposomes were validated. The fluorescent intensities of liposomes containing these modified lipids were measured and observed under a microscope. Neither compound interfered with the expression of GFP plasmid, and live cell images were obtained without interferences. Changes in the fluorescent intensity of liposomes containing Chol-E-NBD were followed by flow cytometry for up to 24h. These fluorescent lipids could be useful probes for trafficking of cationic liposome-mediated gene delivery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Influence of interfacial and bulk properties of cellulose ethers on lipolysis of oil-in-water emulsions.

PubMed

Torcello-Gómez, Amelia; Foster, Timothy J

2016-06-25

Cellulose ethers are usually used as secondary emulsifiers. Different types of commercial hydroxypropylmethylcellulose (HPMC) have been used here as the main emulsifier of oil-in-water emulsions to probe their impact on the lipid digestibility under simulated intestinal conditions. The droplet size distribution and ζ-potential of the emulsions subjected to in-vitro lipolysis have been compared with that of control samples (non-digested). The lipolysis has been quantified over time by means of the pH-stat method. The displacement of HPMC from the oil-water interface by bile salts has been assessed by interfacial tension technique. Results show that HPMC delays the lipid digestion of emulsions regardless of the Mw and methoxyl content. The destabilisation of emulsions under intestinal conditions as well as the resistance of HPMC to be displaced from the emulsion interface by bile salts may contribute to this feature. This provides new insights into the mechanisms whereby dietary fibre reduces fat absorption. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antibacterial liamocins with alternative carbohydrate headgroups

USDA-ARS?s Scientific Manuscript database

Liamocins are unique polyol lipids with biosurfactant, anticancer, and antibacterial properties, produced by certain strains of the fungus Aureobasidium pullulans. Liamocins have potential agricultural and pharmaceutical applications as antibacterials with specificity against Streptococcus sp. There...

Stepwise encapsulation and controlled two-stage release system for cis-Diamminediiodoplatinum

PubMed Central

Chen, Yun; Li, Qian; Wu, Qingsheng

2014-01-01

cis-Diamminediiodoplatinum (cis-DIDP) is a cisplatin-like anticancer drug with higher anticancer activity, but lower stability and price than cisplatin. In this study, a cis-DIDP carrier system based on micro-sized stearic acid was prepared by an emulsion solvent evaporation method. The maximum drug loading capacity of cis-DIDP-loaded solid lipid nanoparticles was 22.03%, and their encapsulation efficiency was 97.24%. In vitro drug release in phosphate-buffered saline (pH =7.4) at 37.5°C exhibited a unique two-stage process, which could prove beneficial for patients with tumors and malignancies. MTT (3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay results showed that cis-DIDP released from cis-DIDP-loaded solid lipid nanoparticles had better inhibition activity than cis-DIDP that had not been loaded. PMID:25061294

From ether to acid: A plausible degradation pathway of glycerol dialkyl glycerol tetraethers

NASA Astrophysics Data System (ADS)

Liu, Xiao-Lei; Birgel, Daniel; Elling, Felix J.; Sutton, Paul A.; Lipp, Julius S.; Zhu, Rong; Zhang, Chuanlun; Könneke, Martin; Peckmann, Jörn; Rowland, Steven J.; Summons, Roger E.; Hinrichs, Kai-Uwe

2016-06-01

Glycerol dialkyl glycerol tetraethers (GDGTs) are ubiquitous microbial lipids with extensive demonstrated and potential roles as paleoenvironmental proxies. Despite the great attention they receive, comparatively little is known regarding their diagenetic fate. Putative degradation products of GDGTs, identified as hydroxyl and carboxyl derivatives, were detected in lipid extracts of marine sediment, seep carbonate, hot spring sediment and cells of the marine thaumarchaeon Nitrosopumilus maritimus. The distribution of GDGT degradation products in environmental samples suggests that both biotic and abiotic processes act as sinks for GDGTs. More than a hundred newly recognized degradation products afford a view of the stepwise degradation of GDGT via (1) ether bond hydrolysis yielding hydroxyl isoprenoids, namely, GDGTol (glycerol dialkyl glycerol triether alcohol), GMGD (glycerol monobiphytanyl glycerol diether), GDD (glycerol dibiphytanol diether), GMM (glycerol monobiphytanol monoether) and bpdiol (biphytanic diol); (2) oxidation of isoprenoidal alcohols into corresponding carboxyl derivatives and (3) chain shortening to yield C39 and smaller isoprenoids. This plausible GDGT degradation pathway from glycerol ethers to isoprenoidal fatty acids provides the link to commonly detected head-to-head linked long chain isoprenoidal hydrocarbons in petroleum and sediment samples. The problematic C80 to C82 tetraacids that cause naphthenate deposits in some oil production facilities can be generated from H-shaped glycerol monoalkyl glycerol tetraethers (GMGTs) following the same process, as indicated by the distribution of related derivatives in hydrothermally influenced sediments.

Composition changes in the cuticular surface lipids of the helophytes Phragmites australis and Juncus effusus as result of pollutant exposure.

PubMed

Macherius, André; Kuschk, Peter; Haertig, Claus; Moeder, Monika; Shtemenko, Natalia I; Bayona, Antonio Heredia; Guerrero, José A Heredia; Gey, Manfred

2011-06-01

Helophytes like rush and reed are increasingly used for phytoremediation of contaminated water. This study characterises the response of rush and reed plants to chemical stressors such as chlorobenzene, benzene and methyl-tert-butyl ether. The extractable wax layer of the cuticle was chosen for detailed investigations due to its multiple, particularly, protective functions for plants and its easy availability for analysis. The chemical composition of the cuticle wax layer of reed and rush was studied in dependence on chemical stress caused by contaminated water under wetland cultivation conditions. The lipid layer of leaves was extracted, derivatised and investigated by GC-MS using retention time locking and a plant-specific data base. In case of rush, a remarkable increase of the total lipid layer and a prolongation of the mean chain length resulted as response on a chlorobenzene exposure. The significant difference in the substance profiles of exposed plants and controls could be confirmed by multivariate data analysis. The lipid layer of reed was not changed significantly when the plants were exposed to water polluted with benzene and methyl-tert-butyl ether. However, scanning electron microscopic images of the exposed reed leaves indicated alterations in the crystal structure of their wax surface. The composition and morphology of cuticular waxes indicated the plants' response to chemical stress very sensitively thus, changes in the wax layer could be used as an indication for growing in a contaminated area.

Simultaneous quantification of epoxy and hydroxy fatty acids as oxidation products of triacylglycerols in edible oils.

PubMed

Xia, Wei; Budge, Suzanne M

2018-02-16

Epoxy and hydroxy fatty acids are important intermediates during lipid oxidation; quantification of both structures may help evaluate the extent of competition among various lipid oxidation pathways. This article describes a method to simultaneously determine saturated- and unsaturated- epoxy and hydroxy fatty acids derived from oxidation of vegetable oils. The experimental procedures employed transesterification with sodium methoxide, separation of epoxy and hydroxy fatty acid methyl esters (FAME) using solid-phase extraction (SPE), and trimethylsilyl (TMS) derivatization of hydroxy groups. GC-MS was used to identify the epoxy and hydroxy FAME in two different SPE fractions, while GC-flame ionization detection (GC-FID) was used to determine their quantities. Epoxy-octadecanoate/octadecenoate and hydroxy-octadecanoate/octadecenoate/octadecadienoate were determined as lipid oxidation products generated from oxidation of sunflower and canola oils. An isomer of methyl 13-hydroxyoctadeca-9,11-dienoate (13-HODE) TMS ether co-eluted with methyl 15-hydroxyoctadeca-9,12-dienoate TMS ether, which was only present in canola oil; thus, GC-MS-selected ion monitoring (GC-MS-SIM) was used to determine the concentration of 13-HODE. The proposed method has been successfully applied to monitor epoxy and hydroxy fatty acids in sunflower oil and canola oil oxidized at 40 °C. Copyright © 2017 Elsevier B.V. All rights reserved.

Fatty Aldehyde and Fatty Alcohol Metabolism: Review and Importance for Epidermal Structure and Function

PubMed Central

Rizzo, William B.

2014-01-01

Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. PMID:24036493

Persistent organic pollutants in red-crowned cranes (Grus japonensis) from Hokkaido, Japan.

PubMed

Kakimoto, Kensaku; Akutsu, Kazuhiko; Nagayoshi, Haruna; Konishi, Yoshimasa; Kajimura, Keiji; Tsukue, Naomi; Yoshino, Tomoo; Matsumoto, Fumio; Nakano, Takeshi; Tang, Ning; Hayakawa, Kazuichi; Toriba, Akira

2018-01-01

The red-crowned crane (Grus japonensis) from eastern Hokkaido is classified as a Special Natural Monument in Japan. In this study, we determined the concentrations of persistent organic pollutants (POPs) in red-crowned crane muscle tissues (n = 47). Polychlorinated biphenyls (PCBs) had the highest median concentration (240ng/g lipid weight), followed by dichlorodiphenyltrichloroethane and its metabolites (DDTs) (150ng/g lipid weight), chlordane-related compounds (CHLs) (36ng/g lipid weight), hexachlorobenzene (HCB) (16ng/g lipid weight), hexachlorocyclohexanes (HCHs) (4.4ng/g lipid weight), polybrominated diphenyl ethers (PBDEs) (1.8ng/g lipid weight), and finally, Mirex (1.5ng/g lipid weight). Additionally, a positive correlation was found among POP concentrations. No sex differences beyond body parameters were observed. Additionally, red-crowned cranes exhibited a high enantiomeric excess of (+)-alpha-HCH, with enantiomer fractions varying from 0.51 to 0.87 (average: 0.69). Copyright © 2017 Elsevier Inc. All rights reserved.

[The composition of lipids and lipid peroxidation in the pancreas of quails exposed to nitrates and correction by the amaranth's seeds].

PubMed

Tsekhmistrenko, S I; Ponomarenko, N V

2013-01-01

Researches of features of lipid composition, functioning of the system of antioxidant defense, maintenance of lipid peroxidation products in the quail's pancreas on the early postnatal ontogenesis stages are conducted for actions of nitrates and feeding with amaranth's seeds in mixed fodder. The arrival of nitrates in the organism of quails results in the decline of general lipids maintenance and nonetherified fat acids in the pancreas. Using of amaranth's seeds in mixed fodder on the background of the nitrate loading results in the increase of activity of the enzimes system of antioxidant defence, the growth of general lipid level in the quail's pancreas. Thus in correlation with separate classes of lipid maintenance of cholesterol goes down for certain, whereas the maintenance of triacylglycerols and ethers of cholesterol rises. The results obtained in the researches show the ability of amaranth's seeds to avert oxidative stress in quail's pancreas under nitrates influence.

Process optimization and photostability of silymarin nanostructured lipid carriers: effect on UV-irradiated rat skin and SK-MEL 2 cell line.

PubMed

Singh, Pooja; Singh, Mahendra; Kanoujia, Jovita; Arya, Malti; Saraf, Shailendra K; Saraf, Shubhini A

2016-10-01

The objective of the present work was to formulate a novel stable delivery system which would not only overcome the solubility issue of silymarin, but also help to increase the therapeutic value by better permeation, anticancer action and reduced toxicity. This was envisaged through the recent developments in nanotechnology, combined with the activity of the phytoconstituent silymarin. A 2(3) full factorial design based on three independent variables was used for process optimization of nanostructured lipid carriers (NLC). Developed formulations were evaluated on the basis of particle size, morphology, in vitro drug release, photostability and cell line studies. Optimized silymarin-NLC was incorporated into carbopol gel and further assessed for rheological parameters. Stable behaviour in presence of light was proven by photostability testing of formulation. Permeability parameters were significantly higher in NLC as compared to marketed phytosome formulation. The NLC based gel described in this study showed faster onset, and prolonged activity up to 24 h and better action against edema as compared to marketed formulation. In case of anticancer activity of silymarin-NLC against SK-MEL 2 cell lines, silymarin-NLC proved to possess anticancer activity in a dose-dependent manner (10-80 μM) and induced apoptosis at 80 μM in SK-MEL 2 cancer cells. This work documents for the first time that silymarin can be formulated into nanostructured lipoidal carrier system for enhanced permeation, greater stability as well as anticancer activity for skin.

Interannual variations in the lipids of the Antarctic pteropods Clione limacina and Clio pyramidata.

PubMed

Phleger, C F; Nelson, M M; Mooney, B D; Nichols, P D

2001-03-01

Antarctic pteropods, Clione limacina (Order Gymnosomata) and Clio pyramidata (order Thecosomata), were collected near Elephant Island, South Shetland Islands, during 1997 and 1998. Total lipid was high in C. limacina (29--36 mg g(-1) wet mass) and included 46% of diacy1glyceryl ether (DAGE, as % of total lipid) for both 1997 and 1998. DAGE was not detected in C. pyramidata, which had mainly polar lipid and triacy1glycerol. 1-O-Alkyl glyceryl ethers (GE) derived from the DAGE consisted primarily of 15:0 and 16:0, with lower 17:0 and a17:0. The principal sterols of both pteropods included trans-dehydrocholesterol, brassicasterol, 24-methylenecholesterol, cholesterol and desmosterol. Levels of 24-methylenecholesterol and desmosterol were lower in both pteropods in 1997 compared to 1998. C. limacina had high levels of the odd-chain fatty acids 17:1(n--8)c and 15:0 in contrast to C. pyramidata. The previously proposed source of elevated odd-chain fatty acids in C. limacina is via propionate derived from phytoplankton DMPT; another possible source may be from thraustochytrids, which are common marine microheterotrophs. C. pyramidata had twice as much PUFA as C. limacina, largely due to higher 20:5(n--3). The PUFA 18:5(n--3) and very long chain fatty acids (C(24), C(26) and C(28) VLC-PUFA) were only detected in 1998 pteropods. In comparison, 1996 samples of C. limacina contained lower DAGE levels, which also may reflect differences in diet and oceanographic conditions. Interannual variations in specific lipid biomarkers are discussed with respect to possible different phytoplankton food sources available in the AMLR survey area.

Selective pressurized liquid extraction of pesticides, polychlorinated biphenyls and polybrominated diphenyl ethers in a whale earplug (earwax): a novel method for analyzing organic contaminants in lipid-rich matrices.

PubMed

Robinson, Eleanor M; Trumble, Stephen J; Subedi, Bikram; Sanders, Rebel; Usenko, Sascha

2013-12-06

Lipid-rich matrices are often sinks for lipophilic contaminants, such as pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). Typically methods for contaminant extraction and cleanup for lipid-rich matrices require multiple cleanup steps; however, a selective pressurized liquid extraction (SPLE) technique requiring no additional cleanup has been developed for the simultaneous extraction and cleanup of whale earwax (cerumen; a lipid-rich matrix). Whale earwax accumulates in select whale species over their lifetime to form wax earplugs. Typically used as an aging technique in cetaceans, layers or laminae that comprise the earplug are thought to be associated with annual or semiannual migration and feeding patterns. Whale earplugs (earwax) represent a unique matrix capable of recording and archiving whales' lifetime contaminant profiles. This study reports the first analytical method developed for identifying and quantifying lipophilic persistent organic pollutants (POPs) in a whale earplug including organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). The analytical method was developed using SPLE to extract contaminants from ∼0.25 to 0.5g aliquots of each lamina of sectioned earplug. The SPLE was optimized for cleanup adsorbents (basic alumina, silica gel, and Florisil(®)), adsorbent to sample ratio, and adsorbent order. In the optimized SPLE method, the earwax homogenate was placed within the extraction cell on top of basic alumina (5g), silica gel (15g), and Florisil(®) (10g) and the target analytes were extracted from the homogenate using 1:1 (v/v) dichloromethane:hexane. POPs were analyzed using gas chromatography-mass spectrometry with electron capture negative ionization and electron impact ionization. The average percent recoveries for the POPs were 91% (±6% relative standard deviation), while limits of detection and quantification ranged from 0.00057 to 0.96ngg(-1) and 0.0017 to 2.9ngg(-1), respectively. Pesticides, PCBs, and PBDEs, were measured in a single blue whale (Balaenoptera musculus) cerumen lamina at concentrations ranging from 0.11 to 150ng g(-1). Copyright © 2013 Elsevier B.V. All rights reserved.

Lipid Metabolism, Apoptosis and Cancer Therapy

PubMed Central

Huang, Chunfa; Freter, Carl

2015-01-01

Lipid metabolism is regulated by multiple signaling pathways, and generates a variety of bioactive lipid molecules. These bioactive lipid molecules known as signaling molecules, such as fatty acid, eicosanoids, diacylglycerol, phosphatidic acid, lysophophatidic acid, ceramide, sphingosine, sphingosine-1-phosphate, phosphatidylinositol-3 phosphate, and cholesterol, are involved in the activation or regulation of different signaling pathways. Lipid metabolism participates in the regulation of many cellular processes such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, motility, membrane homeostasis, chemotherapy response, and drug resistance. Bioactive lipid molecules promote apoptosis via the intrinsic pathway by modulating mitochondrial membrane permeability and activating different enzymes including caspases. In this review, we discuss recent data in the fields of lipid metabolism, lipid-mediated apoptosis, and cancer therapy. In conclusion, understanding the underlying molecular mechanism of lipid metabolism and the function of different lipid molecules could provide the basis for cancer cell death rationale, discover novel and potential targets, and develop new anticancer drugs for cancer therapy. PMID:25561239

Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs.

PubMed

Lukyanov, Anatoly N; Torchilin, Vladimir P

2004-05-07

Polymeric micelles have a whole set of unique characteristics, which make them very promising drug carriers, in particular, for poorly soluble drugs. Our review article focuses on micelles prepared from conjugates of water-soluble polymers, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone (PVP), with phospholipids or long-chain fatty acids. The preparation of micelles from certain polymer-lipid conjugates and the loading of these micelles with various poorly soluble anticancer agents are discussed. The data on the characterization of micellar preparations in terms of their morphology, stability, longevity in circulation, and ability to spontaneously accumulate in experimental tumors via the enhanced permeability and retention (EPR) effect are presented. The review also considers the preparation of targeted immunomicelles with specific antibodies attached to their surface. Available in vivo results on the efficiency of anticancer drugs incorporated into plain micelles and immunomicelles in animal models are also discussed.

Physico-chemical characterisation, cytotoxic activity, and biocompatibility studies of tamoxifen-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification method.

PubMed

Lakkadwala, Sushant; Nguyen, Sanko; Lawrence, Joseph; Nauli, Surya M; Nesamony, Jerry

2014-01-01

Solid lipid nanoparticles (SLNs) can efficiently and efficaciously incorporate anti-cancer agents. To prepare and characterise tamoxifen (TAM)-loaded SLNs. Glyceryl monostearate, Tween-80, and trehalose were used in SLNs. SLNs were tested via dynamic light scattering (DLS), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Characterisation studies revealed SLNs of about 540 nm with a negative surface charge and confirmed the entrapment of TAM in the SLNs. The entrapment efficiency was estimated to be 60%. The in vitro drug release profile demonstrated a gradual increase followed by a release plateau for several days. A drug concentration-dependent increase in cytotoxic activity was observed when the SLNs were evaluated in cell cultures. Biocompatible and stable lyophilised SLNs were successfully prepared and found to possess properties that may be utilised in an anti-cancer drug delivery system.

Quantitative Proteomic Analysis Reveals That Anti-Cancer Effects of Selenium-Binding Protein 1 In Vivo Are Associated with Metabolic Pathways

PubMed Central

Ying, Qi; Ansong, Emmanuel; Diamond, Alan M.; Lu, Zhaoxin; Yang, Wancai; Bie, Xiaomei

2015-01-01

Previous studies have shown the tumor-suppressive role of selenium-binding protein 1 (SBP1), but the underlying mechanisms are unclear. In this study, we found that induction of SBP1 showed significant inhibition of colorectal cancer cell growth and metastasis in mice. We further employed isobaric tags for relative and absolute quantitation (iTRAQ) to identify proteins that were involved in SBP1-mediated anti-cancer effects in tumor tissues. We identified 132 differentially expressed proteins, among them, 53 proteins were upregulated and 79 proteins were downregulated. Importantly, many of the differentially altered proteins were associated with lipid/glucose metabolism, which were also linked to Glycolysis, MAPK, Wnt, NF-kB, NOTCH and epithelial-mesenchymal transition (EMT) signaling pathways. These results have revealed a novel mechanism that SBP1-mediated cancer inhibition is through altering lipid/glucose metabolic signaling pathways. PMID:25974208

Cellular Lipids of a Nocardia Grown on Propane and n-Butane

PubMed Central

Davis, J. B.

1964-01-01

Lipid fractions of propane- and n-butane-grown nocardial cells each contain a chloroform-soluble, ether-insoluble polymer not observed previously in liquid n-alkane-grown cells. The polymer in propane-grown cells is poly-β-hydroxybutyrate. The polymer in n-butane-grown cells apparently contains unsaturation in the molecule, and is identified tentatively as a co-polymer of β-hydroxybutyric and β-hydroxybutenoic (specifically 3-hydroxy 2-butenoic) acids. The other major component of the lipid fraction consists of triglycerides containing principally palmitic and stearic acids. There seems to be little qualitative distinction in the glycerides of propane- or n-butane-grown cells. Oxidative assimilation of n-butane is described. PMID:14199017

Vitamin E and its anticancer effects.

PubMed

Abraham, Annette; Kattoor, Ajoe John; Saldeen, Tom; Mehta, Jawahar L

2018-05-10

Vitamin E is a lipid soluble vitamin comprising of eight natural isoforms, namely, α, β, δ, γ isoforms of tocopherol and α, β, δ, γ isoforms of tocotrienol. Many studies have been performed to elucidate its role in cancer. Until last decade, major focus was on alpha tocopherol and its anticancer effects. However, major clinical trials using alpha-tocopherol like SELECT trial and ATBC trial did not yield meaningful results. Hence there was a shift of focus to gamma-tocopherol, delta-tocopherol and tocotrienol. Unlike alpha-tocopherol, gamma-tocopherol and delta-tocopherol can scavenge reactive nitrogen species in addition to reactive oxygen species. Antiangiogenic effect, inhibition of HMG CoA reductase enzyme and inhibition of NF-κB pathway make the anti-cancer effects of tocotrienols unique compared to other vitamin E isoforms. Preclinical research on non-alpha tocopherol isoforms of vitamin E showed promising data on their anticancer effects. In this review, we deal with the current understanding on the potential mechanisms involved in the anticancer effects of vitamin E and the controversies in this field over last three decades. We also highlight the need to conduct further research on the anticancer effects of non-alpha-tocopherol isoforms in larger population and clinical setting.

Development of Clickable Monophosphoryl Lipid A Derivatives toward Semisynthetic Conjugates with Tumor-Associated Carbohydrate Antigens.

PubMed

Ziaco, Marcello; Górska, Sabina; Traboni, Serena; Razim, Agnieszka; Casillo, Angela; Iadonisi, Alfonso; Gamian, Andrzej; Corsaro, Maria Michela; Bedini, Emiliano

2017-12-14

A semisynthetic strategy to obtain monophosphoryl lipid A derivatives equipped with clickable (azide, alkyne, double bond, or thiol precursor) moieties, starting from the native lipid A isolated from Escherichia coli, is presented. These lipid A derivatives can be conjugated with other interesting biomolecules, such as tumor-associated carbohydrate antigens (TACAs). In this way, the immunostimulant activity of monophosphoryl lipid A can significantly improve the immunogenicity of TACAs, thus opening access to potential self-adjuvant anticancer vaccine candidates. A monophosphoryl lipid A-Thomson-Friedenreich (TF) antigen conjugate was obtained to demonstrate the feasibility of this methodology, which stands as a valuable, rapid, and scalable alternative to the highly complex approaches of total synthesis recently reported to the same aim. A preliminary evaluation of the immunological activity of this conjugate as well as of other semisynthetic lipid A derivatives was also reported.

Isolation and Characterization of the Anticancer Compound Piceatannol from Sophora Interrupta Bedd

PubMed Central

Mathi, Pardhasaradhi; Das, Snehasish; Nikhil, Kumar; Roy, Partha; Yerra, Srikanth; Ravada, Suryachandra Rao; Bokka, Venkata Raman; Botlagunta, Mahendran

2015-01-01

Background: Sophora belongs to the family of Fabaceae and the species in this genus are currently used as a folklore medicine for preventing a variety of ailments including cancer. Our aim was to identify and validate an anticancer compound from Sophora interrupta using multi-spectroscopic, anticancer screening, and molecular docking approach. Methods: The cytotoxicity of the various solvent extracts, petroleum ether, n-butanol, and ethyl acetate (EtOAc) of the S. interrupta root powder was evaluated in a breast cancer cell lines (MCF-7). The extract that had anticancer activity was subjected to column chromatography based on the polarity of the solvents. The anticancer activity of the elution fractions was validated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The isolated metabolite fraction with anticancer activity was run through a C18 column isocratic and gradient high-performance liquid chromatography (HPLC). The structure of the isolated compound was characterized using 1H nuclear magnetic resonance (NMR), 13C-NMR, Fourier transform infrared spectroscopy, and liquid chromatography-mass spectrometer methods. Results: The crude EtAOc extract effectively inhibited the proliferation of MCF-7 cells. The column eluted chloroform and EtOAc (4:6) fraction of the EtOAc extract showed significant anticancer activity in the MCF-7 cells compared with normal mesenchymal stem cells. This fraction showed three major peaks in the HPLC chromatogram and the first major peak with a retention time (RT) of 7.153 was purified using preparative-HPLC. The structure of the compound is a piceatannol, which is a metabolic product of resveratrol. Piceatannol formed direct two hydrogen bond interactions between Cys912 (2H), and Glu878 of vascular endothelial growth factor receptor 1 (VEGFR1) with a glide-score (G-score) of −10.193, and two hydrogen bond interactions between Cys919, and Asp1046 of VEGFR2, with a G-score of −8.359. The structure is similar to that of the crystallized protein for VEGFR1 and R2. Conclusions: Piceatannol is a secondary metabolite of S. interrupta that has anticancer activity. Moreover, piceatannol has been isolated for the first time from S. interrupta. PMID:26605022

An improved high-throughput lipid extraction method for the analysis of human brain lipids.

PubMed

Abbott, Sarah K; Jenner, Andrew M; Mitchell, Todd W; Brown, Simon H J; Halliday, Glenda M; Garner, Brett

2013-03-01

We have developed a protocol suitable for high-throughput lipidomic analysis of human brain samples. The traditional Folch extraction (using chloroform and glass-glass homogenization) was compared to a high-throughput method combining methyl-tert-butyl ether (MTBE) extraction with mechanical homogenization utilizing ceramic beads. This high-throughput method significantly reduced sample handling time and increased efficiency compared to glass-glass homogenizing. Furthermore, replacing chloroform with MTBE is safer (less carcinogenic/toxic), with lipids dissolving in the upper phase, allowing for easier pipetting and the potential for automation (i.e., robotics). Both methods were applied to the analysis of human occipital cortex. Lipid species (including ceramides, sphingomyelins, choline glycerophospholipids, ethanolamine glycerophospholipids and phosphatidylserines) were analyzed via electrospray ionization mass spectrometry and sterol species were analyzed using gas chromatography mass spectrometry. No differences in lipid species composition were evident when the lipid extraction protocols were compared, indicating that MTBE extraction with mechanical bead homogenization provides an improved method for the lipidomic profiling of human brain tissue.

Involvement of ROS-p38-H2AX axis in novel curcumin analogues-induced apoptosis in breast cancer cells.

PubMed

Dong, Yinhui; Yin, Shutao; Song, Xinhua; Huo, Yazhen; Fan, Lihong; Ye, Min; Hu, Hongbo

2016-04-01

Curcumin-based structural modification for developing more effective curcumin analogues has been drawning increasing attention. As alternative approach, using LC/MS guided purification, we previously obtained a series of novel natural terpene-conjugated curcuminoids from turmeric, and some of them exhibited even more potent anti-cancer activity against multiple types of cancer cells than curcumin. The purpose of this follow-up study was designed to decipher the mechanisms involved in anti-cancer activity of these novel curcumin analogues. Apoptosis was evaluated using sub-G1 analysis by flow cytometry and Cell Death ELISA Kit. Changes of protein expression were analyzed by western blotting. RNA interference was employed to inhibit expression of specific protein. We found that bisabolocurcumin ether (T1) and demethoxybisabolocurcumin ether (T2) were able to trigger much stronger apoptosis induction in multiple types of cancer cells than curcumin, which was attributed to persistent and stronger ROS generation. ROS induction by T1 resulted in activation of p38/H2AX axis and p53. Inhibition of p38/H2AX led to a significant reduction of apoptosis, whereas inactivation of p53 caused a dramatically enhanced H2AX phosphorylation and apoptosis induction, suggesting activation of p38/H2AX contributed to apoptosis induction by T1, whereas p53 activation protected novel curcumins-induced apoptosis via suppression of H2AX activation. Our findings provide mechanistic support for the potential use of terpene-conjugated curcuminoids as a novel class of cancer chemopreventive agents. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Microfluidic Synthesis of Hybrid Nanoparticles with Controlled Lipid Layers: Understanding Flexibility-Regulated Cell-Nanoparticle Interaction.

PubMed

Zhang, Lu; Feng, Qiang; Wang, Jiuling; Zhang, Shuai; Ding, Baoquan; Wei, Yujie; Dong, Mingdong; Ryu, Ji-Young; Yoon, Tae-Young; Shi, Xinghua; Sun, Jiashu; Jiang, Xingyu

2015-10-27

The functionalized lipid shell of hybrid nanoparticles plays an important role for improving their biocompatibility and in vivo stability. Yet few efforts have been made to critically examine the shell structure of nanoparticles and its effect on cell-particle interaction. Here we develop a microfluidic chip allowing for the synthesis of structurally well-defined lipid-polymer nanoparticles of the same sizes, but covered with either lipid-monolayer-shell (MPs, monolayer nanoparticles) or lipid-bilayer-shell (BPs, bilayer nanoparticles). Atomic force microscope and atomistic simulations reveal that MPs have a lower flexibility than BPs, resulting in a more efficient cellular uptake and thus anticancer effect than BPs do. This flexibility-regulated cell-particle interaction may have important implications for designing drug nanocarriers.

Effects of different lipid sources on intake, digestibility and purine derivatives in hair lambs.

PubMed

Pereira, E S; Pereira, M W F; Arruda, P C L; Cabral, L S; Oliveira, R L; Mizubuti, I Y; Pinto, A P; Campos, A C N; Gadelha, C R F; Carneiro, M S S

2016-08-01

An experiment was conducted to evaluate the effects of different lipid sources on the nutrient intake, digestibility and purine derivative excretion of lambs. Thirty-five 60-day-old, male, non-castrated Santa Ines lambs with an initial average body weight (BW) of 13.00 ± 1.80 kg were used in a randomized complete block design with seven blocks and five treatments. The experimental treatments consisted of a control diet without supplemental lipids and four test diets with different lipid supplements, selected according to the degree of ruminal protection from hydrogenation: supplementation, being supplementation with whole cottonseed (WC), supplementation with cashew nut meal (CNM), supplementation with both cottonseed and cashew nut meal (WC-CNM) and supplementation with calcium salts of long-chain fatty acids (Ca-LCFA). The lambs were slaughtered after reaching 28 kg average BW for each treatment. The ether extract intake (EEI) was higher (p < 0.01) for the lipid supplemented compared to control diet lambs. Supplementation with WC decreased the digestibility of dry matter (DM), organic matter (OM), neutral detergent fibre (NDF) and total carbohydrate (TC) (p < 0.01), whereas supplementation with CNM, WC-CNM and Ca-LCFA reduced non-fibrous carbohydrate (NFC) digestibility (p < 0.01). The ether extract (EE) digestibility coefficient was higher with CNM, followed by Ca-LCFA and WC, when compared to WC-CNM and control diets. Nitrogen balance (NB) was not influenced (p > 0.05) by the different lipid sources. A lower purine derivative (PD) excretion and thus lower microbial protein supply (MPS) was observed for animals supplemented with Ca-LCFA (p < 0.01) compared to the WC-CNM and control diets. In conclusion, WC, CNM and WC-CNM supplementation did not have negative effects on MPS, although negative effects have been observed on nutrient digestibility. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

Pulverizing processes affect the chemical quality and thermal property of black, white, and green pepper (Piper nigrum L.).

PubMed

Liu, Hong; Zheng, Jie; Liu, Pengzhan; Zeng, Fankui

2018-06-01

In this study, the effects of different pulverizing methods on the chemical attributes and thermal properties of black, white and green pepper were evaluated. Cryogenic grinding minimally damaged the lipid, moisture, crude protein, starch, non-volatile ether extract, piperine, essential oil and the typical pepper essential oil compounds of the spices. The pulverizing methods and storage significantly affected the compositions of the fatty acid in the peppers, except for palmitic acid and lignoceric acid. The amino acid contents and the thermo-gravimetric analysis curve were hardly influenced by the grinding techniques. The use of cryogenic grinding to prepare pepper ensured the highest quality of pepper products. Regardless of grinding technique, the values of moisture, piperine, unsaturated fatty acids, essential oil, monoterpenes, and the absolute concentrations of typical pepper essential oil constituents (except caryophyllene oxide) decreased, whereas the amino acid, lipid, protein, starch, and non-volatile ether extract content as well as the thermal properties were insignificantly changed after storage at 4 °C for 6 months.

Nanostructured lipid carriers employing polyphenols as promising anticancer agents: Quality by design (QbD) approach.

PubMed

Bhise, Ketki; Kashaw, Sushil Kumar; Sau, Samaresh; Iyer, Arun K

2017-06-30

Cancer is one of the leading causes of death worldwide. There are several hurdles in cancer therapy because of side-effects which limits its usage. Nanoparticulate drug delivery systems have been tested against cancer in a range of scientific studies. In the recent years, advanced research on Nanostructured Lipid Carriers (NLCs) has garnered considerable attention owing to the advantages over their first-generation counterparts, Solid Lipid Nanoparticles (SLN). NLCs facilitate efficient loading of poorly water soluble drugs with simple methods of drug loading. Recently, there is an increased interest in polyphenols because of the evidence of their promising role in prevention of cancer. Polyphenols are produced as secondary metabolites by plants. Their role in prevention of development of tumors through variety of mechanisms and reduction of tumor cell mass has been reported. This article aims to review the science behind development of NLCs and role of polyphenols as promising anticancer agents. Principles of Quality by Design (QbD) have also been explained which are used in formulation-development of many nanoparticles, including NLCs, as reported in literature. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of Lipid-Shell and Polymer Core Nanoparticles with Water-Soluble Salidroside for Anti-Cancer Therapy

PubMed Central

Fang, Dai-Long; Chen, Yan; Xu, Bei; Ren, Ke; He, Zhi-Yao; He, Li-Li; Lei, Yi; Fan, Chun-Mei; Song, Xiang-Rong

2014-01-01

Salidroside (Sal) is a potent antitumor drug with high water-solubility. The clinic application of Sal in cancer therapy has been significantly restricted by poor oral absorption and low tumor cell uptake. To solve this problem, lipid-shell and polymer-core nanoparticles (Sal-LPNPs) loaded with Sal were developed by a double emulsification method. The processing parameters including the polymer types, organic phase, PVA types and amount were systemically investigated. The obtained optimal Sal-LPNPs, composed of PLGA-PEG-PLGA triblock copolymers and lipids, had high entrapment efficiency (65%), submicron size (150 nm) and negatively charged surface (−23 mV). DSC analysis demonstrated the successful encapsulation of Sal into LPNPs. The core-shell structure of Sal-LPNPs was verified by TEM. Sal released slowly from the LPNPs without apparent burst release. MTT assay revealed that 4T1 and PANC-1 cancer cell lines were sensitive to Sal treatment. Sal-LPNPs had significantly higher antitumor activities than free Sal in 4T1 and PANC-1 cells. The data indicate that LPNPs are a promising Sal vehicle for anti-cancer therapy and worthy of further investigation. PMID:24573250

Development of lipid-shell and polymer core nanoparticles with water-soluble salidroside for anti-cancer therapy.

PubMed

Fang, Dai-Long; Chen, Yan; Xu, Bei; Ren, Ke; He, Zhi-Yao; He, Li-Li; Lei, Yi; Fan, Chun-Mei; Song, Xiang-Rong

2014-02-25

Salidroside (Sal) is a potent antitumor drug with high water-solubility. The clinic application of Sal in cancer therapy has been significantly restricted by poor oral absorption and low tumor cell uptake. To solve this problem, lipid-shell and polymer-core nanoparticles (Sal-LPNPs) loaded with Sal were developed by a double emulsification method. The processing parameters including the polymer types, organic phase, PVA types and amount were systemically investigated. The obtained optimal Sal-LPNPs, composed of PLGA-PEG-PLGA triblock copolymers and lipids, had high entrapment efficiency (65%), submicron size (150 nm) and negatively charged surface (-23 mV). DSC analysis demonstrated the successful encapsulation of Sal into LPNPs. The core-shell structure of Sal-LPNPs was verified by TEM. Sal released slowly from the LPNPs without apparent burst release. MTT assay revealed that 4T1 and PANC-1 cancer cell lines were sensitive to Sal treatment. Sal-LPNPs had significantly higher antitumor activities than free Sal in 4T1 and PANC-1 cells. The data indicate that LPNPs are a promising Sal vehicle for anti-cancer therapy and worthy of further investigation.

Bone Marrow Lipids in Rats Exposed to Total-Body Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snyder, Fred; Cress, Edgar A.

1963-05-01

ABS>Thin-layer chromatography was used to demonstrate that bone marrow lipids of rats were primarily triglycerides; gas-liquid chromatography of the fraction revealed that palmitic and oleic acids account for more than 80% of the fatty acids. Minor lipid components present in the control and irradiated marrow are glyceryl ethers, cholesterol, fatty acids, and phospholipids. Cholesterol esters were not found. Total-body irradiation (800 r) increases the femur marrow triglyceride fraction approximately six times by 1 week after irradiation, and it remains elevated for many weeks. The relationship between dose and increase in marrow triglycerides appears to fit the equation y = bxmore » a. The water and lipid content of bone marrow bear a reciprocal relation to each other, while both water and residue are significantly reduced in the irradiated femur marrow.« less

Cyclooxgenase-2 Inhibiting Perfluoropoly (Ethylene Glycol) Ether Theranostic Nanoemulsions—In Vitro Study

PubMed Central

Patel, Sravan Kumar; Zhang, Yang; Pollock, John A.; Janjic, Jelena M.

2013-01-01

Cylcooxgenase-2 (COX-2) expressing macrophages, constituting a major portion of tumor mass, are involved in several pro-tumorigenic mechanisms. In addition, macrophages are actively recruited by the tumor and represent a viable target for anticancer therapy. COX-2 specific inhibitor, celecoxib, apart from its anticancer properties was shown to switch macrophage phenotype from tumor promoting to tumor suppressing. Celecoxib has low aqueous solubility, which may limit its tumor inhibiting effect. As opposed to oral administration, we propose that maximum anticancer effect may be achieved by nanoemulsion mediated intravenous delivery. Here we report multifunctional celecoxib nanoemulsions that can be imaged by both near-infrared fluorescence (NIRF) and 19F magnetic resonance. Celecoxib loaded nanoemulsions showed a dose dependent uptake in mouse macrophages as measured by 19F NMR and NIRF signal intensities of labeled cells. Dramatic inhibition of intracellular COX-2 enzyme was observed in activated macrophages upon nanoemulsion uptake. COX-2 enzyme inhibition was statistically equivalent between free drug and drug loaded nanoemulsion. However, nanoemulsion mediated drug delivery may be advantageous, helping to avoid systemic exposure to celecoxib and related side effects. Dual molecular imaging signatures of the presented nanoemulsions allow for future in vivo monitoring of the labeled macrophages and may help in examining the role of macrophage COX-2 inhibition in inflammation-cancer interactions. These features strongly support the future use of the presented nanoemulsions as anti-COX-2 theranostic nanomedicine with possible anticancer applications. PMID:23409048

Identification of the anti-oxidant components in a two-step solvent extract of bovine bile lipid: Application of reverse phase HPLC, mass spectrometry and fluorimetric assays.

PubMed

Singh, Namrata; Bhattacharyya, Debasish

2016-04-15

An ether extract of nine different bacterial metabolites in combination with two solvent extract (ether followed by ethanol) of bile lipids from ox gall bladder is used as an immune stimulator drug. Over the years bile acids are discussed regarding their anti-oxidant and lipid peroxidation properties. Since some of the bile acids are known to be potent antioxidants, presence of similar activity in the solvent extract of ox bile lipid was investigated using TLC and reverse phase HPLC systems. Fractions from HPLC were analyzed with mass spectrometry using electrospray ionization. The presence of twelve different bile acids along with other substances in small proportions including fatty acids, sulfate conjugates and bile pigments were confirmed. The twelve separated peaks had similar retention times as those of tauroursodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid. Subsequently, all fractions were tested for their anti-oxidative property on HepG2 cells exposed to H2O2 that served as an oxidative injury model. Four fluorescent dyes H2DCF DA, MitoSOX red, Amplex red and DAF-2 DA were used for estimation of reactive radicals in the HepG2 cells. Among the separated bile acids, tauroursodeoxycholic acid, glycoursodeoxycholic acid and ursodeoxycholic acid prevented the HepG2 cells from H2O2-induced oxidative stress. Copyright © 2015 Elsevier B.V. All rights reserved.

Phosphatidylserine lipids and membrane order precisely regulate the activity of Polybia-MP1 peptide.

PubMed

Alvares, Dayane S; Ruggiero Neto, João; Ambroggio, Ernesto E

2017-06-01

Polybia-MP1 (IDWKKLLDAAKQIL-NH 2 ) is a lytic peptide from the Brazilian wasp venom with known anti-cancer properties. Previous evidence indicates that phosphatidylserine (PS) lipids are relevant for the lytic activity of MP1. In agreement with this requirement, phosphatidylserine lipids are translocated to the outer leaflet of cells, and are available for MP1 binding, depending on the presence of liquid-ordered domains. Here, we investigated the effect of PS on MP1 activity when this lipid is reconstituted in membranes of giant or large liposomes with different lipid-phase states. By monitoring the membrane and soluble luminal content of giant unilamellar vesicles (GUVs), using fluorescence confocal microscopy, we were able to determine that MP1 has a pore-forming activity at the membrane level. Liquid-ordered domains, which were phase-separated within the membrane of GUVs, influenced the pore-forming activity of MP1. Experiments evaluating the membrane-binding and lytic activity of MP1 on large unilamellar vesicles (LUVs), with the same lipid composition as GUVs, demonstrated that there was synergy between liquid-ordered domains and PS, which enhanced both activities. Based on our findings, we propose that the physicochemical properties of cancer cell membranes, which possess a much higher concentration of PS than normal cells, renders them susceptible to MP1 binding and lytic pore formation. These results can be correlated with MP1's potent and selective anti-cancer activity and pave the way for future research to develop cancer therapies that harness and exploit the properties of MP1. Copyright © 2017 Elsevier B.V. All rights reserved.

Photosynthesis Involvement in the Mechanism of Action of Diphenyl Ether Herbicides 1

PubMed Central

Ensminger, Michael P.; Hess, F. Dan

1985-01-01

Photosynthesis is not required for the toxicity of diphenyl ether herbicides, nor are chloroplast thylakoids the primary site of diphenyl ether herbicide activity. Isolated spinach (Spinacia oleracea L.) chloroplast fragments produced malonyl dialdehyde, indicating lipid peroxidation, when paraquat (1,1′-dimethyl-4,4′-bipyridinium ion) or diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] were added to the medium, but no malonyl dialdehyde was produced when chloroplast fragments were treated with the methyl ester of acifluorfen (methyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid), oxyfluorfen [2-chloro-1-(3-ethoxy-4-nitrophenoxy)-4-(trifluoromethyl)benzene], or MC15608 (methyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-chlorobenzoate). In most cases the toxicity of acifluorfen-methyl, oxyfluorfen, or MC15608 to the unicellular green alga Chlamydomonas eugametos (Moewus) did not decrease after simultaneous treatment with diuron. However, diuron significantly reduced cell death after paraquat treatment at all but the highest paraquat concentration tested (0.1 millimolar). These data indicate electron transport of photosynthesis is not serving the same function for diphenyl ether herbicides as for paraquat. Additional evidence for differential action of paraquat was obtained from the superoxide scavenger copper penicillamine (copper complex of 2-amino-3-mercapto-3-methylbutanoic acid). Copper penicillamine eliminated paraquat toxicity in cucumber (Cucumis sativus L.) cotyledons but did not reduce diphenyl ether herbicide toxicity. PMID:16664206

Photosynthesis involvement in the mechanism of action of diphenyl ether herbicides.

PubMed

Ensminger, M P; Hess, F D

1985-05-01

Photosynthesis is not required for the toxicity of diphenyl ether herbicides, nor are chloroplast thylakoids the primary site of diphenyl ether herbicide activity. Isolated spinach (Spinacia oleracea L.) chloroplast fragments produced malonyl dialdehyde, indicating lipid peroxidation, when paraquat (1,1'-dimethyl-4,4'-bipyridinium ion) or diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] were added to the medium, but no malonyl dialdehyde was produced when chloroplast fragments were treated with the methyl ester of acifluorfen (methyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid), oxyfluorfen [2-chloro-1-(3-ethoxy-4-nitrophenoxy)-4-(trifluoromethyl)benzene], or MC15608 (methyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-chlorobenzoate). In most cases the toxicity of acifluorfen-methyl, oxyfluorfen, or MC15608 to the unicellular green alga Chlamydomonas eugametos (Moewus) did not decrease after simultaneous treatment with diuron. However, diuron significantly reduced cell death after paraquat treatment at all but the highest paraquat concentration tested (0.1 millimolar). These data indicate electron transport of photosynthesis is not serving the same function for diphenyl ether herbicides as for paraquat. Additional evidence for differential action of paraquat was obtained from the superoxide scavenger copper penicillamine (copper complex of 2-amino-3-mercapto-3-methylbutanoic acid). Copper penicillamine eliminated paraquat toxicity in cucumber (Cucumis sativus L.) cotyledons but did not reduce diphenyl ether herbicide toxicity.

Thermodesulfobacterium geofontis sp. nov., a hyperthermophilic, sulfate-reducing bacterium isolated from Obsidian Pool, Yellowstone National Park

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamilton-Brehm, Scott D.; Gibson, Robert A.; Green, Stefan J.

2013-01-24

A novel sulfate-reducing bacterium designated OPF15T was isolated from Obsidian Pool, Yellowstone National Park, Wyoming. The phylogeny of 16S rRNA and functional genes (dsrAB) placed the organism within the family Thermodesulfobacteriaceae. The organism displayed hyperthermophilic temperature requirements for growth with a range of 70 90 C and an optimum of 83 C. Optimal pH was around 6.5 7.0 and the organism required the presence of H2 or formate as an electron donor and CO2 as a carbon source. Electron acceptors supporting growth included sulfate, thiosulfate, and elemental sulfur. Lactate, acetate, pyruvate, benzoate, oleic acid, and ethanol did not serve asmore » electron donors. Membrane lipid analysis revealed diacyl glycerols and acyl/ether glycerols which ranged from C14:0 to C20:0. Alkyl chains present in acyl/ether and diether glycerol lipids ranged from C16:0 to C18:0. Straight, iso- and anteiso-configurations were found for all lipid types. The presence of OPF15T was also shown to increase cellulose consumption during co-cultivation with Caldicellulosiruptor obsidiansis, a fermentative, cellulolytic extreme thermophile isolated from the same environment. On the basis of phylogenetic, phenotypic, and structural analyses, Thermodesulfobacterium geofontis sp. nov. is proposed as a new species with OPF15T representing the type strain.« less

Thermodesulfobacterium geofontis sp. nov., a hyperthermophilic, sulfate-reducing bacterium isolated from Obsidian Pool, Yellowstone National Park.

PubMed

Hamilton-Brehm, Scott D; Gibson, Robert A; Green, Stefan J; Hopmans, Ellen C; Schouten, Stefan; van der Meer, Marcel T J; Shields, John P; Damsté, Jaap S S; Elkins, James G

2013-03-01

A novel sulfate-reducing bacterium designated OPF15(T) was isolated from Obsidian Pool, Yellowstone National Park, Wyoming. The phylogeny of 16S rRNA and functional genes (dsrAB) placed the organism within the family Thermodesulfobacteriaceae. The organism displayed hyperthermophilic temperature requirements for growth with a range of 70-90 °C and an optimum of 83 °C. Optimal pH was around 6.5-7.0 and the organism required the presence of H2 or formate as an electron donor and CO2 as a carbon source. Electron acceptors supporting growth included sulfate, thiosulfate, and elemental sulfur. Lactate, acetate, pyruvate, benzoate, oleic acid, and ethanol did not serve as electron donors. Membrane lipid analysis revealed diacyl glycerols and acyl/ether glycerols which ranged from C14:0 to C20:0. Alkyl chains present in acyl/ether and diether glycerol lipids ranged from C16:0 to C18:0. Straight, iso- and anteiso-configurations were found for all lipid types. The presence of OPF15(T) was also shown to increase cellulose consumption during co-cultivation with Caldicellulosiruptor obsidiansis, a fermentative, cellulolytic extreme thermophile isolated from the same environment. On the basis of phylogenetic, phenotypic, and structural analyses, Thermodesulfobacterium geofontis sp. nov. is proposed as a new species with OPF15(T) representing the type strain.

Variation in lipid classes and fatty acid composition of salmon shark (Lamna ditropis) liver with season and gender.

PubMed

Jayasinghe, Chamila; Gotoh, Naohiro; Wada, Shun

2003-02-01

The influence of season and gender on lipid content, lipid classes, and fatty acid compositions was assessed in livers of salmon shark (Lamna ditropis), caught in the Pacific Ocean. No significant difference in the hepatosomatic index was noted with season, though the lipid content was significantly higher (P<0.05) in winter. Triacylglycerol (TAG) was identified as the predominant lipid class (78.5-82.0%), followed by sterol esters (5.7-9.1%) and hydrocarbons (3.4-5.4%). No significant differences were observed in TAG composition with respect to the season or gender. However, diacylglyceryl ether contents were significantly higher (P<0.05) in winter (3.8-5.3%) than those obtained in summer (1.3-1.1%). Polyunsaturated fatty acids constituted the major fatty acid class of salmon shark total liver lipid and docosahexaenoic acid (C22:6n-3) (22.7-28.4%) was the most abundant fatty acid which was significantly lower (P<0.05) in winter. These results suggested that lipid characteristics of salmon shark liver were influenced by season, but not by gender.

Composition of Hydrothermal Vent Microbial Communities as Revealed by Analyses of Signature Lipids, Stable Carbon Isotopes and Aquificales Cultures

NASA Technical Reports Server (NTRS)

Jahnke, Linda L.; Edger, Wolfgang; Huber, Robert; Hinrichs, Kai-Uwe; Hayes, John M.; DesMarais, David J.; Cady, Sherry; Hope, Janet M.; Summons, Roger E.; DeVincenzi, Donald L. (Technical Monitor)

2001-01-01

Extremely thermophilic microbial communities associated with the siliceous vent walls and outflow channel of Octopus Spring, Yellowstone National Park, have been examined for lipid biomarkers and carbon isotopic signatures. These data were compared with that obtained from representatives of three Aquificales genera. Thermocrinis ruber. "Thermocrinis sp. HI", Hydrogenobacter thermophilus TK-6, Aquifex pyrophilus and Aquifex aeolicus all contained phospholipids composed not only of the usual ester-linked fatty acids, but also ether-linked alkyls. The fatty acids of all cultured organisms were dominated by a very distinct pattern of n-C-20:1 and cy-C-21 compounds. The alkyl glycerol ethers were present primarily as CIS() monoethers with the expection of the Aquifex spp. in which dialkyl glycerol ethers with a boarder carbon-number distribution were also present. These Aquificales biomarker lipids were the major constituents in the lipid extracts of the Octopus Spring microbial samples. Two natural samples, a microbial biofilm growing in association with deposition of amorphous silica on the vent walls at 92 C, and the well-known 'pink-streamers community' (PSC), siliceous filaments of a microbial consortia growing in the upper outflow channel at 87 C were analyzed. Both the biofilm and PSC samples contained mono and dialkyl glycerol ethers with a prevalence of C-18 and C-20 alkyls. Phospholipid fatty acids were comprised of both the characteristic Aquificales n-C-20:1 and cy-C-21, and in addition, a series of iso-branched fatty acids from i-C-15:0 to i-C-21:0, With i-C-17:0 dominant in the PSC and i-C-19:0 in the biofilm, suggesting the presence of two major bacterial groups. Bacteriohopanepolyols were absent and the minute quantities of archaeol detected showed that Archaea were only minor constituents. Carbon isotopic compositions of the PSC yielded information about community structure and likely physiology. Biomass was C-13-depleted (10.9%) relative to available CO2 from the source water inorganic carbon pool with lipids further depleted by 6.3% relative to biomass The C-20-21 Aquificales fatty acids of the PSC were somewhat heavier than the iso-branched fatty acids. The carbon isotopic signatures of lipid biomarkers were also explored using a pure culture, T ruber, previously isolated from the PSC. Cells grown on C02 with O2 and both H2 and thiosulfate as electron donors were only slightly depleted (3.3%) relative to the C-source while cells grown on formate with O2 showed a major discrimination (19.7%), possibly the result of a metabolic branch point involving the assimilation of C-formate to biomass and the dissimilation to CO2 associated with energy production. T. ruber lipids were slightly heavier than biomass (+1.3%) whether cells were grown using CO2 or formate. Fatty acids from CO2 grown T. ruber cells were a so slightly heavier (average +2.1%) than biomass. The relatively depleted PSC C-20-21 fatty acids suggest that any associated Thermocrinis biomass would also be similarly depleted and much too light to be explained by growth on CO2. The C-fractionations determined with the pure culture suggest that growth of Thermocrinis in the PSC is more likely to occur on formate, presumably generated by geothermal activity. This study points to the value of the analysis of the structural and isotopic composition of lipid blomarkers both in pure culture studies, and in establishing community structure and physiology, as a complement to genomic profiles of microbial diversity. This is especially so when the members of the microbial community are novel and difficult to cultivate in the laboratory.

Membrane lipids and the origin of life

NASA Technical Reports Server (NTRS)

Oro, J.; Holzer, G.; Rao, M.; Tornabene, T. G.

1981-01-01

The current state of knowledge regarding the development of biological systems is briefly reviewed. At a crucial stage concerning the evolution of such systems, the mechanisms leading to more complex structures must have evolved within the confines of a protected microenvironment, similar to those provided by the contemporary cell membranes. The major components found normally in biomembranes are phospholipids. The structure of the biomembrane is examined, and attention is given to questions concerning the availability of the structural components which are necessary in the formation of primitive lipid membranes. Two approaches regarding the study of protomembranes are discussed. The probability of obtaining ether lipids under prebiotic conditions is considered, taking into account the formation of cyclic and acyclic isoprenoids by the irradiation of isoprene with UV.

Preclinical development of a non-toxic oral formulation of monoethanolamine, a lipid precursor, for prostate cancer treatment

PubMed Central

Saxena, Roopali; Yang, Chunhua; Rao, Mukkavilli; Turaga, Ravi Chakra; Garlapati, Chakravarthy; Gundala, Sushma Reddy; Myers, Kimberly; Ghareeb, Ahmed; Bhattarai, Shristi; Kamilinia, Golnaz; Bristi, Sangina; Su, Dan; Gadda, Giovanni; Rida, Padmashree C. G.; Cantuaria, Guilherme H.; Aneja, Ritu

2018-01-01

Purpose Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel non-toxic orally-deliverable anticancer formulation of monoethanolamine (Etn), for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design We first evaluated GI-tract stability, drug-drug interaction liability, pharmacokinetic and toxicokinetic properties of Etn to evaluate its suitability as a non-toxic orally-deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results Our data demonstrate that Etn exhibits excellent bioavailability, GI-tract stability, and no drug-drug interaction liability. Remarkably, orally-fed Etn inhibited tumor growth in four weeks by ~67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose non-toxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. PMID:28167510

Water-soluble cationic derivatives of indirubin, the active anticancer component from Indigo naturalis.

PubMed

Ginzinger, Werner; Egger, Alexander; Mühlgassner, Gerhard; Arion, Vladimir B; Jakupec, Michael A; Galanski, Markus; Berger, Walter; Keppler, Bernhard K

2012-10-01

To overcome the problem of poor aqueous solubility and bioavailability of indirubin-3-oximes, the compounds were modified by attaching a quaternary ammonium group at the oxime moiety. Exploring the prodrug concept, an oxime ester with acetyl-l-carnitine was prepared, and the rate of its hydrolysis was investigated to assess its suitability for clinical administration. In addition, the cytotoxic potency of new stable oxime ethers with a choline moiety and their influence on the cell cycle were tested in human cancer cell lines. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.

PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery.

PubMed

Zhao, Yi; Wang, Wei; Guo, Shutao; Wang, Yuhua; Miao, Lei; Xiong, Yang; Huang, Leaf

2016-06-06

Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI both in vitro and in vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy.

The lipid content of cisplatin- and doxorubicin-resistant MCF-7 human breast cancer cells.

PubMed

Todor, I N; Lukyanova, N Yu; Chekhun, V F

2012-07-01

To perform the comparative study both of qualitative and quantitative content of lipids in parental and drug resistant breast cancer cells. Parental (MCF-7/S) and resistant to cisplatin (MCF-7/CP) and doxorubicin (MCF-7/Dox) human breast cancer cells were used in the study. Cholesterol, total lipids and phospholipids content were determined by means of thin-layer chromatography. It was found that cholesterol as well as cholesterol ethers content are significantly higher but diacylglycerols, triacyl-glycerols content are significantly lower in resistant cell strains than in parental (sensitive) cells. Moreover the analysis of individual phospholipids showed the increase of sphingomyelin, phosphatidylserine, cardiolipin, phosphatidic acid and the decrease of phosphatidy-lethanolamine, phosphatidylcholine in MCF-7/CP and MCF-7/Dox cells. Obtained results allow to suggest that the lipid profile changes can mediate the modulation of membrane fluidity in drug resistant MCF-7 breast cancer cells.

Lipid-Polymer Nanoparticles for Folate-Receptor Targeting Delivery of Doxorubicin.

PubMed

Zheng, Mingbin; Gong, Ping; Zheng, Cuifang; Zhao, Pengfei; Luo, Zhenyu; Ma, Yifan; Cai, Lintao

2015-07-01

A biocompatible PLGA-lipid hybrid nanoparticles (NPs) was developed for targeted delivery of anticancer drugs with doxorubicin (DOX). The hydrodynamic diameter and zeta potential of DOX-loaded PLGA-lipid NPs (DNPs) were affected by the mass ratio of Lipid/PLGA or DSPE-PEG-COOH/Lecithin. At the 1:20 drug/polymer mass ratio, the mean hydrodynamic diameter of DNPs was the lowest (99.2 1.83 nm) and the NPs presented the encapsulation efficiency of DOX with 42.69 1.30%. Due to the folate-receptor mediated endocytosis, the PLGA-lipid NPs with folic acid (FA) targeting ligand showed significant higher uptake by folate-receptor-positive MCF-7 cells as compared to PLGA-lipid NPs without folate. Confocal microscopic observation and flow cytometry analysis also supported the enhanced cellular uptake of the FA-targeted NPs. The results indicated that the FA-targeted DNPs exhibited higher cytotoxicity in MCF-7 cells compared with non-targeted NPs. The lipid-polymer nanoparticles provide a solution of biocompatible nanocarrier for cancer targeting therapy.

Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals

PubMed Central

Chuan, Li; Jia, Zhang; Yu-Jiao, Zu; Shu-Fang, Nie; Jun, Cao; Qian, Wang; Shao-Ping, Nie; Ze-Yuan, Deng; Ming-Yong, Xie; Shu, Wang

2017-01-01

Many phytochemicals show promise in cancer prevention and treatment, but their low aqueous solubility, poor stability, unfavorable bioavailability, and low target specificity make administering them at therapeutic doses unrealistic. This is particularly true for (–)-epigallocatechin gallate, curcumin, quercetin, resveratrol, and genistein. There is an increasing interest in developing novel delivery strategies for these natural products. Liposomes, micelles, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers and poly (lactide-co-glycolide) nanoparticles are biocompatible and biodegradable nanoparticles. Those nanoparticles can increase the stability and solubility of phytochemicals, exhibit a sustained release property, enhance their absorption and bioavailability, protect them from premature enzymatic degradation or metabolism, prolong their circulation time, improve their target specificity to cancer cells or tumors via passive or targeted delivery, lower toxicity or side-effects to normal cells or tissues through preventing them from prematurely interacting with the biological environment, and enhance anti-cancer activities. Nanotechnology opens a door for developing phytochemical-loaded nanoparticles for prevention and treatment of cancer. PMID:26412423

A Comparative Evaluation of Hydroxycamptothecin Drug Nanorods With and Without Methotrexate Prodrug Functionalization for Drug Delivery

NASA Astrophysics Data System (ADS)

Guo, Fuqiang; Fan, Zhongxiong; Yang, Jinbin; Li, Yang; Wang, Yange; Zhao, Hai; Xie, Liya; Hou, Zhenqing

2016-08-01

We developed a novel self-targeted multi-drug co-delivery system based on rod-shaped 10-hydroxycamptothecin (CPT) nanoanticancer drug (CPT NRs) followed by a surface functionalization with self-targeting PEGylated lipid-conjugated methotrexate (MTX) pro-anticancer drug. The self-targeting effect and in vitro cell viability of the MTX-PEG-CPT NRs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PEG-CPT NRs. In vitro studies showed the feasibility of using this high drug-loading MTX-PEG-CPT NRs in self-targeted drug delivery, controlled-/sustained-release, and synergistic cancer therapy. More importantly, this work would stimulate interest in the use of PEGylated lipid-conjugated MTX by introducing an early-phase tumor-targeting role and then driving a late-phase anticancer role for the highly convergent design of nanomulti-drug, which may advantageously offer a new and simple strategy for simultaneously targeting and treating FA receptor-overexpressing cancer cells.

[Effect of polyethylene glycol-lipid derivatives on the stability of grafted liposomes].

PubMed

Xu, Yang; Shi, Li; Deng, Yi-hui

2011-10-01

It is reported that polyethylene glycol-lipid (PEG-lipid) derivatives increase liposomes stability, prolong the blood circulation of liposomes, enhance their tumor-targeting efficiency, and improve drug efficacy. Therefore, it is of great importance to investigate the influence of modified PEG-lipid derivatives on the physical, chemical, and biological characteristics of liposomes for the promotion of dealing with the existed problems, such as the accelerated blood clearance (ABC) phenomenon when repeated intravous injection at a certain time-interval, and developing novel targeted pharmaceutical preparations. In this review, the effects of modified PEG-lipid derivatives were summarized in many aspects. It indicats that the chemical bonds (amide, ether, ester, and disulfide) between PEG and lipid, as well as the species of lipids, such as the commonly used phosphatidylethanolamine, cholesterol, and diacylglycerol have substantial effects on the grafted liposomes stability in vitro and in vivo. Besides, the properties of lipids (the fatty acid chain length and saturation) and the groups (methoxy, carboxylic and amino) at the distal ends of the PEG chains were also considered to be important factors. In the end, the influence of the average molecular weight of PEG and the molar ratio of PEG-lipid derivatives in the total lipid were further focused.

Persistent organic pollutants in selected fishes of the Gulf of Finland

NASA Astrophysics Data System (ADS)

Järv, Leili; Kiviranta, Hannu; Koponen, Jani; Rantakokko, Panu; Ruokojärvi, Päivi; Radin, Maia; Raid, Tiit; Roots, Ott; Simm, Mart

2017-07-01

Fish samples of Baltic herring, sprat, flounder, perch, salmon, and river lamprey were collected from the Gulf of Finland in 2013 and 2014 with the aim to get an overview of the occurrence of pollutants in fish caught in Estonian waters. The content of non-dioxin-like polychlorinated biphenyls (ndl PCBs), polybrominated diphenyl ethers (PBDEs), organic tin (OT) and perfluorocompounds (PFAS) are examined and discussed in the study. The results revealed that potentially higher content of organo-tin compounds, perfluorocompounds and polybrominated diphenyl ethers in Baltic herring, salmon and river lamprey may cause concern regarding human exposure. It is important to link pollutant content to lipid content of fish taking into account their seasonal variation in different age classes.

Environmental monitoring of brominated flame retardants

NASA Astrophysics Data System (ADS)

Vagula, Mary C.; Kubeldis, Nathan; Nelatury, Charles F.

2011-06-01

Brominated flame retardants (BFRs) are synthetic organobromide compounds which inhibit ignition and combustion processes. Because of their immense ability to retard fire and save life and property, they have been extensively used in many products such as TVs, computers, foam, plastics etc. The five major classes of BFRs are tetrabromobisphenol-A (TBBPA), hexabromocyclododecane (HBCD), pentabromodiphenyl ether, octabromodiphenyl ether, and decabromodiphenyl ether. The last three are also commonly called PBDEs. BDE-85 and BDE-209 are the two prominent congeners of PBDEs and this study reports the adverse effects of these congeners in rodents. Exposure of rat sciatic nerves to 5 μg/mL and 20 μg/mL of BDE-85 and BDE-209 respectively lead to significant, concentration dependent reduction in nerve conduction function. Glucose absorption in the rat intestinal segments exposed to 5 μg/mL of BDE-85 and BDE-209 was significantly reduced for both the compounds tested. Lastly, mice when exposed to 0.25 mg/kg body weight for four days showed a disruption in oxidant and antioxidant equilibrium. The tissues namely liver and brain have shown increase in the levels of lipid hydroperoxides indicating oxidative stress. Moreover, all the protective enzymes namely superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and glutathione S transferase (GST) have shown tissue specific alterations indicating the induction of damaging oxidative stress and setting in of lipid peroxidation in exposed animals. The results indicate monitoring of PBDEs in the environment is essential because levels as low as 5 μg/mL and 0.25 mg/kg body weight were able to cause damage to the functions of rodents.

A Review on Polychlorinated Biphenyls (PCBs) and Polybrominated Diphenyl Ethers (PBDEs) in South Asia with a Focus on Malaysia.

PubMed

Kaw, Han Yeong; Kannan, Narayanan

Malaysia is a developing country in Southeast Asia, with rapid industrial and economic growth. Speedy population growth and aggressive consumerism in the past five decades have resulted in environmental pollution issues, including products containing polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). PCBs and PBDEs are classified as persistent organic pollutants (POPs) by the Stockholm Convention due to their persistence, bioaccumulation in the environment and toxicity to humans and wildlife. These compounds are known to cause liver dysfunction, thyroid toxicity, developmental neuro-toxicity and possibly cancer. PCBs in air, mussels, pellets, seawater, fresh water, and human breast milk samples were analyzed in Malaysia, while studies on the pollution level of PBDEs in Malaysia were conducted on mussels, soils, leachate and sediment samples. PCBs in breast milk collected from Malaysia was the highest among Asian developing countries, with mean concentration of 80 ng/g lipid weight. On the other hand, the mean concentration of PCBs in mussels collected from Malaysia recorded the second lowest, with 56 ng/g and 89 ng/g lipid weight in two studies respectively. The concentrations of PBDEs in mussels taken from Malaysia fall in the range of 0.84-16 ng/g lipid weight, which is considerably low compared to 104.5 ng/g lipid weight in Philippines and 90.59 ng/g in Korea. Nevertheless, there are limited studies on these compounds in Malaysia, particularly there is no research on PBDEs in breast milk and sediment samples. This review will summarize the contamination levels of PCBs and PBDEs in different samples collected from Asian countries since 1988 until 2010 with a focus on Malaysia and will provide needed information for further research in this field.

Bioactive Lignans from Zanthoxylum alatum Roxb. stem bark with cytotoxic potential.

PubMed

Mukhija, Minky; Lal Dhar, Kanaya; Nath Kalia, Ajudhia

2014-02-27

Zanthoxylum alatum is used in traditional medicinal systems for number of disorders like cholera, diabetes, cough, diarrhea, fever, headache, microbial infections, toothache, inflammation and cancer. The aim of the present study was to evaluate Zanthoxylum alatum stem bark for its cytotoxic potential and to isolate the bioactive constituents. Cytotoxicity of the different extracts and isolated compounds was studied on lung carcinoma cell line (A549) and pancreatic carcinoma cell line (MIA-PaCa) using MTT assay. Isolation of compounds from most active extract (petroleum ether) was done on silica gel column. Structure elucidation was done by using various spectrophotometric techniques like UV, IR, (1)H NMR, (13)C NMR and mass spectroscopy. The type of cell death caused by most active compound C was explored by fluorescence microscopy using the acridine orange/ethidium bromide method. Petroleum ether extract of plant has shown significant cytotoxic potential. Three lignans sesamin (A), kobusin (B), and 4'O demethyl magnolin (C) has been isolated. All lignans showed cytotoxic activities in different ranges. Compound C was the novel bioactive compound from a plant source and found to be most active. In apoptosis study, treatment caused typical apoptotic morphological changes. It enhances the apoptosis at IC50 dose (21.72 µg/mL) however showing necrotic cell death at higher dose after 24h on MIA-PaCa cell lines. Petroleum ether extract (60-80 °C) of Zanthoxylum alatum has cytotoxic potential. The lignans isolated from the petroleum ether extract were responsible for the cytotoxic potential of the extract. 4'O demethyl magnolin was novel compound from Zanthoxylum alatum. Hence the Zanthoxylum alatum can be further explored for the development of anticancer drug. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Glycerophospholipid Profiles of Bats with White-Nose Syndrome.

PubMed

Pannkuk, Evan L; McGuire, Liam P; Warnecke, Lisa; Turner, James M; Willis, Craig K R; Risch, Thomas S

2015-01-01

Pseudogymnoascus destructans is an ascomycetous fungus responsible for the disease dubbed white-nose syndrome (WNS) and massive mortalities of cave-dwelling bats. The fungus infects bat epidermal tissue, causing damage to integumentary cells and pilosebaceous units. Differences in epidermal lipid composition caused by P. destructans infection could have drastic consequences for a variety of physiological functions, including innate immune efficiency and water retention. While bat surface lipid and stratum corneum lipid composition have been described, the differences in epidermal lipid content between healthy tissue and P. destructans-infected tissue have not been documented. In this study, we analyzed the effect of wing damage from P. destructans infection on the epidermal polar lipid composition (glycerophospholipids [GPs] and sphingomyelin) of little brown bats (Myotis lucifugus). We hypothesized that infection would lead to lower levels of total lipid or higher oxidized lipid product proportions. Polar lipids from three damaged and three healthy wing samples were profiled by electrospray ionization tandem mass spectrometry. We found lower total broad lipid levels in damaged tissue, specifically ether-linked phospholipids, lysophospholipids, phosphatidylcholine, and phosphatidylethanolamine. Thirteen individual GP species from four broad GP classes were present in higher amounts in healthy tissue. Six unsaturated GP species were absent in damaged tissue. Our results confirm that P. destructans infection leads to altered lipid profiles. Clinical signs of WNS may include lower lipid levels and lower proportions of unsaturated lipids due to cellular and glandular damage.

Antimutagenic activity of extracts of leaves of four common edible vegetable plants in Nigeria (west Africa).

PubMed

Obaseiki-Ebor, E E; Odukoya, K; Telikepalli, H; Mitscher, L A; Shankel, D M

1993-06-01

Organic solvent extracts of leaves of 4 common edible vegetable plants--Bryophyllum pinnatum, Dialium guincense, Ocimum gratissimum and Vernonia amygdalina--had inhibitory activity for His- to His+ reverse-mutations induced by ethyl methanesulfonate acting on Salmonella typhimurium TA100. The concentrated ethyl acetate, methanol and petroleum ether extracts were heat-stable when dissolved in dimethyl sulfoxide. The Bryophyllum ethyl acetate extract was fractionated into alkaloidal/water-soluble, acids, polar lipid and non-polar lipid fractions. The polar and non-polar lipid fractions inhibited reversion mutations induced by ethyl methanesulfonate acting on TA100 or TA102, and were also active against reversions induced by 4-nitro-O-phenylenediamine and 2-aminofluorene in TA98. The alkaloidal/water-soluble and the acid fractions had no appreciable antimutagenic activities.

Solid lipid nanoparticles for the delivery of 1,3,5-triaza-7-phosphaadamantane (PTA) platinum (II) carboxylates.

PubMed

Sguizzato, Maddalena; Cortesi, Rita; Gallerani, Eleonora; Drechsler, Markus; Marvelli, Lorenza; Mariani, Paolo; Carducci, Federica; Gavioli, Riccardo; Esposito, Elisabetta; Bergamini, Paola

2017-05-01

The use of solid lipid nanoparticles (SLN) is a promising route for the delivery of platinum complexes aimed to anticancer activity. This paper describes the production and characterization of SLN suitable for the loading of Pt complexes containing the biocompatible phosphine 1,3,5-triaza-7-phosphaadamantane (PTA) as neutral ligand. After a screening of several lipidic phases, stearic acid-based SLN were identified as the most appropriate for the purpose. They were produced by emulsion-dilution method and then characterized in terms of dimension, polydispersity, time stability, pH balance and morphological aspect. Stearic acid SLN are designed as a system able to coordinate to platinum, acting as anionic carboxylic ligands, replacing the base carbonate of the Pt synthon [PtCO 3 (DMSO) 2 ], where also DMSO can subsequently be substituted by phosphinic ligands, namely PTA. SLN functionalised with Pt-PTA were produced and characterized by this synthetic route. The toxicity of plain SLN and the antiproliferative effect of SLN functionalised with Pt-PTA were evaluated on two human cancer cell lines K562 and A2780. The results indicate that SLN can be exploited as a delivery system for Pt complexes with potential anticancer activity. Copyright © 2016 Elsevier B.V. All rights reserved.

LipidPioneer: A Comprehensive User-Generated Exact Mass Template for Lipidomics

PubMed Central

Ulmer, Candice Z.; Koelmel, Jeremy P.; Ragland, Jared M.; Garrett, Timothy J.

2017-01-01

Lipidomics, the comprehensive measurement of lipid species in a biological system, has promising potential in biomarker discovery and disease etiology elucidation. Advances in chromatographic separation, mass spectrometric techniques, and novel substrate applications continue to expand the number of lipid species observed. The total number and type of lipid species detected in a given sample are generally indicative of the sample matrix examined (e.g. serum, plasma, cells, bacteria, tissue, etc.). Current exact mass lipid libraries are static and represent the most commonly analyzed matrices. It is common practice for users to manually curate their own lists of lipid species and adduct masses; however, this process is time-consuming. LipidPioneer, an interactive template, can be used to generate exact masses and molecular formulas of lipid species that may be encountered in the mass spectrometric analysis of lipid profiles. Over 60 lipid classes are present in the LipidPioneer template, and include several unique lipid species, such as ether-linked lipids and lipid oxidation products. In the template, users can add any fatty acyl constituents without limitation in the number of carbons or degrees of unsaturation. LipidPioneer accepts naming using the lipid class level (sum composition) and the LIPID MAPS notation for fatty acyl structure level. In addition to lipid identification, user generated lipid m/z values can be used to develop inclusion lists for targeted fragmentation experiments. Resulting lipid names and m/z values can be imported into software such as MZmine or Compound Discoverer to automate exact mass searching and isotopic pattern matching across experimental data. PMID:28074328

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components.

PubMed

Rath, Emma M; Duff, Anthony P; Håkansson, Anders P; Vacher, Catherine S; Liu, Guo Jun; Knott, Robert B; Church, William Bret

2015-01-01

The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Long-Circulating Curcumin-Loaded Liposome Formulations with High Incorporation Efficiency, Stability and Anticancer Activity towards Pancreatic Adenocarcinoma Cell Lines In Vitro.

PubMed

Mahmud, Mohamed; Piwoni, Adriana; Filipczak, Nina; Janicka, Martyna; Gubernator, Jerzy

2016-01-01

The incorporation of hydrophobic drugs into liposomes improve their bioavailability and leads to increased stability and anticancer activity, along with decreased drug toxicity. Curcumin (Cur) is a natural polyphenol compound with a potent anticancer activity in pancreatic adenocarcinoma (PA). In the present study, different types of Cur-loaded liposomal formulations were prepared and characterized in terms of size, shape, zeta potential, optimal drug-to-lipid ratio and stability at 4°C, 37°C; and in human plasma in vitro. The best formulation in terms of these parameters was PEGylated, cholesterol-free formulation based upon hydrogenated soya PC (HSPC:DSPE-PEG2000:Cur, termed H5), which had a 0.05/10 molar ratio of drug-to-lipid, was found to be stable and had a 96% Cur incorporation efficiency. All Cur-loaded liposomal formulations had potent anticancer activity on the PA cancer cell lines AsPC-1 and BxPC-3, and were less toxic to a normal cell line (NHDF). Furthermore, apoptosis-induction induced by Cur in PA cells was associated with morphological changes including cell shrinkage, cytoplasmic blebbing, irregularity in shape and the externalization of cell membrane phosphatidylserine, which was preceded by an increase in intracellular reactive oxygen species (ROS) generation and caspase 3/7 activation. Because the liposomal formulations tested here, especially the H5 variant which exhibited slow release of the Cur in the human plasma test, the formulation may be stable enough to facilitate the accumulation of pharmacologically active amounts of Cur in target cancer tissue by EPR. Therefore, our formulations could serve as a promising therapeutic approach for pancreatic cancer and other cancers.

Development, Characterization and Evaluation of Solid Lipid Nanoparticles as a potential Anticancer Drug Delivery System

NASA Astrophysics Data System (ADS)

Patel, Meghavi

Solid lipid nanoparticles (SLNs) consist of spherical solid lipid particles in the nanometer size range, which are dispersed in water or in an aqueous surfactant solution. SLN technology represents a promising new approach to deliver hydrophilic as well as lipophilic drugs. The commercialization of SLN technology remains limited despite numerous efforts from researchers. The purpose of this research was to advance SLN preparation methodology by investigating the feasibility of preparing glyceryl monostearate (GMS) nanoparticles by using three preparation methods namely microemulsion technique, magnetic stirring technique and temperature modulated solidification technique of which the latter two were developed in our laboratory. An anticancer drug 5-fluorouracil was incorporated in the SLNs prepared via the temperature modulated solidification process. Optimization of the magnetic stirring process was performed to evaluate how the physicochemical properties of the SLN was influenced by systematically varying process parameters including concentration of the lipid, concentration of the surfactant, type of surfactant, time of stirring and temperature of storage. The results demonstrated 1:2 GMS to tween 80 ratio, 150 ml dispersion medium and 45 min stirring at 4000 RPM speed provided an optimum formulation via the temperature modulated solidification process. SLN dispersions were lyophilized to stabilize the solid lipid nanoparticles and the lyophilizates exhibited good redispersibility. The SLNs were characterized by particle size analysis via dynamic light scattering (DLS), zeta potential, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), drug encapsulation efficiency and in vitro drug release studies. Particle size of SLN dispersion prepared via the three preparation techniques was approximately 66 nm and that of redispersed lyophilizates was below 500 nm. TEM images showed spherical to oval particles that were less dense in the core with a well-defined shell and the particle size was in agreement with the particle size analysis data obtained by DLS. DSC thermograms of the lyophilized SLNs indicate a reduction in the crystallinity order of GMS particles. The drug encapsulation efficiency was found to be approximately 30%. In vitro drug release studies from redispersed lyophilized SLNs showed that 17 % of the encapsulated drug was released within 2 h. The SLNs prepared in our lab demonstrated characteristics that can potentially be utilized in an anticancer drug delivery system. Future in vitro cell culture and in vivo animal model studies will delineate compatibility and utility of these formulations in biological systems.

Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines – in vitro studies

PubMed Central

Legut, Mateusz; Lipka, Dominik; Filipczak, Nina; Piwoni, Adriana; Kozubek, Arkadiusz; Gubernator, Jerzy

2014-01-01

This paper describes a novel formulation of antineoplastic drug: mitoxantrone loaded into liposomal carriers enriched with encapsulated anacardic acid in the liposomal bilayer using a vitamin C gradient. Anacardic acid is a potent epigenetic agent with anticancer activity. This is the first liposomal formulation to combine an actively encapsulated drug and anacardic acid. The liposomes were characterized in terms of basic parameters, such as size, zeta potential, optimal drug-to-lipid ratio, loading time and temperature, and stability at 4°C and in human plasma in vitro. The formulation was found to be stable, and the loading process was rapid and efficient (drug-to-lipid ratio of up to 0.3 with over 90% efficiency in 5 minutes). The cytotoxicity of these formulations was assessed using the human melanoma cell lines A375 and Hs294T and the normal human dermal fibroblast line. The results showed that anacardic acid and to a smaller extent vitamin C significantly increased the cytotoxicity of the drug towards melanoma compared to ammonium sulfate liposomes. On the other hand, vitamin C and anacardic acid both protected normal cells from damage caused by the drug. The formulation combining anacardic acid, vitamin C, and mitoxantrone showed promising results in terms of cytotoxicity and cytoprotection. Therefore, it has potential for anticancer treatment. PMID:24489469

Antihypertensive neutral lipid

DOEpatents

Snyder, Fred L.; Blank, Merle L.

1986-01-01

The invention relates to the discovery of a class of neutral acetylated ether-linked glycerolipids having the capacity to lower blood pressure in warm-blooded animals. This physiological effect is structure sensitive requiring a long chain alkyl group at the sn-1 position and a short carbon chain acyl group (acetyl or propionyl) at the sn-2 position, and a hydroxyl group at the sn-3 position.

Lipid digestibility and energy content of distillers corn oil in swine and poultry

USDA-ARS?s Scientific Manuscript database

Two experiments were conducted to determine the DE and ME, and apparent total tract digestibility of ether extract of 3 distillers corn oil (DCO; 4.9, 12.8, or 13.9% FFA), compared with a sample of refined corn oil (CO, 0.04% FFA), and an industrially-hydrolyzed high FFA DCO (93.8% FFA) in young pig...

Gene Transcription, Metabolite and Lipid Profiling in Eco-Indicator Daphnia magna Indicate Diverse Mechanisms of Toxicity by Legacy and Emerging Flame-Retardants

EPA Science Inventory

The use of chemical flame-retardants (FR) in consumer products has steadily increased over the last 30 years. Toxicity data exist for legacy FRs such as pentabromodiphenyl ether (pentaBDE), but less is known about effects of new formulations. To address this issue, the toxicity o...

The spectrophotometric sulfo-phospho-vanillin assessment of total lipids in human meibomian gland secretions.

PubMed

McMahon, Anne; Lu, Hua; Butovich, Igor A

2013-05-01

Human meibomian gland secretions (meibum) are the major lipid component of the human preocular tear film. The predominant lipid classes found in meibum include waxes (WE), cholesteryl esters (CE), and varying amounts of cholesterol (Chl). The classical sulfo-phospho-vanillin assay (SPVA), adapted for a microplate reader, was used to quantitate lipids in meibum. To account for varying reactivities of different lipids in SPVA, a model meibomian lipid mixture (MMx) that approximated the WE/CE/Chl composition of meibum was developed and used to quantitate meibomian lipids. The overall SPV responses of MMx and meibum were found to be close, with similar intermediate and final reaction products for both. Saturated WE that had not been expected to be reactive were found to be SPV-positive. A reaction mechanism for these compounds in SPVA which involves the formation of alkenyl ethers is proposed and discussed. Tested proteins were non-reactive in SPVA. Thus, by comparing the results of gravimetric analyses of meibum samples with the results of a properly calibrated SPVA, it was estimated that the SPV-reactive lipid content of dry meibum in tested samples was about 78 % (w/w). The SPV method can also be adopted for analyzing other types of complex lipids secretions, such as sebum, as well as whole lipid extracts from other lipid-enriched organs and tissues, if proper standards are chosen.

The Spectrophotometric Sulfo-Phospho-Vanillin Assessment of Total Lipids in Human Meibomian Gland Secretions

PubMed Central

McMahon, Anne; Lu, Hua

2013-01-01

Human meibomian gland secretions (meibum) are the major lipid component of the human preocular tear film. The predominant lipid classes found in meibum include waxes (WE), cholesteryl esters (CE), and varying amounts of cholesterol (Chl). The classical sulfo-phospho-vanillin assay (SPVA), adapted for a microplate reader, was used to quantitate lipids in meibum. To account for varying reactivities of different lipids in SPVA, a model meibomian lipid mixture (MMx) that approximated the WE/CE/Chl composition of meibum was developed and used to quantitate meibomian lipids. The overall SPV responses of MMx and meibum were found to be close, with similar intermediate and final reaction products for both. Saturated WE that had not been expected to be reactive were found to be SPV-positive. A reaction mechanism for these compounds in SPVA which involves the formation of alkenyl ethers is proposed and discussed. Tested proteins were non-reactive in SPVA. Thus, by comparing the results of gravimetric analyses of meibum samples with the results of a properly calibrated SPVA, it was estimated that the SPV-reactive lipid content of dry meibum in tested samples was about 78 % (w/w). The SPV method can also be adopted for analyzing other types of complex lipids secretions, such as sebum, as well as whole lipid extracts from other lipid-enriched organs and tissues, if proper standards are chosen. PMID:23345137

Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs.

PubMed

Garbuzenko, Olga B; Winkler, Jennifer; Tomassone, M Silvina; Minko, Tamara

2014-11-04

The aim of the present work is to synthesize, characterize, and test self-assembled anisotropic or Janus particles designed to load anticancer drugs for lung cancer treatment by inhalation. The particles were synthesized using binary mixtures of biodegradable and biocompatible materials. The particles did not demonstrate cyto- and genotoxic effects. Janus particles were internalized by cancer cells and accumulated both in the cytoplasm and nuclei. After inhalation delivery, nanoparticles accumulated preferentially in the lungs of mice and retained there for at least 24 h. Two drugs or other biologically active components with substantially different aqueous solubility can be simultaneously loaded in two-phases (polymer-lipid) of these nanoparticles. In the present proof-of-concept investigation, the particles were loaded with two anticancer drugs: doxorubicin and curcumin as model anticancer drugs with relatively high and low aqueous solubility, respectively. However, there are no obstacles for loading any hydrophobic or hydrophilic chemical agents. Nanoparticles with dual load were used for their local inhalation delivery directly to the lungs of mice with orthotopic model of human lung cancer. In vivo experiments showed that the selected nanoparticles with two anticancer drugs with different mechanisms of action prevented progression of lung tumors. It should be stressed that anticancer effects of the combined treatment with two anticancer drugs loaded in the same nanoparticle significantly exceeded the effect of either drug loaded in similar nanoparticles alone.

AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells

USDA-ARS?s Scientific Manuscript database

Pterostilbene, a bioactive component of blueberries and grapes, shows structural similarity to resveratrol, and exhibits antioxidant, anti-inflammatory, anti-cancer, hypoglycemic, and cholesterol lowering effects. This study examined potential mechanisms that may contribute to its lipid- and glucose...

Grafted self-assembled monolayers derived from naturally occurring phenolic lipids.

PubMed

Pillot, J-P; Birot, M; Tran, T T T; Dao, T M; Belin, C; Desbat, B; Lazare, S

2005-04-12

Self-assembled monolayers grafted onto silicon surfaces were obtained from the hydrosilylation products by trialcoxysilanes of naturally occurring phenolic lipid allyl ethers. The as-obtained materials were characterized by various physical and physicochemical methods. Thus, contact angles of water drops showed that they possess very high hydrophobicity. Their excellent regularity was corroborated by AFM microscopy. The frequencies of the stretching CH2 infrared modes indicate the presence of alkyl chains mainly in the trans/trans conformation. Additionally, optical ellipsometry and quartz microbalance measurements enabled us to estimate the thickness of the films. The results, as a whole, are in good agreement with the formation of densely packed monolayers.

Novel diindolylmethane derivatives based NLC formulations to improve the oral bioavailability and anticancer effects in triple negative breast cancer

PubMed Central

Godugu, Chandraiah; Doddapaneni, Ravi; Safe, Stephen H.; Singh, Mandip

2017-01-01

The present study demonstrates the promising anticancer effects of novel C-substituted diindolylmethane (DIM) derivatives DIM-10 and DIM-14 in aggressive TNBC models. In vitro studies demonstrated that these compounds possess strong anticancer effects. Caco-2 permeability studies resulted in poor permeability and poor oral bioavailability was demonstrated by pharmacokinetic studies. Nano structured lipid carrier (NLC) formulations were prepared to increase the clinical acceptance of these compounds. Significant increase in oral bioavailability was observed with NLC formulations. Compared to DIM-10, DIM-10 NLC formulation showed increase in Cmax and AUC values by 4.73 and 11.19-folds, respectively. Similar pattern of increase was observed with DIM-14 NLC formulations. In dogs DIM-10 NLC formulations showed an increase of 2.65 and 2.94-fold in Cmax and AUC, respectively. The anticancer studies in MDA-MB-231 orthotopic TNBC models demonstrated significant reduction in tumor volumes in DIM-10 and DIM-14 NLC treated animals. Our studies suggest that NLC formulation of both DIM-10 and 14 is effective in TNBC models. PMID:27586082

The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine.

PubMed

Chidley, Christopher; Trauger, Sunia A; Birsoy, Kıvanç; O'Shea, Erin K

2016-07-12

Phenotypic screens allow the identification of small molecules with promising anticancer activity, but the difficulty in characterizing the mechanism of action of these compounds in human cells often undermines their value as drug leads. Here, we used a loss-of-function genetic screen in human haploid KBM7 cells to discover the mechanism of action of the anticancer natural product ophiobolin A (OPA). We found that genetic inactivation of de novo synthesis of phosphatidylethanolamine (PE) mitigates OPA cytotoxicity by reducing cellular PE levels. OPA reacts with the ethanolamine head group of PE in human cells to form pyrrole-containing covalent cytotoxic adducts and these adducts lead to lipid bilayer destabilization. Our characterization of this unusual cytotoxicity mechanism, made possible by unbiased genetic screening in human cells, suggests that the selective antitumor activity displayed by OPA may be due to altered membrane PE levels in cancer cells.

Bauhinia variegata leaf extracts exhibit considerable antibacterial, antioxidant, and anticancer activities.

PubMed

Mishra, Amita; Sharma, Amit Kumar; Kumar, Shashank; Saxena, Ajit K; Pandey, Abhay K

2013-01-01

The present study reports the phytochemical profiling, antimicrobial, antioxidant, and anticancer activities of Bauhinia variegata leaf extracts. The reducing sugar, anthraquinone, and saponins were observed in polar extracts, while terpenoids and alkaloids were present in nonpolar and ethanol extracts. Total flavonoid contents in various extracts were found in the range of 11-222.67 mg QE/g. In disc diffusion assays, petroleum ether and chloroform fractions exhibited considerable inhibition against Klebsiella pneumoniae. Several other extracts also showed antibacterial activity against pathogenic strains of E. coli, Proteus spp. and Pseudomonas spp. Minimum bactericidal concentration (MBC) values of potential extracts were found between 3.5 and 28.40 mg/mL. The lowest MBC (3.5 mg/mL) was recorded for ethanol extract against Pseudomonas spp. The antioxidant activity of the extracts was compared with standard antioxidants. Dose dependent response was observed in reducing power of extracts. Polar extracts demonstrated appreciable metal ion chelating activity at lower concentrations (10-40 μg/mL). Many extracts showed significant antioxidant response in beta carotene bleaching assay. AQ fraction of B. variegata showed pronounced cytotoxic effect against DU-145, HOP-62, IGR-OV-1, MCF-7, and THP-1 human cancer cell lines with 90-99% cell growth inhibitory activity. Ethyl acetate fraction also produced considerable cytotoxicity against MCF-7 and THP-1 cell lines. The study demonstrates notable antibacterial, antioxidant, and anticancer activities in B. variegata leaf extracts.

[STUDY OF LIPIDS SEED'S OIL OF VITEX AGNUS CASTUS GROWING IN GEORGIA].

PubMed

Kikalishvili, B; Zurabashvili, D; Sulakvelidze, Ts; Malania, M; Turabelidze, D

2016-07-01

There was established the lipid composition of the seeds of Vitex agnus castus L. by the qualitative and quantitative methods of analyses. There were received neutral lipids from the seeds by extraction with hexane in the yield 10%, counted on dry material. For the divide of neutral lipids there was used silica gel plates LS 5/40 in the systems of solvents: 1. petroleum ether-diethylether-acidum aceticum (85:14:1), 2. hexane-diethylether (1:1). After obtaining neutral lipids from the residual plant shrot pollar lipids was extracted with the mixture of chloroform-methanol (2:1) and was divided on silica gel plates LS 5/40, mobile phase: 1. chloroform-methanol-25% ammonium hydrate 2. chloroform-methanol icy acetic acid-water (170:25:25:6). In the sum of polar lipids qualitatively were established phospholipids: lisophosphatidylcholine, phosphatidylinosit, phospatidylethanolamine and N-acylphosphatidylethanolamine, in neutral lipids, hydrocarbons, triglycerids, free fatty acids and sterines. By the method of high performance liquid chromatography analyses there were identified following free fatty acids: lauric, myristic, palmitic, stearic, linolic, linolenic, arachidic and begenic, unsaturated oleic and polyunsaturated linolic and linolenic acids. obtained oil with unique composition from the seeds of Vitex agnus-castus indicates to its high biological activity and importance for usage in medicine.

Proximate composition, phytochemical analysis, and in vitro antioxidant potentials of extracts of Annona muricata (Soursop).

PubMed

Agu, Kingsley C; Okolie, Paulinus N

2017-09-01

Numerous bioactive compounds and phytochemicals have been reported to be present Annona muricata (Soursop). Some of these chemical compounds have been linked to the ethnomedicinal properties of the plant and its antioxidant properties. The aim of this study was to assess the proximate composition, phytochemical constituents and in vitro antioxidant properties of A. muricata using standard biochemical procedures. The defatted Annona muricata crude methanolic extracts of the different parts of the plant were used for the estimation of proximate composition and phytochemical screening. The crude methanolic extracts of the different parts of the plant were also fractionated using solvent-solvent partitioning. Petroleum ether, chloroform, ethyl acetate, methanol, and methanol-water (90:10) were the solvents used for the fractionation. The different fractions obtained were then used to perform in vitro antioxidant analyses including, 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging ability, ferric reducing properties, and hydroxyl radical scavenging ability. The leaf methanolic extract had a higher lipid content, whereas its chloroform fraction demonstrated a better ability to quench DPPH free radical. The root-bark methanol-water, leaf methanol, fruit pulp chloroform, and leaf petroleum ether fractions demonstrated potent ferric reducing properties. The leaf and stem-bark petroleum ether fractions demonstrated better hydroxyl-free radical scavenging abilities. The leaf and fruit pulp of Annona muricata have a very potent antioxidant ability compared to the other parts of the plant. This can be associated with the rich phytochemicals and other phytoconstituents like phenols, flavonoids, alkaloids, and essential lipids, etc. Significant correlations were observed between the antioxidant status and phytochemicals present. These results thus suggest that some of the reported ethnomedicinal properties of this plant could be due to its antioxidant potentials.

Combined effects of dissolved humic acids and tourmaline on the accumulation of 2, 2', 4, 4', 5, 5'- hexabrominated diphenyl ether (BDE-153) in Lactuca sativa.

PubMed

Wang, Cuiping; Ma, Chuanxin; Jia, Weili; Wang, Dong; Sun, Hongwen; Xing, Baoshan

2017-12-01

In order to investigate the effects of dissolved humic acid (DHA) and tourmaline on uptake of 2, 2', 4, 4', 5, 5'- hexabrominated diphenyl ether (BDE-153) by Lactuca sativa, different fractions of DHA, including DHA 1 and DHA 4 , as well as different doses of tourmaline were introduced into BDE-153 contaminated solutions for plant growth. The levels of BDE-153 in L. sativa tissues were positively correlated with the Fe levels (R 2  = 0.9264) in seedings of the treatments with different doses of tourmaline. However, when adding DHA 1 and DHA 4 into the system, the correlation coefficients (R 2 ) decreased to 0.6976 and 0.5451 from 0.9264, respectively. In contrast with the Fe contents, the presence of DHAs didn't affect the R 2 between the levels of BDE-153 and the lipid contents in plant tissues. Our results indicated that both DHA 1 and DHA 4 could severely alter the BDE-153 uptake by L. sativa through reducing the Fe uptake instead of the lipid contents. Additionally, DHA 4 exhibited much stronger abilities to alter the BDE-153 accumulation than DHA 1 . Transmission electron microscopy (TEM) observations indicated that either DHA 1 or tourmaline or co-treatment with DHA and tourmaline had no negative impact on L. sativa at the cellular level. The present study provides important information for the impacts of different fractions of DHA extracted from soil on the BDE-153 migration in plant systems. Moreover, we elucidated the importance of the iron in tourmaline for migration of the polybrominated diphenyl ethers (PBDEs) in plant systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Approaches for the Analysis of Chlorinated Lipids

PubMed Central

Wang, Wen-yi; Albert, Carolyn J.; Ford, David A.

2013-01-01

Leukocytes are key cellular mediators of human diseases through their role in inflammation. Identifying unique molecules produced by leukocytes may provide new biomarkers and mechanistic insights into the role of leukocytes in disease. Chlorinated lipids are generated as a result of myeloperoxidase-containing leukocyte-derived hypochlorous acid targeting the vinyl ether bond of plasmalogens. The initial product of this reaction is α-chlorofatty aldehyde. α -Chlorofatty aldehyde is both oxidized to α-chlorofatty acid and reduced to α-chlorofatty alcohol by cellular metabolism. This review focuses on the separation techniques and quantitative analysis for these chlorinated lipids. For α-chlorofatty acid the negative charge of carboxylic acids is exploited to detect the chlorinated lipid species of these acids by electrospray ionization mass spectrometry in the negative ion mode. In contrast, α-chlorofatty aldehyde and α-chlorofatty alcohol are converted to pentafluorobenzyl oxime and pentafluorobenzoyl ester derivatives, which are detected by negative ion-chemical ionization mass spectrometry. These two detection methods coupled with the use of stable isotope internal standards and either liquid chromatography or gas chromatography provide highly sensitive analytical approaches to measure these novel lipids. PMID:24056259

Evaluation of antitumor activity and development of solid lipid nanoparticles of metronidazole analogue.

PubMed

Lages, Eduardo Burgarelli; de Freitas, Maria Betânia; Gonçalves, Isadora Marques Brum; Alves, Ricardo José; Vianna-Soares, Cristina Duarte; Ferreira, Lucas Antônio Miranda; de Oliveira, Mônica Cristina; de Oliveira, Renata Barbosa

2013-11-01

Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.

Curcumin as potential therapeutic natural product: a nanobiotechnological perspective.

PubMed

Shome, Soumitra; Talukdar, Anupam Das; Choudhury, Manabendra Dutta; Bhattacharya, Mrinal Kanti; Upadhyaya, Hrishikesh

2016-12-01

Nanotechnology-based drug delivery systems can resolve the poor bioavailability issue allied with curcumin. The therapeutic potential of curcumin can be enhanced by making nanocomposite preparation of curcumin with metal oxide nanoparticles, poly lactic-co-glycolic acid (PLGA) nanoparticles and solid lipid nanoparticles that increases its bioavailability in the tissue. Curcumin has manifold therapeutic effects which include antidiabetic, antihypertensive, anticancer, anti-inflammatory and antimicrobial properties. Curcumin can inhibit diabetes, heavy metal and stress-induced hypertension with its antioxidant, chelating and inhibitory effects on the pathways that lead to hypertension. Curcumin is an anticancer agent that can prevent abnormal cell proliferation. Nanocurcumin is an improved form of curcumin with enhanced therapeutic properties due to improved delivery to the diseased tissue, better internalization and reduced systemic elimination. Curcumin has multiple pharmacologic effects, but its poor bioavailability reduces its therapeutic effects. By conjugating curcumin to metal oxide nanoparticles or encapsulation in lipid nanoparticles, dendrimers, nanogels and polymeric nanoparticles, the water solubility and bioavailability of curcumin can be improved and thus increase its pharmacological effectiveness. © 2016 Royal Pharmaceutical Society.

Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals.

PubMed

Li, Chuan; Zhang, Jia; Zu, Yu-Jiao; Nie, Shu-Fang; Cao, Jun; Wang, Qian; Nie, Shao-Ping; Deng, Ze-Yuan; Xie, Ming-Yong; Wang, Shu

2015-09-01

Many phytochemicals show promise in cancer prevention and treatment, but their low aqueous solubility, poor stability, unfavorable bioavailability, and low target specificity make administering them at therapeutic doses unrealistic. This is particularly true for (-)-epigallocatechin gallate, curcumin, quercetin, resveratrol, and genistein. There is an increasing interest in developing novel delivery strategies for these natural products. Liposomes, micelles, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers and poly (lactide-co-glycolide) nanoparticles are biocompatible and biodegradable nanoparticles. Those nanoparticles can increase the stability and solubility of phytochemicals, exhibit a sustained release property, enhance their absorption and bioavailability, protect them from premature enzymatic degradation or metabolism, prolong their circulation time, improve their target specificity to cancer cells or tumors via passive or targeted delivery, lower toxicity or side-effects to normal cells or tissues through preventing them from prematurely interacting with the biological environment, and enhance anti-cancer activities. Nanotechnology opens a door for developing phytochemical-loaded nanoparticles for prevention and treatment of cancer. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Clinical experience with drug delivery systems as tools to decrease the toxicity of anticancer chemotherapeutic agents.

PubMed

Maranhão, Raul C; Vital, Carolina G; Tavoni, Thauany M; Graziani, Silvia R

2017-10-01

The toxicity of chemotherapeutic agents, resulting from their low pharmacological index, introduces considerable discomfort and risk to cancer patients. Among several strategies to reduce the toxicity of chemotherapeutic agents, targeted drug delivery is the most promising one. Areas covered: Liposomes, micelles, albumin-based, polymeric, dendritic and lipid core nanoparticles have been used as carriers to concentrate anticancer drugs in neoplastic tissues, and clinical studies of those preparations are reviewed. In most clinical studies, drug delivery systems reduced drug toxicity. Lipid core nanoparticles (LDE) that bind to cell lipoprotein receptors have the ability to concentrate in neoplastic tissues and were the first artificial non-liposomal system shown in in vivo studies to possess targeting properties. The toxicity reduction achieved by LDE as vehicle of carmustine, etoposide and paclitaxel was singularly strong. Expert opinion: The reduced toxicity offered by drug delivery systems has expanded treatment population that may benefit from chemotherapy including feeble, overtreated and elderly patients that would otherwise be offered palliative therapy. Drug delivery systems may either prolong the duration of treatments or allow increases in drug dose.

Potential preventive effect of carvacrol against diethylnitrosamine-induced hepatocellular carcinoma in rats.

PubMed

Jayakumar, Subramaniyan; Madankumar, Arumugam; Asokkumar, Selvamani; Raghunandhakumar, Subramanian; Gokula dhas, Krishnan; Kamaraj, Sattu; Divya, Michael Georget Josephine; Devaki, Thiruvengadam

2012-01-01

Antioxidants are one of the key players in tumorigenesis, several natural and synthetic antioxidants were shown to have anticancer effects. The aim of the present study is to divulge the chemopreventive nature of carvacrol during diethylnitrosamine (DEN)-induced liver cancer in male wistar albino rats. Administration of DEN to rats resulted in increased relative liver weight and serum marker enzymes aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and gamma glutamyl transpeptidase (γGT). The levels of lipid peroxides elevated (in both serum and tissue) with subsequent decrease in the final body weight and tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GPx), and glutathione reductase (GR). Carvacrol supplementation (15 mg/kg body weight) significantly attenuated these alterations, thereby showing potent anticancer effect in liver cancer. Histological observations and transmission electron microscopy studies were also carried out, which added supports to the chemopreventive action of the carvacrol against DEN-induction during liver cancer progression. These findings suggest that carvacrol prevents lipid peroxidation, hepatic cell damage, and protects the antioxidant system in DEN-induced hepatocellular carcinogenesis.

Factors influencing uptake and retention of amino-containing drugs in large unilamellar vesicles exhibiting transmembrane pH gradients.

PubMed

Maurer-Spurej, E; Wong, K F; Maurer, N; Fenske, D B; Cullis, P R

1999-01-12

The level of uptake and retention of amino-containing drugs in large unilamellar vesicles (LUVs) following uptake in response to a transmembrane pH gradient (DeltapH) can vary dramatically depending on the drug. For example, the anticancer drugs doxorubicin and epirubicin can be readily retained, whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly. In this investigation, we examine the influence of the hydrophobicity of the entrapped amines (that induce the DeltapH) and the anionic lipid content of the LUV on drug retention. It is shown that entrapment of increasingly hydrophobic monoamines (methylamine to amylamine) all lead to an induced DeltapH of 3 units and essentially complete drug uptake under the conditions employed, but do not lead to improved retention of vincristine and ciprofloxacin. However, significantly improved retention could be achieved by substitution of the anionic lipid distearoylphosphatidylglycerol (DSPG) for distearoylphosphatidylcholine (DSPC) in the LUV bilayer. Further, it is shown that if the induced DeltapH is reduced to 1.4 units (driven by entrapped diamine) nearly 100% accumulation of doxorubicin and epirubicin could be achieved, whereas only 25% loading for vincristine and ciprofloxacin was observed. Taken together these results provide methodology for improving (weak base) drug retention in liposomes and indicate that drugs that can partition into the lipid bilayer exhibit improved uptake and retention characteristics.

Green design "bioinspired disassembly-reassembly strategy" applied for improved tumor-targeted anticancer drug delivery.

PubMed

Wang, Ruoning; Gu, Xiaochen; Zhou, Jianping; Shen, Lingjia; Yin, Lifang; Hua, Peiying; Ding, Yang

2016-08-10

In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibitory effects of black pepper (Piper nigrum) extracts and compounds on human tumor cell proliferation, cyclooxygenase enzymes, lipid peroxidation and nuclear transcription factor-kappa-B.

PubMed

Liu, Yunbao; Yadev, Vivek R; Aggarwal, Bharat B; Nair, Muraleedharan G

2010-08-01

Black pepper (Piper nigrum) and hot pepper (Capsicum spp.) are widely used in traditional medicines. Although hot Capsicum spp. extracts and its active principles, capsaicinoids, have been linked with anticancer and anti-inflammatory activities, whether black pepper and its active principle exhibit similar activities is not known. In this study, we have evaluated the antioxidant, anti-inflammatory and anticancer activities of extracts and compounds from black pepper by using proinflammatory transcription factor NF-kappaB, COX-1 and -2 enzymes, human tumor cell proliferation and lipid peroxidation (LPO). The capsaicinoids, the alkylamides, isolated from the hot pepper Scotch Bonnet were also used to compare the bioactivities of alkylamides and piperine from black pepper. All compounds derived from black pepper suppressed TNF-induced NF-kappaB activation, but alkyl amides, compound 4 from black pepper and 5 from hot pepper, were most effective. The human cancer cell proliferation inhibitory activities of piperine and alklyl amides in Capsicum and black pepper were dose dependant. The inhibitory concentrations 50% (IC50) of the alklylamides were in the range 13-200 microg/mL. The extracts of black pepper at 200 microg/mL and its compounds at 25 microg/mL inhibited LPO by 45-85%, COX enzymes by 31-80% and cancer cells proliferation by 3.5-86.8%. Overall, these results suggest that black pepper and its constituents like hot pepper, exhibit anti-inflammatory, antioxidant and anticancer activities.

Depositional characteristics of atmospheric polybrominated diphenyl ethers on tree barks

PubMed Central

Chun, Man Young

2014-01-01

Objectives This study was conducted to determine the depositional characteristics of several tree barks, including Ginkgo (Ginkgo biloba), Pine (Pinus densiflora), Platanus (Platanus), and Metasequoia (Metasequoia glyptostroboides). These were used as passive air sampler (PAS) of atmospheric polybrominated diphenyl ethers (PBDEs). Methods Tree barks were sampled from the same site. PBDEs were analyzed by highresolution gas chromatography/high-resolution mass spectrometer, and the lipid content was measured using the gravimetric method by n-hexane extraction. Results Gingko contained the highest lipid content (7.82 mg/g dry), whereas pine (4.85 mg/g dry), Platanus (3.61 mg/g dry), and Metasequoia (0.97 mg/g dry) had relatively lower content. The highest total PBDEs concentration was observed in Metasequoia (83,159.0 pg/g dry), followed by Ginkgo (53,538.4 pg/g dry), Pine (20,266.4 pg/g dry), and Platanus (12,572.0 pg/g dry). There were poor correlations between lipid content and total PBDE concentrations in tree barks (R2=0.1011, p =0.682). Among the PBDE congeners, BDE 206, 207 and 209 were highly brominated PBDEs that are sorbed to particulates in ambient air, which accounted for 90.5% (84.3-95.6%) of the concentration and were therefore identified as the main PBDE congener. The concentrations of particulate PBDEs deposited on tree barks were dependent on morphological characteristics such as surface area or roughness of barks. Conclusions Therefore, when using the tree barks as the PAS of the atmospheric PBDEs, samples belonging to same tree species should be collected to reduce errors and to obtain reliable data. PMID:25116365

Depositional characteristics of atmospheric polybrominated diphenyl ethers on tree barks.

PubMed

Chun, Man Young

2014-07-17

This study was conducted to determine the depositional characteristics of several tree barks, including Ginkgo (Ginkgo biloba), Pine (Pinus densiflora), Platanus (Platanus), and Metasequoia (Metasequoia glyptostroboides). These were used as passive air sampler (PAS) of atmospheric polybrominated diphenyl ethers (PBDEs). Tree barks were sampled from the same site. PBDEs were analyzed by highresolution gas chromatography/high-resolution mass spectrometer, and the lipid content was measured using the gravimetric method by n-hexane extraction. Gingko contained the highest lipid content (7.82 mg/g dry), whereas pine (4.85 mg/g dry), Platanus (3.61 mg/g dry), and Metasequoia (0.97 mg/g dry) had relatively lower content. The highest total PBDEs concentration was observed in Metasequoia (83,159.0 pg/g dry), followed by Ginkgo (53,538.4 pg/g dry), Pine (20,266.4 pg/g dry), and Platanus (12,572.0 pg/g dry). There were poor correlations between lipid content and total PBDE concentrations in tree barks (R(2)=0.1011, p =0.682). Among the PBDE congeners, BDE 206, 207 and 209 were highly brominated PBDEs that are sorbed to particulates in ambient air, which accounted for 90.5% (84.3-95.6%) of the concentration and were therefore identified as the main PBDE congener. The concentrations of particulate PBDEs deposited on tree barks were dependent on morphological characteristics such as surface area or roughness of barks. Therefore, when using the tree barks as the PAS of the atmospheric PBDEs, samples belonging to same tree species should be collected to reduce errors and to obtain reliable data.

Platelet Activating Factor: A Growth Factor for Breast Cancer

DTIC Science & Technology

2006-09-01

synthase (ADS) increases ether lipid content, growth and PAF synthesis in MCF-7 cells. 4. Eicosapentaenoic acid (EPA) inhibits the synthesis of PAF...Schmitt, J. D., Bullock, B. C. Wykle, R. L. Reacylation of platelet activating factor with eicosapentaenoic acid in fish-oil-enriched monkey...breast cancer. Recent studies have shown that the ratio of two families of essential fatty acids is important in regulating many cellular processes

Aqueous solutions of didecyldimethylammonium chloride and octaethylene glycol monododecyl ether: Toward synergistic formulations against enveloped viruses.

PubMed

Nardello-Rataj, Véronique; Leclercq, Loïc

2016-09-10

Micellization of di-n-decyldimethylammonium chloride, [DiC10][Cl], and octaethylene glycol monododecyl ether, C12E8, mixtures have been investigated by surface tension and conductivity measurements. From these results, various physicochemical and thermodynamic key parameters (e.g. micellar mole fraction of [DiC10][Cl], interaction parameter, free energy of micellization, etc.) have been evaluated and discussed in detail. The results prove high synergistic effect between the two surfactants. Based on these results, the virucidal activity of an equimolar mixture of [DiC10][Cl] and C12E8 has been investigated. A marked synergism was observed on lipid-containing deoxyribonucleic and ribonucleic acid viruses, such as herpes virus, respiratory syncytial virus, and vaccinia viruses. In contrast, Coxsackievirus (non-enveloped virus) was not inactivated. These results support that the mechanism is based on the extraction of lipids and/or proteins from the envelope inside the mixed micelles. This extraction creates "holes" the size of which increases with concentration up to a specific value which triggers the virus inactivation. Such a mixture could be used to extend the spectrum of virucidal activity of the amphiphiles virucides commonly employed in numerous disinfectant solutions. Copyright © 2016 Elsevier B.V. All rights reserved.

High tocopherol and triacylglycerol contents in Pinus pinea L. seeds.

PubMed

Nasri, Nizar; Tlili, Nizar; Ben Ammar, Kamel; Khaldi, Abdelhamid; Fady, Bruno; Triki, Saida

2009-01-01

Oleaginous seeds are among the functional foods most recognized for their tocopherols and triacylglycerols because of their role in lipid metabolism. In this paper, the tocopherol and triacylglycerol contents in seeds of several Pinus pinea L. populations around the Mediterranean Basin were investigated. Lipids were extracted from fully ripen seeds with petroleum ether. The tocopherol (alpha-tocopherol, gamma-tocopherol, and delta-tocopherol) contents were, respectively, 15.34+/-3.75 ppm, 1,681.75+/-404.03 ppm and 41.87+/-9.79 ppm. Lipids (mainly triacylglycerols) in P. pinea seeds averaged 48% on a dry weight basis. Triacylglycerols with an equivalent carbon number of 44 (32.27%) and of 46 (30.91%) were dominant. The major triacylglycerol was LLO (24.06%). Tocopherols and triacylglycerols were present at remarkably high levels, thus making P. pinea oil a valuable source of antioxidants and unsaturated fatty acids with varying levels across the geographical range of P. pinea.

Targeting SREBP-1-driven lipid metabolism to treat cancer

PubMed Central

Guo, Deliang; Bell, Erica Hlavin; Mischel, Paul; Chakravarti, Arnab

2014-01-01

Metabolic reprogramming is a hallmark of cancer. Oncogenic growth signaling regulates glucose, glutamine and lipid metabolism to meet the bioenergetics and biosynthetic demands of rapidly proliferating tumor cells. Emerging evidence indicates that sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that controls lipid metabolism, is a critical link between oncogenic signaling and tumor metabolism. We recently demonstrated that SREBP-1 is required for the survival of mutant EGFR-containing glioblastoma, and that this pro-survival metabolic pathway is mediated, in part, by SREBP-1-dependent upregulation of the fatty acid synthesis and low density lipoprotein (LDL) receptor (LDLR). These results have identified EGFR/PI3K/Akt/SREBP-1 signaling pathway that promotes growth and survival in glioblastoma, and potentially other cancer types. Here, we summarize recent insights in the understanding of cancer lipid metabolism, and discuss the evidence linking SREBP-1 with PI3K/Akt signaling-controlled glycolysis and with Myc-regulated glutaminolysis to lipid metabolism. We also discuss the development of potential drugs targeting the SREBP-1-driven lipid metabolism as anti-cancer agents. PMID:23859617

Influence of sample preparation on lipidomics analysis of polar lipids in adipose tissue.

PubMed

López-Bascón, M A; Calderón-Santiago, M; Sánchez-Ceinos, J; Fernández-Vega, A; Guzmán-Ruiz, R; López-Miranda, J; Malagon, M M; Priego-Capote, F

2018-01-15

The main limitations of lipidomics analysis are the chemical complexity of the lipids, the range of concentrations at which they exist, and the variety of samples usually analyzed. These limitations particularly affect the characterization of polar lipids owing to the interference of neutral lipids, essentially acylglycerides, which are at high concentration and suppress ionization of low concentrated lipids in mass spectrometry detection. The influence of sample preparation on lipidomics analysis of polar lipids in adipose tissue by LC-MS/MS was the aim of this research. Two common extractants used for lipids isolation, methanol:chloroform (MeOH:CHCl 3 ) and methyl tert-butyl ether (MTBE), were qualitatively and quantitatively compared for the extraction of the main families of lipids. The obtained results showed that each family of lipids is influenced differently by the extractant used. However, as a general trend, the use of MTBE as extractant led to higher extraction efficiency for unsaturated fatty acids, glycerophospholipids and ceramides, while MeOH:CHCl 3 favored the isolation of saturated fatty acids and plasmalogens. The implementation of a solid-phase extraction (SPE) step for selective isolation of glycerophospholipids prior to LC-MS/MS analysis was assayed to evaluate its influence on lipids detection coverage as compared to direct analysis. This step was critical to enhance the detection coverage of glycerophospholipids by removal of ionization suppression effects caused by acylglycerides. Copyright © 2017 Elsevier B.V. All rights reserved.

Stratification of archaeal membrane lipids in the ocean and implications for adaptation and chemotaxonomy of planktonic archaea.

PubMed

Zhu, Chun; Wakeham, Stuart G; Elling, Felix J; Basse, Andreas; Mollenhauer, Gesine; Versteegh, Gerard J M; Könneke, Martin; Hinrichs, Kai-Uwe

2016-12-01

Membrane lipids of marine planktonic archaea have provided unique insights into archaeal ecology and paleoceanography. However, past studies of archaeal lipids in suspended particulate matter (SPM) and sediments mainly focused on a small class of fully saturated glycerol dibiphytanyl glycerol tetraether (GDGT) homologues identified decades ago. The apparent low structural diversity of GDGTs is in strong contrast to the high diversity of metabolism and taxonomy among planktonic archaea. Furthermore, adaptation of archaeal lipids in the deep ocean remains poorly constrained. We report the archaeal lipidome in SPM from diverse oceanic regimes. We extend the known inventory of planktonic archaeal lipids to include numerous unsaturated archaeal ether lipids (uns-AELs). We further reveal (i) different thermal regulations and polar headgroup compositions of membrane lipids between the epipelagic (≤ 100 m) and deep (>100 m) populations of archaea, (ii) stratification of unsaturated GDGTs with varying redox conditions, and (iii) enrichment of tetra-unsaturated archaeol and fully saturated GDGTs in epipelagic and deep oxygenated waters, respectively. Such stratified lipid patterns are consistent with the typical distribution of archaeal phylotypes in marine environments. We, thus, provide an ecological context for GDGT-based paleoclimatology and bring about the potential use of uns-AELs as biomarkers for planktonic Euryarchaeota. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

Speciation of lipids and humus-like colloidal compounds in a forest soil reclaimed with municipal solid waste compost.

PubMed

Zancada, M Cristina; Almendros, Gonzalo; Sanz, Jesús; Román, Román

2004-02-01

The progressive transformations of lipid and humus-like fractions in soil after massive input (400 Mg ha(-1)) of urban waste have been studied during an 87-week experiment in field plots of a degraded Calcic Regosol in Central Spain. Structural changes in the macromolecular fractions were small when compared with the qualitative and quantitative changes in lipid composition. The intense depletion of the lipid fraction with time and the decrease of the humic acid to fulvic acid ratio were the most significant quantitative indices of the compost transformation in soil. Changes in soil lipid fractions were especially noted in relation to their speciation status and distribution patterns (carbon preference index and relative chain length). Three subfractions were considered: (I) direct extraction with petroleum ether, (II) liquid-liquid extraction after soil treatment with 2 M H3PO4 and (III) after soil treatment with 0.1 M NaOH. Although lipid concentration tends to decrease with time, lipids in the fraction tightly bonded to soil (III) remained qualitatively and quantitatively constant in the course of the field experiment. Gas chromatographic-mass spectrometric analyses showed that the more stable the association of lipid to the soil matrix, the fewer the changes observed in the distribution pattern of the fatty acids during the progressive transformation stages.

Nitroxides as Antioxidants and Anticancer Drugs

PubMed Central

Lewandowski, Marcin; Gwozdzinski, Krzysztof

2017-01-01

Nitroxides are stable free radicals that contain a nitroxyl group with an unpaired electron. In this paper, we present the properties and application of nitroxides as antioxidants and anticancer drugs. The mostly used nitroxides in biology and medicine are a group of heterocyclic nitroxide derivatives of piperidine, pyrroline and pyrrolidine. The antioxidant action of nitroxides is associated with their redox cycle. Nitroxides, unlike other antioxidants, are characterized by a catalytic mechanism of action associated with a single electron oxidation and reduction reaction. In biological conditions, they mimic superoxide dismutase (SOD), modulate hemoprotein’s catalase-like activity, scavenge reactive free radicals, inhibit the Fenton and Haber-Weiss reactions and suppress the oxidation of biological materials (peptides, proteins, lipids, etc.). The use of nitroxides as antioxidants against oxidative stress induced by anticancer drugs has also been investigated. The application of nitroxides and their derivatives as anticancer drugs is discussed in the contexts of breast, hepatic, lung, ovarian, lymphatic and thyroid cancers under in vivo and in vitro experiments. In this article, we focus on new natural spin-labelled derivatives such as camptothecin, rotenone, combretastatin, podophyllotoxin and others. The applications of nitroxides in the aging process, cardiovascular disease and pathological conditions were also discussed. PMID:29165366

Bauhinia variegata Leaf Extracts Exhibit Considerable Antibacterial, Antioxidant, and Anticancer Activities

PubMed Central

Mishra, Amita; Sharma, Amit Kumar; Kumar, Shashank; Saxena, Ajit K.; Pandey, Abhay K.

2013-01-01

The present study reports the phytochemical profiling, antimicrobial, antioxidant, and anticancer activities of Bauhinia variegata leaf extracts. The reducing sugar, anthraquinone, and saponins were observed in polar extracts, while terpenoids and alkaloids were present in nonpolar and ethanol extracts. Total flavonoid contents in various extracts were found in the range of 11–222.67 mg QE/g. In disc diffusion assays, petroleum ether and chloroform fractions exhibited considerable inhibition against Klebsiella pneumoniae. Several other extracts also showed antibacterial activity against pathogenic strains of E. coli, Proteus spp. and Pseudomonas spp. Minimum bactericidal concentration (MBC) values of potential extracts were found between 3.5 and 28.40 mg/mL. The lowest MBC (3.5 mg/mL) was recorded for ethanol extract against Pseudomonas spp. The antioxidant activity of the extracts was compared with standard antioxidants. Dose dependent response was observed in reducing power of extracts. Polar extracts demonstrated appreciable metal ion chelating activity at lower concentrations (10–40 μg/mL). Many extracts showed significant antioxidant response in beta carotene bleaching assay. AQ fraction of B. variegata showed pronounced cytotoxic effect against DU-145, HOP-62, IGR-OV-1, MCF-7, and THP-1 human cancer cell lines with 90–99% cell growth inhibitory activity. Ethyl acetate fraction also produced considerable cytotoxicity against MCF-7 and THP-1 cell lines. The study demonstrates notable antibacterial, antioxidant, and anticancer activities in B. variegata leaf extracts. PMID:24093108

Fat Analysis

NASA Astrophysics Data System (ADS)

Min, David B.; Ellefson, Wayne C.

Lipids, proteins, and carbohydrates constitute the principal structural components of foods. Lipids are a group of substances that, in general, are soluble in ether, chloroform, or other organic solvents but are sparingly soluble in water. However, there exists no clear scientific definition of a lipid, primarily due to the water solubility of certain molecules that fall within one of the variable categories of food lipids (1). Some lipids, such as triacylglycerols, are very hydrophobic. Other lipids, such as di- and monoacylglycerols, have both hydrophobic and hydrophilic moieties in their molecules and are soluble in relatively polar solvents (2). Short-chain fatty acids such as C1-C4 are completely miscible in water and insoluble in nonpolar solvents (1). The most widely accepted definition is based on solubility as previously stated. While most macromolecules are characterized by common structural features, the designation of "lipid" being defined by solubility characteristics is unique to lipids (2). Lipids comprise a broad group of substances that have some common properties and compositional similarities (3). Triacylglycerols are fats and oils that represent the most prevalent category of the group of compounds known as lipids. The terms lipids, fats, and oils are often used interchangeably. The term "lipid" commonly refers to the broad, total collection of food molecules that meet the definition previously stated. Fats generally refer to those lipids that are solid at room temperature and oils generally refer to those lipids that are liquid at room temperature. While there may not be an exact scientific definition, the US Food and Drug Administration (FDA) has established a regulatory definition for nutrition labeling purposes. The FDA has defined total fat as the sum of fatty acids from C4 to C24, calculated as triglycerides. This definition provides a clear path for resolution of any nutrition labeling disputes.

A relative quantitative positive/negative ion switching method for untargeted lipidomics via high resolution LC-MS/MS from any biological source

PubMed Central

Breitkopf, Susanne B.; Ricoult, Stéphane J. H.; Yuan, Min; Xu, Ying; Peake, David A.; Manning, Brendan D.

2017-01-01

Introduction Advances in high-resolution mass spectrometry have created renewed interest for studying global lipid biochemistry in disease and biological systems. Objectives Here, we present an untargeted 30 min. LC-MS/MS platform that utilizes positive/negative polarity switching to perform unbiased data dependent acquisitions (DDA) via higher energy collisional dissociation (HCD) fragmentation to profile more than 1000–1500 lipid ions mainly from methyl-tert-butyl ether (MTBE) or chloroform:methanol extractions. Methods The platform uses C18 reversed-phase chromatography coupled to a hybrid QExactive Plus/HF Orbitrap mass spectrometer and the entire procedure takes ~10 h from lipid extraction to identification/quantification for a data set containing 12 samples (~4 h for a single sample). Lipids are identified by both accurate precursor ion mass and fragmentation features and quantified using Lipid-Search and Elements software. Results Using this approach, we are able to profile intact lipid ions from up to 18 different main lipid classes and 66 subclasses. We show several studies from different biological sources, including cultured cancer cells, resected tissues from mice such as lung and breast tumors and biological fluids such as plasma and urine. Conclusions Using mouse embryonic fibroblasts, we showed that TSC2−/− KD significantly abrogates lipid biosynthesis and that rapamycin can rescue triglyceride (TG) lipids and we show that SREBP−/− shuts down lipid biosynthesis significantly via mTORC1 signaling pathways. We show that in mouse EGFR driven lung tumors, a large number of TGs and phosphatidylmethanol (PMe) lipids are elevated while some phospholipids (PLs) show some of the largest decrease in lipid levels from ~ 2000 identified lipid ions. In addition, we identified more than 1500 unique lipid species from human blood plasma. PMID:28496395

Temporal trend studies on tetra- and pentabrominated diphenyl ethers and hexabromocyclododecane in guillemot egg from the Baltic Sea.

PubMed

Sellström, Ulla; Bignert, Anders; Kierkegaard, Amelie; Häggberg, Lisbeth; de Wit, Cynthia A; Olsson, Mats; Jansson, Bo

2003-12-15

Guillemot eggs from the Baltic Sea, sampled between 1969 and 2001, were analyzed for tetra- and pentabromodiphenyl ethers (2,2',4,4'-tetraBDE (BDE-47), 2,2',4,4',5-pentaBDE (BDE-99), and 2,2',4,4',6-pentaBDE (BDE-100)), and hexabromocyclododecane (HBCD). This temporal trend study indicates that the concentrations of the polybrominated diphenyl ether compounds increased from the 1970s to the 1980s, peaking around the mid- to the late-1980s. These peaks are then followed by a rapid decrease in concentrations during the rest of the study period, with the concentrations of the major BDE congener below 100 ng/g lipid weight at the end of the period. This corresponds to less than 10% of its peak values. The concentrations of HBCD show a different pattern over time. After a peak in the middle of the 1970s followed by a decrease, the concentrations increased during the latter part of the 1980s. During the recent 10-yr period no significant change has occurred, and the annual mean concentrations are more or less stable at a higher level as compared to the beginning of the study period.

Supercritical Fluid Extraction of Bacterial and Archaeal Lipid Biomarkers from Anaerobically Digested Sludge

PubMed Central

Hanif, Muhammad; Atsuta, Yoichi; Fujie, Koichi; Daimon, Hiroyuki

2012-01-01

Supercritical fluid extraction (SFE) was used in the analysis of bacterial respiratory quinone (RQ), bacterial phospholipid fatty acid (PLFA), and archaeal phospholipid ether lipid (PLEL) from anaerobically digested sludge. Bacterial RQ were determined using ultra performance liquid chromatography (UPLC). Determination of bacterial PLFA and archaeal PLEL was simultaneously performed using gas chromatography-mass spectrometry (GC-MS). The effects of pressure, temperature, and modifier concentration on the total amounts of RQ, PLFA, and PLEL were investigated by 23 experiments with five settings chosen for each variable. The optimal extraction conditions that were obtained through a multiple-response optimization included a pressure of 23.6 MPa, temperature of 77.6 °C, and 10.6% (v/v) of methanol as the modifier. Thirty nine components of microbial lipid biomarkers were identified in the anaerobically digested sludge. Overall, the SFE method proved to be more effective, rapid, and quantitative for simultaneously extracting bacterial and archaeal lipid biomarkers, compared to conventional organic solvent extraction. This work shows the potential application of SFE as a routine method for the comprehensive analysis of microbial community structures in environmental assessments using the lipid biomarkers profile. PMID:22489140

Structural analysis of inositol phospholipids from Trypanosoma cruzi epimastigote forms.

PubMed Central

Bertello, L E; Gonçalvez, M F; Colli, W; de Lederkremer, R M

1995-01-01

Inositol phospholipids (IPL) from epimastigote forms of Trypanosoma cruzi have been investigated by metabolic labelling with [3H]palmitic acid and by GLC-MS analysis of the lipids obtained from non-labelled parasites. The IPL fraction was separated into phosphatidylinositol (PI) and inositol-phosphoceramide subfractions, the latter accounting for 80-85% of the total IPL. The neutral lipids released from the IPLs by PI-specific phospholipase C (PI-PLC) from Bacillus thuringiensis were analysed by silica-gel and reverse-phase TLC for the radioactive lipids and by GLC-MS for the non-radioactive samples. Ceramides containing dihydrosphingosine and sphingosine with C16:0 and C18:0 fatty acids were identified. The main component in the [3H]palmitic acid-labelled ceramides was palmitoyldihydrospingosine, while in the non-labelled sample the ceramides contained mainly sphingosine. This could reflect partial uptake of phospholipid from the medium. The PI contain both alkylacyl- and diacyl-glycerol lipids, with the ether lipid being more abundant. The latter was identified as 1-O-hexadecylglycerol esterified by C18:2 and C18:1 fatty acids. Interestingly, the same lipid had been identified in the anchor of the 1G7 glycoprotein of T. cruzi metacyclic forms. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:7646454

Development of curcumin-loaded solid lipid nanoparticles utilizing glyceryl monostearate as single lipid using QbD approach: Characterization and Evaluation of anticancer activity against human breast cancer cell line.

PubMed

Bhatt, Himanshu; Rompicharla, Sri Vishnu Kiran; Komanduri, Neeraja; Shah, Aashma; Paradkar, Sateja; Ghosh, Balaram; Biswas, Swati

2018-05-03

Solid lipid nanoparticles (SLNs) represent an affordable, easily scalable, stable and biocompatible drug delivery system with a high drug to lipid ratio which also improves solubility of poorly soluble drugs. SLNs were developed by using glyceryl monostearate as the single lipid in presence of surfactant Poloxamer 188 and evaluated the efficiency of the SLNs to load the therapeutic cargo, curcumin (CUR). The nano-formulation was optimized by Quality by Design approach to understand the effect of various process parameters on various quality attributes, including drug loadability, particle size and polydispersity. The nanoparticles were characterized using Differential scanning calorimetry (DSC), Fourier Transform Infra-red Spectroscopy (FT-IR) and X-Ray Diffraction (XRD) analysis. These novel SLNs were evaluated for in-vitro anticancer activity using breast adenocarcinoma cells (MDA-MB-231). The optimized formulation had particle size of 226.802±3.92 nm with low polydispersity index of 0.244±0.018. The % encapsulation of CUR into SLNs was found to be 67.88±2.08 %. DSC, FT-IR and XRD confirmed that the CUR was encapsulated stably into the lipid matrix, thereby improving the solubility of the drug. CUR-SLN showed sustained drug release in comparison to the free CUR solution. CUR-SLNs exhibited higher cellular uptake in human breast adenocarcinoma cells compared to free CUR at both 1 and 4 h time points. CUR-SLNs demonstrated decreased cell viability (43.97±1.53%) compared to free CUR (59.33±0.95%) at a concentration of 50 μg/mL after 24 h treatment. Further, treatment of MDA-MB-231 cells with CUR-SLNs for 24 h induced significantly higher apoptosis (37.28±5.3%) in cells compared to the free CUR (21.06±0.97%). The results provide strong rationale for further exploration of the newly developed CUR-SLN to be utilized as a potent chemotherapeutic agent in cancer therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Nanoscale coordination polymers for anticancer drug delivery

NASA Astrophysics Data System (ADS)

Phillips, Rachel Huxford

This dissertation reports the synthesis and characterization of nanoscale coordination polymers (NCPs) for anticancer drug delivery. Nanoparticles have been explored in order to address the limitations of small molecule chemotherapeutics. NCPs have been investigated as drug delivery vehicles as they can exhibit the same beneficial properties as the bulk metal-organic frameworks as well as interesting characteristics that are unique to nanomaterials. Gd-MTX (MTX = methotrexate) NCPs with a MTX loading of 71.6 wt% were synthesized and stabilized by encapsulation within a lipid bilayer containing anisamide (AA), a small molecule that targets sigma receptors which are overexpressed in many cancer tissues. Functionalization with AA allows for targeted delivery and controlled release to cancer cells, as shown by enhanced efficacy against leukemia cells. The NCPs were doped with Ru(bpy)32+ (bpy = 2,2'-bipyridine), and this formulation was utilized as an optical imaging agent by confocal microscopy. NCPs containing the chemotherapeutic pemetrexed (PMX) were synthesized using different binding metals. Zr-based materials could not be stabilized by encapsulation with a lipid bilayer, and Gd-based materials showed that PMX had degraded during synthesis. However, Hf-based NCPs containing 19.7 wt% PMX were stabilized by a lipid coating and showed in vitro efficacy against non-small cell lung cancer (NSCLC) cell lines. Enhanced efficacy was observed for formulations containing AA. Additionally, NCP formulations containing the cisplatin prodrug disuccinatocisplatin were prepared; one of these formulations could be stabilized by encapsulation within a lipid layer. Coating with a lipid layer doped with AA rendered this formulation an active targeting agent. The resulting formulation proved more potent than free cisplatin in NSCLC cell lines. Improved NCP uptake was demonstrated by confocal microscopy and competitive binding assays. Finally, a Pt(IV) oxaliplatin prodrug was synthesized and incorporated in different NCPs using various binding metals. A moderate drug loading of 44.9 wt% was determined for Zr-based NCPs. This drug loading, along with a diameter less than 200 nm, make these particles promising candidates for further stabilization via lipid encapsulation.

Hepatoprotective activity of petroleum ether, diethyl ether, and methanol extract of Scoparia dulcis L. against CCl4-induced acute liver injury in mice.

PubMed

Praveen, T K; Dharmaraj, S; Bajaj, Jitendra; Dhanabal, S P; Manimaran, S; Nanjan, M J; Razdan, Rema

2009-06-01

The present study was aimed at assessing the hepatoprotective activity of 1:1:1 petroleum ether, diethyl ether, and methanol (PDM) extract of Scoparia dulcis L. against carbon tetrachloride-induced acute liver injury in mice. The PDM extract (50, 200, and 800 mg/kg, p.o.) and standard, silymarin (100 mg/kg, p.o) were tested for their antihepatotoxic activity against CCl4-induced acute liver injury in mice. The hepatoprotective activity was evaluated by measuring aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total proteins in serum, glycogen, lipid peroxides, superoxide dismutase, and glutathione reductase levels in liver homogenate and by histopathological analysis of the liver tissue. In addition, the extract was also evaluated for its in vitro antioxidant activity using 1, 1-Diphenyl-2-picrylhydrazyl scavenging assay. The extract at the dose of 800 mg/kg, p.o., significantly prevented CCl4-induced changes in the serum and liver biochemistry (P < 0.05) and changes in liver histopathology. The above results are comparable to standard, silymarin (100 mg/kg, p.o.). In the in vitro 1, 1-diphenyl-2-picrylhydrazyl scavenging assay, the extract showed good free radical scavenging potential (IC 50 38.9 +/- 1.0 mug/ml). The results of the study indicate that the PDM extract of Scoparia dulcis L. possesses potential hepatoprotective activity, which may be attributed to its free radical scavenging potential, due to the terpenoid constituents.

Nuclear glutathione S-transferase pi prevents apoptosis by reducing the oxidative stress-induced formation of exocyclic DNA products.

PubMed

Kamada, Kensaku; Goto, Shinji; Okunaga, Tomohiro; Ihara, Yoshito; Tsuji, Kentaro; Kawai, Yoshichika; Uchida, Koji; Osawa, Toshihiko; Matsuo, Takayuki; Nagata, Izumi; Kondo, Takahito

2004-12-01

We previously found that nuclear glutathione S-transferase pi (GSTpi) accumulates in cancer cells resistant to anticancer drugs, suggesting that it has a role in the acquisition of resistance to anticancer drugs. In the present study, the effect of oxidative stress on the nuclear translocation of GSTpi and its role in the protection of DNA from damage were investigated. In human colonic cancer HCT8 cells, the hydrogen peroxide (H(2)O(2))-induced increase in nuclear condensation, the population of sub-G(1) peak, and the number of TUNEL-positive cells were observed in cells pretreated with edible mushroom lectin, an inhibitor of the nuclear transport of GSTpi. The DNA damage and the formation of lipid peroxide were dependent on the dose of H(2)O(2) and the incubation time. Immunological analysis showed that H(2)O(2) induced the nuclear accumulation of GSTpi but not of glutathione peroxidase. Formation of the 7-(2-oxo-hepyl)-substituted 1,N(2)-etheno-2'-deoxyguanosine adduct by the reaction of 13-hydroperoxyoctadecadienoic acid (13-HPODE) with 2'-deoxyguanosine was inhibited by GSTpi in the presence of glutathione. The conjugation product of 4-oxo-2-nonenal, a lipid aldehyde of 13-HPODE, with GSH in the presence of GSTpi, was identified by LS/MS. These results suggested that nuclear GSTpi prevents H(2)O(2)-induced DNA damage by scavenging the formation of lipid-peroxide-modified DNA.

Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment.

PubMed

Michael, James V; Wurtzel, Jeremy G T; Goldfinger, Lawrence E

2016-10-01

The goal of this study was to develop combinatorial application of two drugs currently either in active use as anticancer agents (rapamycin) or in clinical trials (OTX008) as a novel strategy to inhibit Harvey RAS (HRAS)-driven tumor progression. HRAS anchored to the plasma membrane shuttles from the lipid ordered (L o ) domain to the lipid ordered/lipid disordered border upon activation, and retention of HRAS at these sites requires galectin-1. We recently showed that genetically enforced L o sequestration of HRAS inhibited mitogen-activated protein kinase (MAPK) signaling, but not phoshatidylinositol 3-kinase (PI3K) activation. Here we show that inhibition of galectin-1 with OTX008 sequestered HRAS in the L o domain, blocked HRAS-mediated MAPK signaling, and attenuated HRAS-driven tumor progression in mice. HRAS-driven tumor growth was also attenuated by treatment with mammalian target of rapamycin (mTOR) inhibitor rapamycin, and this effect was further enhanced in tumors driven by L o -sequestered HRAS. These drugs also revealed bidirectional cross-talk in HRAS pathways. Moreover, dual pathway inhibition with OTX008 and rapamycin resulted in nearly complete ablation of HRAS-driven tumor growth. These findings indicate that membrane microdomain sequestration of HRAS with galectin-1 inhibition, coupled with mTOR inhibition, may support a novel therapeutic approach to treat HRAS-mutant cancer. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Comparisons of PBDE composition and concentration in fish collected from the Detroit River, MI and Des Plaines River, IL

USGS Publications Warehouse

Rice, C.P.; Chernyak, S.M.; Begnoche, L.; Quintal, R.; Hickey, J.

2002-01-01

Polybrominated diphenyl ethers (PBDEs) were identified in fish collected from the Detroit River, MI and Des Plaines Rivers, IL. In the Detroit River fish, carp and large mouth bass, the congener patterns were dominated by the 2,2′,4,4′-tetrabromo (BDE-47) congener; however, in Des Plaines River carp the dominant isomers were the heptabromo congeners BDE-181 and BDE-183 and lesser amounts of another heptabromo congener, BDE-190, and two hexabromo congeners, BDE-154 and BDE-153. Three possible sources exist for these less-commonly identified PBDE congeners: (a) waste discharge from manufacturing or discarded products near the river, (b) public owned treatment work (POTW) effluents which constitute more than 75% of the flow in the Des Plaines River, (c) or formation of these congeners by debromination of in-place deposits of decabromodiphenyl ether. Average concentration totals (sum of concentrations for seven of the dominant PBDE congeners) were similar on a wet weight bases for the carp (5.39 ng/g wet weight) and large mouth bass (5.25 ng/g) in the Detroit River samples; however, the bass were significantly higher, ρ=0.01, when compared on a lipid basis (bass-163 ng/g vs. carp-40.5 ng/g lipid weight). Some of the PBDE congeners were positively correlated with increasing lipid levels in both fish species. Average total PBDE concentrations in the carp from the Des Plaines River (12.48 ng/g wet weight) were significantly higher, ρ=0.01, than in carp from the Detroit River. The residues were isolated using standard organochlorine methods for fish and analyzed using gas chromatography/mass spectrometry-negative chemical ionization methods.

Inhalable particulate drug delivery systems for lung cancer therapy: Nanoparticles, microparticles, nanocomposites and nanoaggregates.

PubMed

Abdelaziz, Hadeer M; Gaber, Mohamed; Abd-Elwakil, Mahmoud M; Mabrouk, Moustafa T; Elgohary, Mayada M; Kamel, Nayra M; Kabary, Dalia M; Freag, May S; Samaha, Magda W; Mortada, Sana M; Elkhodairy, Kadria A; Fang, Jia-You; Elzoghby, Ahmed O

2018-01-10

There is progressive evolution in the use of inhalable drug delivery systems (DDSs) for lung cancer therapy. The inhalation route offers many advantages, being non-invasive method of drug administration as well as localized delivery of anti-cancer drugs to tumor tissue. This article reviews various inhalable colloidal systems studied for tumor-targeted drug delivery including polymeric, lipid, hybrid and inorganic nanocarriers. The active targeting approaches for enhanced delivery of nanocarriers to lung cancer cells were illustrated. This article also reviews the recent advances of inhalable microparticle-based drug delivery systems for lung cancer therapy including bioresponsive, large porous, solid lipid and drug-complex microparticles. The possible strategies to improve the aerosolization behavior and maintain the critical physicochemical parameters for efficient delivery of drugs deep into lungs were also discussed. Therefore, a strong emphasis is placed on the approaches which combine the merits of both nanocarriers and microparticles including inhalable nanocomposites and nanoaggregates and on the optimization of such formulations using the proper techniques and carriers. Finally, the toxicological behavior and market potential of the inhalable anti-cancer drug delivery systems are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Transplacental transfer of polychlorinated biphenyls and polybrominated diphenyl ethers in arctic beluga whales (Delphinapterus leucas).

PubMed

Desforges, Jean-Pierre W; Ross, Peter S; Loseto, Lisa L

2012-02-01

This study found that arctic beluga whales (Delphinapterus leucas) transferred, on average, 11.4% (7.5 mg) and 11.1% (0.1 mg) of their polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) blubber burden to their near-term fetuses. A single physicochemical parameter, log K(OW), largely explained this transplacental transfer for PCBs (r(2) =0.79, p < 0.00001) and PBDEs (r(2) = 0.37, p = 0.007), with congeners having a log K(OW) < 6.5 preferentially transferred to the fetus. Blubber concentrations of 257 ng/g lipid weight (lw) PCBs and 3.8 ng/g (lw) PBDEs in beluga fetuses highlights the exposure to endocrine-disrupting compounds during a critical developmental stage. The implications of detecting these levels of legacy PCBs and the flame retardant PBDEs in unborn arctic beluga are unclear. Copyright © 2011 SETAC.

A fruitful decade from 2005 to 2014 for anthraquinone patents.

PubMed

Hussain, Hidayat; Al-Harrasi, Ahmed; Al-Rawahi, Ahmed; Green, Ivan R; Csuk, René; Ahmed, Ishtiaq; Shah, Afzah; Abbas, Ghulam; Rehman, Najeeb Ur; Ullah, Riaz

2015-01-01

Anthraquinones are aromatic compounds whose structures are related to anthracene (parent structure: 9,10-dioxoanthracene) for which various methods for their synthesis have been developed. In the past decade (2005 - 2014), much work has been done regarding anthraquinone chemistry in order to discover new compounds related to this scaffold as anticancer, antibacterial, antidiabetic, antiviral, anti-HCV, antifibrotic, fungicidal and anti-inflammatory agents. This review covers the patents on therapeutic activities of anthraquinones and their derivatives in the years between 2005 and 2014. A large portion of the therapeutic applications that were reported in international patents will be presented and discussed. Although a large number of patents have been registered over the last decade, this review is focused on important patents related to cancer, inflammation, infectious diseases, diabetic conditions and hepatitis C. The tricyclic planar ring system of anthraquinones displays a wide range of important pharmaceutical properties. By linking active anthraquinone analogs to other important pharmacophores or conjugates such as oximes, N-heterocycles, benzodiazepines or glycosyl ethers, their anticancer potential is enhanced. The ability of anthraquinone analogs to become more prominent as novel pharmaceutical agents may further be enhanced by fusing functionalized heterocyclic rings onto established anthraquinone cores.

miktoarm polymer: controlled synthesis, characterization, and application as anticancer drug carrier

NASA Astrophysics Data System (ADS)

Lin, Wenjing; Nie, Shuyu; Xiong, Di; Guo, Xindong; Wang, Jufang; Zhang, Lijuan

2014-05-01

Amphiphilic A2(BC)2 miktoarm star polymers [poly(ɛ-caprolactone)]2-[poly(2-(diethylamino)ethyl methacrylate)- b- poly(poly(ethylene glycol) methyl ether methacrylate)]2 [(PCL)2(PDEA- b-PPEGMA)2] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC50 of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)2(PDEA- b-PPEGMA)2 micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.

Seeds of Peganum Harmala L. chemical analysis, antimalarial and antioxidant activities, and cytotoxicity against human breast cancer cells.

PubMed

Chabir, Naziha; Ibrahim, Hany; Romdhane, Hany; Valentin, Alexis; Moukarzel, Beatrice; Mars, Mohamed; Bouajila, Jalloul

2014-01-01

The present study evaluated the levels of total phenolics, flavonoids, tannins and anthocyanins from Peganum harmala L. seeds and determined their antioxidant, antiplasmodial and anticancer potentials. Antioxidant activity was determined by DPPH and ABTS assays. Extracts of P. harmala seeds from Oudref and Djerba (two places in Tunisia) were obtained by successive extraction solvents: petroleum ether, chloroform, ethyl acetate, ethanol and water. Their composition was evaluated for phenolics (gallic acid equivalent 2.48 to 72.52 g/kg), tannins (catechin equivalent 0 to 25.27 g/kg), anthocyanins (cyanidin equivalent 0 to 20.56 mg/kg) and flavonoids (quercetin equivalent 0 to 3.12 g/kg). Ethanolic extract exerted the highest activities against a chloroquine-resistant strain of Plasmodium falciparum (IC₅₀=23 mg/L), against human breast cancer cells MCF7 (IC₅₀=32 mg/L) and against free radical (IC₅₀=19.09±3.07 mg/L). Correlations were studied between each chemical family and the three activities. Total phenolics content exhibited the highest correlation with antiplasmodial activity (R²=0.92) and with anticancer activity (R²=0.86), respectively.

Nucleoside-Lipid-Based Nanocarriers for Sorafenib Delivery

NASA Astrophysics Data System (ADS)

Benizri, Sebastien; Ferey, Ludivine; Alies, Bruno; Mebarek, Naila; Vacher, Gaelle; Appavoo, Ananda; Staedel, Cathy; Gaudin, Karen; Barthélémy, Philippe

2018-01-01

Although the application of sorafenib, a small inhibitor of tyrosine protein kinases, to cancer treatments remains a worldwide option in chemotherapy, novel strategies are needed to address the low water solubility (< 5 μM), toxicity, and side effects issues of this drug. In this context, the use of nanocarriers is currently investigated in order to overcome these drawbacks. In this contribution, we report a new type of sorafenib-based nanoparticles stabilized by hybrid nucleoside-lipids. The solid lipid nanoparticles (SLNs) showed negative or positive zeta potential values depending on the nucleoside-lipid charge. Transmission electron microscopy of sorafenib-loaded SLNs revealed parallelepiped nanoparticles of about 200 nm. Biological studies achieved on four different cell lines, including liver and breast cancers, revealed enhanced anticancer activities of Sorafenib-based SLNs compared to the free drug. Importantly, contrast phase microscopy images recorded after incubation of cancer cells in the presence of SLNs at high concentration in sorafenib (> 80 μM) revealed a total cancer cell death in all cases. These results highlight the potential of nucleoside-lipid-based SLNs as drug delivery systems.

Effects of lipid extraction on nutritive composition of winged bean (Psophocarpus tetragonolobus), rubber seed (Hevea brasiliensis), and tropical almond (Terminalia catappa).

PubMed

Jayanegara, Anuraga; Harahap, Rakhmad P; Rozi, Richard F; Nahrowi

2018-04-01

This experiment aimed to evaluate the nutritive composition and in vitro rumen fermentability and digestibility of intact and lipid-extracted winged bean, rubber seed, and tropical almond. Soybean, winged bean, rubber seed, and tropical almond were subjected to lipid extraction and chemical composition determination. Lipid extraction was performed through solvent extraction by Soxhlet procedure. Non-extracted and extracted samples of these materials were evaluated for in vitro rumen fermentation and digestibility assay using rumen: Buffer mixture. Parameters measured were gas production kinetics, total volatile fatty acid (VFA) concentration, ammonia, in vitro dry matter (IVDMD) and in vitro organic matter digestibility (IVOMD). Data were analyzed by analysis of variance and Duncan's multiple range test. Soybean, winged bean, rubber seed, and tropical almond contained high amounts of ether extract, i.e., above 20% DM. Crude protein contents of soybean, winged bean, rubber seed, and tropical almond increased by 17.7, 4.7, 55.2, and 126.5% after lipid extraction, respectively. In vitro gas production of intact winged bean was the highest among other materials at various time point intervals (p<0.05), followed by soybean > rubber seed > tropical almond. Extraction of lipid increased in vitro gas production, total VFA concentration, IVDMD, and IVOMD of soybean, winged bean, rubber seed, and tropical almond (p<0.05). After lipid extraction, all feed materials had similar IVDMD and IVOMD values. Lipid extraction improved the nutritional quality of winged bean, rubber seed, and tropical almond.

Down-regulation of lipid raft-associated onco-proteins via cholesterol-dependent lipid raft internalization in docosahexaenoic acid-induced apoptosis.

PubMed

Lee, Eun Jeong; Yun, Un-Jung; Koo, Kyung Hee; Sung, Jee Young; Shim, Jaegal; Ye, Sang-Kyu; Hong, Kyeong-Man; Kim, Yong-Nyun

2014-01-01

Lipid rafts, plasma membrane microdomains, are important for cell survival signaling and cholesterol is a critical lipid component for lipid raft integrity and function. DHA is known to have poor affinity for cholesterol and it influences lipid rafts. Here, we investigated a mechanism underlying the anti-cancer effects of DHA using a human breast cancer cell line, MDA-MB-231. We found that DHA decreased cell surface levels of lipid rafts via their internalization, which was partially reversed by cholesterol addition. With DHA treatment, caveolin-1, a marker for rafts, and EGFR were colocalized with LAMP-1, a lysosomal marker, in a cholesterol-dependent manner, indicating that DHA induces raft fusion with lysosomes. DHA not only displaced several raft-associated onco-proteins, including EGFR, Hsp90, Akt, and Src, from the rafts but also decreased total levels of those proteins via multiple pathways, including the proteasomal and lysosomal pathways, thereby decreasing their activities. Hsp90 overexpression maintained its client proteins, EGFR and Akt, and attenuated DHA-induced cell death. In addition, overexpression of Akt or constitutively active Akt attenuated DHA-induced apoptosis. All these data indicate that the anti-proliferative effect of DHA is mediated by targeting of lipid rafts via decreasing cell surface lipid rafts by their internalization, thereby decreasing raft-associated onco-proteins via proteasomal and lysosomal pathways and decreasing Hsp90 chaperone function. © 2013.

Preparation of siRNA encapsulated nanoliposomes suitable for siRNA delivery by simply discontinuous mixing.

PubMed

Mokhtarieh, Amir Abbas; Lee, Jieun; Kim, Semi; Lee, Myung Kyu

2018-06-01

Previously a scalable and extrusion-free method has been developed for efficient liposomal encapsulation of DNA by twice stepwise mixing of lipids in ethanol and DNA solution using T-shape mixing chamber. In this study, we prepared nanoliposomes encapsulating siRNA by simply discontinuous mixing of lipids in ethanol/ether/water mixture and acidic siRNA solution without use of special equipment. The simple mixing siRNA/liposomal particles (siRNA/SMLs) prepared using ethanol/ether/water (3:1:1) mixture showed 120.4 ± 20.2 nm particle size, 0.174 ± 0.033 polydispersity and 86.5 ± 2.76% siRNA encapsulation rate. In addition, the SMLs almost completely protected the encapsulated siRNA from RNase A digestion. Coupling of anti-human epidermal growth factor receptor (EGFR) Fab' to siRNA/SMLs enhanced EGFR-specific cell penetration of SMLs and induced siRNA dependent gene silencing. Unexpectedly, the Cy5.5-labeled Fab' showed almost no in vivo targeting to the xenografted A549 tumors in SCID-NOD mice. However, multiple injection of the unmodified siRNA/SMLs accumulated in the tumors and induced siRNA-dependent in vivo gene silencing. These results demonstrate that the siRNA/SMLs can be used as a siRNA delivery tool for gene therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Evaluation of ethyl tert-butyl ether biodegradation in a contaminated aquifer by compound-specific isotope analysis and in situ microcosms.

PubMed

Bombach, Petra; Nägele, Norbert; Rosell, Mònica; Richnow, Hans H; Fischer, Anko

2015-04-09

Ethyl tert-butyl ether (ETBE) is an upcoming groundwater pollutant in Europe whose environmental fate has been less investigated, thus far. In the present study, we investigated the in situ biodegradation of ETBE in a fuel-contaminated aquifer using compound-specific stable isotope analysis (CSIA), and in situ microcosms in combination with total lipid fatty acid (TLFA)-stable isotope probing (SIP). In a first field investigation, CSIA revealed insignificant carbon isotope fractionation, but low hydrogen isotope fractionation of up to +14‰ along the prevailing anoxic ETBE plume suggesting biodegradation of ETBE. Ten months later, oxygen injection was conducted to enhance the biodegradation of petroleum hydrocarbons (PH) at the field site. Within the framework of this remediation measure, in situ microcosms loaded with [(13)C6]-ETBE (BACTRAP(®)s) were exposed for 119 days in selected groundwater wells to assess the biodegradation of ETBE by TLFA-SIP under the following conditions: (i) ETBE as main contaminant; (ii) ETBE as main contaminant subjected to oxygen injection; (iii) ETBE plus other PH; (iv) ETBE plus other PH subjected to oxygen injection. Under all conditions investigated, significant (13)C-incorporation into microbial total lipid fatty acids extracted from the in situ microcosms was found, providing clear evidence of ETBE biodegradation. Copyright © 2014 Elsevier B.V. All rights reserved.

Lipid based nanoemulsifying resveratrol for improved physicochemical characteristics, in vitro cytotoxicity and in vivo antiangiogenic efficacy.

PubMed

Pund, Swati; Thakur, Rohit; More, Umesh; Joshi, Amita

2014-08-01

Resveratrol, a dietary non-flavonoid polyphenolic phytoalexin, has gained attention in cancer chemoprevention. However, poor aqueous solubility and cellular bioavailability has limited its therapeutic application. We formulated a lipid based delivery system of resveratrol with self nanoemulsifying ability. Several edible and safe lipids, surfactants and cosolvents were screened for solubilization of resevratrol. Developed formulation comprised of Acrysol K 150 as a lipid and mixture of Labrasol and Transcutol HP as the surfactant system, as these components showed higher solubility. Pseudoternary phase diagram was constructed to identify the region of nanoemulsification. The formulations showed rapid emulsification with an average globule diameter; 85nm to 120nm and slight negative zeta potential. The nanocompositions exhibited cloud point above 55°C and were stable toward the gastrointestinal pH and thermodynamic stress testing. As compared to pristine resveratrol, the developed delivery system showed significant increase in vitro cytotoxicity in MCF-7 breast cancer cells. In vivo chick chorioallantoic membrane assay revealed enhanced antiangiogenic activity of composition with high lipid level. Briefly, lipid based nanoemulsifying resveratrol dramatically enhanced the anticancer and antiangiogenic activities, thus increasing its potential application in cancer chemotherapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Mutual anti-oxidative effect of gossypol acetic acid and gossypol-iron complex on hepatic lipid peroxidation in male rats.

PubMed

El-Sharaky, A S; Wahby, M M; Bader El-Dein, M M; Fawzy, R A; El-Shahawy, I N

2009-11-01

Gossypol displays anticancer behavior and anti-fertility in males. Male rats were treated with either gossypol acetic acid (GAA) or gossypol-iron complex (GIC). Serum alanine transaminase (ALT) activity elevated of GAA. However, GIC-treated animals showed a decrease in hepatic glutathione (GSH) content with increased malondialdehyde (MDA) content. Whereas, GSH-Px specific activity increased in GAA group. GAA and GIC induce significant increases in the hepatic NEFA with remarkable decrease in the total saturated fatty acids with a significant increase of PUFA. Lipid peroxidation is inhibited by gossypol, which shield lipids against oxidative damage. Phenols are oxidized to phenoxy radicals, which do not permit anti-oxidation due to resonance stabilization. GAA stimulate hydroxyl radicals (()OH) generation and DNA damage. GAA and GIC produce increase in lipid peroxidation as proved by a steep rise in thiobarbituric acid reactive species (TBARS). Controversy of specificity of TBARS towards compounds other than MDA was reported. If TBARS increased, more specific assay to be employed. Assay of lipid classes and fatty acids pattern, reveled the significance of the technique in assessment of lipid peroxidation in tissues. GAA and GIC were powerful inhibitors of lipid peroxidation and exhibit pro- and antioxidant behavior, with less toxicity of GIC.

Archaeosomes: an excellent carrier for drug and cell delivery.

PubMed

Kaur, Gurmeet; Garg, Tarun; Rath, Goutam; Goyal, Amit K

2016-09-01

Archaeosomes as liposomes made with one or more ether lipids that are unique to the domain of Archaeobacteria, found in Archaea constitute a novel family of liposome. Achaean-type lipids consist of archaeol (diether) and/or caldarchaeol (tetraether) core structures. Archaeosomes can be produced using standard procedures (hydrated film submitted to sonication, extrusion and detergent dialysis) at any temperature in the physiological range or lower, therefore making it possible to encapsulate thermally stable compounds. Various physiological as well as environmental factors affect its stability. Archaeosomes are widely used as drug delivery systems for cancer vaccines, Chagas disease, proteins and peptides, gene delivery, antigen delivery and delivery of natural antioxidant compounds. In this review article, our major aim was to explore the applications of this new carrier system in pharmaceutical field.

Extraction of brewer's yeasts using different methods of cell disruption for practical biodiesel production.

PubMed

Řezanka, Tomáš; Matoulková, Dagmar; Kolouchová, Irena; Masák, Jan; Viden, Ivan; Sigler, Karel

2015-05-01

The methods of preparation of fatty acids from brewer's yeast and its use in production of biofuels and in different branches of industry are described. Isolation of fatty acids from cell lipids includes cell disintegration (e.g., with liquid nitrogen, KOH, NaOH, petroleum ether, nitrogenous basic compounds, etc.) and subsequent processing of extracted lipids, including analysis of fatty acid and computing of biodiesel properties such as viscosity, density, cloud point, and cetane number. Methyl esters obtained from brewer's waste yeast are well suited for the production of biodiesel. All 49 samples (7 breweries and 7 methods) meet the requirements for biodiesel quality in both the composition of fatty acids and the properties of the biofuel required by the US and EU standards.

Polymer grafted magnetic nanoparticles for delivery of anticancer drug at lower pH and elevated temperature.

PubMed

Dutta, Sujan; Parida, Sheetal; Maiti, Chiranjit; Banerjee, Rakesh; Mandal, Mahitosh; Dhara, Dibakar

2016-04-01

Efficient and controlled delivery of therapeutics to tumor cells is one of the important issues in cancer therapy. In the present work, a series of pH- and temperature-responsive polymer grafted iron oxide nanoparticles were prepared by simple coupling of aminated iron oxide nanoparticle with poly(N-isopropylacrylamide-ran-poly(ethylene glycol) methyl ether acrylate)-block-poly(acrylic acid) (P(NIPA-r-PEGMEA)-b-PAA). For this, three water soluble block polymers were prepared via reversible addition fragmentation transfer (RAFT) polymerization technique. At first, three different block copolymers were prepared by polymerizing mixture of NIPA and PEGMEA (with varying mole ratio) in presence of poly(tert-butyl acrylate) (PtBA) macro chain transfer agent. Subsequently, P(NIPA-r-PEGMEA)-b-PAA copolymers were synthesized by hydrolyzing tert-butyl acrylate groups of the P(NIPA-r-PEGMEA)-b-PtBA copolymers. The resulting polymers were then grafted to iron oxide nanoparticles, and these functionalized nanoparticles were thoroughly characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), zeta potential measurements, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), vibrating sample magnetometer (VSM) and Fourier transform infrared spectroscopy (FTIR). Doxorubicin (DOX), an anti-cancer drug, was loaded into the polymer coated nanoparticles and its release behavior was subsequently studied at different pH and temperatures. The drug release pattern revealed a sustained release of DOX preferentially at the desired lysosomal pH of cancer cells (pH 5.0) and slightly above the physiological temperature depending upon the composition of the copolymers. The potential anticancer activity of the polymer grafted DOX loaded nanoparticles were established by MTT assay and apoptosis study of cervical cancer ME 180cells in presence of the nanoparticles. Thus, these particles can be utilized for controlled delivery of anticancer drugs at the desired lysosomal pH and/or by slightly heating the cells using magnetic hyperthermia. Copyright © 2016 Elsevier Inc. All rights reserved.

A novel ether-linked phytol-containing digalactosylglycerolipid in the marine green alga, Ulva pertusa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishibashi, Yohei; Nagamatsu, Yusuke; Miyamoto, Tomofumi

2014-10-03

Highlights: • Alkaline-resistant galactolipid, AEGL, was found in marine algae. • The sugar moiety of AEGL is identical to that of digalactosyldiacylglycerol. • AEGL is the first identified glycolipid that possesses an ether-linked phytol. • AEGL is ubiquitously distributed in green, red and brown marine algae. - Abstract: Galactosylglycerolipids (GGLs) and chlorophyll are characteristic components of chloroplast in photosynthetic organisms. Although chlorophyll is anchored to the thylakoid membrane by phytol (tetramethylhexadecenol), this isoprenoid alcohol has never been found as a constituent of GGLs. We here described a novel GGL, in which phytol was linked to the glycerol backbone via anmore » ether linkage. This unique GGL was identified as an Alkaline-resistant and Endogalactosylceramidase (EGALC)-sensitive GlycoLipid (AEGL) in the marine green alga, Ulva pertusa. EGALC is an enzyme that is specific to the R-Galα/β1-6Galβ1-structure of galactolipids. The structure of U. pertusa AEGL was determined following its purification to 1-O-phytyl-3-O-Galα1-6Galβ1-sn-glycerol by mass spectrometric and nuclear magnetic resonance analyses. AEGLs were ubiquitously distributed in not only green, but also red and brown marine algae; however, they were rarely detected in terrestrial plants, eukaryotic phytoplankton, or cyanobacteria.« less

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

PubMed Central

Cao, Yang; Chen, Yuli; Yu, Tao; Guo, Yuan; Liu, Fengqiu; Yao, Yuanzhi; Li, Pan; Wang, Dong; Wang, Zhigang; Chen, Yu; Ran, Haitao

2018-01-01

Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery. Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets). Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy. Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release. PMID:29507623

Functionalized Lipid-Polymer Hybrid Nanoparticles Mediated Codelivery of Methotrexate and Aceclofenac: A Synergistic Effect in Breast Cancer with Improved Pharmacokinetics Attributes.

PubMed

Garg, Neeraj K; Tyagi, Rajeev K; Sharma, Gajanand; Jain, Ashay; Singh, Bhupinder; Jain, Sanyog; Katare, O P

2017-06-05

The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85-90% and 10-12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8-10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1β, COX2, and MMP1) at both transcript and proteome level.

Hepatoprotective activity of petroleum ether, diethyl ether, and methanol extract of Scoparia dulcis L. against CCl4-induced acute liver injury in mice

PubMed Central

Praveen, T.K.; Dharmaraj, S.; Bajaj, Jitendra; Dhanabal, S.P.; Manimaran, S.; Nanjan, M.J.; Razdan, Rema

2009-01-01

Objectives: The present study was aimed at assessing the hepatoprotective activity of 1:1:1 petroleum ether, diethyl ether, and methanol (PDM) extract of Scoparia dulcis L. against carbon tetrachloride-induced acute liver injury in mice. Materials and Methods: The PDM extract (50, 200, and 800 mg/kg, p.o.) and standard, silymarin (100 mg/kg, p.o) were tested for their antihepatotoxic activity against CCl4-induced acute liver injury in mice. The hepatoprotective activity was evaluated by measuring aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total proteins in serum, glycogen, lipid peroxides, superoxide dismutase, and glutathione reductase levels in liver homogenate and by histopathological analysis of the liver tissue. In addition, the extract was also evaluated for its in vitro antioxidant activity using 1, 1-Diphenyl-2-picrylhydrazyl scavenging assay. Results: The extract at the dose of 800 mg/kg, p.o., significantly prevented CCl4-induced changes in the serum and liver biochemistry (P < 0.05) and changes in liver histopathology. The above results are comparable to standard, silymarin (100 mg/kg, p.o.). In the in vitro 1, 1-diphenyl-2-picrylhydrazyl scavenging assay, the extract showed good free radical scavenging potential (IC 50 38.9 ± 1.0 μg/ml). Conclusions: The results of the study indicate that the PDM extract of Scoparia dulcis L. possesses potential hepatoprotective activity, which may be attributed to its free radical scavenging potential, due to the terpenoid constituents. PMID:20442817

Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications.

PubMed

Deslouches, Berthony; Di, Y Peter

2017-07-11

In the last several decades, there have been significant advances in anticancer therapy. However, the development of resistance to cancer drugs and the lack of specificity related to actively dividing cells leading to toxic side effects have undermined these achievements. As a result, there is considerable interest in alternative drugs with novel antitumor mechanisms. In addition to the recent approach using immunotherapy, an effective but much cheaper therapeutic option of pharmaceutical drugs would still provide the best choice for cancer patients as the first line treatment. Ribosomally synthesized cationic antimicrobial peptides (AMPs) or host defense peptides (HDP) display broad-spectrum activity against bacteria based on electrostatic interactions with negatively charged lipids on the bacterial surface. Because of increased proportions of phosphatidylserine (negatively charged) on the surface of cancer cells compared to normal cells, cationic amphipathic peptides could be an effective source of anticancer agents that are both selective and refractory to current resistance mechanisms. We reviewed herein the prospect for AMP application to cancer treatment, with a focus on modes of action of cationic AMPs.

Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications

PubMed Central

Deslouches, Berthony; Di, Y. Peter

2017-01-01

In the last several decades, there have been significant advances in anticancer therapy. However, the development of resistance to cancer drugs and the lack of specificity related to actively dividing cells leading to toxic side effects have undermined these achievements. As a result, there is considerable interest in alternative drugs with novel antitumor mechanisms. In addition to the recent approach using immunotherapy, an effective but much cheaper therapeutic option of pharmaceutical drugs would still provide the best choice for cancer patients as the first line treatment. Ribosomally synthesized cationic antimicrobial peptides (AMPs) or host defense peptides (HDP) display broad-spectrum activity against bacteria based on electrostatic interactions with negatively charged lipids on the bacterial surface. Because of increased proportions of phosphatidylserine (negatively charged) on the surface of cancer cells compared to normal cells, cationic amphipathic peptides could be an effective source of anticancer agents that are both selective and refractory to current resistance mechanisms. We reviewed herein the prospect for AMP application to cancer treatment, with a focus on modes of action of cationic AMPs. PMID:28422728

Mono-, di- and trimethylated homologues of isoprenoid tetraether lipid cores in archaea and environmental samples: mass spectrometric identification and significance.

PubMed

Knappy, Chris; Barillà, Daniela; Chong, James; Hodgson, Dominic; Morgan, Hugh; Suleman, Muhammad; Tan, Christine; Yao, Peng; Keely, Brendan

2015-12-01

Higher homologues of widely reported C(86) isoprenoid diglycerol tetraether lipid cores, containing 0-6 cyclopentyl rings, have been identified in (hyper)thermophilic archaea, representing up to 21% of total tetraether lipids in the cells. Liquid chromatography-tandem mass spectrometry confirms that the additional carbon atoms in the C(87-88) homologues are located in the etherified chains. Structures identified include dialkyl and monoalkyl ('H-shaped') tetraethers containing C(40-42) or C(81-82) hydrocarbons, respectively, many representing novel compounds. Gas chromatography-mass spectrometric analysis of hydrocarbons released from the lipid cores by ether cleavage suggests that the C(40) chains are biphytanes and the C(41) chains 13-methylbiphytanes. Multiple isomers, having different chain combinations, were recognised among the dialkyl lipids. Methylated tetraethers are produced by Methanothermobacter thermautotrophicus in varying proportions depending on growth conditions, suggesting that methylation may be an adaptive mechanism to regulate cellular function. The detection of methylated lipids in Pyrobaculum sp. AQ1.S2 and Sulfolobus acidocaldarius represents the first reported occurrences in Crenarchaeota. Soils and aquatic sediments from geographically distinct mesotemperate environments that were screened for homologues contained monomethylated tetraethers, with di- and trimethylated structures being detected occasionally. The structural diversity and range of occurrences of the C(87-89) tetraethers highlight their potential as complementary biomarkers for archaea in natural environments. Copyright © 2015 John Wiley & Sons, Ltd.

Combination of three metals for the treatment of cancer: gallium, rhenium and platinum. 1. Determination of the optimal schedule of treatment.

PubMed

Collery, Philippe; Mohsen, Ahmed; Kermagoret, Anthony; D'Angelo, Jean; Morgant, Georges; Desmaele, Didier; Tomas, Alain; Collery, Thomas; Wei, Ming; Badawi, Abdelfattah

2012-07-01

Platinum is well known for its anticancer activity, firstly used as cis-diaminedichloroplatinum (II) (CDDP), with a wide range of activity. Its main mechanism of action involves its binding to DNA. Gallium, another metal, has also demonstrated apoptotic effects on malignant cells, but through interaction with targets other than DNA, such as the membrane, cytoskeleton and proteasome, and on enzyme activities. An antitumor synergism between CDDP and both gallium and rhenium compounds has been demonstrated. For these reasons, we proposed to combine these three metals and to determine at which doses each compound could be administered without major toxicity. CDDP, tetrakis(1-octanol) tris(5-aminosalicylate)gallium(III), and a diseleno-ether rhenium(I) complex were used in this experimental study in breast cancer MCF-7 tumor-bearing mice. CDDP was administered intraperitoneally (i.p.) twice a week at the dose of 3 mg/kg. Tetrakis(1-octanol) tris(5-aminosalicylate) gallium (III) and rhenium(I) diseleno-ether complexes were administered orally, daily, five days a week for three weeks, at doses ranging from 20 to 100 mg/kg for the gallium compound and from 10 to 50 mg/kg for the rhenium compound. Doses of 10 mg/kg of rhenium(I) diseleno-ether, and 100 mg/kg of the salicylate gallium compound, in combination with CDDP induced a significant decrease of 50% of the tumor volume, by comparison with the control group. In contrast, the decrease of the tumor volume in mice treated by CDDP alone was less than 25%. Changes in the sequence of administration of the three metals will be discussed to improve the therapeutic index.

Bioassays guided isolation of compounds from Chaetomium globosum.

PubMed

Awad, N E; Kassem, H A; Hamed, M A; El-Naggar, M A A; El-Feky, A M M

2014-06-01

The aim of the present study was to evaluate different biological activities of the fungus Chaetomium globosum (family Chaetomiaceae). The evaluation was done through testing its antimicrobial, antioxidant and anticancer effects. C. globosum was isolated from the Cucumber soil (rhizosphere) and caused inhibition of the mycelial growth of Fusarium solani, Rhizoctonia solani and Sclerotium rolfsii in the biculture test. Petroleum ether and ethyl acetate extracts of the liquid culture of C. globosum showed potent in vitro antioxidant activity. C. globosum proved potent antibacterial activity against Bacillus subtilis, Escherichia coli and Pseudomonas fluorescens. It also recorded significant antifungal activity against Candida albicans, F. solani, Fusarium oxysporum, R. solani and Pythium ultimum. It exerted cytotoxic effect on human hepatocellular carcinoma cell line (HepG2). Unsaponifiable and saponifiable matters of the petroleum ether extract showed the presence of hydrocarbons, sterols and fatty acids. The ethyl acetate extract showed the presence of prenisatin, chrysophanol, chrysazin, chaetoviridin A and B. The isolated secondary metabolites proved significant antioxidant and antimicrobial activity on B. subtilis, E. coli and R. solani. In conclusion, this fungus showed different biological activities. Further studies must be done to apply its use in the agricultural and medicinal field. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Metabolic incorporation of unsaturated fatty acids into boar spermatozoa lipids and de novo formation of diacylglycerols.

PubMed

Svetlichnyy, Valentin; Müller, Peter; Pomorski, Thomas G; Schulze, Martin; Schiller, Jürgen; Müller, Karin

2014-01-01

Lipids play an important role in the maturation, viability and function of sperm cells. In this study, we examined the neutral and polar lipid composition of boar spermatozoa by thin-layer chromatography/mass spectrometry. Main representatives of the neutral lipid classes were diacylglycerols containing saturated (myristoyl, palmitoyl and stearoyl) fatty acyl residues. Glycerophosphatidylcholine and glycerophosphatidylethanolamine with alk(en)yl ether residues in the sn-1 position and unsaturated long chained fatty acyl residues in sn-2 position were identified as the most prominent polar lipids. The only glycoglycerolipid was sulfogalactosylglycerolipid carrying 16:0-alkyl- and 16:0-acyl chains. Using stable isotope-labelling, the metabolic incorporation of exogenously supplied fatty acids was analysed. Boar spermatozoa incorporated hexadecenoic (16:1), octadecenoic (18:1), octadecadienoic (18:2) and octadecatrienoic (18:3) acids primarily in the diacylglycerols and glycerophosphatidylcholines. In contrast, incorporation of eicosapentaenoic acid (20:5) was not detected. The analysis of molecular species composition subsequent to the incorporation of exogenous [(14)C]-octadecadienoic acid suggests two pathways for incorporation of exogenous fatty acids into glycerophosphatidylcholine: (1) de novo synthesis of glycerophosphatidylcholine via the CDP-choline pathway and (2) reacylation of lysophosphatidylcholine via an acyltransferase. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Exploring the Potential Role of Chemopreventive Agent, Hesperetin Conjugated Pegylated Gold Nanoparticles in Diethylnitrosamine-Induced Hepatocellular Carcinoma in Male Wistar Albino Rats.

PubMed

Gokuladhas, Krishnan; Jayakumar, Subramaniyan; Rajan, Balan; Elamaran, Ramasamy; Pramila, Chengalvarayan Subramani; Gopikrishnan, Mani; Tamilarasi, Sasivarman; Devaki, Thiruvengadam

2016-04-01

Liver cancer is the fifth most common cancer and is still one of the leading causes of death world wide, due to food additives, alcohol, fungal toxins, air, toxic industrial chemicals, and water pollutants. Chemopreventive drugs play a potential role in liver cancer treatment. Obviously in the production of anticancer drugs, the factors like poor solubility, bioavailability, biocompatibility, limited chemical stability, large amount of dose etc., plays a major role. Against this backdrop, the idea of designing the chemopreventive nature of bio flavanoid hesperetin (HP) drug conjugated with pegylated gold nanoparticles to increasing the solubility, improve bioavailability and enhance the targeting capabilities of the drug during diethylnitrosamine (DEN) induced liver cancer in male wistar albino rats. The dose fixation studies and the toxicity of pure HP and HP conjugated gold nanoparticles (Au-mPEG(5000)-S-HP) were analysed. After concluded the dose fixation and toxicity studies the experimental design were segregated in six groups for the anticancer analysis of DEN induced HCC for 16 weeks. After the experimental period the body weight, relative liver weight, number of nodules and size of nodules, the levels of tumor markers like CEA, AFP and the level of lipid peroxidation, lipid hydroperoxides and the activities of antioxidant enzymes were assessed. The administration of DEN to rats resulted in increased relative liver weight and serum marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma glutamyl transpeptidase. The levels of lipid peroxides elevated (in both serum and tissue) with subsequent decrease in the final body weight and tissue antioxidants like superoxide dismutase, catalase, reduced glutathione, glutathione peroxidise, and glutathione reductase. HP supplementation (20 mg/kg b.wt) significantly attenuated these alterations, thereby showing potent anticancer effect in liver cancer and the HP loaded gold nanoparticels (Au-mPEG(5000)-S-HP) treated animals shows the better treatment than the pure HP due to the solubility of drug, bioavailability and the target drug delivery of the biodegradable polymer. Histological observations were also carried out, which added supports to the chemopreventive action of the pure HP and HP loaded gold nanoparticles (Au-mPEG(5000)-S-HP) against DEN induction during liver cancer progression. These findings suggest that HP loaded gold nanoparticels (Au-mPEG(5000)-S-HP) shows better efficacy than the pure HP against lipid peroxidation, hepatic cell damage and protects the antioxidant system in DEN induced hepatocellular carcinogenesis.

Advances in non-invasive drug delivery for atherosclerotic heart disease.

PubMed

Maranhão, Raul C; Tavares, Elaine R

2015-07-01

Apart from statins, anti-platelet agents and invasive procedures, the anti-atherosclerotic medical weaponry for coronary heart disease (CHD) is scarce and only partially protects CHD patients from major adverse cardiac events. Several novel non-invasive strategies are being developed to widen the therapeutic options. Among them, drug delivery tools were tested in vivo encompassing liposomes, micelles, polymeric, metallic and lipid nanoparticles used as carriers of statins, corticosteroids, a bisphosphonate, a glitazone, anti-cancer agents, a mycotoxin, a calcium channel blocker and a compound of traditional Chinese medicine. All preparations improved parameters related to atherosclerotic lesions induced in rabbits, rats and mice and reduced neointima formation in experiments aiming to prevent post-stenting restenosis. In subjects submitted to percutaneous coronary intervention, nanoparticle formulations of paclitaxel and alendronate showed safety but are still not conclusive regarding in-stent late loss. The experience of our group in atherosclerotic rabbits treated with non-protein lipid nanoparticles associated with anti-cancer drugs such as paclitaxel, etoposide and methotrexate is summarized, and preliminary safety data in CHD patients are anticipated. Taken together, these studies show that non-invasive drug-delivery systems may become promising tools to rescue CHD patients from the risks of severe and life-threatening lesions that should be more energetically treated.

Characterization and evaluation of 5-fluorouracil-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification technique.

PubMed

Patel, Meghavi N; Lakkadwala, Sushant; Majrad, Mohamed S; Injeti, Elisha R; Gollmer, Steven M; Shah, Zahoor A; Boddu, Sai Hanuman Sagar; Nesamony, Jerry

2014-12-01

The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU-loaded SLNs can potentially be utilized in an anticancer drug delivery system.

Role of Lipid Metabolism in Plant Pollen Exine Development.

PubMed

Zhang, Dabing; Shi, Jianxin; Yang, Xijia

2016-01-01

Pollen plays important roles in the life cycle of angiosperms plants. It acts as not only a biological protector of male sperms but also a communicator between the male and the female reproductive organs, facilitating pollination and fertilization. Pollen is produced within the anther, and covered by the specialized outer envelope, pollen wall. Although the morphology of pollen varies among different plant species, the pollen wall is mainly comprised of three layers: the pollen coat, the outer exine layer, and the inner intine layer. Except the intine layer, the other two layers are basically of lipidic nature. Particularly, the outer pollen wall layer, the exine, is a highly resistant biopolymer of phenylpropanoid and lipidic monomers covalently coupled by ether and ester linkages. The precise molecular mechanisms underlying pollen coat formation and exine patterning remain largely elusive. Herein, we summarize the current genetic, phenotypic and biochemical studies regarding to the pollen exine development and underlying molecular regulatory mechanisms mainly obtained from monocot rice (Oryza sativa) and dicot Arabidopsis thaliana, aiming to extend our understandings of plant male reproductive biology. Genes, enzymes/proteins and regulatory factors that appear to play conserved and diversified roles in lipid biosynthesis, transportation and modification during pollen exine formation, were highlighted.

Apoptosis induction and anti-cancer activity of LeciPlex formulations.

PubMed

Dhawan, Vivek V; Joshi, Ganesh V; Jain, Ankitkumar S; Nikam, Yuvraj P; Gude, Rajiv P; Mulherkar, Rita; Nagarsenker, Mangal S

2014-10-01

Cationic agents have been reported to possess anti-neoplastic properties against various cancer cell types. However, their complexes with lipids appear to interact differently with different cancer cells. The purpose of this study was to (i) design and generate novel cationic lecithin nanoparticles, (ii) assess and understand the mechanism underlying their putative cytotoxicity and (iii) test their effect on cell cycle progression in various cancer-derived cell lines. In addition, we aimed to evaluate the in vivo potential of these newly developed nanoparticles in oral anti-cancer delivery. Cationic lecithin nanoparticles were generated using a single step nanoprecipitation method and they were characterized for particle size, zeta potential, stability and in vitro release. Their cytotoxic potential was assessed using a sulforhodamine B assay, and their effect on cell cycle progression was evaluated using flow cytometry. The nanoparticle systems were also tested in vivo for their anti-tumorigenic potential. In contrast to cationic agents alone, the newly developed nanoformulations showed a specific toxicity against cancer cells. The mechanism of toxic cell death included apoptosis, S and G2/M cell cycle phase arrest, depending on the type of cationic agent and the cancer-derived cell line used. Both blank and drug-loaded systems exhibited significant anti-cancer activity, suggesting a synergistic anti-tumorigenic effect of the drug and its delivery system. Both in vitro and in vivo data indicate that cationic agents themselves exhibit broad anti-neoplastic activities. Complex formation of the cationic agents with phospholipids was found to provide specificity to the anti-cancer activity. These formulations thus possess potential for the design of effective anti-cancer delivery systems.

Anti-glioma activity and the mechanism of cellular uptake of asiatic acid-loaded solid lipid nanoparticles.

PubMed

Garanti, Tanem; Stasik, Aneta; Burrow, Andrea Julie; Alhnan, Mohamed A; Wan, Ka-Wai

2016-03-16

Asiatic acid (AA), a pentacyclic triterpene found in Centella Asiatica, has shown neuroprotective and anti-cancer activity against glioma. However, owing to its poor aqueous solubility, effective delivery and absorption across biological barriers, in particular the blood brain barrier (BBB), are challenging. Solid lipid nanoparticles (SLNs) have shown a promising potential as a drug delivery system to carry lipophilic drugs across the BBB, a major obstacle in brain cancer therapy. Nevertheless, limited information is available about the cytotoxic mechanisms of nano-lipidic carriers with AA on normal and glioma cells. This study assessed the anti-cancer efficacy of AA-loaded SLNs against glioblastoma and their cellular uptake mechanism in comparison with SVG P12 (human foetal glial) cells. SLNs were systematically investigated for three different solid lipids; glyceryl monostearate (MS), glyceryl distearate (DS) and glyceryl tristearate (TS). The non-drug containing MS-SLNs (E-MS-SLNs) did not show any apparent toxicity towards normal SVG P12 cells, whilst the AA-loaded MS-SLNs (AA-MS-SLNs) displayed a more favourable drug release profile and higher cytotoxicity towards U87 MG cells. Therefore, MS-SLNs were chosen for further in vitro studies. Cytotoxicity studies of SLNs (± AA) were performed using MTT assay where AA-SLNs showed significantly higher cytotoxicity towards U87 MG cells than SVG P12 normal cells, as confirmed by flow cell cytometry. Cellular uptake of SLNs also appeared to be preferentially facilitated by energy-dependent endocytosis as evidenced by fluorescence imaging and flow cell cytometry. Using the Annexin V-PI double staining technique, it was found that these AA-MS-SLNs displayed concentration-dependent apoptotic activity on glioma cells, which further confirms the potential of exploiting these AA-loaded MS-SLNs for brain cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review.

PubMed

Hadinoto, Kunn; Sundaresan, Ajitha; Cheow, Wean Sin

2013-11-01

Lipid-polymer hybrid nanoparticles (LPNs) are core-shell nanoparticle structures comprising polymer cores and lipid/lipid-PEG shells, which exhibit complementary characteristics of both polymeric nanoparticles and liposomes, particularly in terms of their physical stability and biocompatibility. Significantly, the LPNs have recently been demonstrated to exhibit superior in vivo cellular delivery efficacy compared to that obtained from polymeric nanoparticles and liposomes. Since their inception, the LPNs have advanced significantly in terms of their preparation strategy and scope of applications. Their preparation strategy has undergone a shift from the conceptually simple two-step method, involving preformed polymeric nanoparticles and lipid vesicles, to the more principally complex, yet easier to perform, one-step method, relying on simultaneous self-assembly of the lipid and polymer, which has resulted in better products and higher production throughput. The scope of LPNs' applications has also been extended beyond single drug delivery for anticancer therapy, to include combinatorial and active targeted drug deliveries, and deliveries of genetic materials, vaccines, and diagnostic imaging agents. This review details the current state of development for the LPNs preparation and applications from which we identify future research works needed to bring the LPNs closer to its clinical realization. Copyright © 2013 Elsevier B.V. All rights reserved.

ent-Kaurane-Based Regio- and Stereoselective Inverse Electron Demand Hetero-Diels-Alder Reactions: Synthesis of Dihydropyran-Fused Diterpenoids†

PubMed Central

Ding, Chunyong; Wang, Lili; Chen, Haijun; Wild, Christopher; Ye, Na; Ding, Ye; Wang, Tianzhi; White, Mark A.; Shen, Qiang; Zhou, Jia

2014-01-01

A mild and concise approach for the construction of 3,4-dihydro-2H-pyran ring integrated into the A-ring of the natural product oridonin using an optimized inverse electron demand hetero-Diels-Alder (IED HDA) reaction is reported herein. A self-dimerization of the exocyclic enone installed in the A-ring through a homo-HDA reaction was identified to exclusively give a dimeric ent-kaurane diterpenoid with the spirochroman core. Moreover, the efficient cross-HDA cycloadditions of this enone with various vinyl ethers or vinyl sulfides, instead of its own homo-HDA dimerization, were achieved in regio- and stereoselective manners, thus providing the access to novel dihydropyran-fused diterpenoids as potential anticancer agents to overcome chemoresistance. PMID:25225052

Surface functionalization of liposomes with proteins and carbohydrates for use in anti-cancer applications

NASA Astrophysics Data System (ADS)

Platt, Virginia M.

Liposomes can be used to exploit the altered biology of cancer thereby increasing delivery of liposome-associated anti-cancer drugs. In this dissertation, I explore methods that utilize the unique cancer expression of the polymeric glycosaminoglycan hyaluronan (HA) and the HA receptor CD44 to target liposomes to tumors, using liposomes functionalized with proteins or oligosaccharides on their surface. To make it easier to prepare protein-functionalized liposomes, a non-covalent protein/liposome association method based upon metal chelation/his 6 interaction was devised and characterized. I evaluated non-covalent attachment of the prodrug converting enzyme yeast cytosine deaminase, the far-red fluorescent protein mKate, two antigens ovalbumin and the membrane proximal region of an HIV GAG and hyaluronidase, a HA-degrading enzyme. In Chapter 2, I describe the synthesis of hyaluronan-oligosaccharide (HA-O) lipid conjugates and their incorporation into liposomes to target CD44-overexpressing cancer cells. HA-O ligands of defined-length, up to 10 monosaccharides, were attached to lipids via various linkers by reductive amination. The HA-lipids were easily incorporated into liposomes but did not mediate binding of liposomes to CD44 overexpressing cells. In Chapter 3, I evaluate the capacity of tris-NTA-Ni-lipids incorporated within a liposome bilayer to associate with his6-tagged proteins. Tris-NTA-lipids of differing structures and avidities were used to associate yeast cytosine deaminase and mKate to the surface of liposomes. Two tris-NTA-lipids and a mono-NTA lipid associated his-tagged proteins to a 1:1 molar ratio in solution. The proteins remained active while associated with the liposome surface. When challenged in vitro with fetal calf serum, tris-NTA-containing liposomes retained his-tagged proteins longer than mono-NTA. However, the tris-NTA/his6 interaction was found to be in a dynamic state; free yeast cytosine deaminase rapidly competed with pre-bound mKate for NTA occupancy. In the circulation of mice, his-tagged proteins associated with NTA-liposomes were cleared as rapidly as free protein. In Chapter 4, I study the effect of NTA/his-tag avidity on immune response when NTA-containing liposomes are used as non-covalent, particulate adjuvants. Two his-tagged antigens, ovalbumin and the membrane proximal portion of HIV Gag, were associated with NTA-liposomes containing either mono-NTA or tris-NTA lipids. The immune response to each antigen was compared to control adjuvant formulations in which antigens were admixed with or covalently-conjugated to liposomes. The weaker antigen, the HIV Gag peptide, induced a stronger immune response when associated with NTA-containing liposomes than when admixed with liposomes. Ovalbumin preparations in which the protein was admixed with particles or non-covalently associated with NTA-liposomes elicited a higher immune response than free ovalbumin or ovalbumin admixed with the control adjuvant alum. For both antigens, NTA-liposome responses were less than the response to antigens covalently linked to the liposome. In Chapter 5, I evaluate the potential for hyaluronidase to target conjugated liposomes to tumors or improve liposome motility within hyaluronan-rich tumors. Ovine hyaluronidase was modified using iminothiolane to introduce sulfhydryl groups into the enzyme. The enzyme was attached to liposomes via maleimide lipids or to maleimidehis10 in order to engineer non-covalent NTA-liposome association. Enzyme activity was retained after sulfhydryl addition and after attachment to liposomes. Liposome-conjugated hyaluronidase degraded an HA-gel at the same rate as admixed liposomes. When hyaluronidase-liposomes were injected intravenously in mice, the hyaluronidase conjugated-liposomes experienced faster clearance than control liposomes but slower clearance than free hyaluronidase. As a whole, these studies may help develop universal methods for a range of protein therapeutics and anti-cancer targeting agents.

Inhibition of protein N-myristoylation: a therapeutic protocol in developing anticancer agents.

PubMed

Das, U; Kumar, S; Dimmock, J R; Sharma, R K

2012-07-01

N-myristoyltransferase (NMT) is an essential eukaryotic enzyme which catalyzes the transfer of the myristoyl group to the terminal glycine residue of a number of proteins including those involved in signal transduction and apoptotic pathways. Myristoylation is crucial for the cellular proliferation process and is required for the growth and development in a number of organisms including many human pathogens and viruses. Targeting the myristoylation process thus has emerged as a novel therapeutic strategy for anticancer drug design. The expression/activity of NMT is considerably elevated in a number of cancers originating in the colon, stomach, gallbladder, brain and breast and attenuation of NMT levels has been shown to induce apoptosis in cancerous cell lines and reduce tumor volume in murine xenograft models for cancer. A focus of current therapeutic interventions in novel cancer treatments is therefore directed at developing specific NMT inhibitors. The inhibition of the myristoyl lipidation process with respect to cancer drug development lies in the fact that many proteins involved in oncogenesis such as src and various kinases require myristoylation to perform their cellular functions. Inhibiting NMT functions to control malignancy is a novel approach in the area of anticancer drug design and there are rapidly expanding discoveries of synthetic NMT inhibitors as potential chemotherapeutic agents to be employed in the warfare against cancer. The current review focuses on developments of various chemical NMT inhibitors with potential roles as anticancer agents.

A brominated flame retardant 2,2',4,4' tetrabrominated diphenyl ether (BDE-47) leads to lipogenesis in the copepod Tigriopus japonicus.

PubMed

Lee, Min-Chul; Han, Jeonghoon; Lee, Seung-Hwi; Kim, Duck-Hyun; Kang, Hye-Min; Won, Eun-Ji; Hwang, Dae-Sik; Park, Jun Chul; Om, Ae-Son; Lee, Jae-Seong

2016-09-01

De novo lipogenesis (DNL) is a fatty acid synthesis process that requires several genes, including sterol regulatory element binding protein (SREBP), ATP-citrate lyase (ACLY), and acetyl-CoA carboxylase (ACC). DNL up-regulation is able to induce fat accumulation through an increase in fatty acids. To investigate the relationship between DNL up-regulation and the accumulation of fatty acids and lipid droplets in response to 2,2',4,4' tetrabrominated diphenyl ether (BDE-47), we examined DNL in the copepod Tigriopus japonicus. Transcription levels of DNL-related genes were increased after exposure to 2.5μg/L BDE-47 for 24h. After exposure to 2.5μg/L BDE-47, palmitic acid was significantly increased (P<0.05) at days 1 and 4, along with upregulation of fatty acid synthesis-related genes (e.g., desaturases and elongases). However, docosahexaenoic acid and arachidonic acid were down-regulated at days 1 and 4, showing an antagonistic effect. Lipid droplet area significantly increased in Nile red staining analysis after 24h of exposure to 2.5μg/L BDE-47 in T. japonicus, while DNL was down-regulated in response to 500μM salicylate (a lipogenesis inhibitor), indicating that BDE-47 exposure is closely associated with an increase in fatty acids in this copepod. This study provides a better understanding of the effects of BDE-47 on DNL in copepods. Copyright © 2016 Elsevier B.V. All rights reserved.

Uptake and biotransformation of 2,2‧,4,4‧-tetrabromodiphenyl ether (BDE-47) in four marine microalgae species

NASA Astrophysics Data System (ADS)

Po, Beverly H. K.; Ho, Ka-Lok; Lam, Michael H. W.; Giesy, John P.; Chiu, Jill M. Y.

2017-03-01

Hydroxylated- and methoxylated- polybrominated diphenyl ethers (OH-PBDEs and MeO-PBDEs) are more toxic than PBDEs and occur widely in the marine environment, and yet their origins remain controversial. In this study, four species of microalgae (Isochrysis galbana, Prorocentrum minimum, Skeletonema grethae and Thalassiosira pseudonana) were exposed to BDE-47, which is synthetic and is the predominant congener of PBDEs in the environment. By chemical analysis after incubation of 2 to 6 days, the efficiency of uptake of BDE-47 and, more importantly, the potential of undergoing biotransformation to form OH-PBDEs and MeO-PBDEs by the microalgae were investigated. Growth rates of these axenic microalgae were not affected upon exposure to environmentally relevant concentrations (0.2-20 μg BDE-47 L-1), and accumulation ranged from 0.772 ± 0.092 μg BDE-47 g-1 lipid to 215 ± 54 μg BDE-47 g-1 lipid within 2 days. Debromination of BDE-47 and formation of BDE-28 occurred in all microalgae species (0.01 to 0.87%), but biotransformation to OH-PBDEs was only found in I. galbana upon exposure to extremely high concentration. The results of this study showed that biotransformation of microalgae species is unlikely an explanation for the OH-PBDEs and MeO-PBDEs found in the marine environment.

Polybrominated diphenyl ether (PBDE) accumulation by earthworms (Eisenia fetida) exposed to biosolids-, polyurethane foam microparticle-, and Penta-BDE-amended soils.

PubMed

Gaylor, Michael O; Harvey, Ellen; Hale, Robert C

2013-12-03

Polybrominated diphenyl ether (PBDE) flame retardants have been used in consumer polymers at up to percent levels. While long viewed as biologically inaccessible therein, PBDEs may become bioaccessible following volatilization or polymer deterioration. PBDEs may then enter soils via polymer fragmentation or following land application of sewage sludge-derived biosolids. Studies of direct PBDE uptake from these materials by soil organisms are scarce. We thus exposed earthworms ( Eisenia fetida ) to artificial soil amended with a Class B anaerobically digested biosolid (ADB), an exceptional quality composted biosolid (CB), PBDE-containing polyurethane foam (PUF) microparticles, and Penta-BDE-spiked artificial soil (SAS). Worms accumulated mg/kg (lipid) ∑Penta-PBDE burdens from all substrates. Biota-soil accumulation factors (BSAFs) for worms exposed to ADB- and CB-amended soils were comparable after 28 d. BSAFs generally decreased with increasing congener KOW and substrate dosage. Biosolids-associated PBDE bioavailability was lower than spiked PBDEs. BSAFs for worms exposed to PUF microparticles ranged from 3.9 to 33.4, with ∑Penta-PBDE tissue burdens reaching 3740 mg/kg lipid. Congener accumulation patterns were similar in worms and polyethylene passive sampling devices immersed in ADB-amended soil coincident with exposed worms. However, passive sampler accumulation factors were lower than BSAFs. Our results demonstrate that PBDEs may accumulate in organisms ingesting soils containing biosolids or waste plastics. Such organisms may then transfer their burdens to predators or translocate them from the site of application/disposal.

Cytotoxic potential of few Indian fruit peels through 3-(4,5-dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide assay on HepG2 cells.

PubMed

Garg, Munish; Lata, Kusum; Satija, Saurabh

2016-01-01

To investigate in vitro anticancer activity of a few Indian fruit peels through 3-(4,5-dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against HepG2 cells. Hydroalcoholic extracts were prepared of five fruit peels, i.e., banana, lemon, guava, orange, and papaya by maceration and thereafter subjected for MTT assay to evaluate anticancer potential on HepG2 cells. Plant extract showed best activity was further fractionated with petroleum ether, chloroform, and ethyl acetate successively and screened again. Phytochemical analysis was then carried out to find out responsible components for the observed activity. Out of the 40 samples from five fruit peel extracts with rich folklore usage, papaya extract showed maximum activity with least inhibitory concentration50 (IC50) value of 18.5 μg/ml. Further analysis after fractionation of the papaya peel extract, aqueous fraction showed the maximum inhibitory activity with least IC50 value of 17.3 μg/ml. Phytochemical analysis of the aqueous fraction of papaya peel extract revealed the presence of flavonoids and glycosides. Total flavonoid content found to be 72.25 mg/g. Papaya fruit extract demonstrated the best activity against MTT assay which may be due to the presence of flavonoids.

pH-responsive micelles based on (PCL)2(PDEA-b-PPEGMA)2 miktoarm polymer: controlled synthesis, characterization, and application as anticancer drug carrier.

PubMed

Lin, Wenjing; Nie, Shuyu; Xiong, Di; Guo, Xindong; Wang, Jufang; Zhang, Lijuan

2014-01-01

Amphiphilic A2(BC)2 miktoarm star polymers [poly(ϵ-caprolactone)]2-[poly(2-(diethylamino)ethyl methacrylate)-b- poly(poly(ethylene glycol) methyl ether methacrylate)]2 [(PCL)2(PDEA-b-PPEGMA)2] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC50 of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)2(PDEA-b-PPEGMA)2 micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.

Metabolite characterization of a novel anti-cancer agent, icotinib, in humans through liquid chromatography/quadrupole time-of-flight tandem mass spectrometry.

PubMed

Liu, Dongyang; Jiang, Ji; Zhang, Li; Tan, Fenlai; Wang, Yingxiang; Hu, Pei

2011-08-15

Icotinib is a novel anti-cancer drug that has shown promising clinical efficacy and safety in patients with non-small-cell lung cancer (NSCLC). At this time, the metabolic fate of icotinib in humans is unknown. In the present study, a liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (LC/Q-TOF MS) method was established to characterize metabolites of icotinib in human plasma, urine and feces. In addition, nuclear magnetic resonance (NMR) detection was utilized to determine the connection between side-chain and quinazoline groups for some complex metabolites. In total, 29 human metabolites (21 isomer metabolites) were characterized, of which 23 metabolites are novel compared to the metabolites in rats. This metabolic study revealed that icotinib was extensively metabolized at the 12-crown-4 ether moiety (ring-opening and further oxidation), carbon 15 (hydroxylation) and an acetylene moiety (oxidation) to yield 19 oxidized metabolites and to further form 10 conjugates with sulfate acid or glucuronic acid. To our knowledge, this is the first report of the human metabolic profile of icotinib. Study results indicated that significant attention should be paid to the metabolic profiles of NSCLC patients during the development of icotinib. Copyright © 2011 John Wiley & Sons, Ltd.

Method and Apparatus for Forming Nanodroplets

NASA Technical Reports Server (NTRS)

Ackley, Donald; Forster, Anita

2011-01-01

This innovation uses partially miscible fluids to form nano- and microdroplets in a microfluidic droplet generator system. Droplet generators fabricated in PDMS (polydimethylsiloxane) are currently being used to fabricate engineered nanoparticles and microparticles. These droplet generators were first demonstrated in a T-junction configuration, followed by a cross-flow configuration. All of these generating devices have used immiscible fluids, such as oil and water. This immiscible fluid system can produce mono-dispersed distributions of droplets and articles with sizes ranging from a few hundred nanometers to a few hundred microns. For applications such as drug delivery, the ability to encapsulate aqueous solutions of drugs within particles formed from the droplets is desirable. Of particular interest are non-polar solvents that can dissolve lipids for the formation of liposomes in the droplet generators. Such fluids include ether, cyclohexane, butanol, and ethyl acetate. Ethyl acetate is of particular interest for two reasons. It is relatively nontoxic and it is formed from ether and acetic acid, and maybe broken down into its constituents at relatively low concentrations.

Polybrominated diphenyl ethers in human placenta associated with neonatal physiological development at a typical e-waste recycling area in China.

PubMed

Xu, Long; Huo, Xia; Zhang, Yuling; Li, Weiqiu; Zhang, Jianqing; Xu, Xijin

2015-01-01

Our aim of this study was to characterize the exposure pattern of polybrominated diphenyl ethers(PBDEs) in human placenta and assess their potential effects on neonates. Placenta samples were obtained from a typical e-waste area in Guiyu and a reference area in Haojiang, China. The median ΣPBDE concentration was 32.25 ng/g lipid weight (lw) in placenta samples from Guiyu, and 5.13 ng/g lw from Haojiang. BDE-209 predominated in placenta samples, followed by BDE-28, -47, -99 -153, -183. Residence in Guiyu contributed the most to elevated PDBE levels. Neonatal physiological indices, including bodymass index (BMI), Apgar 1 score and head circumference, were reduced in Guiyu group. No significant difference was found in neonatal weight between the two groups, but neonatal body length in Guiyu was increased. Our data suggest prenatal exposure to PBDEs is high at the e-waste recycling area, and may lead to adverse physiological development in the fetus.

Design and synthesis of potent antileishmanial cycloalkylidene-substituted ether phospholipid derivatives.

PubMed

Calogeropoulou, Theodora; Angelou, Panagiotis; Detsi, Anastasia; Fragiadaki, Irene; Scoulica, Effie

2008-02-28

Two series of novel ether phospholipids (EPs) have been synthesized. The first includes cyclodecylidene- or cyclopentadecylidene-substituted EPs carrying N,N,N-trimethylammonium or N-methylpiperidino or N-methylmorpholino head groups. The second series encompasses more rigid head groups in combination with cycloalkylidene moieties in the lipid portion. In addition, hydrogenated derivatives were obtained. All the new analogues, except 33, were 1.5- to 62-fold more potent than miltefosine against the intracellular L. infantum, and the most active ones were also less cytotoxic against the human monocytic cell line THP1 and less hemolytic than miltefosine. The analogues that combine high potency with low cytotoxicity and hemolytic activity were 19, 37, 21 23, 38, 39, and 40. Cyclopentadecylpentylphosphocholine (38) possesses an IC50 of 0.7 microM against L. infantum amastigotes and is the least cytotoxic analogue, since it does not present toxicity against THP1 macrophages, even at a concentration that is 800-fold the antiparasitic IC50 value, and does not present significant hemolytic activity.

Development of amino acid substituted gemini surfactant-based mucoadhesive gene delivery systems for potential use as noninvasive vaginal genetic vaccination.

PubMed

Singh, Jagbir; Michel, Deborah; Getson, Heather M; Chitanda, Jackson M; Verrall, Ronald E; Badea, Ildiko

2015-02-01

Recently, we synthesized amino acid- and peptide-substituted gemini surfactants, 'biolipids' that exhibited high transfection efficiency in vitro. In this study, we developed these plasmid DNA and gemini surfactant lipid particles for noninvasive administration in vaginal cavity. Novel formulations of these gene delivery systems were prepared with poloxamer 407 to induce in situ gelling of the formulation and diethylene glycol monoethyl ether to improve their penetration across mucosal tissue. Poloxamer at 16% w/v concentration in diethylene glycol monoethyl ether aqueous solution produced dispersions that gelled near body temperature and had a high yield value, preventing leakage of the formulation from the vaginal cavity. Intravaginal administration in rabbits showed that the glycyl-lysine-substituted gemini surfactant led to a higher gene expression compared with the parent unsubstituted gemini surfactant. This provides a proof-of-concept that amino acid substituted gemini surfactants can be used as noninvasive mucosal (vaginal) gene delivery systems to treat diseases associated with mucosal epithelia.

MR-Visible Lipids and the Tumor Microenvironment

PubMed Central

Delikatny, E. James; Chawla, Sanjeev; Leung, Daniel-Joseph; Poptani, Harish

2013-01-01

MR-visible lipids or mobile lipids are defined as lipids that are observable using proton magnetic resonance spectroscopy in cells and in tissues. These MR-visible lipids are composed of triglycerides and cholesterol esters that accumulate in intracellular neutral lipid droplets, where their MR visibility is conferred as a result of the increased molecular motion available in this unique physical environment. This review will discuss factors that lead to the biogenesis of MR-visible lipids in cancer cells and in other cell types such as immune cells and fibroblasts. We focus on the accumulations of mobile lipids that are inducible in cultured cells by a number of stresses, including culture conditions and in response to activating stimuli or apoptotic cell death induced by anticancer drugs. This is compared with animal tumor models, where increases in mobile lipids are observed in response to chemo and radiotherapy, and to human tumors where mobile lipids are observed predominantly in high-grade brain tumors and in regions of necrosis. Conducive conditions for mobile lipid formation in the tumor microenvironment will be discussed including low pH, oxygen availability and the presence of inflammatory cells. It is concluded that MR-visible lipids appear in cancer cells and human tumors as a stress response. Mobile lipids stored as neutral lipid droplets may play a role in detoxification of the cell or act as an alternate energy source, especially in cancer cells, which often grow in ischemic/hypoxic environments. The role of MR-visible lipids in cancer diagnosis and assessment of treatment response both in animal models of cancer as well as human brain tumors will also be discussed. Although technical limitations exist in the accurate detection of intratumoral mobile lipids, early increases in mobile lipids after therapeutic interventions may be used as a potential biomarker for assessing treatment response in cancer. PMID:21538631

Structural Basis for Binding and Selectivity of Antimalarial and Anticancer Ethylenediamine Inhibitors to Protein Farnesyltransferase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hast, Michael A.; Fletcher, Steven; Cummings, Christopher G.

Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison tomore » a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.« less

Nanocarriers for delivery of siRNA and co-delivery of siRNA and other therapeutic agents.

PubMed

Zhao, Jing; Feng, Si-Shen

2015-07-01

A major problem in cancer treatment is the multidrug resistance. siRNA inhibitors have great advantages to solve the problem, if the bottleneck of their delivery could be well addressed by the various nanocarriers. Moreover, co-delivery of siRNA together with the various anticancer agents in one nanocarrier may maximize their additive or synergistic effect. This review provides a comprehensive summary on the state-of-the-art of the nanocarriers, which may include prodrugs, micelles, liposomes, dendrimers, nanohydrogels, solid lipid nanoparticles, nanoparticles of biodegradable polymers and nucleic acid nanocarriers for delivery of siRNA and co-delivery of siRNA together with anticancer agents with focus on synthesis of the nanocarrier materials, design and characterization, in vitro and in vivo evaluation, and prospect and challenges of nanocarriers.

Heat Stress Dictates Microbial Lipid Composition along a Thermal Gradient in Marine Sediments

PubMed Central

Sollich, Miriam; Yoshinaga, Marcos Y.; Häusler, Stefan; Price, Roy E.; Hinrichs, Kai-Uwe; Bühring, Solveig I.

2017-01-01

Temperature exerts a first-order control on microbial populations, which constantly adjust the fluidity and permeability of their cell membrane lipids to minimize loss of energy by ion diffusion across the membrane. Analytical advances in liquid chromatography coupled to mass spectrometry have allowed the detection of a stunning diversity of bacterial and archaeal lipids in extreme environments such as hot springs, hydrothermal vents and deep subsurface marine sediments. Here, we investigated a thermal gradient from 18 to 101°C across a marine sediment field and tested the hypothesis that cell membrane lipids provide a major biochemical basis for the bioenergetics of archaea and bacteria under heat stress. This paper features a detailed lipidomics approach with the focus on membrane lipid structure-function. Membrane lipids analyzed here include polar lipids of bacteria and polar and core lipids of archaea. Reflecting the low permeability of their ether-linked isoprenoids, we found that archaeal polar lipids generally dominate over bacterial lipids in deep layers of the sediments influenced by hydrothermal fluids. A close examination of archaeal and bacterial lipids revealed a membrane quandary: not only low permeability, but also increased fluidity of membranes are required as a unified property of microbial membranes for energy conservation under heat stress. For instance, bacterial fatty acids were composed of longer chain lengths in concert with higher degree of unsaturation while archaea modified their tetraethers by incorporation of additional methyl groups at elevated sediment temperatures. It is possible that these configurations toward a more fluidized membrane at elevated temperatures are counterbalanced by the high abundance of archaeal glycolipids and bacterial sphingolipids, which could reduce membrane permeability through strong intermolecular hydrogen bonding. Our results provide a new angle for interpreting membrane lipid structure-function enabling archaea and bacteria to survive and grow in hydrothermal systems. PMID:28878741

Decomposition of food lipids by ionizing radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nawar, W.W.

1973-01-01

A number of animal and vegetable fats as well as model systems of triglycerides were used in a study to examine the effects of irradiation on the lipid fraction of foods. More than one hundred compounds were identified as radiolytic products. These include a series of hydrocarbons, aldehydes, esters, free acids, ethane- and propanediol diesters, propenediol diesters, diglycerides, triglycerides, ketones, glyceryl ether diesters, and 2-alkyl cyclobutanones. Reaction mechanism are proposed to explain the formation of the decomposition products. Bascially, these compounds result via the formation of free radicals according to preferential cleavages in the vicinity of the carbonyl groups. Sincemore » some of these compounds are unique to radiation effects, a method was developed to detect irradiation treatment in foods. Variables affecting the radiolytic pattern are discussed, and a comparison between thermolytic and radiolytic effects is presented. (GE)« less

Beneficial Effect of Bis(Hinokitiolato)Zn Complex on High-fat Diet-induced Lipid Accumulation in Mouse Liver and Kidney.

PubMed

Naito, Yuki; Yoshikawa, Yutaka; Yoshizawa, Katsuhiko; Takenouchi, Akiko; Yasui, Hiroyuki

2017-01-01

Metabolic syndrome-induced lifestyle-related diseases include diabetes mellitus (DM) and hypertension, and Zn-based compounds have effects on DM. We aimed to investigate the ameliorating effects of bis(hinokitiolato)Zn, [Zn(hkt) 2 ] on lipid metabolism in the liver and kidney, histopathologically. We used a high-fat diet (HFD)-fed C57BL/6J mouse model and administered a diet containing 10-20 mg Zn/kg body weight (BW) or 20 mg pioglitazone/kg BW as the positive control. After the treatments, we collected blood, liver, and kidney samples and morphologically evaluated the mouse organs for fat accumulation. After a 4-month HFD administration, ectopic fat deposition was detected in the liver and kidney. Furthermore, Zn accumulation in the liver and kidney increased following [Zn(hkt) 2 ] treatment, that reduced lipid accumulations and lipid toxicity in these tissues. The results of this study suggest that [Zn(hkt) 2 ] could be a novel anti-dyslipidaemia compound for treating diet-induced obesity. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance.

PubMed

Zhou, Jin; Farah, Benjamin Livingston; Sinha, Rohit Anthony; Wu, Yajun; Singh, Brijesh Kumar; Bay, Boon-Huat; Yang, Chung S; Yen, Paul Michael

2014-01-01

Epigallocatechin gallate (EGCG) is a major polyphenol in green tea that has been shown to have anti-inflammatory, anti-cancer, anti-steatotic effects on the liver. Autophagy also mediates similar effects; however, it is not currently known whether EGCG can regulate hepatic autophagy. Here, we show that EGCG increases hepatic autophagy by promoting the formation of autophagosomes, increasing lysosomal acidification, and stimulating autophagic flux in hepatic cells and in vivo. EGCG also increases phosphorylation of AMPK, one of the major regulators of autophagy. Importantly, siRNA knockdown of AMPK abrogated autophagy induced by EGCG. Interestingly, we observed lipid droplet within autophagosomes and autolysosomes and increased lipid clearance by EGCG, suggesting it promotes lipid metabolism by increasing autophagy. In mice fed with high-fat/western style diet (HFW; 60% energy as fat, reduced levels of calcium, vitamin D3, choline, folate, and fiber), EGCG treatment reduces hepatosteatosis and concomitantly increases autophagy. In summary, we have used genetic and pharmacological approaches to demonstrate EGCG induction of hepatic autophagy, and this may contribute to its beneficial effects in reducing hepatosteatosis and potentially some other pathological liver conditions.

Triclosan antimicrobial polymers

PubMed Central

Petersen, Richard C.

2016-01-01

Triclosan antimicrobial molecular fluctuating energies of nonbonding electron pairs for the oxygen atom by ether bond rotations are reviewed with conformational computational chemistry analyses. Subsequent understanding of triclosan alternating ether bond rotations is able to help explain several material properties in Polymer Science. Unique bond rotation entanglements between triclosan and the polymer chains increase both the mechanical properties of polymer toughness and strength that are enhanced even better through secondary bonding relationships. Further, polymer blend compatibilization is considered due to similar molecular relationships and polarities. With compatibilization of triclosan in polymers a more uniform stability for nonpolar triclosan in the polymer solid state is retained by the antimicrobial for extremely low release with minimum solubility into aqueous solution. As a result, triclosan is projected for long extended lifetimes as an antimicrobial polymer additive. Further, triclosan rapid alternating ether bond rotations disrupt secondary bonding between chain monomers in the resin state to reduce viscosity and enhance polymer blending. Thus, triclosan is considered for a polymer additive with multiple properties to be an antimicrobial with additional benefits as a nonpolar toughening agent and a hydrophobic wetting agent. The triclosan material relationships with alternating ether bond rotations are described through a complete different form of medium by comparisons with known antimicrobial properties that upset bacterial cell membranes through rapid fluctuating mechanomolecular energies. Also, triclosan bond entanglements with secondary bonding can produce structural defects in weak bacterial lipid membranes requiring pliability that can then interfere with cell division. Regarding applications with polymers, triclosan can be incorporated by mixing into a resin system before cure, melt mixed with thermoplastic polymers that set on cooling into a solid or alternatively applied as a coating through several different methods with dissolving into an organic solvent and dried on by evaporation as a common means. PMID:27280150

Evaluation of a recent product to remove lipids and other matrix co-extractives in the analysis of pesticide residues and environmental contaminants in foods.

PubMed

Han, Lijun; Matarrita, Jessie; Sapozhnikova, Yelena; Lehotay, Steven J

2016-06-03

This study demonstrates the application of a novel lipid removal product to the residue analysis of 65 pesticides and 52 environmental contaminants in kale, pork, salmon, and avocado by fast, low pressure gas chromatography - tandem mass spectrometry (LPGC-MS/MS). Sample preparation involves QuEChERS extraction followed by use of EMR-Lipid ("enhanced matrix removal of lipids") and an additional salting out step for cleanup. The optimal amount of EMR-Lipid was determined to be 500mg for 2.5mL extracts for most of the analytes. The co-extractive removal efficiency by the EMR-Lipid cleanup step was 83-98% for fatty samples and 79% for kale, including 76% removal of chlorophyll. Matrix effects were typically less than ±20%, in part because analyte protectants were used in the LPGC-MS/MS analysis. The recoveries of polycyclic aromatic hydrocarbons and diverse pesticides were mostly 70-120%, whereas recoveries of nonpolar polybrominated diphenyl ethers and polychlorinated biphenyls were mostly lower than 70% through the cleanup procedure. With the use of internal standards, method validation results showed that 76-85 of the 117 analytes achieved satisfactory results (recoveries of 70-120% and RSD≤20%) in pork, avocado, and kale, while 53 analytes had satisfactory results in salmon. Detection limits were 5-10ng/g for all but a few analytes. EMR-Lipid is a new sample preparation tool that serves as another useful option for cleanup in multiresidue analysis, particularly of fatty foods. Published by Elsevier B.V.

Changes in physiological responses of an Antarctic fish, the emerald rock cod (Trematomus bernacchii), following exposure to polybrominated diphenyl ethers (PBDEs).

PubMed

Ghosh, Ruma; Lokman, P Mark; Lamare, Miles D; Metcalf, Victoria J; Burritt, David J; Davison, William; Hageman, Kimberly J

2013-03-15

Although polybrominated diphenyl ethers (PBDEs) have the ability to undergo long-range atmospheric transport to remote ecosystems like Antarctica, a recent study found evidence for a local source within the Antarctic. PBDEs from sewage treatment outfalls of McMurdo Station and Scott Base on Ross Island have been attributed to the high concentrations measured in emerald rock cod (Trematomus bernacchii). The potential impact of PBDEs on Antarctic fish physiology is unknown and therefore, the aim of this study was to obtain a greater understanding of physiological responses of emerald rock cod for assessing changes in ecosystem quality. A PBDE mixture (ΣPBDE 8 congeners) was administered fortnightly over 42 days and physiological changes were observed throughout this period and for a further 14 days thereafter. Changes in liver composition, molecular level changes and enzyme activities of selected detoxification-mediated and antioxidant defence markers were measured. Changes in total lipid, lipid peroxide and protein carbonyl concentrations in emerald rock cod liver were consistent with increases in nucleus surface area in the PBDE-treated groups, suggesting alterations in cellular function. Changes in the activities of selected antioxidant enzymes indirectly indicated oxidative stress, possibly resulting in the changes in liver composition. Additionally, glutathione-S-transferase (GST) activity reached its peak faster than that of ethoxyresorufin-O-deethylase (EROD), suggesting that during the early response to PBDE exposures there could be a greater involvement of GST-mediated detoxification. Thus, for at least the species examined here, protein carbonyl and lipid peroxides were useful and informative biomarkers for cellular level responses following PBDE-related exposure. Furthermore, our findings suggest that emerald rock cod exposed to PBDEs develop oxidative stress - a condition with potential consequences for fish growth, health and reproduction. Copyright © 2012 Elsevier B.V. All rights reserved.

PEGylated lipid nanocapsules with improved drug encapsulation and controlled release properties.

PubMed

Hervella, Pablo; Alonso-Sande, Maria; Ledo, Francisco; Lucero, Maria L; Alonso, Maria J; Garcia-Fuentes, Marcos

2014-01-01

Drugs with poor lipid and water solubility are some of the most challenging to formulate in nanocarriers, typically resulting in low encapsulation efficiencies and uncontrolled release profiles. PEGylated nanocapsules (PEG-NC) are known for their amenability to diverse modifications that allow the formation of domains with different physicochemical properties, an interesting feature to address a drug encapsulation problem. We explored this problem by encapsulating in PEG-NC the promising anticancer drug candidate F10320GD1, used herein as a model for compounds with such characteristics. The nanocarriers were prepared from Miglyol(®), lecithin and PEG-sterate through a solvent displacement technique. The resulting system was a homogeneous suspension of particles with size around 200 nm. F10320GD1 encapsulation was found to be very poor (<15%) if PEG-NC were prepared using water as continuous phase; but we were able to improve this value to 85% by fixing the pH of the continuous phase to 9. Interestingly, this modification also improved the controlled release properties and the chemical stability of the formulation during storage. These differences in pharmaceutical properties together with physicochemical data suggest that the pH of the continuous phase used for PEG-NC preparation can modify drug allocation, from the external shell towards the inner lipid core of the nanocapsules. Finally, we tested the bioactivity of the drug-loaded PEG-NC in several tumor cell lines, and also in endothelial cells. The results indicated that drug encapsulation led to an improvement on drug cytotoxicity in tumor cells, but not in non-tumor endothelial cells. Altogether, the data confirms that PEG-NC show adequate delivery properties for F10320GD1, and underlines its possible utility as an anticancer therapy.

In vitro antioxidant and cytotoxic properties of ethanol extract of Alpinia oxyphylla fruits.

PubMed

Wang, Cheng-zhong; Yuan, Hui-hui; Bao, Xiao-li; Lan, Min-bo

2013-11-01

Alpinia oxyphylla Miquel (Zingiberaceae) is a traditional Chinese herbal medicine widely used for the treatment of intestinal disorders, urosis and diuresis. However, information about antioxidant and cytotoxic properties of its fruits remains to be elucidated. The ethanol crude extract (CE) and its fractions [petroleum ether fraction (PF), ethyl acetate fraction (EF), n-butanol fraction (BF) and water fraction (WF) extracted by petroleum ether, ethyl acetate, n-butanol and water, respectively] of A. oxyphylla fruits were investigated for their antioxidant activity and cytotoxicity. The total phenolic content (TPC) and antioxidant activity of the extracts were determined by Folin-Ciocalteu reagent, 1,1-diphenyl-2-picrylhydrazyl (DPPH(•)), Trolox equivalent antioxidant capacity and reducing power assay. Cytotoxicity of the extracts (0-200 μg/mL) was tested on six human cancer cell lines (breast cancer cell line, cervix carcinoma cell line, lung adenocarcinoma cell line, liver carcinoma cell line, gastric cancer cell line and colon cancer cell line) using the sulforhodamine B assay. The TPC of extracts varied from 8.2 to 20.3 mg gallic acid equivalents/g dry weight. DPPH radical scavenging effect of extracts decreased in the order of EF > BF > CE > PF > WF, with IC50 values ranging from 74.7 to 680.8 μg/mL. 2,2-azo-bis(3-Ethylbenzothiazoline-6-sulfoic acid) diammonium salt scavenging activity ranged from 0.118 to 0.236 mmol Trolox equivalence/mg extract. The extracts exhibited concentration-dependent reducing power, and EF showed the highest reducing ability. A satisfactory correlation (R(2) > 0.826) between TPC and antioxidant activity was observed. In addition, EF, PF and CE exhibited potent anticancer effects on six cancer cell lines with IC50 values ranging from 40.1 to 166.3 μg/mL. The ethanol extract of A. oxyphylla fruit, especially the EF, was found to possess potent antioxidant and anticancer activities, and thus a great potential for the application in food and drug products.

Self-assembly of a chiral lipid gelator controlled by solvent and speed of gelation.

PubMed

Xue, Pengchong; Lu, Ran; Yang, Xinchun; Zhao, Li; Xu, Defang; Liu, Yan; Zhang, Hanzhuang; Nomoto, Hiroyuki; Takafuji, Makoto; Ihara, Hirotaka

2009-09-28

Glutamine derivative 1 with two-photon absorbing units has been synthesized and was found to show gelation ability in some solvents. Its self-assembly in the gel phase could be controlled by the solvent and speed of gelation. For example, in DMSO the organogelator self-assembled into H-aggregates with weak exciton coupling between the aromatic moieties. On the other hand, in DMSO/diphenyl ether (1:9, v/v) the molecules formed 1D aggregates, but with strong exciton coupling due to the small distance between the chromophores. Moreover, the formation of these two kinds of aggregates could be adjusted by the ratio of DMSO to diphenyl ether. In DMSO/toluene, DMSO/butanol, DMSO/butyl acetate, and DMSO/acetic acid systems similar results were observed. Therefore, conversion of the packing model occurs irrespective of the nature of the solvent. Notably, a unique sign inversion in the CD spectra could be realized by controlling the speed of gelation in the DMSO/diphenyl ether (1:9, v/v) system. It was found that a low speed of gelation induces the gelator to adopt a packing model with strong pi-pi interactions between the aromatic units. Moreover, the gels, when excited at 800 nm, emit strong green fluorescence and the quantum chemical calculations suggest that intramolecular charge transfer leads to two-photon absorption of the gelator molecule.

Formulation Studies of InhA inhibitors and Combination therapy to improve efficacy against Mycobacterium tuberculosis

PubMed Central

Knudson, Susan E.; Cummings, Jason E.; Bommineni, Gopal R.; Pan, Pan; Tonge, Peter J.; Slayden, Richard A.

2016-01-01

Summary Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log10 CFU reduction in the spleen of animals co-treated with SB-PT091 and RIF and an additional 1.7 log10 reduction in the spleen with animals treated with both SB-PT070 and RIF. PMID:27865404

Inactivation of Herpes Simplex Viruses by Nonionic Surfactants

PubMed Central

Asculai, Samuel S.; Weis, Margaret T.; Rancourt, Martha W.; Kupferberg, A. B.

1978-01-01

Nonionic surface-active agents possessing ether or amide linkages between the hydrophillic and hydrophobic portions of the molecule rapidly inactivated the infectivity of herpes simplex viruses. The activity stemmed from the ability of nonionic surfactants to dissolve lipid-containing membranes. This was confirmed by observing surfactant destruction of mammalian cell plasma membranes and herpes simplex virus envelopes. Proprietary vaginal contraceptive formulations containing nonionic surfactants also inactivated herpes simplex virus infectivity. This observation suggests that nonionic surfactants in appropriate formulation could effectively prevent herpes simplex virus transmission. Images PMID:208460

Nanocarrier for poorly water-soluble anticancer drugs--barriers of translation and solutions.

PubMed

Narvekar, Mayuri; Xue, Hui Yi; Eoh, June Young; Wong, Ho Lun

2014-08-01

Many existing chemotherapeutic drugs, repurposed drugs and newly developed small-molecule anticancer compounds have high lipophilicity and low water-solubility. Currently, these poorly water-soluble anticancer drugs (PWSAD) are generally solubilized using high concentrations of surfactants and co-solvents, which frequently lead to adverse side effects. In recent years, researchers have been actively exploring the use of nanotechnology as an alternative to the solvent-based drug solubilization approach. Several classes of nanocarrier systems (lipid-based, polymer-based and albumin-based) are widely studied for encapsulation and delivery of the existing and new PWSAD. These nanocarriers were also shown to offer several additional advantages such as enhanced tumour accumulation, reduced systemic toxicity and improved therapeutic effectiveness. In this article, the recent nanotechnological advances in PWSAD delivery will be reviewed. The barriers commonly encountered in the development of PWSAD nanoformulations (e.g. formulation issues and nanotoxicity issues) and the strategies to overcome these barriers will also be discussed. It is our goal to provide the pharmaceutical scientists and clinicians with more in-depth information about the nanodelivery approach, thus, more efficacious and safe PWSAD nanoformulations can be developed with improved translational success.

Anticancer β-hairpin peptides: membrane-induced folding triggers activity

PubMed Central

Sinthuvanich, Chomdao; Veiga, Ana Salomé; Gupta, Kshitij; Gaspar, Diana; Blumenthal, Robert; Schneider, Joel P.

2012-01-01

Several cationic antimicrobial peptides (AMPs) have recently been shown to display anticancer activity via a mechanism that usually entails the disruption of cancer cell membranes. In this work, we designed an 18-residue anticancer peptide, SVS-1, whose mechanism of action is designed to take advantage of the aberrant lipid composition presented on the outer leaflet of cancer cell membranes, which makes the surface of these cells relatively electronegative relative to non-cancerous cells. SVS-1 is designed to remain unfolded and inactive in aqueous solution but preferentially fold at the surface of cancer cells, adopting an amphiphilic β-hairpin structure capable of membrane disruption. Membrane-induced folding is driven by electrostatic interaction between the peptide and the negatively charge membrane surface of cancer cells. SVS-1 is active against a variety of cancer cell lines such as A549 (lung carcinoma), KB (epidermal carcinoma), MCF-7 (breast carcinoma) and MDA-MB-436 (breast carcinoma). However, the cytotoxicity towards non-cancerous cells having typical membrane compositions, such as HUVEC and erythrocytes, is low. CD spectroscopy, appropriately designed peptide controls, cell-based studies, liposome leakage assays and electron microscopy support the intended mechanism of action, which leads to preferential killing of cancerous cells. PMID:22413859

Synergetic Effect of SLN-Curcumin and LDH-5-Fu on SMMC-7721 Liver Cancer Cell Line

PubMed Central

Zhu, Rongrong; Wu, Xianzheng; Xiao, Yu; Gao, Bo; Xie, Qian

2013-01-01

Abstract Curcumin and 5-Fluorouracil (5-Fu) have been reported to have anticancer potentials and show certain synergetic effect on some cancer cell lines. However, the poor bioavailability and rapid metabolism limited their medical application. In this study, we encapsulated curcumin with solid lipid nanoparticles (SLN), 5-Fu with Layered double hydroxides (LDHs) separately and tested its properties and anticancer potentials. SLN-curcumin and LDH-5-Fu were determined to be 100 and 60 nm by Transmission Electron Microscopy detection, and the loading efficiency were 28%±2.5% and 16.7%±1.8%, individually. Furthermore, SLN-curcumin and LDH-5-Fu showed a significantly synergetic effect on SMMC-7721 cell stronger than plain drugs together, of which the Idrug loaded nano-carriers was only 0.315. FACS analysis revealed that the combination of SLN-curcumin and LDH-5-Fu induced 80.1% apoptosis in SMMC-7721 cells, which were 1.7-folds of the sum of the two plain drug loaded carriers. The results demonstrated the significant synergetic anticancer potentials of nano-encapsulated curcumin and 5-Fu, which could be further explored for the treatment of other carcinoma. PMID:23808828

[Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs].

PubMed

Kik, Krzysztof; Szmigiero, Leszek

2006-01-01

The nthracycline antibiotics are among the most widely used and effective anticancer drugs. The therapeutic efficacy of this class of drugs is limited by cumulative cardiac toxicity. Dexrazoxane is the only clinically approved cardioprotective agent used in anthracycline-containing anticancer therapy. Its cardioprotective action allows the use of a much higher cumulative dose of anthracyclines and improvement in the effectiveness of treatment. Anthracyclines form complexes with iron ions, which are very active in the production of reactive oxygen species responsible for the lipid peroxidation of mitochondrial and endoplasmatic reticulum membranes. This process seems to be the major cause of anthracycline-induced cardiotoxicity. Dexrazoxane exerts its protective effects by rapid and complete binding of ferric and ferrous ions, even by displacing the metal ions from complexes with anthracyclines. Besides its cardioprotective effect, dexrazoxane also exhibits anticancer properties. Like other derivatives of bisdioxopiperazine, dexrazoxane is a catalytic inhibitor of eukaryotic DNA topoisomerase II, the key enzyme controlling DNA topology and contributing to the replication and transcription processes. Dexrazoxane is able to lock topoisomerase II at the stage of the enzyme reaction cycle where the enzyme forms a closed clamp around the DNA. This phenomenon seems to be the main reason for the generation of DNA double-strand breaks by dexrazoxane as well as its cytotoxicity against quickly proliferating cancer cells. Other effects of its topoisomerase II catalytic inhibition is the induction of cell differentiation and apoptosis. Dexrazoxane may be used not only as a cardioprotective agent, but also as a modulator of action of some anticancer drugs by enhancing their selectivity or by delaying the development of multidrug resistance.

The cytotoxic effect of Elephantopus scaber Linn extract against breast cancer (T47D) cells

NASA Astrophysics Data System (ADS)

Sulistyani, N.; Nurkhasanah

2017-11-01

Breast cancer is one of the main cause of death. Elephantopus scaber Linn (ES) which has been used as a traditional medicine contains an antitumor compounds. This study aimed to explore the active fraction from ethanolic extract of ES as anticancer and to determine its inhibition effect on the cell proliferation cycle of breast cancer (T47D) cells. The ES leaf was macerated with ethanol and then evaporated to get the concentrated extract. The extract was fractionated using petroleum ether, chloroform, and methanol respectively. The cytotoxic activity of each fraction was carried out with MTT method, and the inhibition of cell cycle test were observed by flowcytometry method. The result showed that ES and the fractions have cytotoxic activity against T47D cell lines with IC50 values of extract, petroleum ether, chloroform, and methanol fractions were 58.36±2.38, 132.17±9.69, 7.08±2.11, and 572.89±69.23 µg/mL. The inhibition effect of ethanol extract on the lifecycle of cells was occured in sub G1 phase. There was no prolonging of G1, S, G2/M and polyploidy phase of T47D cell lines. The chloroform fraction of ES is the most cytotoxic fraction against T47D cells without prolonging the cell lifecycle.

The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation

PubMed Central

Wu, Qiong; Madany, Pasil; Dobson, Jason R.; Schnabl, Jake M.; Sharma, Soni; Smith, Tara C.; van Wijnen, Andre J.; Stein, Janet L.; Lian, Jane B.; Stein, Gary S.; Muthuswami, Rohini; Imbalzano, Anthony N.; Nickerson, Jeffrey A.

2016-01-01

Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer. PMID:27223259

Stimuli-responsive Smart Liposomes in Cancer Targeting.

PubMed

Jain, Ankit; Jain, Sanjay K

2018-02-08

Liposomes are vesicular carriers which possess aqueous core entrapped within the lipid bilayer. These are carriers of choice because of biocompatible and biodegradable features in addition to flexibility of surface modifications at surface and lipid compositions of lipid bilayers. Liposomes have been reported well for cancer treatment using both passive and active targeting approaches however tumor microenvironment is still the biggest hurdle for safe and effective delivery of anticancer agents. To overcome this problem, stimuli-responsive smart liposomes have emerged as promising cargoes pioneered to anomalous tumor milieu in response to pH, temperature, and enzymes etc. as internal triggers, and magnetic field, ultrasound, and redox potential as external guides for enhancement of drug delivery to tumors. This review focuses on all such stimuli-responsive approaches using fabrication potentiality of liposomes in combination to various ligands, linkers, and PEGylation etc. Scientists engaged in cancer targeting approaches can get benefited greatly with this knowledgeable assemblage of advances in liposomal nanovectors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Chitosan Nanolayered Cisplatin-Loaded Lipid Nanoparticles for Enhanced Anticancer Efficacy in Cervical Cancer

NASA Astrophysics Data System (ADS)

Wang, Jing-yi; Wang, Yu; Meng, Xia

2016-11-01

In this study, cisplatin (CDDP)-loaded chitosan-coated solid lipid nanoparticles (SLN) was successfully formulated to treat HeLa cervical carcinoma. The formulation nanoparticles were nanosized and exhibited a controlled release of drug in physiological conditions. The blank nanoparticles exhibited an excellent biocompatibility profile indicating its suitability for cancer targeting. The incorporation of CDDP in SLN remarkably increased the cancer cell death as evident from the MTT assay. Importantly, CDDP-loaded chitosan-coated SLN (CChSLN) significantly ( P < 0.05) decreased the viability of cancer cells even at low concentration. The higher cytotoxicity potential of CChSLN was attributed to the higher cellular uptake as well as the sustained drug release manner in comparison with CSLN. Consistent with the cytotoxicity assay, CChSLN showed the lowest IC50 value of 0.6125 μg/ml while CSLN presented 1.156 μg/ml. CChSLN showed a significantly higher apoptosis in cancer cells compared to that of CSLN and CDDP, which is attributed to the better internalization of nanocarriers and controlled release of anticancer drugs in the intracellular environment. Our findings suggest that this new formulation could be a promising alternative for the treatment of cervical cancers. These findings are encouraging us to continue our research, with a more extended investigation of cellular response in real time and in animal models.

Arginine-Modified Nanostructured Lipid Carriers with Charge-Reversal and pH-Sensitive Membranolytic Properties for Anticancer Drug Delivery.

PubMed

Sun, Minjie; Li, Jing; Zhang, Cuiting; Xie, Ying; Qiao, Hongzhi; Su, Zhigui; Oupický, David; Ping, Qineng

2017-04-01

The ability to escape endo/lysosomal trafficking is critically important to prevent entrapment of nanomedicines in lysosomes and to achieve maximum therapeutic efficacy of drugs delivered to cells through endocytosis. In this study, a novel pH-sensitive chitosan carrier with the ability to reverse its charge during endo/lysosomal trafficking is developed as a way of improving lysosomal disruption. N-Arginine-N-octyl chitosan (AOCS) is synthesized by grafting l-arginine onto carboxymethyl chitosan. The AOCS is used to modify the surface of nanostructured lipid carriers (NLC) to prepare pH-sensitive charge-reversal lysosomolytic nanocarriers (ANLC). The ANLC is loaded with 10-hydroxycamptothecin (HCPT). The results show that ANLC is able to reverse surface zeta potential from negative to positive at lysosomal pH, which contributes to improved release of encapsulated drugs into cytoplasm. The lysosomolytic capability of ANLC is confirmed by confocal microscopy and transmission electron microscopy. In vitro studies demonstrate that the anticancer activity of HCPT-loaded ANLC is improved when compared with HCPT-NLC and free HCPT. In vivo pharmacokinetics and tissue distribution analysis show improved delivery of HCPT-ANLC to subcutaneous Heps mouse liver tumors and greatly improved antitumor activity. The results present ANLC as a promising drug delivery carrier for improved antitumor therapy. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Traditional Uses, Pharmacological Efficacy, and Phytochemistry of Moringa peregrina (Forssk.) Fiori. —A Review

PubMed Central

Senthilkumar, Annadurai; Karuvantevida, Noushad; Rastrelli, Luca; Kurup, Shyam S.; Cheruth, Abdul J.

2018-01-01

Moringa is a sole genus of Moringaceae family with 13 species distributed in the tropical and sub-tropical regions. Among them, Moringa peregrina is one of the species which has wide range of traditional, nutritional, industrial, and medicinal values. The plant parts are used in folk medicine for many human health care purposes including diabetes, wound healing, disinfectant, fever, constipation, muscle pains, slimness, burns, labor pain, hypertension, malaria, stomach disorder, asthma, skin problems, and to expel a retained placenta. In addition to medicinal value, M. peregrina has cultural, spiritual, and religious connections with the native people of Arabian Peninsula. M. peregrina plant parts were tested for many pharmacological activities viz, antioxidant, anti-microbial, anti-diabetic, anti-spasmodic, hypertension, hepatotoxicity, lipid lowering activity, anti-inflammatory, anti-cancer, and memory disorders. Few active molecules belong to the class isothiocyanate, flavonoid, triterpenoid, phytosterol, polyphenol, and glycoside were also isolated, identified and reported for anti-microbial, anti-oxidant, anthelmintic, anti-mutagenic, neuroprotective, anti-cancer, anti-hypertensive, anti-diabetic, anti-infective, anti-allergic, anti-inflammatory, herbicidal, lipid lowering potential, anti-trypanosomal, and cytotoxic activities. So, the aim of the present review is to provide comprehensive information from recognized sources on the traditional uses, pharmacological efficacy and phytochemistry of the desert medicinal plant, M. peregrina. The information provided in this review will be very useful for further studies to develop novel therapeutic drugs. PMID:29867473

Traditional Uses, Pharmacological Efficacy, and Phytochemistry of Moringa peregrina (Forssk.) Fiori. -A Review.

PubMed

Senthilkumar, Annadurai; Karuvantevida, Noushad; Rastrelli, Luca; Kurup, Shyam S; Cheruth, Abdul J

2018-01-01

Moringa is a sole genus of Moringaceae family with 13 species distributed in the tropical and sub-tropical regions. Among them, Moringa peregrina is one of the species which has wide range of traditional, nutritional, industrial, and medicinal values. The plant parts are used in folk medicine for many human health care purposes including diabetes, wound healing, disinfectant, fever, constipation, muscle pains, slimness, burns, labor pain, hypertension, malaria, stomach disorder, asthma, skin problems, and to expel a retained placenta. In addition to medicinal value, M. peregrina has cultural, spiritual, and religious connections with the native people of Arabian Peninsula. M. peregrina plant parts were tested for many pharmacological activities viz , antioxidant, anti-microbial, anti-diabetic, anti-spasmodic, hypertension, hepatotoxicity, lipid lowering activity, anti-inflammatory, anti-cancer, and memory disorders. Few active molecules belong to the class isothiocyanate, flavonoid, triterpenoid, phytosterol, polyphenol, and glycoside were also isolated, identified and reported for anti-microbial, anti-oxidant, anthelmintic, anti-mutagenic, neuroprotective, anti-cancer, anti-hypertensive, anti-diabetic, anti-infective, anti-allergic, anti-inflammatory, herbicidal, lipid lowering potential, anti-trypanosomal, and cytotoxic activities. So, the aim of the present review is to provide comprehensive information from recognized sources on the traditional uses, pharmacological efficacy and phytochemistry of the desert medicinal plant, M. peregrina . The information provided in this review will be very useful for further studies to develop novel therapeutic drugs.

Anticancer mechanisms and clinical application of alkylphospholipids.

PubMed

van Blitterswijk, Wim J; Verheij, Marcel

2013-03-01

Synthetic alkylphospholipids (ALPs), such as edelfosine, miltefosine, perifosine, erucylphosphocholine and erufosine, represent a relatively new class of structurally related antitumor agents that act on cell membranes rather than on DNA. They selectively target proliferating (tumor) cells, inducing growth arrest and apoptosis, and are potent sensitizers of conventional chemo- and radiotherapy. ALPs easily insert in the outer leaflet of the plasma membrane and cross the membrane via an ATP-dependent CDC50a-containing 'flippase' complex (in carcinoma cells), or are internalized by lipid raft-dependent endocytosis (in lymphoma/leukemic cells). ALPs resist catabolic degradation, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. At the same time, stress pathways (e.g. stress-activated protein kinase/JNK) are activated to promote apoptosis. In many preclinical and clinical studies, perifosine was the most effective ALP, mainly because it inhibits Akt activity potently and consistently, also in vivo. This property is successfully exploited clinically in highly malignant tumors, such as multiple myeloma and neuroblastoma, in which a tyrosine kinase receptor/Akt pathway is amplified. In such cases, perifosine therapy is most effective in combination with conventional anticancer regimens or with rapamycin-type mTOR inhibitors, and may overcome resistance to these agents. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. Copyright © 2012 Elsevier B.V. All rights reserved.

pH-Triggered Echogenicity and Contents Release from Liposomes

PubMed Central

2015-01-01

Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%). PMID:25271780

pH-triggered echogenicity and contents release from liposomes.

PubMed

Nahire, Rahul; Hossain, Rayat; Patel, Rupa; Paul, Shirshendu; Meghnani, Varsha; Ambre, Avinash H; Gange, Kara N; Katti, Kalpana S; Leclerc, Estelle; Srivastava, D K; Sarkar, Kausik; Mallik, Sanku

2014-11-03

Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%).

Determination of the acid value of instant noodles: interlaboratory study.

PubMed

Hakoda, Akiko; Sakaida, Kenichi; Suzuki, Tadanao; Yasui, Akemi

2006-01-01

An interlaboratory study was performed to evaluate the method for determining the acid value of instant noodles, based on the Japanese Agricultural Standard (JAS), with extraction of lipid using petroleum ether at a volume of 100 mL to the test portion of 25 g. Thirteen laboratories participated and analyzed 5 test samples as blind duplicates. Statistical treatment revealed that the repeatability (RSDr) of acid value was <6.5%, and the reproducibility (RSDR) of acid value was <9.6%. The HorRat values (RSDR/predicted RSDR) were 1.2-1.8, where the RSDR and the predicted RSDR were obtained in terms of free fatty acids in the noodles per unit weight, using the equation [acid value = percent free fatty acids (as oleic) x 1.99] and the extracted lipid contents. This method was shown to have acceptable precision by the present study.

Nanostructured lipid dispersions for topical administration of crocin, a potent antioxidant from saffron (Crocus sativus L.).

PubMed

Esposito, Elisabetta; Drechsler, Markus; Mariani, Paolo; Panico, Anna Maria; Cardile, Venera; Crascì, Lucia; Carducci, Federica; Graziano, Adriana Carol Eleonora; Cortesi, Rita; Puglia, Carmelo

2017-02-01

Crocin, a potent antioxidant obtained from saffron, shows anticancer activity in in vivo models. Unfortunately unfavorable physicochemical features compromise its use in topical therapy. The present study describes the preparation and characterization of nanostructured lipid dispersions as drug delivery systems for topical administration of crocin and the evaluation of antioxidant and antiproliferative effects of crocin once encapsulated into nanostructured lipid dispersions. Nanostructured lipid dispersions based on monoolein in mixture with sodium cholate and sodium caseinate have been characterized by cryo-TEM and PCS. Crocin permeation was evaluated in vitro by Franz cells, while the oxygen radical absorbance capacity assay was used to evaluate the antioxidant activity. Furthermore, the antiproliferative activity was tested in vitro by the MTT test using a human melanoma cell line. The emulsification of monoolein with sodium cholate and sodium caseinate led to dispersions of cubosomes, hexasomes, sponge systems and vesicles, depending on the employed emulsifiers. Permeation and shelf life studies demonstrated that nanostructured lipid dispersions enabled to control both rate of crocin diffusion through the skin and crocin degradation. The oxygen radical absorbance capacity assay pointed out an interesting and prolonged antioxidant activity of crocin while the MTT test showed an increase of crocin cytotoxic effect after incorporation in nanostructured lipid dispersions. This work has highlighted that nanostructured lipid dispersions can protect the labile molecule crocin from degradation, control its skin diffusion and prolong antioxidant activity, therefore suggesting the suitability of nanostructured lipid dispersions for crocin topical administration. Copyright © 2016 Elsevier B.V. All rights reserved.

Nonelectrolyte diffusion across lipid bilayer systems

PubMed Central

1976-01-01

The permeability coefficients of a homologous series of amides from formamide through valeramide have been measured in spherical bilayers prepared by the method described by Jung. They do not depend directly on the water:ether partition coefficient which increases regularly with chain length. Instead there is a minimum at acetamide. This has been ascribed to the effect of steric hindrance on diffusion within the bilayer which increases with solute molar volume. This factor is of the same magnitude, though opposite in sign to the effect of lipid solubility, thus accounting for the minimum. The resistance to passage across the interface has been compared to the resistance to diffusion within the membrane. As the solute chain length increases the interface becomes more important, until for valeramide it comprises about 90% of the total resistance. Interface resistance is also important in urea permeation, causing urea to permeate much more slowly than an amide of comparable size, after allowance is made for the difference in the water:ether partition coefficient. Amide permeation coefficients have been compared with relative liposome permeation data measured by the rate of liposome swelling. The ratios of the two measures of permeation vary between 3 and 16 for the homologous amides. The apparent enthalpy of liposome permeation has been measured and found to be in the neighborhood of 12 kcal mol-1 essentially independent of chain length. Comparison of the bilayer permeability coefficients with those of red cells shows that red cell permeation by the lipophilic solutes resembles that of the bilayers, whereas permeation by the hydrophilic solutes differs significantly. PMID:1245835

Kinetic characterization of Escherichia coli outer membrane phospholipase A using mixed detergent-lipid micelles.

PubMed

Horrevoets, A J; Hackeng, T M; Verheij, H M; Dijkman, R; de Haas, G H

1989-02-07

The substrate specificity of Escherichia coli outer membrane phospholipase A was analyzed in mixed micelles of lipid with deoxycholate or Triton X-100. Diglycerides, monoglycerides, and Tweens 40 and 85 in Triton X-100 are hydrolyzed at rates comparable to those of phospholipids and lysophospholipids. p-Nitrophenyl esters of fatty acids with different chain lengths and triglycerides are not hydrolyzed. The minimal substrate characteristics consist of a long acyl chain esterified to a more or less hydrophilic headgroup as is the case for the substrate monopalmitoylglycol. Binding occurs via the hydrocarbon chain of the substrate; diacyl compounds are bound three to five times better than monoacyl compounds. When acting on lecithins, phospholipase A1 activity is six times higher than phospholipase A2 activity or 1-acyl lysophospholipase activity. Activity on the 2-acyl lyso compound is about two times less than that on the 1-acyl lysophospholipid. The enzyme therefore has a clear preference for the primary ester bond of phospholipids. In contrast to phospholipase A1 activity, phospholipase A2 activity is stereospecific. Only the L isomer of a lecithin analogue in which the primary acyl chain was replaced by an alkyl ether group is hydrolyzed. The D isomer of this analogue is a competitive inhibitor, bound with the same affinity as the L isomer. On these ether analogues the enzyme shows the same preference for the primary acyl chain as with the natural diester phospholipids. Despite its broad specificity, the enzyme will initially act as a phospholipase A1 in the E. coli envelope where it is embedded in phospholipids.

Phospatidylserine or ganglioside--which of anionic lipids determines the effect of cationic dextran on lipid membrane?

PubMed

Hąc-Wydro, Katarzyna; Wydro, Paweł; Cetnar, Andrzej; Włodarczyk, Grzegorz

2015-02-01

In this work the influence of cationic polymer, namely diethylaminoethyl DEAE-dextran on model lipid membranes was investigated. This polymer is of a wide application as a biomaterial and a drug carrier and its cytotoxicity toward various cancer cells was also confirmed. It was suggested that anticancer effect of cationic dextran is connected with the binding of the polymer to the negatively charged sialic acid residues overexpressed in cancer membrane. This fact encouraged us to perform the studies aimed at verifying whether the effect of cationic DEAE-dextran on membrane is determined only by the presence of the negatively charged lipid in the system or the kind of anionic lipid is also important. To reach this goal systematic investigations on the effect of dextran on various one-component lipid monolayers and multicomponent hepatoma cell model membranes differing in the level and the kind of anionic lipids (phosphatidylserine, sialic acid-containing ganglioside GM3 or their mixture) were done. As evidenced the results the effect of DEAE-dextran on the model system is determined by anionic lipid-polymer electrostatic interactions. However, the magnitude of the effect of cationic polymer is strongly dependent on the kind of anionic lipid in the model system. Namely, the packing and ordering of the mixtures containing ganglioside GM3 were more affected by DEAE-dextran than phosphatidylserine-containing monolayers. Although the experiments were done on model systems and therefore further studies are highly needed, the collected data may indicate that ganglioside may be important in the differentiation of the effect of cationic dextran on membranes. Copyright © 2014 Elsevier B.V. All rights reserved.

Physicochemical properties of liposomes as potential anticancer drugs carriers. Interaction of etoposide and cytarabine with the membrane: Spectroscopic studies

NASA Astrophysics Data System (ADS)

Pentak, Danuta

2014-03-01

The interactions between etoposide, cytarabine and 1,2-dihexadecanoyl-sn-glycerol-3-phosphocholine bilayers were studied using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR). These techniques have proven to be a very powerful tool in studying the structure and dynamics of phospholipid bilayers. In particular, DSC can provide information on the phase transition temperature and cooperativity of the lipid molecules in the absence and presence of the drug. Vibrational spectroscopy is well suited to the study of drug-lipid interactions, since it allows for an investigation of the conformation of phospholipid molecules at different levels in lipid bilayers and follows structural changes that occur during the gel to liquid-crystalline phase transition. NMR supported the determination of the main phase transition temperatures (TC) of 1,2-dihexadecanoyl-sn-glycerol-3-phosphocholine (DPPC). The main phase transition temperature (TC) determined by 1H NMR is comparable with values obtained by DSC for all studied liposomes. The location of cytarabine and etoposide in liposomes was also determined by NMR. Atomic force microscopy (AFM) images, acquired immediately after sample deposition on a mica surface, revealed the spherical shape of lipid vesicles.

Plastids of Marine Phytoplankton Produce Bioactive Pigments and Lipids

PubMed Central

Heydarizadeh, Parisa; Poirier, Isabelle; Loizeau, Damien; Ulmann, Lionel; Mimouni, Virginie; Schoefs, Benoît; Bertrand, Martine

2013-01-01

Phytoplankton is acknowledged to be a very diverse source of bioactive molecules. These compounds play physiological roles that allow cells to deal with changes of the environmental constrains. For example, the diversity of light harvesting pigments allows efficient photosynthesis at different depths in the seawater column. Identically, lipid composition of cell membranes can vary according to environmental factors. This, together with the heterogenous evolutionary origin of taxa, makes the chemical diversity of phytoplankton compounds much larger than in terrestrial plants. This contribution is dedicated to pigments and lipids synthesized within or from plastids/photosynthetic membranes. It starts with a short review of cyanobacteria and microalgae phylogeny. Then the bioactivity of pigments and lipids (anti-oxidant, anti-inflammatory, anti-mutagenic, anti-cancer, anti-obesity, anti-allergic activities, and cardio- neuro-, hepato- and photoprotective effects), alone or in combination, is detailed. To increase the cellular production of bioactive compounds, specific culture conditions may be applied (e.g., high light intensity, nitrogen starvation). Regardless of the progress made in blue biotechnologies, the production of bioactive compounds is still limited. However, some examples of large scale production are given, and perspectives are suggested in the final section. PMID:24022731

Synthesis, spectroscopic, thermogravimetric and antimicrobial studies of mixed ligands complexes

NASA Astrophysics Data System (ADS)

Mahmoud, Walaa H.; Mahmoud, Nessma F.; Mohamed, Gehad G.; El-Sonbati, Adel Z.; El-Bindary, Ashraf A.

2015-09-01

An interesting series of mixed ligand complexes have been synthesized by the reaction of metal chloride with guaifenesin (GFS) in the presence of 2-aminoacetic acid (HGly) (1:1:1 molar ratio). The elemental analysis, magnetic moments, molar conductance, spectral (UV-Vis, IR, 1H NMR and ESR) and thermal studies were used to characterize the isolated complexes. The molecular structure of GFS is optimized theoretically and the quantum chemical parameters are calculated. The IR showed that the ligand (GFS) acts as monobasic tridentate through the hydroxyl, phenoxy etheric and methoxy oxygen atoms and co-ligand (HGly) as monobasic bidentate through the deprotonated carboxylate oxygen atom and nitrogen atom of amino group. The molar conductivities showed that all the complexes are non-electrolytes except Cr(III) complex is electrolyte. Electronic and magnetic data proposed the octahedral structure for all complexes under investigation. ESR spectrum for Cu(II) revealed data which confirm the proposed structure. Antibacterial screening of the compounds were carried out in vitro on gram positive (Bacillus subtilis and Staphylococcus aureus), gram negative (Escherichia coli and Neisseria gonorrhoeae) bacteria and for in vitro antifungal activity against Candida albicans organism. However, some complexes showed more chemotherapeutic efficiency than the parent GFS drug. The complexes were also screened for their in vitro anticancer activity against the breast cell line (MFC7) and the results obtained showed that they exhibit a considerable anticancer activity.

Cytotoxic potential of few Indian fruit peels through 3-(4,5-dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide assay on HepG2 cells

PubMed Central

Garg, Munish; Lata, Kusum; Satija, Saurabh

2016-01-01

Objective: To investigate in vitro anticancer activity of a few Indian fruit peels through 3-(4,5-dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against HepG2 cells. Materials and Methods: Hydroalcoholic extracts were prepared of five fruit peels, i.e., banana, lemon, guava, orange, and papaya by maceration and thereafter subjected for MTT assay to evaluate anticancer potential on HepG2 cells. Plant extract showed best activity was further fractionated with petroleum ether, chloroform, and ethyl acetate successively and screened again. Phytochemical analysis was then carried out to find out responsible components for the observed activity. Results: Out of the 40 samples from five fruit peel extracts with rich folklore usage, papaya extract showed maximum activity with least inhibitory concentration50 (IC50) value of 18.5 μg/ml. Further analysis after fractionation of the papaya peel extract, aqueous fraction showed the maximum inhibitory activity with least IC50 value of 17.3 μg/ml. Phytochemical analysis of the aqueous fraction of papaya peel extract revealed the presence of flavonoids and glycosides. Total flavonoid content found to be 72.25 mg/g. Conclusion: Papaya fruit extract demonstrated the best activity against MTT assay which may be due to the presence of flavonoids. PMID:26997725

Design and Synthesis of Archaea-Inspired Tetraether Lipids

NASA Astrophysics Data System (ADS)

Koyanagi, Takaoki

Maintaining the correct ion homeostasis across membranes is a major challenge in both nature and artificial systems. Archaea, have evolved to solve membrane permeability problems to survive in extreme environments by incorporating unique structural features found in their lipid. Specifically, inclusion of phytanyl side chains, ether glycerol linkages, tethering of lipids, cycloalkanes, and different polar lipid headgroups into their lipid membrane are believed to contribute to membrane stability. We sought to gain a better understanding of the functional benefits attributed to these structural features to membrane stability to design a new class of synthetic Archaea inspired lipid membranes that can be used to overcome limitations (i.e. unstable in serum environment, high background leakage, and prone to hydrolysis) found in current lipid based technologies. Leakage experiments revealed liposomes made from GMGTPC (glycerol monoalkyl glycerol tetraether lipid with phosphatidylcholine headgroup) demonstrated a two order magnitude reduction in membrane leakage to small ions when compared with liposomes made from EggPC. Additionally, liposomes composed of GMGTPC-CH (cyclohexane integrated) lipid displayed an additional 40% decrease in membrane leakage to small ions when compared with liposomes made from GMGTPC lipids. Furthermore, leakage experiments revealed a higher degree of tolerance to headgroup modifications to membrane leakage for liposomes made from GMGT lipid analogs when compared with liposomes made from POPC. After designing an optimal tetraether lipid scaffold that incorporates key Archaeal structural features for membrane leakage, we explored to integrate strategies employed by eukaryotes to improve membrane properties (i.e. addition of cholesterol). Liposomes made from the hybrid lipid, GcGTPC-CH, displayed a five-fold decrease in membrane leakage when compared with liposomes made from GMGTPC-CH, while maintaining functional membrane properties similar to membranes made from diacyl lipids. Lastly, we engineered a thiol responsive hybrid lipid, GcGT(S-S)PC-CH, that demonstrated similar membrane stability in serum as GcGTPC-CH. Gratifyingly, doxorubicin loaded liposomes composed of GcGT(S-S)PC-CH liposomes displayed a 4 or 20-fold increase in toxicity to HeLa cells when compared with liposomes made from GcGTPC-CH or Doxil, respectively. This work represents a first step towards development of stimuli-responsive tetraether lipids that may offer advantages in membrane properties to be used in cancer therapy.

Synthetic lipoprotein as nano-material vehicle in the targeted drug delivery.

PubMed

Zhang, Xueqin; Huang, Gangliang

2017-12-01

High-density lipoprotein (HDL) and low-density lipoprotein (LDL), as human endogenous lipoprotein particles, have low toxicity, high selectivity, and good safety. They can avoid the recognition and clearance of human reticuloendothelial system. These synthetic lipoproteins (sLPs) have been attracted extensive attention as the nanovectors for tumor-targeted drug and gene delivery. Herein, recent advances in the field of anticancer based on these two lipid proteins and recombinant lipoproteins (rLPs) as target delivery vectors were analyzed and discussed.

Systematic profiling and comparison of the lipidomes from Panax ginseng, P. quinquefolius, and P. notoginseng by ultrahigh performance supercritical fluid chromatography/high-resolution mass spectrometry and ion mobility-derived collision cross section measurement.

PubMed

Shi, Xiaojian; Yang, Wenzhi; Qiu, Shi; Hou, Jinjun; Wu, Wanying; Guo, Dean

2018-05-04

Lipidomics currently is still confronted with challenges from chromatographic separation and lipids identification. Here we report a lipidomics platform by integrating ultrahigh performance supercritical fluid chromatography/quadrupole time-of-flight mass spectrometry (UHPSFC/QTOF-MS) and collision cross section (CCS) measurement using ion mobility spectroscopy/time-of-flight mass spectrometry (IMS/QTOF-MS), aiming to enhance the profiling performance and identification reliability of lipids. The lipidomes extracted from three congeneric Panax species (P. ginseng, P. quinquefolius, and P. notoginseng) by methyl tert-butyl ether are comprehensively profiled and compared by use of this platform. A potent UHPSFC/QTOF-MS approach was developed on a 1.7-μm particles packed Torus 2-PIC column using CH 3 OH (in CO 2 ) as a modifier and CH 3 OH/0.2 mM ammonium acetate as the makeup liquid, enabling well resolution of six lipid subclasses by both positive and negative MS E modes. In contrast to the reversed-phase chromatography, "normal-phase" like elution order and better resolution of polar lipids and some lipid isomers were achieved by UHPSFC separation. Pattern recognition chemometric analysis of 60 batches of Ginseng samples ultimately unveiled 24 lipid markers, of which triacylglycerols were the most important. Aside from the automated MS database searching against HMDB and LIPID MAPS, the application of CCS retrieval or CCS prediction improved lipid identification by reducing the possible hits. In conclusion, this integral platform can significantly improve the chromatographic separation and the reliability of lipids identification in lipidomics studies. It is the first report that systematically compares the lipidomic difference of three reputable Panax species, providing useful information for their quality control in addition to ginsenoside analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

Dietary accumulation efficiencies and biotransformation of polybrominated diphenyl ethers in farmed Atlantic salmon (Salmo salar).

PubMed

Isosaari, P; Lundebye, A-K; Ritchie, G; Lie, O; Kiviranta, H; Vartiainen, T

2005-09-01

The consumer safety of farm-raised salmon could be improved by determining the transfer efficiency of hazardous pollutants from fish feed to the salmon. A controlled feeding trial for 30 weeks was carried out to investigate the transfer of polybrominated diphenyl ethers (PBDEs) in Atlantic salmon (Salmo salar). Using three feed concentrations, an average of 95% of the total PBDE content of feed accumulated in whole salmon. Skinned fillet accumulated 42-59% of the PBDE intake. Equal partitioning according to the lipid content of the tissue was demonstrated. The formation of less brominated PBDEs via preferential debromination from the meta-position was thought to explain the exceptional accumulation efficiencies of BDE 47, BDE 66, BDE 75, BDE 119 and BDE 183 that were either >100% or else increasing with the exposure dose. Monitoring of a larger number of PBDE congeners is recommended to verify the biotransformation routes. The PBDE concentration in salmon of different ages, fed on a known concentration of PBDEs in fish feed, could be predicted by using the accumulation efficiencies determined in this study.

Induction of Adipocyte Differentiation by Polybrominated Diphenyl Ethers (PBDEs) in 3T3-L1 Cells

PubMed Central

Tung, Emily W. Y.; Boudreau, Adèle; Wade, Michael G.; Atlas, Ella

2014-01-01

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants that were extensively used in commercial products. PBDEs are ubiquitous environmental contaminants that are both lipophilic and bioaccumulative. Effects of PBDEs on adipogenesis were studied in the 3T3-L1 preadipocyte cell model in the presence and absence of a known adipogenic agent, dexamethasone (DEX). A PBDE mixture designed to mimic body burden of North Americans was tested, in addition to the technical mixture DE-71 and the individual congener BDE-47. The mixture, DE-71, and BDE-47 all induced adipocyte differentiation as assessed by markers for terminal differentiation [fatty acid binding protein 4 (aP2) and perilipin] and lipid accumulation. Characterization of the differentiation process in response to PBDEs indicated that adipogenesis induced by a minimally effective dose of DEX was enhanced by these PBDEs. Moreover, C/EBPα, PPARγ, and LXRα were induced late in the differentiation process. Taken together, these data indicate that adipocyte differentiation is induced by PBDEs; they act in the absence of glucocorticoid and enhance glucocorticoid-mediated adipogenesis. PMID:24722056

Hepatoprotective activity of Trichilia roka on carbon tetrachloride-induced liver damage in rats.

PubMed

Germanò, M P; D'Angelo, V; Sanogo, R; Morabito, A; Pergolizzi, S; De Pasquale, R

2001-11-01

Trichilia roka Chiov. (Meliaceae) is a tree widely distributed in tropical Africa. It has been used in Mali folk medicine for the treatment of various illnesses. A decoction of the roots is taken as a remedy for colds and pneumonia, and it is used as a diuretic and in hepatic disorders. We have evaluated the hepatoprotective effects of a decoction of Trichilia roka root on CCl4-induced acute liver damage in rats. Treatment with the decoction showed a significant protective action made evident by its effect on the levels of glutamate oxalacetate transaminase and glutamate pyruvate transaminase in the serum, on the protein content and lipid peroxidation levels in the liver homogenate. Histopathological changes produced by CCl4, such as necrosis, fatty change, ballooning degeneration and inflammatory infiltration of lymphocytes around the central veins, were clearly recovered by the treatment with Trichilia root decoction. On fractionating this extract into diethyl ether-soluble and water-soluble fractions, the activity was retained in the diethyl ether-soluble fraction. Moreover, the administration of decoction prevented a preferential deposition of collagen around the sinusoidal cell layer, which is responsible for the perisinusoidal fibrosis in the early stage of CCl4 damage. This study showed that treatment with Trichilia roka extracts or silymarin (as reference) appeared to enhance the recovery from CCl4-induced hepatotoxicity. The hepatoprotective properties of Trichilia roka may be correlated to polyphenol content of the decoction and its diethyl ether-soluble fraction.

Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis.

PubMed

Knudson, Susan E; Cummings, Jason E; Bommineni, Gopal R; Pan, Pan; Tonge, Peter J; Slayden, Richard A

2016-12-01

Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log 10  CFU reduction in the spleen of animals co-treated with SB-PT091 and RIF and an additional 1.7 log 10 reduction in the spleen with animals treated with both SB-PT070 and RIF. Copyright © 2016 Elsevier Ltd. All rights reserved.

Anticancer Properties of PPARα-Effects on Cellular Metabolism and Inflammation

PubMed Central

Grabacka, Maja; Reiss, Krzysztof

2008-01-01

Peroxisome proliferator-activated receptors (PPARs) have lately attracted much attention as therapeutic targets. Previously, PPAR ligands were associated with the treatment of diabetes, hyperlipidemia and cardiovascular diseases, as they modulate the expression of genes regulating glucose and lipid metabolism. Recently, PPAR ligands have been also considered as potential anticancer agents, with relatively low systemic toxicity. The emerging evidence for antiproliferative, proapoptotic, antiinflammatory and potential antimetastatic properties of PPARα ligands prompted us to discuss possible roles of PPARα in tumor suppression. PPARα activation can target cancer cells energy balance by blocking fatty acid synthesis and by promoting fatty acid β-oxidation. In the state of limited nutrient availability, frequently presents in the tumor microenvironment, PPARα cooperates with AMP-dependent protein kinase in: (i) repressing oncogenic Akt activity, (ii) inhibiting cell proliferation, and (iii) forcing glycolysis-dependent cancer cells into “metabolic catastrophe.” Other potential anticancer effects of PPARα include suppression of inflammation, and upregulation of uncoupling proteins (UCPs), which attenuates mitochondrial reactive oxygen species production and cell proliferation. In conclusion, there are strong premises that the low-toxic and well-tolerated PPAR ligands should be considered as new therapeutic agents to fight disseminating cancer, which represents the major challenge for modern medicine and basic research. PMID:18509489

Progress in nanotechnology-based drug carrier in designing of curcumin nanomedicines for cancer therapy: current state-of-the-art.

PubMed

Ahmad, Mohammad Zaki; Alkahtani, Saad Ahmed; Akhter, Sohail; Ahmad, Farhan Jalees; Ahmad, Javed; Akhtar, Mohammad Shabib; Mohsin, Nehal; Abdel-Wahab, Basel A

2016-01-01

Comprehensive pharmacological screening of curcumin (CUR) has given the evidence that it is an excellent naturally occurring therapeutic moiety for cancer. It is very well tolerated with insignificant toxicity even after high doses of oral administration. Irrespective of its better quality as an anticancer agent, therapeutic application of CUR is hampered by its extremely low-aqueous solubility and poor bioavailability, rapid clearance and low-cellular uptake. A simple means of breaking up the restrictive factor of CUR is to perk-up its aqueous solubility, improve its bioavailability, protect it from degradation, and metabolism and potentiate its targeting capacity towards the cancer cell. The development in the field of nanomedicine has made excellent progresses toward enhancing the bioavailability of lipophilic drugs like CUR. Nanoparticles (NPs) are capable to deliver the CUR at specific area and thereby prevent it from physiological degradation and systemic clearance. In recent year, an assortment of nanomedicine-based novel drug delivery system has been designed to potentiate the bioavailability of CUR towards anticancer therapy. In this review, we discuss the recent development in the field of nanoCUR (NanoCur), including polymeric micelles, liposome, polymeric NPs, nanoemulsion, nanosuspension, solid lipid NPs (SLNPs), polymer conjugates, nanogel, etc. in anticancer application.

Implication of STARD5 and cholesterol homeostasis disturbance in the endoplasmic reticulum stress-related response induced by pro-apoptotic aminosteroid RM-133.

PubMed

Perreault, Martin; Maltais, René; Kenmogne, Lucie Carolle; Létourneau, Danny; LeHoux, Jean-Guy; Gobeil, Stéphane; Poirier, Donald

2018-02-01

The aminosteroid derivative RM-133 is an effective anticancer molecule for which proof of concept has been achieved in several mouse xenograph models (HL-60, MCF-7, PANC-1 and OVCAR-3). To promote this new family of molecules toward a clinical phase 1 trial, the mechanism of action governing the anticancer properties of the representative candidate RM-133 needs to be characterized. In vitro experiments were first used to determine that RM-133 causes apoptosis in cancer cells. Then, using proteomic and transcriptomic experiments, RM-133 cytotoxicity was proven to be achieved via the endoplasmic reticulum (ER)-related apoptosis, which characterizes RM-133 as an endoplasmic reticulum stress aggravator (ERSA) anticancer drug. Furthermore, an shRNA-genome-wide screening has permitted to identify the steroidogenic acute regulator-related lipid transfer protein 5 (STARD5) as a major player in the RM-133 ER-related apoptosis mechanism, which was validated by an in vitro binding experiment. Altogether, the results presented herein suggest that RM-133 provokes a disturbance of cholesterol homeostasis via the implication of STARD5, which delivers an ERSA molecule to the ER. These results will be a springboard for RM-133 in its path toward clinical use. Copyright © 2017 Elsevier Ltd. All rights reserved.

Binding, folding and insertion of a β-hairpin peptide at a lipid bilayer surface: Influence of electrostatics and lipid tail packing.

PubMed

Reid, Keon A; Davis, Caitlin M; Dyer, R Brian; Kindt, James T

2018-03-01

Antimicrobial peptides (AMPs) act as host defenses against microbial pathogens. Here we investigate the interactions of SVS-1 (KVKVKVKV d P l PTKVKVKVK), an engineered AMP and anti-cancer β-hairpin peptide, with lipid bilayers using spectroscopic studies and atomistic molecular dynamics simulations. In agreement with literature reports, simulation and experiment show preferential binding of SVS-1 peptides to anionic over neutral bilayers. Fluorescence and circular dichroism studies of a Trp-substituted SVS-1 analogue indicate, however, that it will bind to a zwitterionic DPPC bilayer under high-curvature conditions and folds into a hairpin. In bilayers formed from a 1:1 mixture of DPPC and anionic DPPG lipids, curvature and lipid fluidity are also observed to promote deeper insertion of the fluorescent peptide. Simulations using the CHARMM C36m force field offer complementary insight into timescales and mechanisms of folding and insertion. SVS-1 simulated at an anionic mixed POPC/POPG bilayer folded into a hairpin over a microsecond, the final stage in folding coinciding with the establishment of contact between the peptide's valine sidechains and the lipid tails through a "flip and dip" mechanism. Partial, transient folding and superficial bilayer contact are seen in simulation of the peptide at a zwitterionic POPC bilayer. Only when external surface tension is applied does the peptide establish lasting contact with the POPC bilayer. Our findings reveal the influence of disruption to lipid headgroup packing (via curvature or surface tension) on the pathway of binding and insertion, highlighting the collaborative effort of electrostatic and hydrophobic interactions on interaction of SVS-1 with lipid bilayers. Copyright © 2017 Elsevier B.V. All rights reserved.

Changes in patterns of persistent halogenated compounds through a pelagic food web in the Baltic Sea.

PubMed

Stephansen, Diana A; Svendsen, Tore C; Vorkamp, Katrin; Frier, Jens-Ole

2012-02-01

The concentrations and patterns of persistent halogenated compounds (PHCs), including polychlorinated biphenyls (PCBs), DDT, hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB) and polybrominated diphenyl ethers (PBDEs) were examined in a pelagic food web from the southern Baltic Sea consisting of sediment, zooplankton, sprat, Atlantic salmon and anadromous brown trout. Lipid-normalized concentrations generally increased from low trophic levels to high trophic levels, with the exception of HCHs. Due to high concentrations of PBDEs in some zooplankton samples, biomagnification of BDE-47 was only observed for salmon/sprat and trout/sprat. Sprat collected individually and from salmon stomach had significantly different lipid-normalized concentrations and varied in their PHC pattern as well, possibly indicating a large natural variation within the Baltic Sea. The highest lipid-normalized concentrations were found in brown trout. Salmon and brown trout were similar in their PHC pattern suggesting similar food sources. Variation in PHC patterns among trophic levels was not smaller than that among geographically distinct locations, confirming the importance of comparable trophic levels for the assessment of PHC patterns, e.g. for tracing migratory fish. Copyright © 2011 Elsevier Ltd. All rights reserved.

Delivering anti-cancer drugs with endosomal pH-sensitive anti-cancer liposomes.

PubMed

Moku, Gopikrishna; Gulla, Suresh Kumar; Nimmu, Narendra Varma; Khalid, Sara; Chaudhuri, Arabinda

2016-04-01

Numerous prior studies have been reported on the use of pH-sensitive drug carriers such as micelles, liposomes, peptides, polymers, nanoparticles, etc. that are sensitive to the acidic (pH = ∼6.5) microenvironments of tumor tissues. Such systems have been primarily used in the past as effective drug/gene/microRNA carriers for releasing their anti-cancer payloads selectively to tumor cells/tissues. Herein, we report on the development of new liposomal drug carriers prepared from glutamic acid backbone-based cationic amphiphiles containing both endosomal pH-sensitive histidine as well as cellular uptake & solubility enhancing guanidine moieties in their polar head-group regions. The most efficient one among the four presently described endosomal pH-sensitive liposomal drug carriers not only effectively delivers potent anti-cancer drugs (curcumin & paclitaxel) to mouse tumor, but also significantly contributes to inhibiting mouse tumor growth. The findings in the in vitro mechanistic studies are consistent with apoptosis of tumor cells being mediated through increased cell cycle arrest in the G2/M phase. Findings in the FRET assay and in vitro drug release studies conducted with the liposomes of the most efficient pH-sensitive lipid demonstrated its pH dependent fusogenic and controlled curcumin release properties. Importantly, the presently described liposomal formulation of curcumin & paclitaxel enhanced overall survivability of tumor bearing mice. To the best of our knowledge, the presently described system (curcumin, paclitaxel and liposomal carrier itself) is the first of its kind pH-sensitive liposomal formulation of potent chemotherapeutics in which the liposomal drug itself exhibits significant mouse tumor growth inhibition properties.

Neutron scattering shows a droplet of oleic acid at the center of the BAMLET complex.

PubMed

Rath, Emma M; Duff, Anthony P; Gilbert, Elliot P; Doherty, Greg; Knott, Robert B; Church, W Bret

2017-07-01

The anti-cancer complex, Bovine Alpha-lactalbumin Made LEthal to Tumors (BAMLET), has intriguing broad-spectrum anti-cancer activity. Although aspects of BAMLET's anti-cancer mechanism are still not known, it is understood that it involves the oleic acid or oleate component of BAMLET being preferentially released into cancer cell membranes leading to increased membrane permeability and lysis. The structure of the protein component of BAMLET has previously been elucidated by small angle X-ray scattering (SAXS) to be partially unfolded and dramatically enlarged. However, the structure of the oleic acid component of BAMLET and its disposition with respect to the protein component was not revealed as oleic acid has the same X-ray scattering length density (SLD) as water. Employing the difference in the neutron SLDs of hydrogen and deuterium, we carried out solvent contrast variation small angle neutron scattering (SANS) experiments of hydrogenated BAMLET in deuterated water buffers, to reveal the size, shape, and disposition of the oleic acid component of BAMLET. Our resulting analysis and models generated from SANS and SAXS data indicate that oleic acid forms a spherical droplet of oil incompletely encapsulated by the partially unfolded protein component. This model provides insight into the anti-cancer mechanism of this cache of lipid. The model also reveals a protein component "tail" not associated with the oleic acid component that is able to interact with the tail of other BAMLET molecules, providing a plausible explanation of how BAMLET readily forms aggregates. Proteins 2017; 85:1371-1378. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Vitamin C-driven epirubicin loading into liposomes.

PubMed

Lipka, Dominik; Gubernator, Jerzy; Filipczak, Nina; Barnert, Sabine; Süss, Regine; Legut, Mateusz; Kozubek, Arkadiusz

2013-01-01

The encapsulation of anticancer drugs in a liposome structure protects the drug during circulation and increases drug accumulation in the cancer tissue and antitumor activity while decreasing drug toxicity. This paper presents a new method of active drug loading based on a vitamin C pH/ion gradient. Formulations were characterized in terms of the following parameters: optimal external pH, time and drug-to-lipid ratio for the purpose of remote loading, and in vitro stability. In the case of the selected drug, epirubicin (EPI), its coencapsulation increases its anticancer activity through a possibly synergistic effect previously reported by other groups for a free nonencapsulated drug/vitamin C cocktail. The method also has another advantage over other remote-loading methods: it allows faster drug release through liposome destabilization at the tumor site, thanks to the very good solubility of the EPI vitamin C salt, as seen on cryogenic transmission electron microscopy images. This influences the drug-release process and increases the anticancer activity of the liposome formulation. The liposomes are characterized as stable, with very good pharmacokinetics (half-life 18.6 hours). The antitumor activity toward MCF-7 and 4T-1 breast cancer cells was higher in the case of EPI loaded via our gradient than via an ammonium sulfate gradient. Finally, the EPI liposomal formulation and the free drug were tested using the murine 4T-1 breast cancer model. The antitumor activity of the encapsulated drug was confirmed (tumor-growth inhibition over 40% from day 16 until the end of the experiment), and the free drug was shown to have no anticancer activity at the tested dose.

Peroxisome Proliferator Activated Receptor A Ligands as Anticancer Drugs Targeting Mitochondrial Metabolism

PubMed Central

Grabacka, Maja; Pierzchalska, Malgorzata; Reiss, Krzysztof

2011-01-01

Tumor cells show metabolic features distinctive from normal tissues, with characteristically enhanced aerobic glycolysis, glutaminolysis and lipid synthesis. Peroxisome proliferator activated receptor α (PPAR α) is activated by nutrients (fatty acids and their derivatives) and influences these metabolic pathways acting antagonistically to oncogenic Akt and c-Myc. Therefore PPAR α can be regarded as a candidate target molecule in supplementary anticancer pharmacotherapy as well as dietary therapeutic approach. This idea is based on hitting the cancer cell metabolic weak points through PPAR α mediated stimulation of mitochondrial fatty acid oxidation and ketogenesis with simultaneous reduction of glucose and glutamine consumption. PPAR α activity is induced by fasting and its molecular consequences overlap with the effects of calorie restriction and ketogenic diet (CRKD). CRKD induces increase of NAD+/NADH ratio and drop in ATP/AMP ratio. The first one is the main stimulus for enhanced protein deacetylase SIRT1 activity; the second one activates AMP-dependent protein kinase (AMPK). Both SIRT1 and AMPK exert their major metabolic activities such as fatty acid oxidation and block of glycolysis and protein, nucleotide and fatty acid synthesis through the effector protein peroxisome proliferator activated receptor gamma 1 α coactivator (PGC-1α). PGC-1α cooperates with PPAR α and their activities might contribute to potential anticancer effects of CRKD, which were reported for various brain tumors. Therefore, PPAR α activation can engage molecular interplay among SIRT1, AMPK, and PGC-1α that provides a new, low toxicity dietary approach supplementing traditional anticancer regimen. PMID:21133850

Influence of the state of phase of lipid bilayer on the exposure of glucose residues on the surface of liposomes.

PubMed

Villalva, Denise Gradella; Giansanti, Luisa; Mauceri, Alessandro; Ceccacci, Francesca; Mancini, Giovanna

2017-11-01

The presence of carbohydrate-binding proteins (i.e. lectins) on the surface of various bacterial strains and their overexpression in some tumor tissues makes the use of glycosylated liposomes a promising approach for the specific drug delivery in antibacterial and anti-cancer therapies. However, the functionalization of liposome surface with sugar moieties by glycosylated amphiphiles does not ensure the binding of sugar-coated vesicles with lectins. In fact, the composition and properties of lipid bilayer play a pivotal role in the exposure of sugar residues and in the interaction with lectins. The influence of the length of the hydrophilic spacer that links the sugar to liposome surface and of the presence of saturated or unsaturated phospholipids in the lipid bilayer on the ability of glucosylated liposomes to interact with a model lectin, Concanavalin A, was investigated. Our results demonstrate that both the chain length and the prensece of unsaturation, parameters that strongly affect the fluidity of the lipid bilayer, affect agglutination. In particular, agglutination is favored when liposomes are in the gel phase within a defined range of temperature. Moreover, the obtained results confirm that the length of the PEG spacer, that influences both lipid organization and the exposure of sugar moieties to the bulk, plays a crucial role in liposome/lectin interaction. Copyright © 2017 Elsevier B.V. All rights reserved.

Antitumor Lipids--Structure, Functions, and Medical Applications.

PubMed

Kostadinova, Aneliya; Topouzova-Hristova, Tanya; Momchilova, Albena; Tzoneva, Rumiana; Berger, Martin R

2015-01-01

Cell proliferation and metastasis are considered hallmarks of tumor progression. Therefore, efforts have been made to develop novel anticancer drugs that inhibit both the proliferation and the motility of tumor cells. Synthetic antitumor lipids (ATLs), which are chemically divided into two main classes, comprise (i) alkylphospholipids (APLs) and (ii) alkylphosphocholines (APCs). They represent a new entity of drugs with distinct antiproliferative properties in tumor cells. These compounds do not interfere with the DNA or mitotic spindle apparatus of the cell, instead, they incorporate into cell membranes, where they accumulate and interfere with lipid metabolism and lipid-dependent signaling pathways. Recently, it has been shown that the most commonly studied APLs inhibit proliferation by inducing apoptosis in malignant cells while leaving normal cells unaffected and are potent sensitizers of conventional chemo- and radiotherapy, as well as of electrical field therapy. APLs resist catabolic degradation to a large extent, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. They are internalized in the cell membrane via raft domains and cause downstream reactions as inhibition of cell growth and migration, cell cycle arrest, actin stress fibers collapse, and apoptosis. This review summarizes the in vitro, in vivo, and clinical trials of most common ATLs and their mode of action at molecular and biochemical levels. © 2015 Elsevier Inc. All rights reserved.

Corosolic Acid Induces Non-Apoptotic Cell Death through Generation of Lipid Reactive Oxygen Species Production in Human Renal Carcinoma Caki Cells.

PubMed

Woo, Seon Min; Seo, Seung Un; Min, Kyoung-Jin; Im, Seung-Soon; Nam, Ju-Ock; Chang, Jong-Soo; Kim, Shin; Park, Jong-Wook; Kwon, Taeg Kyu

2018-04-27

Corosolic acid is one of the pentacyclic triterpenoids isolated from Lagerstroemia speciose and has been reported to exhibit anti-cancer and anti-proliferative activities in various cancer cells. In the present study, we investigated the molecular mechanisms of corosolic acid in cancer cell death. Corosolic acid induces a decrease of cell viability and an increase of cell cytotoxicity in human renal carcinoma Caki cells. Corosolic acid-induced cell death is not inhibited by apoptosis inhibitor (z-VAD-fmk, a pan-caspase inhibitor), necroptosis inhibitor (necrostatin-1), or ferroptosis inhibitors (ferrostatin-1 and deferoxamine (DFO)). Furthermore, corosolic acid significantly induces reactive oxygen species (ROS) levels, but antioxidants ( N -acetyl-l-cysteine (NAC) and trolox) do not inhibit corosolic acid-induced cell death. Interestingly, corosolic acid induces lipid oxidation, and α-tocopherol markedly prevents corosolic acid-induced lipid peroxidation and cell death. Anti-chemotherapeutic effects of α-tocopherol are dependent on inhibition of lipid oxidation rather than inhibition of ROS production. In addition, corosolic acid induces non-apoptotic cell death in other renal cancer (ACHN and A498), breast cancer (MDA-MB231), and hepatocellular carcinoma (SK-Hep1 and Huh7) cells, and α-tocopherol markedly inhibits corosolic acid-induced cell death. Therefore, our results suggest that corosolic acid induces non-apoptotic cell death in cancer cells through the increase of lipid peroxidation.

Comparative studies on the constituents, antioxidant and anticancer activities of extracts from different varieties of corn silk.

PubMed

Tian, Jingge; Chen, Haixia; Chen, Shuhan; Xing, Lisha; Wang, Yanwei; Wang, Jia

2013-10-01

The purpose of this study was to analyze the influence of varieties on the constituents, antioxidant and anticancer activities of corn silk. The contents of total phenolic and flavonoids and individual flavonoids in six corn silk varieties (Denghai6702, Delinong988, Tunyu808, Zhongdan909, Liangyu208, Jingke968) were comparatively analyzed by colourimetric methods, high performance liquid chromatography (HPLC) methods and antioxidant activities were assessed using a panel of in vitro assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity assay, the inhibitory effects on lipid peroxidation (MDA) assay and ferric reducing/antioxidant power (FRAP) assay, and the cytotoxicity against human prostatic carcinoma cells PC3 and breast carcinoma cells MDA-MB-231 and MCF7 were also evaluated. Results showed that Zhongdan909 exhibited the highest total phenolic content while Tunyu808 had the highest flavonoid content among the six species. Zhongdan909 showed the highest DPPH radical scavenging activity, the highest inhibitory effect on lipid peroxidation and the strongest cytotoxicity against breast carcinoma cells MCF7, while Tunyu808 exhibited the highest reducing power. There were good relationships between the total phenolic and flavonoid contents and antioxidant activities (r > 0.78) and the cytotoxicity against breast carcinoma cells MCF7 (r > 0.79). This study suggested that corn silk could be potentially used as a readily accessible source of natural antioxidants and formononetin was one of the main antioxidant constituents in corn silk.

Gallic acid grafting modulates the oxidative potential of ferrimagnetic bioactive glass-ceramic SC-45.

PubMed

Corazzari, Ingrid; Tomatis, Maura; Turci, Francesco; Ferraris, Sara; Bertone, Elisa; Prenesti, Enrico; Vernè, Enrica

2016-12-01

Magnetite-containing glass-ceramics are promising bio-materials for replacing bone tissue after tumour resection. Thanks to their ferrimagnetic properties, they generate heat when subjected to an alternated magnetic field. In virtue of this they can be employed for the hyperthermic treatment of cancer. Moreover, grafting anti-cancer drugs onto their surface produces specific anti-neoplastic activity in these biomaterials. Gallic acid (GA) exhibits antiproliferative activity which renders it a promising candidate for anticancer applications. In the present paper, the reactivity of ferrimagnetic glass-ceramic SC-45 grafted with GA (SC-45+GA) was studied in terms of ROS release, rupture of the C-H bond of the formate molecule and Fenton reactivity by EPR/spin trapping in acellular systems. The ability of these materials to cause lipid peroxidation was assessed by UV-vis/TBA assay employing linoleic acid as a model of membrane lipid. The results, compared to those obtained with SC-45, showed that GA grafting (i) significantly enhanced the Fenton reactivity and (ii) restored the former reactivity of SC-45 towards both the C-H bond and linoleic acid which had been completely suppressed by prolonged contact with water. Fe 2+ centres at the surface are probably implicated. GA, acting as a pro-oxidant, reduces Fe 3+ to Fe 2+ by maintaining a supply of Fe 2+ at the surface of SC-45+GA. Copyright © 2016 Elsevier B.V. All rights reserved.

Apigenin, a dietary flavonoid, induces apoptosis, DNA damage, and oxidative stress in human breast cancer MCF-7 and MDA MB-231 cells.

PubMed

Vrhovac Madunić, Ivana; Madunić, Josip; Antunović, Maja; Paradžik, Mladen; Garaj-Vrhovac, Vera; Breljak, Davorka; Marijanović, Inga; Gajski, Goran

2018-05-01

Apigenin is found in several dietary plant foods such as vegetables and fruits. To investigate potential anticancer properties of apigenin on human breast cancer, ER-positive MCF-7 and triple-negative MDA MB-231 cells were used. Moreover, toxicological safety of apigenin towards normal cells was evaluated in human lymphocytes. Cytotoxicity of apigenin towards cancer cells was evaluated by MTT assay whereas further genotoxic and oxidative stress parameters were measured by comet and lipid peroxidation assays, respectively. In order to examine the type of cell death induced by apigenin, several biomarkers were used. Toxicological safety towards normal cells was evaluated by cell viability and comet assays. After the treatment with apigenin, we observed changes in cell morphology in a dose- (10 to 100 μM) and time-dependent manner. Moreover, apigenin caused cell death in both cell lines leading to significant toxicity and dominantly to apoptosis. Furthermore, apigenin proved to be genotoxic towards the selected cancer cells with a potential to induce oxidative damage to lipids. Of great importance is that no significant cytogenotoxic effects were detected in normal cells. The observed cytogenotoxic and pro-cell death activities of apigenin coupled with its low toxicity towards normal cells indicate that this natural product could be used as a future anticancer modality. Therefore, further analysis to determine the exact mechanism of action and in vivo studies on animal models are warranted.

Trans -cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis –induced inflammation and virulence

PubMed Central

Rao, Vivek; Gao, Feng; Chen, Bing; Jacobs, William R.; Glickman, Michael S.

2006-01-01

Recent studies have shown that fine structural modifications of Mycobacterium tuberculosis cell envelope lipids mediate host cell immune activation during infection. One such alteration in lipid structure is cis-cyclopropane modification of the mycolic acids on trehalose dimycolate (TDM) mediated by proximal cyclopropane synthase of α mycolates (pcaA), a proinflammatory lipid modification during early infection. Here we examine the pathogenetic role and immunomodulatory function of mycolic acid cyclopropane stereochemistry by characterizing an M. tuberculosis cyclopropane–mycolic acid synthase 2 (cmaA2) null mutant (ΔcmaA2) that lacks trans-cyclopropanation of mycolic acids. Although titers of WT and ΔcmaA2 organisms were identical during mouse infection, ΔcmaA2 bacteria were hypervirulent while inducing larger granulomas than WT M. tuberculosis. The hypervirulence of the ΔcmaA2 strain depended on host TNF-α and IFN-γ. Loss of trans-cyclopropanation enhanced M. tuberculosis–induced macrophage inflammatory responses, a phenotype that was transferable with petroleum ether extractable lipids. Finally, purified TDM lacking trans-cyclopropane rings was 5-fold more potent in stimulating macrophages. These results establish cmaA2-dependent trans-cyclopropanation of TDM as a suppressor of M. tuberculosis–induced inflammation and virulence. In addition, cyclopropane stereochemistries on mycolic acids interact directly with host cells to both positively and negatively influence host innate immune activation. PMID:16741578

Sub-Chronic Neuropathological and Biochemical Changes in Mouse Visual System after Repetitive Mild Traumatic Brain Injury

PubMed Central

Tzekov, Radouil; Dawson, Clint; Orlando, Megan; Mouzon, Benoit; Reed, Jon; Evans, James; Crynen, Gogce; Mullan, Michael; Crawford, Fiona

2016-01-01

Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI. PMID:27088355

Effect of chemical permeation enhancers on stratum corneum barrier lipid organizational structure and interferon alpha permeability.

PubMed

Moghadam, Shadi H; Saliaj, Evi; Wettig, Shawn D; Dong, Chilbert; Ivanova, Marina V; Huzil, J Torin; Foldvari, Marianna

2013-06-03

The outermost layer of the skin, known as the stratum corneum (SC), is composed of dead corneocytes embedded in an intercellular lipid matrix consisting of ceramides, free fatty acids, and cholesterol. The high level of organization within this matrix protects the body by limiting the permeation of most compounds through the skin. While essential for its protective functions, the SC poses a significant barrier for the delivery of topically applied pharmaceutical agents. Chemical permeation enhancers (CPEs) can increase delivery of small drug compounds into the skin by interacting with the intercellular lipids through physical processes including extraction, fluidization, increased disorder, and phase separation. However, it is not clear whether these same mechanisms are involved in delivery of biotherapeutic macromolecules, such as proteins. Here we describe the effect of three categories of CPEs {solvents [ethanol, propylene glycol, diethylene glycol monoethyl ether (transcutol), oleic acid], terpenes [menthol, nerol, camphor, methyl salicylate], and surfactants [Tween 80, SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (Cremophor RH40), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB)]} on the lipid organizational structure of human SC as determined by X-ray scattering studies. Small- and wide-angle X-ray scattering studies were conducted to correlate the degree of structural changes and hydrocarbon chain packing in SC lipids caused by these various classes of CPEs to the extent of permeation of interferon alpha-2b (IFNα), a 19 kDa protein drug, into human skin. With the exception of solvents, propylene glycol and ethanol, all classes of CPEs caused increased disordering of lamellar and lateral packing of lipids. We observed that the highest degree of SC lipid disordering was caused by surfactants (especially SDS, DDAB, and DTAB) followed by terpenes, such as nerol. Interestingly, in vitro skin permeation studies indicated that, in most cases, absorption of IFNα was low and that an increase in SC lipid disorder does not correspond to an increase in IFNα absorption.

Biomagnification of polybrominated diphenyl ether and hexabromocyclododecane flame retardants in the polar bear food chain in Svalbard, Norway.

PubMed

Sørmo, Eugen Gravningen; Salmer, Maria Pettersvik; Jenssen, Bjørn Munro; Hop, Haakon; Baek, Kine; Kovacs, Kit Maureen; Lydersen, Christian; Falk-Petersen, Stig; Gabrielsen, Geir Wing; Lie, Elisabeth; Skaare, Janneche Utne

2006-09-01

Concentrations of brominated flame retardants (BFRs), including polybrominated diphenylethers (PBDEs) and hexabromocyclododecane (HBCD), were investigated in an arctic marine food chain consisting of four invertebrate species: polar cod (Boreogadus saida), ringed seals (Pusa hispida), and polar bears (Ursus maritimus). The most abundant BFR, brominated diphenyl ether (BDE)-47, was found in detectable concentrations even in zooplankton, the lowest trophic level examined in this study. Most of the investigated BFRs biomagnified as function of tropic level in the food chain. A noticeable exception occurred at the highest trophic level, the polar bear, in which only BDE-153 was found to increase from its main prey, the ringed seal, indicating that polar bears appear to be able to metabolize and biodegrade most BFRs. In contrast, lower-brominated PBDEs, particularly BDE-47, showed clear signs of bioaccumulation in zooplankton, polar cod, and ringed seals. We suggest that this discrepancy in the fate of BFRs among the different species may be related to greater induction of oxidative detoxification activities in the polar bear. Absorption and debromination rates may be more important for bioaccumulation rates of BFRs in zooplankton, polar cod, and ringed seals. Lipid weight-based concentrations (LWCs) and whole body-based concentrations (WBCs) of BFRs were used to assess biomagnification factors (BMFs). Whole-body concentrations gave the most realistic BMFs, as BMFs derived from LWCs seem to be confounded by the large variability in lipid content of tissues from the investigated species. This study demonstrates that PBDEs and HBCD have reached measurable concentrations even in the lower trophic levels (invertebrates and fish) in the Arctic and biomagnifies in the polar bear food chain.

Effect of ether glycerol lipids on interleukin-1β release and experimental autoimmune encephalomyelitis.

PubMed

Boomkamp, Stephanie D; Byun, Hoe-Sup; Ubhi, Satvir; Jiang, Hui-Rong; Pyne, Susan; Bittman, Robert; Pyne, Nigel J

2016-01-01

We have assessed the effect of two ether glycerol lipids, 77-6 ((2S, 3R)-4-(Tetradecyloxy)-2-amino-1,3-butanediol) and 56-5 ((S)-2-Amino-3-O-hexadecyl-1-propanol), which are substrates for sphingosine kinases, on inflammatory responses. Treatment of differentiated U937 macrophage-like cells with 77-6 but not 56-5 enhanced IL-1β release; either alone or in the presence of LPS. The stimulatory effect of sphingosine or 77-6 on LPS-stimulated IL-1β release was reduced by pretreatment of cells with the caspase-1 inhibitor, Ac-YVAD-CHO, thereby indicating a role for the inflammasome. The enhancement of LPS-stimulated IL-1β release in response to sphingosine, but not 77-6, was reduced by pretreatment of cells with the cathepsin B inhibitor, CA074Me, indicating a role for lysosomal destabilization in the effect of sphingosine. Administration of 56-5 to mice increased disease progression in an experimental autoimmune encephalomyelitis model and this was associated with a considerable increase in the infiltration of CD4(+) T-cells, CD11b(+) monocytes and F4/80(+) macrophages in the spinal cord. 56-5 and 77-6 were without effect on the degradation of myc-tagged sphingosine 1-phosphate 1 receptor in CCL39 cells. Therefore, the effect of 56-5 on EAE disease progression is likely to be independent of the inflammasome or the sphingosine 1-phosphate 1 receptor. However, 56-5 is chemically similar to platelet activating factor and the exacerbation of EAE disease progression might be linked to platelet activating factor receptor signaling. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Biomonitoring polybrominated diphenyl ethers in human milk as a function of environment, dietary intake, and demographics in New Hampshire.

PubMed

Dunn, Rebecca L; Huwe, Janice K; Carey, Gale B

2010-08-01

Human milk is a valuable biological specimen for biomonitoring lipid-soluble polybrominated diphenyl ethers (PBDEs). The purpose of this study was to determine the levels of PBDEs in human milk from New Hampshire and to examine potential relationships between PBDE levels in human milk and stage of lactation, maternal characteristics, living environment and dietary intake. Forty women provided up to three human milk samples at the end of their first, second and third month of breastfeeding for evaluation of day-to-day and month-to-month variation in PBDE levels. Participants completed four questionnaires, which provided maternal, living environment, and diet information. The sigma PBDE concentrations in human milk over the 3-month collection period ranged from 6.5 to 166.7 ng g(-1) lipid. The median for the 3-month period was 29.7 ng g(-1). BDE-47 was the predominant congener, however, BDE-153 predominated in 20% of the participants' samples. Day-to-day variation in sigma PBDEs was negligible; there was no significant difference in mean PBDE levels from month-to-month. Positive associations were seen between BDE-153 and age, postpartum saturated fat consumption, and the home model. There was a negative association between PBDE levels and fruit consumption during the third trimester. Our results indicate that PBDE levels in human milk from New Hampshire are within the range that has been reported in the US, and levels are stable during the first 3-months of lactation. Our findings revealed a higher predominance pattern with BDE-153 compared to other studies, and indicate that PBDE levels are influenced by diet and the home environment. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Glyceryl monooleyl ether-based liquid crystalline nanoparticles as a transdermal delivery system of flurbiprofen: characterization and in vitro transport.

PubMed

Uchino, Tomonobu; Murata, Akiko; Miyazaki, Yasunori; Oka, Toshihiko; Kagawa, Yoshiyuki

2015-01-01

Liquid crystalline nanoparticles (LCNs) were prepared using glyceryl monooleyl ether (GME) by the modified film rehydration method. Hydrogenated lecithin (HL), 1,3-butylene glycol (1,3-BG), and Poloxamer 407 were used as additives. The prepared LCN formulations were evaluated based on particle size, small-angle X-ray diffraction (SAXS) analysis, (1)H- and (19)F-NMR spectra, and in vitro skin permeation across Yucatan micropig skin. The composition (weight percent) of the LCN formulations were GME-HL-1,3-BG (4 : 1 : 15), 4% GME-based LCN and GME-HL-1,3-BG (8 : 1 : 15), 8% GME-based LCN and their mean particle sizes were 130-175 nm. Flurbiprofen 5 and 10 mg was loaded into 4% GME-based LCN and 8% GME-based LCN systems, respectively. The results of SAXS and NMR suggested that both flurbiprofen-loaded formulations consist of particles with reverse type hexagonal phase (formation of hexosome) and flurbiprofen molecules were localized in the lipid domain through interaction of flurbiprofen with the lipid components. Flurbiprofen transport from the LCN systems across the Yucatan micropig skin was increased compared to flurbiprofen in citric buffer (pH=3.0). The 8% GME-based LCN systems was superior to the 4% GME-based LCN for flurbiprofen transport. Since the internal hexagonal phase in the 8% GME-based LCN systems had a higher degree of order compared to the 4% GME-based LCN in SAXS patterns, the 8% GME-based LCN system had a larger surface area, which might influence flurbiprofen permeation. These results indicated that the GME-based LCN system is effective in improving the skin permeation of flurbiprofen across the skin.

Comparative embryotoxicity of a pentabrominated diphenyl ether mixture to common terns (Sterna hirundo) and American kestrels (Falco sparverius)

USGS Publications Warehouse

Rattner, Barnett A.; Lazarus, Rebecca S.; Heinz, Gary H.; Karouna-Reiner, Natalie K.; Schultz, Sandra L.; Hale, Robert C.

2013-01-01

Concentrations of polybrominated diphenyl ethers (PBDEs) in Forster’s tern (Sterna forsteri) eggs from San Francisco Bay have been reported to range up to 63 μg g−1 lipid weight. This value exceeds the lowest-observed-adverse-effect level (1.8 μg g−1 egg wet weight; ∼32 μg−1 lipid weight) reported in an embryotoxicity study with American kestrels (Falco sparverius). As a surrogate for Forster’s terns, common tern (Sterna hirundo) eggs were treated by air cell injection with corn oil vehicle (control) or a commercial penta-BDE formulation (DE-71) at nominal concentrations of 0.2, 2, and 20 μg g−1 egg. As a positive control, kestrel eggs received vehicle or 20 μg DE-71 g−1 egg. In terns, there were no effects of DE-71 on embryonic survival, and pipping or hatching success; however, treated eggs hatched later (0.44 d) than controls. Organ weights, organ-to-body weight ratios, and bone lengths did not differ, and histopathological observations were unremarkable. Several measures of hepatic oxidative stress in hatchling terns were not affected by DE-71, although there was some evidence of oxidative DNA damage (8-hydroxy-deoxyguanosine; 8-OH-dG). Although DE-71 did not impair pipping and hatching of kestrels, it did result in a delay in hatch, shorter humerus length, and reduced total thyroid weight. Concentrations of oxidized glutathione, reduced glutathione, thiobarbituric acid reactive substances, and 8-OH-dG in liver were greater in DE-71-treated kestrels compared to controls. Our findings suggest common tern embryos, and perhaps other tern species, are less sensitive to PBDEs than kestrel embryos.

Individual variation in body burden, lipid status, and reproductive investment is related to maternal transfer of a brominated diphenyl ether (BDE-99) to eggs in the zebra finch.

PubMed

Eng, Margaret L; Elliott, John E; Letcher, Robert J; Williams, Tony D

2013-02-01

Avian eggs are exposed to hydrophobic contaminants through maternal transfer. How maternal transfer of contaminants within a species is influenced by individual variation in characteristics such as body burden, yolk precursor levels, or reproductive investment is not understood. The authors investigated sources of variation in the maternal transfer of 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) in zebra finches (Taeniopygia guttata). The authors dosed adult female zebra finches with levels of BDE-99 relevant to exposure in wild birds (0, 33.7 or 173.8 ng/g body wt/d) for three weeks prior to pairing. Maternal BDE-99 and very-low-density lipoprotein (VLDL) in plasma were measured during egg formation and at clutch completion, and BDE-99 was measured in the corresponding egg. The lipid-normalized egg-to-maternal tissue BDE-99 relationship decreased with increasing maternal burden. Individual variation in maternal VLDL was related to BDE-99 transfer to the eggs when BDE-99 was at background levels in control birds, but not when BDE-99 was elevated in dosed birds. The decrease in maternal plasma BDE-99 over the laying period was only significant (p < 0.05) in the high-dose birds. Finally, the decrease in BDE-99 in maternal plasma during egg-laying was significantly positively correlated with clutch mass in the high-dose group. These results suggest that the relationship between maternal and egg contaminant levels can be highly variable. This has significant implications for using eggs as indicators of adult or environmental concentrations. Copyright © 2012 SETAC.

Levels and Concentration Ratios of Polychlorinated Biphenyls and Polybrominated Diphenyl Ethers in Serum and Breast Milk in Japanese Mothers

PubMed Central

Inoue, Kayoko; Harada, Kouji; Takenaka, Katsunobu; Uehara, Shigeki; Kono, Makoto; Shimizu, Takashi; Takasuga, Takumi; Senthilkumar, Kurunthachalam; Yamashita, Fumiyoshi; Koizumi, Akio

2006-01-01

Blood and/or breast milk have been used to assess human exposure to various environmental contaminants. Few studies have been available to compare the concentrations in one matrix with those in another. The goals of this study were to determine the current levels of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in Japanese women, with analysis of the effects of lifestyle and dietary habits on these levels, and to develop a quantitative structure–activity relationship (QSAR) with which to predict the ratio of serum concentration to breast milk concentration. We measured PBDEs and PCBs in 89 paired samples of serum and breast milk collected in four regions of Japan in 2005. The geometric means of the total concentrations of PBDE (13 congeners) in milk and serum were 1.56 and 2.89 ng/g lipid, respectively, whereas those of total PCBs (15 congeners) were 63.9 and 37.5 ng/g lipid, respectively. The major determinant of total PBDE concentration in serum and milk was the geographic area within Japan, whereas nursing duration was the major determinant of PCB concentration. BDE-209 was the most predominant PBDE congener in serum but not in milk. The excretion of BDE 209 in milk was lower than that of BDE 47 and BDE 153. QSAR analysis revealed that two parameters, calculated octanol/water partition and number of hydrogen-bond acceptors, were significant descriptors. During the first weeks of lactation, the predicted partitioning of PBDE and PCB congeners from serum to milk agreed with the observed values. However, the prediction became weaker after 10 weeks of nursing. PMID:16882522

Exposure Assessment to Environmental Chemicals in Children from Ciudad Juarez, Chihuahua, Mexico.

PubMed

Ochoa-Martinez, Angeles C; Orta-Garcia, Sandra T; Rico-Escobar, Edna M; Carrizales-Yañez, Leticia; Del Campo, Jorge D Martin; Pruneda-Alvarez, Lucia G; Ruiz-Vera, Tania; Gonzalez-Palomo, Ana K; Piña-Lopez, Iris G; Torres-Dosal, Arturo; Pérez-Maldonado, Ivan N

2016-05-01

It has been demonstrated that the human biomonitoring of susceptible populations is a valuable method for the identification of critical contaminants. Therefore, the purpose of this study was to assess the exposure profile for arsenic (As), lead (Pb), mercury (Hg), 1-hydroxypyrene (1-OHP), 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) in children living in Ciudad Juarez, Chihuahua, Mexico (a major manufacturing center in Mexico). In 2012, we evaluated a total of 135 healthy children living in Ciudad Juarez since birth. The total PBDEs levels ranged from nondetectable (< LOD) to 215 ng/g lipid, with a mean total PBDEs level of 29.5 ± 53.0 ng/g lipid (geometric mean ± standard deviation). The mean total PCBs level in the study participants was 29.0 ± 10.5 ng/g lipid (range 4.50-50.0 ng/g lipid). The mean concentration of total DDT (DDT + DDE) was 11.9 ± 6.70 ng/g lipid (range 3.00-26.0 ng/g lipid). The mean 1-OHP levels was 1.2 ± 1.1 µmol/mol creatinine (range

Identification of lipidomic markers of chronic 3,3',4,4',5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver.

PubMed

Kania-Korwel, Izabela; Wu, Xianai; Wang, Kai; Lehmler, Hans-Joachim

2017-09-01

Exposure to PCB 126, an environmentally relevant aryl hydrocarbon receptor agonist, is an environmental factor causing hepatic steatosis in rodent models; however, the lipidome of PCB 126-exposed rats has not been investigated in-depth. The objective of the present study was therefore to characterize dose-dependent changes in the lipid profile in the liver of male Sprague-Dawley rats exposed to PCB 126. Rats were exposed for three month to intraperitoneal injections of 0.01, 0.05 and 0.2μmol/kg bw PCB 126 in corn oil. Control animals were exposed in parallel and received corn oil alone. Lipids were extracted from whole liver homogenate and levels of polar lipids and fatty acids incorporated into triglycerides (FA TAGs ) were determined with tandem mass spectrometry using electrospray ionization. PCB 126 exposure increased the hepatic content of polar lipids and FA TAGs . Protein adjusted levels of several polar lipid classes, in particular phosphatidylserine levels, decreased, whereas FA TAGs levels typically increased with increasing PCB 126 dose. Sensitive, dose-dependent endpoints of PCB 126 exposure included an increase in levels of adrenic acid incorporated into triglycerides and changes in levels of certain ether-linked phospholipid and 1-alkyl/1-alkenyldiacylglycerol species, as determined using partial least square discriminant analysis (PLS-DA) and ANOVA. These changes in the composition of polar lipids and fatty acid in the liver of PCB 126 exposed rats identified several novel markers of PCB 126-mediated fatty liver disease that need to be validated in further studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Heat stress dictates microbial lipid composition in hydrothermal marine sediments

NASA Astrophysics Data System (ADS)

Sollich, M.; Yoshinaga, M. Y.; Häusler, S.; Hinrichs, K. U.; Bühring, S. I.

2016-02-01

Abundant and diverse microbial communities inhabit hydrothermal marine sediments. Since ion permeability of membranes increases with temperature archaea and bacteria that use proton/sodium as coupling ions for bioenergetics must constantly adjust their cytoplasmic membrane permeability, which in turn is mostly controlled by the lipid composition. Here, we investigated a thermal gradient across a marine sediment field (ranging from 18 to over 100°C) and tested the concept that membrane lipids provide a major biochemical basis for cellular bioenergetics of archaea and bacteria under stressful conditions. Reflecting the lower ion permeability of the ether-linked isoprenoidal lipids, we found that archaea dominate over bacteria in sediments of >50 °C. Moreover, a detailed examination of the molecular lipid species revealed a quandary: low membrane permeability concomitantly with increased fluidity is required for energy conservation of both archaea and bacteria under heat stress. For instance, bacterial fatty acids were found to increase chain length in concert with a higher degree of unsaturation at elevated sediment temperatures while archaeal tetraethers were observed to show a higher degree of bulking (e.g. methylation and H-shaped) and fluidity (i.e. cyclization) under elevated temperatures. In addition, our data indicate that strong intermolecular hydrogen bonding at the headgroup level of archaeal glycolipids and bacterial sphingolipids may provide ideal membrane stability to attain the required balance between low permeability and a more fluidized configuration. For example, sphingolipids may stabilize bacterial phospholipids into lipid domains, enabling bacteria to thrive in heated sediments under unfavorable thermodynamic conditions. The scientific marriage of lipidomics and bioenergetics described here provides a new dimension for understanding microbial life in natural environments.

Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis.

PubMed

Halama, Anna; Kulinski, Michal; Dib, Shaima S; Zaghlool, Shaza B; Siveen, Kodappully S; Iskandarani, Ahmad; Zierer, Jonas; Prabhu, Kirti S; Satheesh, Noothan J; Bhagwat, Aditya M; Uddin, Shahab; Kastenmüller, Gabi; Elemento, Olivier; Gross, Steven S; Suhre, Karsten

2018-08-28

Suppressing glutaminolysis does not always induce cancer cell death in glutamine dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis in cancer cells. Glutaminolysis inhibition with C.968 suppressed cell proliferation but was insufficient to induce cancer cell death. We found that lipid catabolism was activated as a compensation for glutaminolysis inhibition. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. Simultaneously inhibiting glutaminolysis and either beta oxidation with trimetazidine or autophagy with chloroquine both induced cancer cell death. Here we identified metabolic escape mechanisms contributing to cancer cell survival under treatment and we suggest potentially translational strategy for combined cancer therapy, given that chloroquine is an FDA approved drug. Our findings are first to show efficiency of combined inhibition of glutaminolysis and beta oxidation as potential anti-cancer strategy as well as add to the evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention.

PubMed

Blask, David E; Dauchy, Robert T; Dauchy, Erin M; Mao, Lulu; Hill, Steven M; Greene, Michael W; Belancio, Victoria P; Sauer, Leonard A; Davidson, Leslie

2014-01-01

The central circadian clock within the suprachiasmatic nucleus (SCN) plays an important role in temporally organizing and coordinating many of the processes governing cancer cell proliferation and tumor growth in synchrony with the daily light/dark cycle which may contribute to endogenous cancer prevention. Bioenergetic substrates and molecular intermediates required for building tumor biomass each day are derived from both aerobic glycolysis (Warburg effect) and lipid metabolism. Using tissue-isolated human breast cancer xenografts grown in nude rats, we determined that circulating systemic factors in the host and the Warburg effect, linoleic acid uptake/metabolism and growth signaling activities in the tumor are dynamically regulated, coordinated and integrated within circadian time structure over a 24-hour light/dark cycle by SCN-driven nocturnal pineal production of the anticancer hormone melatonin. Dim light at night (LAN)-induced melatonin suppression disrupts this circadian-regulated host/cancer balance among several important cancer preventative signaling mechanisms, leading to hyperglycemia and hyperinsulinemia in the host and runaway aerobic glycolysis, lipid signaling and proliferative activity in the tumor.

Improvement of curcuminoid bioaccessibility from turmeric by a nanostructured lipid carrier system.

PubMed

Park, Sung Jin; Garcia, Coralia V; Shin, Gye Hwa; Kim, Jun Tae

2018-06-15

Turmeric contains curcumin and its analogues, which show anticancer and antiinflammatory effects; however, curcuminoids are lipophilic and are poorly absorbed by the human body. Nanostructured lipid carriers for encapsulating whole turmeric powder were successfully produced by ultrasonication, and their physicochemical properties and stability in simulated gastric and intestinal media were evaluated. The turmeric nanostructured lipid carriers (TNLCs) exhibited a round shape, small diameter (282 ± 7.19 nm), adequate zeta potential (-22.75 ± 1.20 mV), and high encapsulation efficiency (93.3 ± 0.01%). The TNLCs were able to protect the encapsulated curcuminoids under acidic gastric conditions, and effectively released 95 ± 2.51% of the curcuminoids in the simulated intestinal medium, demonstrating their suitability for controlled release. The in vitro bioaccessibility of the encapsulated curcuminoids was 75 ± 1.24%, representing more than a fourfold increase compared to that of free turmeric. Therefore, the proposed TNLCs are a promising delivery system for increasing the bioaccessibility of curcuminoids from turmeric. Copyright © 2018 Elsevier Ltd. All rights reserved.

Entrapment of an EGFR inhibitor into nanostructured lipid carriers (NLC) improves its antitumor activity against human hepatocarcinoma cells

PubMed Central

2014-01-01

Background In hepatocellular carcinoma (HCC), different signaling pathways are de-regulated, and among them, the expression of the epidermal growth factor receptor (EGFR). Tyrphostin AG-1478 is a lipophilic low molecular weight inhibitor of EGFR, preferentially acting on liver tumor cells. In order to overcome its poor drug solubility and thus improving its anticancer activity, it was entrapped into nanostructured lipid carriers (NLC) by using safe ingredients for parenteral delivery. Results Nanostructured lipid carriers (NLC) carrying tyrphostin AG-1478 were prepared by using the nanoprecipitation method and different matrix compositions. The best system in terms of mean size, PDI, zeta potential, drug loading and release profile was chosen to evaluate the anti-proliferative effect of drug-loaded NLC versus free drug on human hepatocellular carcinoma HA22T/VGH cells. Conclusions Thanks to the entrapment into NLC systems, tyrphostin AG-1478 shows an enhanced in vitro anti-tumor activity compared to free drug. These finding raises hope of future drug delivery strategy of tyrphostin AG-1478 -loaded NLC targeted to the liver for the HCC treatment. PMID:24886097

Polybrominated diphenyl ethers (PBDEs) in U.S. mothers' milk.

PubMed Central

Schecter, Arnold; Pavuk, Marian; Päpke, Olaf; Ryan, John Jake; Birnbaum, Linda; Rosen, Robin

2003-01-01

No previous reports exist on polybrominated diphenyl ether (PBDE) congeners in human milk from individual U.S. mothers. This article on PBDEs is an extension of our previous studies on concentrations of dioxins, dibenzofurans, polychlorinated biphenyls, and other chlorinated organic compounds in human milk in a number of countries. PBDE commercial products are used as flame retardants in flexible polyurethane foam (penta-BDE), in acrylonitrile-butadiene-styrene resins (octa-BDE), and in high-impact polystyrene resins (deca-BDE). Their use is permitted in the United States but is banned in some European countries because of presumed toxicity, demonstrated persistence, and bioaccumulation. Different commercial products can be found in various consumer products such as television sets, computers, computer monitors and printers, carpets, and upholstery. Analyses of human levels of these compounds suggest low but rising levels in European human milk, which may have peaked, at least in Sweden, in the late 1990s. Very few data exist on levels of PBDEs in humans in the United States, and none from milk from individual nursing mothers. To address this issue, we analyzed 47 individual milk samples from nursing mothers, 20-41 years of age, from a milk bank in Austin, Texas, and a community women's health clinic in Dallas, Texas. Up to 13 PBDE congeners were measured. The concentrations of the sum of PBDE congeners varied from 6.2 to 419 ng/g (or parts per billion) lipid, with a median of 34 ng/g and a mean of 73.9 ng/g lipid. The PBDE levels in breast milk from Texas were similar to levels found in U.S. blood and adipose tissue lipid from California and Indiana and are 10-100 times greater than human tissue levels in Europe. Their detection in breast milk raises concern for potential toxicity to nursing infants, given the persistence and bioaccumulative nature of some of the PBDE congeners. These results indicate a need for more detailed investigation of the levels of PBDE in people and food, as well as determining if animal fat in food is the major route of exposure of the general U.S. population. Other routes of intake may also be significant. PMID:14594622

In vitro determination of the efficacy of scorpion venoms as anti-cancer agents against colorectal cancer cells: a nano-liposomal delivery approach.

PubMed

Al-Asmari, Abdulrahman K; Ullah, Zabih; Al Balowi, Ali; Islam, Mozaffarul

2017-01-01

The use of liposomes in biological and medicinal sciences is a relatively new approach. The liposomal strategy greatly depends on the technological advancement in the formation of vesicles of various sizes and properties. In the current study, we encapsulated the venoms obtained from medically important scorpions such as Androctonus bicolor (AB), Androctonus crassicauda (AC), and Leiurus quinquestriatus (LQ). To begin with, our first and foremost aim was to prepare biocompatible and biodegradable nanovesicles. Additionally, we intended to enhance the anti-cancer potential of these encapsulated venoms. The liposomal venoms were prepared by rehydration and dehydration methods. Morphology, particle size, and size distribution of the liposomes were examined by scanning electron microscope (SEM), transmission electron microscope (TEM), and Zetasizer. We found that the prepared liposomes had a smooth surface and a spherical/ovoid shape and existed mainly as single unilamellar vesicles (SUVs). Furthermore, the liposomal formulation of all three venoms exhibited excellent stability and good encapsulation efficiency (EE). Additionally, the anti-cancer potential of the encapsulated venoms was also evaluated on a colorectal cancer cell line (HCT-8). The venom-loaded liposomes showed elevated anti-cancer properties such as low rate of cell survival, higher reactive oxygen species (ROS) generation, and enhancement in the number of apoptotic cells. In addition to this, cell cycle analysis revealed G0/G1 enrichment upon venom treatment. The effect of treatment was more pronounced when venom-liposome was used as compared to free venom on the HCT-8 cell line. Furthermore, we did not observe any interference of liposomal lipids used in these preparations on the progression of cancer cells. Considering these findings, we can conclude that the encapsulated scorpion venoms exhibit better efficacy and act more vigorously as an anti-cancer agent on the colorectal cancer cell line when compared with their free counterpart.

In vitro determination of the efficacy of scorpion venoms as anti-cancer agents against colorectal cancer cells: a nano-liposomal delivery approach

PubMed Central

Al-Asmari, Abdulrahman K; Ullah, Zabih; Al Balowi, Ali; Islam, Mozaffarul

2017-01-01

The use of liposomes in biological and medicinal sciences is a relatively new approach. The liposomal strategy greatly depends on the technological advancement in the formation of vesicles of various sizes and properties. In the current study, we encapsulated the venoms obtained from medically important scorpions such as Androctonus bicolor (AB), Androctonus crassicauda (AC), and Leiurus quinquestriatus (LQ). To begin with, our first and foremost aim was to prepare biocompatible and biodegradable nanovesicles. Additionally, we intended to enhance the anti-cancer potential of these encapsulated venoms. The liposomal venoms were prepared by rehydration and dehydration methods. Morphology, particle size, and size distribution of the liposomes were examined by scanning electron microscope (SEM), transmission electron microscope (TEM), and Zetasizer. We found that the prepared liposomes had a smooth surface and a spherical/ovoid shape and existed mainly as single unilamellar vesicles (SUVs). Furthermore, the liposomal formulation of all three venoms exhibited excellent stability and good encapsulation efficiency (EE). Additionally, the anti-cancer potential of the encapsulated venoms was also evaluated on a colorectal cancer cell line (HCT-8). The venom-loaded liposomes showed elevated anti-cancer properties such as low rate of cell survival, higher reactive oxygen species (ROS) generation, and enhancement in the number of apoptotic cells. In addition to this, cell cycle analysis revealed G0/G1 enrichment upon venom treatment. The effect of treatment was more pronounced when venom–liposome was used as compared to free venom on the HCT-8 cell line. Furthermore, we did not observe any interference of liposomal lipids used in these preparations on the progression of cancer cells. Considering these findings, we can conclude that the encapsulated scorpion venoms exhibit better efficacy and act more vigorously as an anti-cancer agent on the colorectal cancer cell line when compared with their free counterpart. PMID:28144138

Protective Effect of Morus alba Leaf Extract on N-Nitrosodiethylamine-induced Hepatocarcinogenesis in Rats.

PubMed

Kujawska, Małgorzata; Ewertowska, Małgorzata; Adamska, Teresa; Ignatowicz, Ewa; Flaczyk, Ewa; Przeor, Monika; Kurpik, Monika; Liebert, Jadwiga Jodynis

The leaves of white mulberry (Morus alba L.) contain various polyphenolic compounds possessing strong antioxidant activity and anticancer potential. This study was designed to investigate the chemopreventive effect of aqueous extract of mulberry leaves against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis. Wistar rats were divided into four groups: control, mulberry extract-treated, NDEA-treated, and mulberry extract plus NDEA-treated. Mulberry extract was given in the diet (1,000 mg/kg b.w./day); NDEA was given in drinking water. Mulberry extract reduced the incidence of hepatocellular carcinoma, dysplastic nodules, lipid peroxidation, protein carbonyl formation, and DNA degradation. Treatment with mulberry leaf extract along with NDEA challenge did not affect the activity of antioxidant enzymes and glutathione content. Treatment with mulberry leaf extract partially protected the livers of rats from NDEA-induced hepatocarcinogenesis and a direct antioxidant mechanism appears to contribute to its anticarcinogenic activity. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Silibinin stimluates apoptosis by inducing generation of ROS and ER stress in human choriocarcinoma cells.

PubMed

Ham, Jiyeon; Lim, Whasun; Bazer, Fuller W; Song, Gwonhwa

2018-02-01

Silibinin is a flavonolignan extracted from seeds of milk thistles. Traditionally, it has been used as a therapeutic agent for liver disorders, and now it is well-known for its anti-cancer effects. However, studies on anti-cancer effects of silibinin on choriocarcinoma are very limited. Therefore, we performed proliferation and apoptosis assays to determine effects of silibinin on the viability of human choriocarcinoma (JAR and JEG3) cells. Our results showed that silibinin significantly inhibited proliferation and induced apoptosis in both JAR and JEG3 cells, and significantly increased reactive oxygen species (ROS) and lipid peroxidation. Moreover, silibinin disrupted mitochondrial function by inducing permeabilization of mitochondrial membrane potential and calcium ion efflux in JAR and JEG3 cells. Furthermore, silibinin-induced apoptosis in choriocarcinoma cells via AKT, mitogen-activated protein kinases (MAPK) and unfolded protein response (UPR) signal transduction. Collectively, our results suggest that silibinin is a novel therapeutic agent or dietary supplement for management of human placental choriocarcinomas. © 2017 Wiley Periodicals, Inc.

APETx4, a Novel Sea Anemone Toxin and a Modulator of the Cancer-Relevant Potassium Channel KV10.1.

PubMed

Moreels, Lien; Peigneur, Steve; Galan, Diogo T; De Pauw, Edwin; Béress, Lászlo; Waelkens, Etienne; Pardo, Luis A; Quinton, Loïc; Tytgat, Jan

2017-09-13

The human ether-à-go-go channel (hEag1 or K V 10.1) is a cancer-relevant voltage-gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively inhibit this channel can be lead compounds in the search for new anticancer drugs. Here, we report the activity-guided purification and electrophysiological characterization of a novel K V 10.1 inhibitor from the sea anemone Anthopleura elegantissima . Purified sea anemone fractions were screened for inhibitory activity on K V 10.1 by measuring whole-cell currents as expressed in Xenopus laevis oocytes using the two-microelectrode voltage clamp technique. Fractions that showed activity on Kv10.1 were further purified by RP-HPLC. The amino acid sequence of the peptide was determined by a combination of MALDI- LIFT-TOF/TOF MS/MS and CID-ESI-FT-ICR MS/MS and showed a high similarity with APETx1 and APETx3 and was therefore named APETx4. Subsequently, the peptide was electrophysiologically characterized on K V 10.1. The selectivity of the toxin was investigated on an array of voltage-gated ion channels, including the cardiac human ether-à-go-go-related gene potassium channel (hERG or Kv11.1). The toxin inhibits K V 10.1 with an IC 50 value of 1.1 μM. In the presence of a similar toxin concentration, a shift of the activation curve towards more positive potentials was observed. Similar to the effect of the gating modifier toxin APETx1 on hERG, the inhibition of Kv10.1 by the isolated toxin is reduced at more positive voltages and the peptide seems to keep the channel in a closed state. Although the peptide also induces inhibitory effects on other K V and Na V channels, it exhibits no significant effect on hERG. Moreover, APETx4 induces a concentration-dependent cytotoxic and proapoptotic effect in various cancerous and noncancerous cell lines. This newly identified K V 10.1 inhibitor can be used as a tool to further characterize the oncogenic channel K V 10.1 or as a scaffold for the design and synthesis of more potent and safer anticancer drugs.

Transmembrane delivery of anticancer drugs through self-assembly of cyclic peptide nanotubes

NASA Astrophysics Data System (ADS)

Chen, Jian; Zhang, Bei; Xia, Fei; Xie, Yunchang; Jiang, Sifan; Su, Rui; Lu, Yi; Wu, Wei

2016-03-01

Breaking the natural barriers of cell membranes achieves fast entry of therapeutics, which leads to enhanced efficacy and helps overcome multiple drug resistance. Herein, transmembrane delivery of a series of small molecule anticancer drugs was achieved by the construction of artificial transmembrane nanochannels formed by self-assembly of cyclic peptide (cyclo[Gln-(d-Leu-Trp)4-d-Leu], CP) nanotubes (CPNTs) in the lipid bilayers. Our in vitro study in liposomes indicated that the transport of molecules with sizes smaller than 1.0 nm, which is the internal diameter of the CPNTs, could be significantly enhanced by CPNTs in a size-selective and dose-dependent manner. Facilitated uptake of 5-fluorouracil (5-FU) was also confirmed in the BEL7402 cell line. On the contrary, CPs could facilitate neither the transport across liposomal membranes nor the uptake by cell lines of cytarabine, a counterevidence drug with a size of 1.1 nm. CPs had a very weak anticancer efficacy, but could significantly reduce the IC50 of 5-FU in BEL7402, HeLa and S180 cell lines. Analysis by a q test revealed that a combination of 5-FU and CP had a synergistic effect in BEL7402 at all CP levels, in S180 at CP levels higher than 64 μg mL-1, but not in HeLa, where an additive effect was observed. Temporarily, intratumoral injection is believed to be the best way for CP administration. In vivo imaging using 125I radio-labelled CP confirmed that CPNPTs were completely localized in the tumor tissues, and translocation to other tissues was negligible. In vivo anticancer efficacy was studied in the grafted S180 solid tumor model in mice, and the results indicated that tumor growth was greatly inhibited by the combinatory use of 5-FU and CP, and a synergistic effect was observed at CP doses of 0.25 mg per kg bw. It is concluded that facilitated transmembrane delivery of anticancer drugs with sizes smaller than 1.0 nm was achieved, and the synergistic anticancer effect was confirmed both in cell lines and in vivo through the combinatory use of 5-FU and CP.Breaking the natural barriers of cell membranes achieves fast entry of therapeutics, which leads to enhanced efficacy and helps overcome multiple drug resistance. Herein, transmembrane delivery of a series of small molecule anticancer drugs was achieved by the construction of artificial transmembrane nanochannels formed by self-assembly of cyclic peptide (cyclo[Gln-(d-Leu-Trp)4-d-Leu], CP) nanotubes (CPNTs) in the lipid bilayers. Our in vitro study in liposomes indicated that the transport of molecules with sizes smaller than 1.0 nm, which is the internal diameter of the CPNTs, could be significantly enhanced by CPNTs in a size-selective and dose-dependent manner. Facilitated uptake of 5-fluorouracil (5-FU) was also confirmed in the BEL7402 cell line. On the contrary, CPs could facilitate neither the transport across liposomal membranes nor the uptake by cell lines of cytarabine, a counterevidence drug with a size of 1.1 nm. CPs had a very weak anticancer efficacy, but could significantly reduce the IC50 of 5-FU in BEL7402, HeLa and S180 cell lines. Analysis by a q test revealed that a combination of 5-FU and CP had a synergistic effect in BEL7402 at all CP levels, in S180 at CP levels higher than 64 μg mL-1, but not in HeLa, where an additive effect was observed. Temporarily, intratumoral injection is believed to be the best way for CP administration. In vivo imaging using 125I radio-labelled CP confirmed that CPNPTs were completely localized in the tumor tissues, and translocation to other tissues was negligible. In vivo anticancer efficacy was studied in the grafted S180 solid tumor model in mice, and the results indicated that tumor growth was greatly inhibited by the combinatory use of 5-FU and CP, and a synergistic effect was observed at CP doses of 0.25 mg per kg bw. It is concluded that facilitated transmembrane delivery of anticancer drugs with sizes smaller than 1.0 nm was achieved, and the synergistic anticancer effect was confirmed both in cell lines and in vivo through the combinatory use of 5-FU and CP. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06804e

Tumor-targeting peptide conjugated pH-responsive micelles as a potential drug carrier for cancer therapy.

PubMed

Wu, Xiang Lan; Kim, Jong Ho; Koo, Heebeom; Bae, Sang Mun; Shin, Hyeri; Kim, Min Sang; Lee, Byung-Heon; Park, Rang-Woon; Kim, In-San; Choi, Kuiwon; Kwon, Ick Chan; Kim, Kwangmeyung; Lee, Doo Sung

2010-02-17

Herein, we prepared tumor-targeting peptide (AP peptide; CRKRLDRN) conjugated pH-responsive polymeric micelles (pH-PMs) in cancer therapy by active and pH-responsive tumor targeting delivery systems, simultaneously. The active tumor targeting and tumoral pH-responsive polymeric micelles were prepared by mixing AP peptide conjugated PEG-poly(d,l-lactic acid) block copolymer (AP-PEG-PLA) into the pH-responsive micelles of methyl ether poly(ethylene glycol) (MPEG)-poly(beta-amino ester) (PAE) block copolymer (MPEG-PAE). These mixed amphiphilic block copolymers were self-assembled to form stable AP peptide-conjugated and pH-responsive AP-PEG-PLA/MPEG-PAE micelles (AP-pH-PMs) with an average size of 150 nm. The AP-pH-PMs containing 10 wt % of AP-PEG-PLA showed a sharp pH-dependent micellization/demicellization transition at the tumoral acid pH. Also, they presented the pH-dependent drug release profile at the acidic pH of 6.4. The fluorescence dye, TRITC, encapsulated AP-pH-PMs (TRITC-AP-pH-PMs) presented the higher tumor-specific targeting ability in vitro cancer cell culture system and in vivo tumor-bearing mice, compared to control pH-responsive micelles of MPEG-PAE. For the cancer therapy, the anticancer drug, doxorubicin (DOX), was efficiently encapsulated into the AP-pH-PMs (DOX-AP-pH-PMs) with a higher loading efficiency. DOX-AP-pH-PMs efficiently deliver anticancer drugs in MDA-MB231 human breast tumor-bearing mice, resulted in excellent anticancer therapeutic efficacy, compared to free DOX and DOX encapsulated MEG-PAE micelles, indicating the excellent tumor targeting ability of AP-pH-PMs. Therefore, these tumor-targeting peptide-conjugated and pH-responsive polymeric micelles have great potential application in cancer therapy.

Inhibition of Fatty Acid Synthesis Induces Apoptosis of Human Pancreatic Cancer Cells.

PubMed

Nishi, Koji; Suzuki, Kenta; Sawamoto, Junpei; Tokizawa, Yuma; Iwase, Yumiko; Yumita, Nagahiko; Ikeda, Toshihiko

2016-09-01

Cancer cells tend to have a high requirement for lipids, including fatty acids, cholesterol and triglyceride, because of their rapid proliferative rate compared to normal cells. In this study, we investigated the effects of inhibition of lipid synthesis on the proliferation and viability of human pancreatic cancer cells. Of the inhibitors of lipid synthesis that were tested, 5-(tetradecyloxy)-2-furoic acid (TOFA), which is an inhibitor of acetyl-CoA carboxylase, and the fatty acid synthase (FAS) inhibitors cerulenin and irgasan, significantly suppressed the proliferation of MiaPaCa-2 and AsPC-1 cells. Treatment of MiaPaCa-2 cells with these inhibitors significantly increased the number of apoptotic cells. In addition, TOFA increased caspase-3 activity and induced cleavage of poly (ADP-ribose) polymerase in MiaPaCa-2 cells. Moreover, addition of palmitate to MiaPaCa-2 cells treated with TOFA rescued cells from apoptotic cell death. These results suggest that TOFA induces apoptosis via depletion of fatty acids and that, among the various aspects of lipid metabolism, inhibition of fatty acid synthesis may be a notable target for the treatment of human pancreatic cancer cells. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Rational design of dendrimer/lipid nanoassemblies in drug delivery for cancer chemotherapy

NASA Astrophysics Data System (ADS)

Sun, Qihang

Nanocarriers can minimize the side effects and improve therapeutic efficacy of anticancer drugs. Although some success has been achieved via active or passive drug delivery to tumor cells, the known nanocarriers are far from satisfying therapeutic efficacy expectations. This is because they usually fail in one of the four crucial requirements, that is, to retain drug in blood circulation but release it reliably in tumor cells and to be stealthy in transport in circulation and tumor tissue but sticky upon arrival at the tumor cell. Therefore, the goal of this work is to fabricate nanoassemblies of dendrimers and lipids to address all these challenges. Particularly, nanoassemblies designed and prepared in this work are illustrated to improve the tumor tissue penetration. Examples of dendrimers synthesized in this work are water-insoluble, pH-dependent water-insoluble and water-soluble biodegradable polyester dendrimers. These dendrimers are shown to be encapsulated by commonly used fusogenic and long-circulating lipids to form reliable nanoassemblies. The dendrimer/lipid nanocarriers are used to demonstrate a cascade drug delivery. They are expected to be stable in circulation, due to their appropriately large size, but to release the drug-loaded dendrimers in tumor tissue. The released dendrimers carrying drugs are much smaller and hence expected to have a much deeper penetration throughout the tumor tissue.

[Dipeptide nootropic agent GVS-111 prevents accumulation of the lipid peroxidation products during immobilization].

PubMed

Lysenko, A V; Uskova, N I; Ostrovskaia, R U; Gudasheva, T A; Voronina, T A

1997-01-01

Immobilization of rats in a narrow plastic chamber for 24 h caused a sharp increase in the level of diene conjugates and the content of schiff bases in the synaptosomes of the brain cortex as well as accumulation of extraerythrocytic hemoglobin in blood serum. The dipeptide nootropic agent GVS-111 (ethyl ether of phenylacetylprolylglycine), when administered 15 and particularly 60 min before immobilization reduced the accumulation of these products of lipid peroxidation in the brain and blood. GVS-111 demonstrated these signs of its antioxidant effect after a single i.p. injection in doses of 0.12 and 0.5 mg/kg. Pyracetam produced a similar effect on the listed parameters in injection in a dose of 300 mg/kg for three successive days. The protective effect of the new pyracetam dipeptide analog GVS-111 in relation to activation of free-radical processes induced by immobilization is additional proof of the antistress action of this dipeptide.

Serial-omics characterization of equine urine

PubMed Central

Yuan, Min; Breitkopf, Susanne B.

2017-01-01

Horse urine is easily collected and contains molecules readily measurable using mass spectrometry that can be used as biomarkers representative of health, disease or drug tampering. This study aimed at analyzing microliter levels of horse urine to purify, identify and quantify proteins, polar metabolites and non-polar lipids. Urine from a healthy 12 year old quarter horse mare on a diet of grass hay and vitamin/mineral supplements with limited pasture access was collected for serial-omics characterization. The urine was treated with methyl tert-butyl ether (MTBE) and methanol to partition into three distinct layers for protein, non-polar lipid and polar metabolite content from a single liquid-liquid extraction and was repeated two times. Each layer was analyzed by high performance liquid chromatography—high resolution tandem mass spectrometry (LC-MS/MS) to obtain protein sequence and relative protein levels as well as identify and quantify small polar metabolites and lipids. The results show 46 urine proteins, many related to normal kidney function, structural and circulatory proteins as well as 474 small polar metabolites but only 10 lipid molecules. Metabolites were mostly related to urea cycle and ammonia recycling as well as amino acid related pathways, plant diet specific molecules, etc. The few lipids represented triglycerides and phospholipids. These data show a complete mass spectrometry based—omics characterization of equine urine from a single 333 μL mid-stream urine aliquot. These omics data help serve as a baseline for healthy mare urine composition and the analyses can be used to monitor disease progression, health status, monitor drug use, etc. PMID:29028822

Influence of liver cancer on lipid and lipoprotein metabolism

PubMed Central

Jiang, Jingting; Nilsson-Ehle, Peter; Xu, Ning

2006-01-01

Liver plays a key role in the metabolism of plasma apolipoproteins, endogenous lipids and lipoproteins. Hepatocellular carcinoma (HCC) is one of the most common fatal malignant tumors in China and in other Southeast Asian countries. This has been attributed to the high incidence of hepatitis B infection. Hepatitis B proteins, such as the hepatitis B X protein (HBx) that is large hepatitis B surface protein could regulate transcription of many candidate genes for liver carcinogenesis. It has known that patients who suffered from acute hepatitis B could have lipid disorders such as decreased plasma level of high-density lipoproteins (HDL). Furthermore, aberrations of lipid metabolism are often seen in the chronic hepatitis B infection. Plasma lipid profiles could be changed under HCC. In majority of the reports in HCC, plasma levels of triglycerides (TG), cholesterol, free fatty acids (FFA), HDL, low-density lipoproteins (LDL), lipoprotein (a) (Lp(a)), apolipoprotein AI (apoAI) and apoB were slight to significantly decreased, however, in some cases plasma levels of TG and Lp(a) might be increased. It has been suggested that analysis of plasma levels of lipids, lipoproteins and apolipoproteins in the patients suffered from HCC reflects on the hepatic cellular impairment status. Studies revealed that alterations seen in the plasma levels of lipids, lipoproteins and apolipoproteins reflecting patients' pathologic conditions. Decreased serum levels of cholesterol and apoAI may indicate a poor prognosis. Human leukaemic cells and certain tumor tissues have a higher receptor-mediated uptake of HDL and LDL than the corresponding normal cells or tissues. LDL and HDL have therefore been proposed as a carrier for the water-insoluble anti-cancer agents. PMID:16515689

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

PubMed Central

Parkinson, James R; Parkes, Harry G; So, Po Wah; Hajji, Nabil; Thomas, E Louise; Frost, Gary S

2017-01-01

Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53−/−. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo. PMID:28932113

Oral and intraperitoneal LD50 of thymoquinone, an active principle of Nigella sativa, in mice and rats.

PubMed

Al-Ali, Amein; Alkhawajah, Abdul Aziz; Randhawa, Mohammad Akram; Shaikh, Nisar Ahmed

2008-01-01

Thymoquinone is the major active principle of Nigella sativa (N. sativa) and constitutes about 30% of its volatile oil or ether extract. N. sativa oil and seed are commonly used as a natural remedy for many ailments. Using modern scientific techniques, a number of pharmacological actions of N. sativa have been investigated including immunostimulant, anti-inflammatory, anticancer, antioxidant, antihistaminic, antiasthmatic, hypoglycemic, antimicrobial and antiparasitic. There are only few reports regarding the toxicity of thymoquinone. The present study was carried out to determine LD50 of thymoquinone both in mice and rats, orally as well as intraperitoneall, by the method of Miller and Tainter. Autopsy and histopathology of liver, kidney, heart and lungs were also determined. The LD50 in mice after intraperitoneal injection was determined to be 104.7 mg/kg (89.7-119.7, 95% confidence interval) and after oral ingestion was 870.9 mg/kg (647.1-1094.8, 95% confidence interval). Whereas, LD50 in rats after intraperitoneal injection was determined to be 57.5 mg/kg (45.6-69.4, 95% confidence intervals) and after oral ingestion was 794.3 mg/kg (469.8-1118.8, 95% confidence intervals). The LD50 values presented here after intraperitoneal injection and oral gavages are 10-15 times and 100-150 times greater than doses of thymoquinone reported for its anti-inflammatory, anti-oxidant and anti-cancer effects. Thymoquinone is a relatively safe compound, particularly when given orally to experimental animals.

Interaction of Salicylate and a Terpenoid Plant Extract with Model Membranes: Reconciling Experiments and Simulations

PubMed Central

Khandelia, Himanshu; Witzke, Sarah; Mouritsen, Ole G.

2010-01-01

We investigate the effects of two structurally similar small cyclic molecules: salicylic acid and perillic acid on a zwitterionic model lipid bilayer, and show that both molecules might have biological activity related to membrane thinning. Salicylic acid is a nonsteroidal antiinflammatory drug, some of the pharmacological properties of which arise from its interaction with the lipid bilayer component of the plasma membrane. Prior simulations show that salicylate orders zwitterionic lipid membranes. However, this is in conflict with Raman scattering and vesicle fluctuation analysis data, which suggest the opposite. We show using extensive molecular dynamics simulations, cumulatively >2.5 μs, that salicylic acid indeed disorders membranes with concomitant membrane thinning and that the conflict arose because prior simulations suffered from artifacts related to the sodium-ion induced condensation of zwitterionic lipids modeled by the Berger force field. Perillic acid is a terpenoid plant extract that has antiinfective and anticancer properties, and is extensively used in eastern medicine. We found that perillic acid causes large-scale membrane thinning and could therefore exert its antimicrobial properties via a membrane-lytic mechanism reminiscent of antimicrobial peptides. Being more amphipathic, perillic acid is more potent in disrupting lipid headgroup packing, and significantly modifies headgroup dipole orientation. Like salicylate, the membrane thinning effect of perillic acid is masked by the presence of sodium ions. As an alternative to sodium cations, we advocate the straightforward solution of using larger countercations like potassium or tetra-methyl-ammonium that will maintain electroneutrality but not interact strongly with, and thus not condense, the lipid bilayer. PMID:21156130

40 CFR Table 6 to Subpart Jj of... - VHAP of Potential Concern

Code of Federal Regulations, 2011 CFR

2011-07-01

... glycol butyl ether, ethylene glycol ethyl ether (2-ethoxy ethanol), ethylene glycol hexyl ether, ethylene..., ethylene glycol mono-2-ethylhexyl ether, diethylene glycol butyl ether, diethylene glycol ethyl ether... glycol propyl ether, triethylene glycol butyl ether, triethylene glycol ethyl ether, triethylene glycol...

Comparison of patient-derived high and low phosphatidylserine-exposing colorectal carcinoma cells in their interaction with anti-cancer peptides.

PubMed

Wilms, Dominik; Andrä, Jörg

2017-01-01

Current cancer treatment is frequently compromised by severe adverse effects on healthy cells and tissues as well as by the increasing burden of (multi-)drug resistances. Some representatives of small, amphipathic peptides known as host defense peptides possess the potential to overcome these limitations and to evolve as future anti-cancer therapeutics. Peptide NK-2, derived from porcine NK-lysin, was originally discovered due to its broad-spectrum antimicrobial activities. Today, also potent anti-cancer activity is proven and accompanied by low toxicity towards normal human cells. The molecular basis underlying this target selectivity remains rather elusive. Nevertheless, it is presumptive that preferential peptide interactions with surface factors non-abundant on healthy human cells play a key role. Here, we investigated the cytotoxicity of peptide NK-2 and structurally improved anti-cancer variants thereof against two patient-derived colorectal cancer cell lines, exposing high and low levels of phosphatidylserine on their cell surfaces, respectively. Concluding from a range of in vitro tests involving cellular as well as lipid vesicle-based methods, it is proposed that the magnitude of the accessible membrane surface charge is not a primarily decisive factor for selective peptide interactions. Instead, it is suggested that the level of membrane surface-exposed phosphatidylserine is of crucial importance for the activity of peptide NK-2 and enhanced variants thereof in terms of their cancer cell selectivity, the overall efficacy, as well as the underlying mode of action and kinetics. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Design and development of PEGylated liposomal formulation of HER2 blocker Lapatinib for enhanced anticancer activity and diminshed cardiotoxicity.

PubMed

Shrivastava, Richa; Trivedi, Shruti; Singh, Pankaj Kumar; Asif, Mohammad; Chourasia, Manish Kumar; Khanna, Amit; Bhadauria, Smrati

2018-06-13

Breast cancer is most frequently diagnosed cancer and fifth leading cause of death in women. About 20-30% of all breast cancers overexpress HER2/neu receptors. Lapatinib is a dual tyrosin kinase inhibitor of EGFR and HER2. It exhibits its anticancer effect via blocking intracellular domain of HER2 receptor in breast cancer. Lapatinib belongs to class II of BSC classification due to its poor solubility restricting its clinical application. Due to presence of HER2 receptor on cardiomyocytes, it is associated with generation of cardiotoxicity. The present study was aimed to design a PEGylated liposomal formulation of Lapatinib and evaluate its anticancer potential. Lapatinib liposomes were prepared using lipid layer hydration method and its characterization was done by determining its particle size, zeta potential, entrapment efficiency and in vitro release profiling. The anti-tumor activity of PEGylated liposomal formulation was evaluated in xenografted tumor induced by MDA-MB-453 breast cancer cells in chick embryos. The anti-tumor effect of lapatinib was enhanced by its PEGylated liposomal preparation as it led to the reduction in tumor size to a greater extent compared to the embryos treated with free lapatinib. Flowcytometric analysis and immunofluroscence study using cleaved PARP antibody demonstrated the enhaced apoptotic potential of PEGylated liposomes of lapatonib. SGOT levels, marker for cardiotoxicity and hepatotoxicity, significantly decreased in serum of embryos treated with PEGylated liposmes of lapatinib compared to free drug treated embryos. Hence, the PEGylated liposomal formulation of lapatininb can be used as a therapeutic strategy against HER2 positive breast cancer either alone or in combination with conventional anticancer agents and hormonal therapies. Copyright © 2018. Published by Elsevier Inc.

Vitamin C-driven epirubicin loading into liposomes

PubMed Central

Lipka, Dominik; Gubernator, Jerzy; Filipczak, Nina; Barnert, Sabine; Süss, Regine; Legut, Mateusz; Kozubek, Arkadiusz

2013-01-01

The encapsulation of anticancer drugs in a liposome structure protects the drug during circulation and increases drug accumulation in the cancer tissue and antitumor activity while decreasing drug toxicity. This paper presents a new method of active drug loading based on a vitamin C pH/ion gradient. Formulations were characterized in terms of the following parameters: optimal external pH, time and drug-to-lipid ratio for the purpose of remote loading, and in vitro stability. In the case of the selected drug, epirubicin (EPI), its coencapsulation increases its anticancer activity through a possibly synergistic effect previously reported by other groups for a free nonencapsulated drug/vitamin C cocktail. The method also has another advantage over other remote-loading methods: it allows faster drug release through liposome destabilization at the tumor site, thanks to the very good solubility of the EPI vitamin C salt, as seen on cryogenic transmission electron microscopy images. This influences the drug-release process and increases the anticancer activity of the liposome formulation. The liposomes are characterized as stable, with very good pharmacokinetics (half-life 18.6 hours). The antitumor activity toward MCF-7 and 4T-1 breast cancer cells was higher in the case of EPI loaded via our gradient than via an ammonium sulfate gradient. Finally, the EPI liposomal formulation and the free drug were tested using the murine 4T-1 breast cancer model. The antitumor activity of the encapsulated drug was confirmed (tumor-growth inhibition over 40% from day 16 until the end of the experiment), and the free drug was shown to have no anticancer activity at the tested dose. PMID:24101870

The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy.

PubMed

Jørgenrud, Benedicte; Jalanko, Mikko; Heliö, Tiina; Jääskeläinen, Pertti; Laine, Mika; Hilvo, Mika; Nieminen, Markku S; Laakso, Markku; Hyötyläinen, Tuulia; Orešič, Matej; Kuusisto, Johanna

2015-01-01

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters. 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.

Synthesis and biological studies of positron-emitting radiopharmaceuticals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dischino, D.D.

The development and clinical evaluation of two-positron emitting radiopharmaceuticals designed to image myelin in humans is reported. Carbon-11-labeled benzyl methyl ether was synthesized by the reaction of carbon-11-labeled methanol and benzyl chloride in dimethyl sulfoxide containing powdered potassium hydroxide in a radiochemical yield of 43% and a synthesis and purification time of 40 minutes. Carbon-11-labeled diphenylmethanol was synthesized by the reaction of carbon-11-labeled carbon dioxide and phenyllithium followed by the reduction of the carbon-11-labeled intermediate to diphenylmethanol via lithium aluminum hydride in a radiochemical yield of 71% and a synthesis and purification time of 38 minutes. Carbon-11-labeled benzyl methyl ethermore » and diphenylmethanol were each evaluated as myelin imaging agents in three patients with multiple sclerosis via positron-emission tomography. In two out of three patients studied with carbon-11-labeled benzyl methyl ether, the distribution of activity in the brain was not consistent with local lipid content. A new synthesis of carbon-11-labeled-DL-phenylalanine labeled in the benzylic position and the synthesis of fluorine-18-labeled 1-(2-nitro-1-imidazolyl)-3-fluoro-2-propanol, a potential in vivo marker of hypoxic tissue, are reported.« less

Anti-Parkinson Activity of Petroleum Ether Extract of Ficus religiosa (L.) Leaves

PubMed Central

Bhangale, Jitendra O.; Acharya, Sanjeev R.

2016-01-01

In the present study, we evaluated anti-Parkinson's activity of petroleum ether extract of Ficus religiosa (PEFRE) leaves in haloperidol and 6 hydroxydopamine (6-OHDA) induced experimental animal models. In this study, effects of Ficus religiosa (100, 200, and 400 mg/kg, p.o.) were studied using in vivo behavioral parameters like catalepsy, muscle rigidity, and locomotor activity and its effects on neurochemical parameters (MDA, CAT, SOD, and GSH) in rats. The experiment was designed by giving haloperidol to induce catalepsy and 6-OHDA to induce Parkinson's disease-like symptoms. The increased cataleptic scores (induced by haloperidol) were significantly (p < 0.001) found to be reduced, with the PEFRE at a dose of 200 and 400 mg/kg (p.o.). 6-OHDA significantly induced motor dysfunction (muscle rigidity and hypolocomotion). 6-OHDA administration showed significant increase in lipid peroxidation level and depleted superoxide dismutase, catalase, and reduced glutathione level. Daily administration of PEFRE (400 mg/kg) significantly improved motor performance and also significantly attenuated oxidative damage. Thus, the study proved that Ficus religiosa treatment significantly attenuated the motor defects and also protected the brain from oxidative stress. PMID:26884755

Polybrominated diphenyl ether flame retardants in Virginia freshwater fishes (USA).

PubMed

Hale, R C; La Guardia, M J; Harvey, E P; Mainor, T M; Duff, W H; Gaylor, M O

2001-12-01

Polybrominated diphenyl ethers (PBDEs) were examined in fish fillets collected from two large Virginia watersheds. Emphasis was on the tetra- to hexabrominated congeners since these exhibit the greatest bioaccumulation and toxicological potentials. These congeners are dominant constituents of Penta-, a commercial PBDE product used to flame retard polyurethane foam. In 1999, North America accounted for98% of global Penta-demand. Concentrations of total tetra- to hexabrominated congeners in fillets ranged from <5 to 47,900 microg/kg (lipid basis). BDE-47, one of the two major constituents of Penta-, was detected in 89% of samples and contributed 40-70% of the total PBDEs observed. Concentrations of BDE-99, the second major constituent of the Penta- commercial mixture, were much lower in fish. While some differences in PBDE profiles between fish species were apparent, dominant congeners were consistent with those in surficial sediments from the Virginia sites and recently published data for U.S. air samples. PCB and PBDE concentrations in fish were generally associated. These factors point to exposure from nonpoint sources. Exceptions existed, likely due to inputs from local sources. The Virginia study area has historically served as a center for furniture and textile manufacturing, although polyurethane foam production here has been limited.

Polybrominated diphenyl ethers (PBDEs) in US meat and poultry: 2012-13 levels, trends and estimated consumer exposures.

PubMed

Lupton, Sara J; Hakk, Heldur

2017-09-01

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants whose use has contaminated foods and caused subsequent human exposures. To address the issue of possible human exposure, samples from a 2012-13 US meat and poultry (beef, pork, chicken, turkey) study were analysed for seven PBDEs. The mean summed concentrations of the seven BDE congeners (ΣPBDE) from beef, pork, chicken and turkey were 0.40, 0.36, 0.19, and 0.76 ng g -1 lipid weight (lw). The range of ΣPBDEs for all meat classes was 0.01-15.78 ng g -1 lw. A comparison of this study with a 2007-08 study revealed a decline in the median ΣPBDEs for all four meat classes, a reduction of 25.9% to 70.0%, with pork, chicken and turkey PBDE residues being statistically lower relative to the 2007-08 study. BDEs 47 and 99 contributed the most to the ΣPBDE concentrations, indicating likely animal exposures to the penta-BDE formulation. Based on the reported data an estimate of US consumer daily intake of PBDEs from meat and poultry was 6.42 ng day -1 .

In vitro α-glucosidase inhibition, antioxidant, anticancer, and antimycobacterial properties of ethyl acetate extract of Aegle tamilnadensis Abdul Kader (Rutaceae) leaf.

PubMed

R, Pratap Chandran; S, Nishanth Kumar; S, Manju; S, Abdul Kader; B S, Dileep Kumar

2015-01-01

The present study was aimed to investigate in vitro α-glucosidase inhibition, antioxidant, anticancer, and antimycobacterial activities of the ethyl acetate extract of A. tamilnadensis leaves. The extract recorded strong α-glucosidase inhibition with an IC50 value of 100 μg/ml. The antioxidant potential of the extract was evaluated by nitric oxide radical inhibition, lipid peroxidation inhibition, ferric thiocyanate, and ABTS radical scavenging assay, and the extract recorded significant antioxidant activity. The ferric thiocyanate activity of extract was superior to butylated hydroxyl anisol (BHA), the standard antioxidant agent. The anticancer activity of the extract was evaluated against (1) breast cancer cell lines (MDAM B-231), (2) cervical cancer cell lines (HeLa), and (3) lung cancer cell line (A 549) using MTT assay, and significant activity was recorded against A 549 with an IC50 value of 64 μg/ml. Further studies on the morphology, acridine orange/ethidium bromide staining, and cell cycle analysis by flow cytometry confirm the extract-induced apoptosis in A 549. This extract also recorded significant anti-tuberculosis activity against Mycobacterium smegmatis. The current study suggests that the ethyl acetate extract of A. tamilnadensis is a potential source of natural α-glucosidase inhibitor and antioxidant for protection as well as prevention of life-threatening diseases like cancer.

Detection of Independent Associations of Plasma Lipidomic Parameters with Insulin Sensitivity Indices Using Data Mining Methodology.

PubMed

Kopprasch, Steffi; Dheban, Srirangan; Schuhmann, Kai; Xu, Aimin; Schulte, Klaus-Martin; Simeonovic, Charmaine J; Schwarz, Peter E H; Bornstein, Stefan R; Shevchenko, Andrej; Graessler, Juergen

2016-01-01

Glucolipotoxicity is a major pathophysiological mechanism in the development of insulin resistance and type 2 diabetes mellitus (T2D). We aimed to detect subtle changes in the circulating lipid profile by shotgun lipidomics analyses and to associate them with four different insulin sensitivity indices. The cross-sectional study comprised 90 men with a broad range of insulin sensitivity including normal glucose tolerance (NGT, n = 33), impaired glucose tolerance (IGT, n = 32) and newly detected T2D (n = 25). Prior to oral glucose challenge plasma was obtained and quantitatively analyzed for 198 lipid molecular species from 13 different lipid classes including triacylglycerls (TAGs), phosphatidylcholine plasmalogen/ether (PC O-s), sphingomyelins (SMs), and lysophosphatidylcholines (LPCs). To identify a lipidomic signature of individual insulin sensitivity we applied three data mining approaches, namely least absolute shrinkage and selection operator (LASSO), Support Vector Regression (SVR) and Random Forests (RF) for the following insulin sensitivity indices: homeostasis model of insulin resistance (HOMA-IR), glucose insulin sensitivity index (GSI), insulin sensitivity index (ISI), and disposition index (DI). The LASSO procedure offers a high prediction accuracy and and an easier interpretability than SVR and RF. After LASSO selection, the plasma lipidome explained 3% (DI) to maximal 53% (HOMA-IR) variability of the sensitivity indexes. Among the lipid species with the highest positive LASSO regression coefficient were TAG 54:2 (HOMA-IR), PC O- 32:0 (GSI), and SM 40:3:1 (ISI). The highest negative regression coefficient was obtained for LPC 22:5 (HOMA-IR), TAG 51:1 (GSI), and TAG 58:6 (ISI). Although a substantial part of lipid molecular species showed a significant correlation with insulin sensitivity indices we were able to identify a limited number of lipid metabolites of particular importance based on the LASSO approach. These few selected lipids with the closest connection to sensitivity indices may help to further improve disease risk prediction and disease and therapy monitoring.

Biointerfacing polymeric microcapsules for in vivo near-infrared light-triggered drug release

NASA Astrophysics Data System (ADS)

Shao, Jingxin; Xuan, Mingjun; Si, Tieyan; Dai, Luru; He, Qiang

2015-11-01

Seeking safe and effective water-soluble drug carriers is of great significance in nanomedicine. To achieve this goal, we present a novel drug delivery system based on biointerfacing hollow polymeric microcapsules for effectively encapsulating water-soluble antitumor drug and gold nanorod (GNR) functionalization for triggered release of therapeutic drugs on-demand using low power near-infrared (NIR) radiation. The surface of polymeric microcapsules is covered with fluidic lipid bilayers to decrease the permeability of the wall of polymeric capsules. The temperature increase upon NIR illumination deconstructs the structure of the lipid membrane and polyelectrolyte multilayers, which in turn results in the rapid release of encapsulated water-soluble drug. In vivo antitumor tests demonstrate that this microcapsule has the effective ability of inhibiting tumor growth and preventing metastases. Real time in vivo fluorescence imaging results confirm that capsules can be excreted gradually from the animal body which in turn demonstrates the biocompatibility and biodegradation of these biointerfacing GNR-microcapsules. This intelligent system provides a novel anticancer platform with the advantages of controlled release, biological friendliness and credible biosafety.Seeking safe and effective water-soluble drug carriers is of great significance in nanomedicine. To achieve this goal, we present a novel drug delivery system based on biointerfacing hollow polymeric microcapsules for effectively encapsulating water-soluble antitumor drug and gold nanorod (GNR) functionalization for triggered release of therapeutic drugs on-demand using low power near-infrared (NIR) radiation. The surface of polymeric microcapsules is covered with fluidic lipid bilayers to decrease the permeability of the wall of polymeric capsules. The temperature increase upon NIR illumination deconstructs the structure of the lipid membrane and polyelectrolyte multilayers, which in turn results in the rapid release of encapsulated water-soluble drug. In vivo antitumor tests demonstrate that this microcapsule has the effective ability of inhibiting tumor growth and preventing metastases. Real time in vivo fluorescence imaging results confirm that capsules can be excreted gradually from the animal body which in turn demonstrates the biocompatibility and biodegradation of these biointerfacing GNR-microcapsules. This intelligent system provides a novel anticancer platform with the advantages of controlled release, biological friendliness and credible biosafety. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06350g

Biocompatible Lipid Nanoparticles as Carriers To Improve Curcumin Efficacy in Ovarian Cancer Treatment.

PubMed

Bondì, Maria Luisa; Emma, Maria Rita; Botto, Chiara; Augello, Giuseppa; Azzolina, Antonina; Di Gaudio, Francesca; Craparo, Emanuela Fabiola; Cavallaro, Gennara; Bachvarov, Dimcho; Cervello, Melchiorre

2017-02-22

Curcumin is a natural molecule with proved anticancer efficacy on several human cancer cell lines. However, its clinical application has been limited due to its poor bioavailability. Nanocarrier-based drug delivery approaches could make curcumin dispersible in aqueous media, thus overtaking the limits of its low solubility. The aim of this study was to increase the bioavailability and the antitumoral activity of curcumin, by entrapping it into nanostructured lipid carriers (NLCs). For this purpose here we describe the preparation and characterization of three kinds of curcumin-loaded NLCs. The nanosystems allowed the achievement of a controlled release of curcumin, the amounts of curcumin released after 24 h from Compritol-Captex, Compritol-Miglyol, and Compritol NLCs being, respectively, equal to 33, 28, and 18% w/w on the total entrapped curcumin. Considering the slower curcumin release profile, Compritol NLCs were chosen to perform successive in vitro studies on ovarian cancer cell lines. The results show that curcumin-loaded NLCs maintain anticancer activity, and reduce cell colony survival more effectively than free curcumin. As an example, the ability of A2780S cells to form colonies was decreased after treatment with 5 μM free curcumin by 50% ± 6, whereas, at the same concentration, the delivery of curcumin with NLC significantly (p < 0.05) inhibited colony formation to approximately 88% ± 1, therefore potentiating the activity of curcumin to inhibit A2780S cell growth. The obtained results clearly suggest that the entrapment of curcumin into NLCs increases curcumin efficacy in vitro, indicating the potential use of NLCs as curcumin delivery systems.

Total lipid extraction of homogenized and intact lean fish muscles using pressurized fluid extraction and batch extraction techniques.

PubMed

Isaac, Giorgis; Waldebäck, Monica; Eriksson, Ulla; Odham, Göran; Markides, Karin E

2005-07-13

The reliability and efficiency of pressurized fluid extraction (PFE) technique for the extraction of total lipid content from cod and the effect of sample treatment on the extraction efficiency have been evaluated. The results were compared with two liquid-liquid extraction methods, traditional and modified methods according to Jensen. Optimum conditions were found to be with 2-propanol/n-hexane (65:35, v/v) as a first and n-hexane/diethyl ether (90:10, v/v) as a second solvent, 115 degrees C, and 10 min of static time. PFE extracts were cleaned up using the same procedure as in the methods according to Jensen. When total lipid yields obtained from homogenized cod muscle using PFE were compared yields obtained with original and modified Jensen methods, PFE gave significantly higher yields, approximately 10% higher (t test, P < 0.05). Infrared and NMR spectroscopy suggested that the additional material that inflates the gravimetric results is rather homogeneous and is primarily consists of phospholipid with headgroups of inositidic and/or glycosidic nature. The comparative study demonstrated that PFE is an alternative suitable technique to extract total lipid content from homogenized cod (lean fish) and herring (fat fish) muscle showing a precision comparable to that obtained with the traditional and modified Jensen methods. Despite the necessary cleanup step, PFE showed important advantages in the solvent consumption was cut by approximately 50% and automated extraction was possible.

Tryptophan scanning mutagenesis of the HERG K+ channel: the S4 domain is loosely packed and likely to be lipid exposed

PubMed Central

Subbiah, Rajesh N; Kondo, Mari; Campbell, Terence J; Vandenberg, Jamie I

2005-01-01

Inherited mutations or drug-induced block of voltage-gated ion channels, including the human ether-à-go-go-related gene (HERG) K+ channel, are significant causes of malignant arrhythmias and sudden death. The fourth transmembrane domain (S4) of these channels contains multiple positive charges that move across the membrane electric field in response to changes in transmembrane voltage. In HERG K+ channels, the movement of the S4 domain across the transmembrane electric field is particularly slow. To examine the basis of the slow movement of the HERG S4 domain and specifically to probe the relationship between the S4 domain with the lipid bilayer and rest of the channel protein, we individually mutated each of the S4 amino acids in HERG (L524–L539) to tryptophan, and characterized the activation and deactivation properties of the mutant channels in Xenopus oocytes, using two-electrode voltage-clamp methods. Tryptophan has a large bulky hydrophobic sidechain and so should be tolerated at positions that interact with lipid, but not at positions involved in close protein–protein interactions. Significantly, we found that all S4 tryptophan mutants were functional. These data indicate that the S4 domain is loosely packed within the rest of the voltage sensor domain and is likely to be lipid exposed. Further, we identified residues K525, R528 and K538 as being the most important for slow activation of the channels. PMID:16166152

Changes in visceral adipose tissue plasma membrane lipid composition in old rats are associated with adipocyte hypertrophy with aging.

PubMed

Bonzón-Kulichenko, Elena; Moltó, Eduardo; Pintado, Cristina; Fernández, Alejandro; Arribas, Carmen; Schwudke, Dominik; Gallardo, Nilda; Shevchenko, Andrej; Andrés, Antonio

2018-04-16

Increased adiposity, through adipocyte hypertrophy and/or hyperplasia, characterizes aging and obesity. Both are leptin-resistant states, associated to disturbed lipid metabolism, reduced insulin sensitivity and inflammation. Nevertheless, fat tissue dysfunction appears earlier in obesity than in normal aging. In contrast, lipodystrophy is accompanied by diabetes, and improving the fat cell capacity to expand rescues the diabetic phenotype. Fat tissue dysfunction is extensively studied in the diet-induced obesity, but remains relatively neglected in the aging-associated obesity. In the Wistar rat, as occurs in humans, early or middle aging is accompanied by an increase in adiposity. Using this experimental model, we describe the molecular mechanisms contributing to the white adipose tissue (WAT) hypertrophy. WAT from middle-old age rats is characterized by decreased basal lipogenesis and lipolysis, increased esterification, as demonstrated by the higher TAG and cholesterol content in visceral WAT, and the maintenance of total ceramide levels within normal values. In addition, we describe alterations in the adipose tissue plasma membrane lipid composition, as increased total ether-phosphatidylcholine, sphingomyelin and free cholesterol levels that favor an enlarged fat cell size with aging. All these metabolic changes may be regarded as a survival advantage that prevents the aged rats from becoming overtly diabetic.

Concentrations of persistent organic pollutants (POPs) in human blood samples from Mexico City, Mexico.

PubMed

Orta-García, Sandra; Pérez-Vázquez, Francisco; González-Vega, Carolina; Varela-Silva, José Antonio; Hernández-González, Lidia; Pérez-Maldonado, Iván

2014-02-15

Studies in Mexico have demonstrated exposure to persistent organic pollutants (POPs) in people living in different sites through the country. However, studies evaluating exposure to POPs in people living in Mexico City (one of most contaminated places in the world) are scarce. Therefore, the aim of this study was to assess the levels of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) in the blood as exposure biomarkers in people living in Mexico City. A total of 123 participants (blood donors aged 20-60 years) were recruited during 2010 in Mexico City. Quantitative analyses of blood samples were performed using gas chromatography coupled with mass spectrometry. Levels of the assessed compounds ranged from non-detectable (

Microbial communities in liquid and fiber fractions of food waste digestates are differentially resistant to inhibition by ammonia.

PubMed

Peng, Wei; Lü, Fan; Shao, Liming; He, Pinjing

2015-04-01

The effect of different concentrations of ammonia (1.0-7.0 g/L) during mesophilic anaerobic digestion with fiber or liquid digestate as inoculum was examined. Evolution of microbial community within fiber and liquid digestates was quantitatively assessed by the intact lipid analysis methods and qualitatively by DNA fingerprint methods in order to determine their resistance to ammonia inhibition. The results showed that an increased level of total ammonia nitrogen prolonged the lag phase of fiber digestates while reduced the metabolic rate of liquid digestates. Fiber digestates had 19.6-50.9-fold higher concentrations of phospholipid fatty acids (PLFA) compared to liquid digestates, whereas concentrations of phospholipid ether lipids (PLEL) in the fiber digestates were only 2.91-17.6-fold higher compared to liquid digestates. Although the cell concentration in liquid fraction was far lower than that in the fiber one, the ammonia-resistant ability and the methanization efficiency of the liquid digestate was superior to the fiber digestate. The bacterial profiles were affected more by the type of digestate inoculum compared to the concentration of ammonia. Principal component analysis indicated that the lipids technique was superior to the DNA technique for bacterial quantification but detected less archaeal diversity.

Accumulation, metabolism, and food-chain transfer of chlorinated and brominated contaminants in subadult white whales (Delphinapterus leucas) and narwhals (Monodon monoceros) from Svalbard, Norway.

PubMed

Wolkers, H; Lydersen, C; Kovacs, K M; Burkow, I; van Bavel, B

2006-01-01

The concentrations and patterns of polychlorinated biphenyls (PCBs), chlorinated pesticides, and polybrominated diphenyl ethers (PBDEs) were studied in white whales (Delphinapterus leucas) and narwhals (Monodon monoceros) from Svalbard, Norway. In addition, their main food items were included in the study. In the whales, a broad range of pollutants was found in relatively high concentrations. PCBs and pesticides were approximately 3000 and 8000 ng/g lipid, respectively, for white whales and three times higher for narwhals. PBDEs 47 were approximately 70 ng/g lipid for white whales and 170 ng/g lipid for narwhals. Compared with other marine mammals from the same area, contaminant levels are among the highest levels ever measured. These high levels are likely in part because of a decreased capacity to metabolize contaminants. Metabolic indices indicated that most compounds accumulate to the same degree in white whales and narwhals, but for some toxaphenes and chlordanes, narwhals might have a decreased metabolism and consequently a higher accumulation. The three-times-higher contaminant levels in blubber of narwhals was further explained by substantially higher contaminant levels in their more benthic diet. The high levels and broad pattern of accumulating pollutants make white whales and narwhals excellent indicators for a wide range of contaminants in the Arctic.

Mapping an atlas of tissue-specific Drosophila melanogaster metabolomes by high resolution mass spectrometry.

PubMed

Chintapalli, Venkateswara R; Al Bratty, Mohammed; Korzekwa, Dominika; Watson, David G; Dow, Julian A T

2013-01-01

Metabolomics can provide exciting insights into organismal function, but most work on simple models has focussed on the whole organism metabolome, so missing the contributions of individual tissues. Comprehensive metabolite profiles for ten tissues from adult Drosophila melanogaster were obtained here by two chromatographic methods, a hydrophilic interaction (HILIC) method for polar metabolites and a lipid profiling method also based on HILIC, in combination with an Orbitrap Exactive instrument. Two hundred and forty two polar metabolites were putatively identified in the various tissues, and 251 lipids were observed in positive ion mode and 61 in negative ion mode. Although many metabolites were detected in all tissues, every tissue showed characteristically abundant metabolites which could be rationalised against specific tissue functions. For example, the cuticle contained high levels of glutathione, reflecting a role in oxidative defence; the alimentary canal (like vertebrate gut) had high levels of acylcarnitines for fatty acid metabolism, and the head contained high levels of ether lipids. The male accessory gland uniquely contained decarboxylated S-adenosylmethionine. These data thus both provide valuable insights into tissue function, and a reference baseline, compatible with the FlyAtlas.org transcriptomic resource, for further metabolomic analysis of this important model organism, for example in the modelling of human inborn errors of metabolism, aging or metabolic imbalances such as diabetes.

Sulfonimide-containing poly(arylene ether)s and poly(arylene ether sulfone)s, methods for producing the same, and uses thereof

DOEpatents

Hofmann, Michael A.

2006-11-14

The present invention is directed to sulfonimide-containing polymers, specifically sulfonimide-containing poly(arylene ether)s and sulfonimide-containing poly(arylene ether sulfone)s, and processes for making the sulfonimide-containing poly(arylene ether)s and sulfonimide-containing poly(arylene ether sulfone)s, for use conductive membranes and fuel cells.

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

PubMed Central

Masi, A; Becchetti, A; Restano-Cassulini, R; Polvani, S; Hofmann, G; Buccoliero, A M; Paglierani, M; Pollo, B; Taddei, G L; Gallina, P; Di Lorenzo, N; Franceschetti, S; Wanke, E; Arcangeli, A

2005-01-01

Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K+ channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K+ channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1's biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K+ channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies. PMID:16175187

Decoration of a Poly(methyl vinyl ether-co-maleic anhydride)-Shelled Selol Nanocapsule with Folic Acid Increases Its Activity Against Different Cancer Cell Lines In Vitro.

PubMed

Ganassin, Rayane; Souza, Ludmilla Regina de; Py-Daniel, Karen Rapp; Longo, João Paulo Figueiró; Coelho, Janaína Moreira; Rodrigues, Mosar Correa; Jiang, Cheng-Shi; Gu, Jinsong; Morais, Paulo César de; Mosiniewicz-Szablewska, Ewa; Suchocki, Piotr; Báo, Sônia Nair; Azevedo, Ricardo Bentes; Muehlmann, Luis Alexandre

2018-01-01

Due to the low therapeutic index of different chemotherapeutic drugs used for cancer treatment, the development of new anticancer drugs remains an intense field of research. A recently developed mixture of selenitetriacylglycerides, selol, was shown to be active against different cancer cells in vitro. As this compound is highly hydrophobic, it was encapsulated, in a previous study, into poly(methyl vinyl ether-co-maleic anhydride)-shelled nanocapsules in order to improve its dispersibility in aqueous media. Following this line of research, the present report aimed at enhancing the In Vitro activity of the selol nanocapsules against cancerous cells by decorating their surface with folic acid. It is known that several cancer cells overexpress folate receptors. Stable folic acid-decorated selol nanocapsules (SNP-FA) were obtained, which showed to be spherical, with a hydro-dynamic diameter of 364 nm, and zeta potential of -24 mV. In comparison to non-decorated selol nanocapsules, SNP-FA presented higher activity against 4T1, MCF-7 and HeLa cells. Moreover, the decoration of the nanocapsules did not alter their toxicity towards fibroblasts, NIH-3T3 cells. These results show that the decoration with folic acid increased the toxicity of selol nanocapsules to cancer cells. These nanocapsules, besides enabling to disperse selol in an aqueous medium, increased the toxicity of this drug In Vitro, and may be useful to treat cancer in vivo, potentially increasing the specificity of selol towards cancer cells.

Stabilization of Resveratrol in Blood Circulation by Conjugation to mPEG and mPEG-PLA Polymers: Investigation of Conjugate Linker and Polymer Composition on Stability, Metabolism, Antioxidant Activity and Pharmacokinetic Profile

PubMed Central

Siddalingappa, Basavaraj; Benson, Heather A. E.; Brown, David H.; Batty, Kevin T.; Chen, Yan

2015-01-01

Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol. PMID:25799413

Designed Synthesis of Lipid-Coated Polyacrylic Acid/Calcium Phosphate Nanoparticles as Dual pH-Responsive Drug-Delivery Vehicles for Cancer Chemotherapy.

PubMed

Wang, Xin; Zhang, Manjie; Zhang, Lingyu; Li, Lu; Li, Shengnan; Wang, Chungang; Su, Zhongmin; Yuan, Yue; Pan, Weisan

2017-05-11

Herein, we report a facile strategy to prepare supported lipid-bilayer-coated polyacrylic acid/calcium phosphate nanoparticles (designated as PAA/CaP@SLB NPs) as a new dual pH-responsive drug-delivery platform for cancer chemotherapy. The synthesized PAA/CaP NPs exhibited both a high payload of doxorubicin (DOX) and dual pH-responsive drug-release properties. Additionally, the coated lipid bilayer had the ability to enhance the cellular uptake of PAA/CaP NPs without affecting the pH-responsive drug release. Moreover, the blank PAA/CaP@SLB NPs exhibited excellent biocompatibility and the DOX-loaded PAA/CaP@SLB NPs markedly increased the cellular accumulation of DOX and its cytotoxic effects on HepG-2 cells. Furthermore, when used to evaluate the in vivo therapeutic efficacy in mice with the hepatocarcinoma cell line (H-22), the DOX-loaded PAA/CaP@SLB NPs exhibited superior inhibition of tumor growth compared with the free DOX group. Thus, PAA/CaP@SLB NPs are a promising drug-delivery vehicle to increase the therapeutic efficacy of anticancer drugs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure of Protein Geranylgeranyltransferase-I from the Human Pathogen Candida albicans Complexed with a Lipid Substrate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hast, Michael A.; Beese, Lorena S.

2008-11-21

Protein geranylgeranyltransferase-I (GGTase-I) catalyzes the transfer of a 20-carbon isoprenoid lipid to the sulfur of a cysteine residue located near the C terminus of numerous cellular proteins, including members of the Rho superfamily of small GTPases and other essential signal transduction proteins. In humans, GGTase-I and the homologous protein farnesyltransferase (FTase) are targets of anticancer therapeutics because of the role small GTPases play in oncogenesis. Protein prenyltransferases are also essential for many fungal and protozoan pathogens that infect humans, and have therefore become important targets for treating infectious diseases. Candida albicans, a causative agent of systemic fungal infections in immunocompromisedmore » individuals, is one pathogen for which protein prenylation is essential for survival. Here we present the crystal structure of GGTase-I from C. albicans (CaGGTase-I) in complex with its cognate lipid substrate, geranylgeranylpyrophosphate. This structure provides a high-resolution picture of a non-mammalian protein prenyltransferase. There are significant variations between species in critical areas of the active site, including the isoprenoid-binding pocket, as well as the putative product exit groove. These differences indicate the regions where specific protein prenyltransferase inhibitors with antifungal activity can be designed.« less

Single-step assembly of polymer-lipid hybrid nanoparticles for mitomycin C delivery

PubMed Central

2014-01-01

Mitomycin C is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its clinical use is still hindered by the mitomycin C (MMC) delivery systems. In this study, the MMC-loaded polymer-lipid hybrid nanoparticles (NPs) were prepared by a single-step assembly (ACS Nano 2012, 6:4955 to 4965) of MMC-soybean phosphatidyhlcholine (SPC) complex (Mol. Pharmaceutics 2013, 10:90 to 101) and biodegradable polylactic acid (PLA) polymers for intravenous MMC delivery. The advantage of the MMC-SPC complex on the polymer-lipid hybrid NPs was that MMC-SPC was used as a structural element to offer the integrity of the hybrid NPs, served as a drug preparation to increase the effectiveness and safety and control the release of MMC, and acted as an emulsifier to facilitate and stabilize the formation. Compared to the PLA NPs/MMC, the PLA NPs/MMC-SPC showed a significant accumulation of MMC in the nuclei as the action site of MMC. The PLA NPs/MMC-SPC also exhibited a significantly higher anticancer effect compared to the PLA NPs/MMC or free MMC injection in vitro and in vivo. These results suggested that the MMC-loaded polymer-lipid hybrid NPs might be useful and efficient drug delivery systems for widening the therapeutic window of MMC and bringing the clinical use of MMC one step closer to reality. PMID:25324707

New Updates Pertaining to Drug Delivery of Local Anesthetics in Particular Bupivacaine Using Lipid Nanoparticles

NASA Astrophysics Data System (ADS)

Beiranvand, Siavash; Eatemadi, Ali; Karimi, Arash

2016-06-01

Lipid nanoparticles (liposomes) were first described in 1965, and several work have led to development of important technical advances like triggered release liposomes and drug-loaded liposomes. These advances have led to numerous clinical trials in such diverse areas such as the delivery of anti-cancer, antifungal, and antibiotic drugs; the delivery of gene medicines; and most importantly the delivery of anesthesia drugs. Quite a number of liposomes are on the market, and many more are still in developmental stage. Lipid nanoparticles are the first nano-medicine delivery system to be advanced from laboratory concept to clinical application with high considerable clinical acceptance. Drug delivery systems for local anesthetics (LAs) have caught the interest of many researchers because there are many biomedical advantages connected to their application. There have been several formulation techniques to systemically deliver LA that include encapsulation in liposomes and complexation in cyclodextrins, nanoparticles, and to a little extent gold nanoparticles. The proposed formulations help to decrease the LA concentration utilized, increase its permeability, and most importantly increase the localization of the LA for a long period of time thereby leading to increase in the duration of the LA effect and finally to reduce any local and systemic toxicity. In this review, we will highlight on new updates pertaining to drug delivery of local anesthetics in particular bupivacaine using lipid nanoparticles.

New Updates Pertaining to Drug Delivery of Local Anesthetics in Particular Bupivacaine Using Lipid Nanoparticles.

PubMed

Beiranvand, Siavash; Eatemadi, Ali; Karimi, Arash

2016-12-01

Lipid nanoparticles (liposomes) were first described in 1965, and several work have led to development of important technical advances like triggered release liposomes and drug-loaded liposomes. These advances have led to numerous clinical trials in such diverse areas such as the delivery of anti-cancer, antifungal, and antibiotic drugs; the delivery of gene medicines; and most importantly the delivery of anesthesia drugs. Quite a number of liposomes are on the market, and many more are still in developmental stage. Lipid nanoparticles are the first nano-medicine delivery system to be advanced from laboratory concept to clinical application with high considerable clinical acceptance. Drug delivery systems for local anesthetics (LAs) have caught the interest of many researchers because there are many biomedical advantages connected to their application. There have been several formulation techniques to systemically deliver LA that include encapsulation in liposomes and complexation in cyclodextrins, nanoparticles, and to a little extent gold nanoparticles. The proposed formulations help to decrease the LA concentration utilized, increase its permeability, and most importantly increase the localization of the LA for a long period of time thereby leading to increase in the duration of the LA effect and finally to reduce any local and systemic toxicity. In this review, we will highlight on new updates pertaining to drug delivery of local anesthetics in particular bupivacaine using lipid nanoparticles.

Curcumin-loaded solid lipid nanoparticles have prolonged in vitro antitumour activity, cellular uptake and improved in vivo bioavailability.

PubMed

Sun, Jiabei; Bi, Chao; Chan, Hok Man; Sun, Shaoping; Zhang, Qingwen; Zheng, Ying

2013-11-01

The aim of the present study was to blend liquid lipids with solid lipids to encapsulate curcumin in solid lipid nanoparticles (SLNs), thereby improving the dispersibility and chemical stability of curcumin, prolonging its antitumour activity and cellular uptake and enhancing its bioavailability. Curcumin-loaded SLNs (C-SLNs) were prepared by high-pressure homogenisation with liquid lipid Sefsol-218(®). The morphology, stability and release of curcumin in the optimised formulation were investigated. The anti-cancer activity of the formulation was evaluated in MCF-7 cells. Fluorescence spectrophotometry was used to quantify cellular uptake of the drug. The pharmacokinetic profiles of curcumin in SLNs after intravenous administration were studied in rats. Blending Sefsol-218(®) into a lipid matrix reduced the particle size without improving drug loading. An optimised formulation consisting of Dynasan 114(®), Sefsol-218(®), and Pluronic F68(®) (630:70:300, w/w) loaded with 0.8% drug was prepared. This formulation could be dispersed in water with a mean particle size of 152.8 ± 4.7 nm and a 90% entrapment efficiency. Curcumin displayed a two-phase sustained release profile from C-SLNs with improved chemical stability. Compared to the solubilised solution, C-SLNs exhibited prolonged inhibitory activity in cancer cells, as well as time-dependent increases in intracellular uptake. After intravenous administration to rats, the bioavailability of curcumin was increased by 1.25-fold. C-SLNs with improved dispersibility and chemical stability in an aqueous system have been successfully developed. C-SLNs may represent a potentially useful cancer therapeutic curcumin delivery system. Copyright © 2013 Elsevier B.V. All rights reserved.

Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.

PubMed

Di Scala, Coralie; Fantini, Jacques; Yahi, Nouara; Barrantes, Francisco J; Chahinian, Henri

2018-05-22

Anandamide is a lipid neurotransmitter derived from arachidonic acid, a polyunsaturated fatty acid. The chemical differences between anandamide and arachidonic acid result in a slightly enhanced solubility in water and absence of an ionisable group for the neurotransmitter compared with the fatty acid. In this review, we first analyze the conformational flexibility of anandamide in aqueous and membrane phases. We next study the interaction of the neurotransmitter with membrane lipids and discuss the molecular basis of the unexpected selectivity of anandamide for cholesterol and ceramide from among other membrane lipids. We show that cholesterol behaves as a binding partner for anandamide, and that following an initial interaction mediated by the establishment of a hydrogen bond, anandamide is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu. The complex is then directed to the anandamide cannabinoid receptor (CB1) which displays a high affinity binding pocket for anandamide. We propose that cholesterol may regulate the entry and exit of anandamide in and out of CB1 by interacting with low affinity cholesterol recognition sites (CARC and CRAC) located in transmembrane helices. The mirror topology of cholesterol binding sites in the seventh transmembrane domain is consistent with the delivery, extraction and flip-flop of anandamide through a coordinated cholesterol-dependent mechanism. The binding of anandamide to ceramide illustrates another key function of membrane lipids which may occur independently of protein receptors. Interestingly, ceramide forms a tight complex with anandamide which blocks the degradation pathway of both lipids and could be exploited for anti-cancer therapies.

Accumulation of polybrominated diphenyl ethers in breast milk of women from an e-waste recycling center in China.

PubMed

Li, Xinghong; Tian, Yuan; Zhang, Yun; Ben, Yujie; Lv, Quanxia

2017-02-01

Polybrominated diphenyl ethers (PBDEs) can be transferred to infants through the ingestion of breast milk, resulting in potential health risk. In this study, PBDEs, hydroxylated polybrominated diphenyl ethers (OH-PBDEs) and 2,2',4,4',5,6'-hexachlorobiphenyl (CB-153) in human milk from women living adjacent to e-waste recycling sites of Wenling, China, were investigated. The median level of PBDEs in samples from residents living in the e-waste recycling environment >20years (R 20 group, 19.5ng/g lipid weight (lw)) was significantly higher than that for residents living in Wenling <3years (R 3 group, 3.88ng/g lw) (p<0.05), likely ascribable to specific exposure to PBDEs from e-waste recycling activities. In the R 20 group, most congeners (except for BDE-209) were correlated with each other (p<0.05). Moreover, CB-153 showed significant association with most PBDE congeners, rather than BDE-209. The relationship indicated that most BDE congeners other than BDE-209 shared common sources and/or pathways with CB-153, e.g., dietary ingestion. The correlations between BDE-209 and other congeners were different in the two groups, likely suggesting their different exposure sources and/or pathways for PBDEs. Although estimated dietary intake of PBDEs for infants via breast milk was lower than the minimum value affecting human health, the PBDE exposure of infants should be of great concern because of their potential effect on the development of neonates over long-term exposure. OH-PBDEs were not detected in the collected samples, which is in accordance with reports in published literature, likely indicating that they were not apt to be accumulated in human milk. Copyright © 2016. Published by Elsevier B.V.

Pharmacological Potential of Sea Cucumbers

PubMed Central

Khotimchenko, Yuri

2018-01-01

This review presents a detailed analysis of published research data focused on the pharmacological activity exerted by biologically active compounds isolated from sea cucumbers belonging to the class of Holothuroidea, phylum Echinodermata. The review contains descriptions of the structure, physico-chemical properties and pharmacological effects of these active substances. Particular attention is given to compounds with anticoagulant, antithrombotic, antioxidant, anticancer, anti-infectious, immune-stimulating and anti-ACE (angiotensin converting enzyme) activities as well as to the substances exerting a regulating influence on lipid and carbohydrate metabolism. All these compounds may be considered as prototypes for development of new pharmaceutical substances and medicines. PMID:29724051

Cinnamon: A Multifaceted Medicinal Plant

PubMed Central

Rao, Pasupuleti Visweswara; Gan, Siew Hua

2014-01-01

Cinnamon (Cinnamomum zeylanicum, and Cinnamon cassia), the eternal tree of tropical medicine, belongs to the Lauraceae family. Cinnamon is one of the most important spices used daily by people all over the world. Cinnamon primarily contains vital oils and other derivatives, such as cinnamaldehyde, cinnamic acid, and cinnamate. In addition to being an antioxidant, anti-inflammatory, antidiabetic, antimicrobial, anticancer, lipid-lowering, and cardiovascular-disease-lowering compound, cinnamon has also been reported to have activities against neurological disorders, such as Parkinson's and Alzheimer's diseases. This review illustrates the pharmacological prospective of cinnamon and its use in daily life. PMID:24817901

Plasma Lipidomic Profiles Improve on Traditional Risk Factors for the Prediction of Cardiovascular Events in Type 2 Diabetes Mellitus.

PubMed

Alshehry, Zahir H; Mundra, Piyushkumar A; Barlow, Christopher K; Mellett, Natalie A; Wong, Gerard; McConville, Malcolm J; Simes, John; Tonkin, Andrew M; Sullivan, David R; Barnes, Elizabeth H; Nestel, Paul J; Kingwell, Bronwyn A; Marre, Michel; Neal, Bruce; Poulter, Neil R; Rodgers, Anthony; Williams, Bryan; Zoungas, Sophia; Hillis, Graham S; Chalmers, John; Woodward, Mark; Meikle, Peter J

2016-11-22

Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization-tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with ≥1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework. Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678-0.682) to 0.700 (95% CI, 0.698-0.702; P<0.0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219-0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738-0.742) to 0.760 (95% CI, 0.757-0.762; P<0.0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317-0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease). The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus. URL: https://clinicaltrials.gov. Unique identifier: NCT00145925. © 2016 American Heart Association, Inc.

A Review on the Pharmacological Activities and Phytochemicals of Alpinia officinarum (Galangal) Extracts Derived from Bioassay-Guided Fractionation and Isolation

PubMed Central

Basri, Aida Maryam; Taha, Hussein; Ahmad, Norhayati

2017-01-01

The rhizomes of Alpinia officinarum Hance have been used conventionally for the treatment of various ailments, triggering a wide interest from the scientific research community on this ethnomedicinal plant. This review summarizes the phytochemical and pharmacological properties of the extracts and fractions from A. officinarum, a plant species of the Zingiberaceae family. Different parts of the plant – leaves, roots, rhizomes, and aerial parts – have been extracted in various solvents – methanol, ethanol, ethyl acetate, hexane, dichloromethane, aqueous, chloroform, and petroleum ether, using various techniques – Soxhlet extraction, maceration, ultrasonication, and soaking, whereas fractionation of the plant extracts involves the solvent–solvent partition method. The extracts, fractions, and isolated compounds have been studied for their biological activities – antioxidant, antibacterial, anti-inflammatory, anticancer, antiproliferative, inhibition of enzymes, as well as the inhibition of nitric oxide production. More findings on A. officinarum are certainly important to further develop potential bioactive drug compounds. PMID:28503054

Development In Drug Targeting And Delivery In Cervical Cancer.

PubMed

Aggarwal, Urvashi; Goyal, Amit Kumar; Rath, Goutam

2017-10-09

Cervical cancer is the second most common cancer in women. Standard treatment options available for cervical cancer including chemotherapy, surgery and radiation therapy associated with their own side effects and toxicities. Tumor-targeted delivery of anticancer drugs is perhaps one of the most appropriate strategies to achieve optimal outcomes from treatment and improve quality of life. Recently nanocarriers based drug delivery systems owing to their unique properties have been extensively investigated for anticancer drug delivery. In addition to that addressing the anatomical significance of cervical cancer, various local drug delivery strategies for the cancer treatment are introduced like: gels, nanoparticles, polymeric films, rods and wafers, lipid based nanocarrier. Localized drug delivery systems allows passive drug targeting results in high drug concentration at the target site. Further they can be tailor made to achieve both sustained and controlled release behavior, substantially improving therapeutic outcomes and minimizing side effects. This review summarizes the meaningful advances in drug delivery strategies to treat cervical cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Nanoscale Reaction Vessels Designed for Synthesis of Copper-Drug Complexes Suitable for Preclinical Development

PubMed Central

Wehbe, Mohamed; Anantha, Malathi; Backstrom, Ian; Leung, Ada; Chen, Kent; Malhotra, Armaan; Edwards, Katarina; Bally, Marcel B.

2016-01-01

The development of copper-drug complexes (CDCs) is hindered due to their very poor aqueous solubility. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anticancer activity of DDC is dependent on complexation with copper to form copper bis-diethyldithiocarbamate (Cu(DDC)2), a highly insoluble complex that has not been possible to develop for indications requiring parenteral administration. We have resolved this issue by synthesizing Cu(DDC)2 inside liposomes. DDC crosses the liposomal lipid bilayer, reacting with the entrapped copper; a reaction that can be observed through a colour change as the solution goes from a light blue to dark brown. This method is successfully applied to other CDCs including the anti-parasitic drug clioquinol, the natural product quercetin and the novel targeted agent CX-5461. Our method provides a simple, transformative solution enabling, for the first time, the development of CDCs as viable candidate anticancer drugs; drugs that would represent a brand new class of therapeutics for cancer patients. PMID:27055237

Nanoscale Reaction Vessels Designed for Synthesis of Copper-Drug Complexes Suitable for Preclinical Development.

PubMed

Wehbe, Mohamed; Anantha, Malathi; Backstrom, Ian; Leung, Ada; Chen, Kent; Malhotra, Armaan; Edwards, Katarina; Bally, Marcel B

2016-01-01

The development of copper-drug complexes (CDCs) is hindered due to their very poor aqueous solubility. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anticancer activity of DDC is dependent on complexation with copper to form copper bis-diethyldithiocarbamate (Cu(DDC)2), a highly insoluble complex that has not been possible to develop for indications requiring parenteral administration. We have resolved this issue by synthesizing Cu(DDC)2 inside liposomes. DDC crosses the liposomal lipid bilayer, reacting with the entrapped copper; a reaction that can be observed through a colour change as the solution goes from a light blue to dark brown. This method is successfully applied to other CDCs including the anti-parasitic drug clioquinol, the natural product quercetin and the novel targeted agent CX-5461. Our method provides a simple, transformative solution enabling, for the first time, the development of CDCs as viable candidate anticancer drugs; drugs that would represent a brand new class of therapeutics for cancer patients.

Entrapment into nanoemulsions potentiates the anticancer activity of tocotrienols against the highly malignant (+SA) mouse mammary epithelial cells.

PubMed

Alayoubi, Alaadin; Ayoub, Nehad M; Malaviya, Abhita; Sylvester, Paul W; Nazzal, Sami

2014-05-01

The highly malignant +SA mouse mammary epithelial cells were used as the model cell line over the years to establish the anticancer activity of tocotrienols. Tocotrienols, however, have poor oral bioavailability and were therefore entrapped into parenteral nanoemulsions for parenteral administration. The objective of this work was to test whether the activity of tocotrienols in lipid nanoemulsions against the +SA cells was retained. A secondary objective was to test whether stabilizing the nanoemulsions with poloxamer or sodium oleate would affect their activity. Nanoemulsions were found to be significantly more potent than tocotrienol/albumin conjugate. The IC50 values of the poloxamer and sodium oleate nanoemulsions were 3 and 6 microM, respectively, whereas the IC50 value of the conjugate was 10 microM. The antiproliferative activity of the nanoemulsions was also found to inversely correlate with particle size. No activity was observed with nanoemulsions loaded with alpha-tocopherol or vehicle, which confirmed the cytotoxic activity of tocotrienols and the potential use of nanoemulsions in cancer therapy.

Scavenging amphipods: sentinels for penetration of mercury and persistent organic chemicals into food webs of the deep Arctic Ocean.

PubMed

Bidleman, Terry F; Stern, Gary A; Tomy, Gregg T; Hargrave, Barry T; Jantunen, Liisa M; Macdonald, Robie W

2013-06-04

Archived specimens of the scavenging amphipod Eurythenes gryllus, collected from 2075 to 4250 m below the surface on five expeditions to the western and central Arctic Ocean between 1983 and 1998, were analyzed for total mercury (∑Hg), methyl mercury (MeHg), polychlorinated biphenyls (PCBs) and other industrial or byproduct organochlorines (chlorobenzenes, pentachloroanisole, octachlorostyrene), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs). Median ∑Hg concentrations ranged from 70 to 366 ng g(-1) wet weight (ww). MeHg concentrations (3.55 to 23.5 ng g(-1) ww) accounted for 1.7 to 20.1% (median 3.7%) of ∑Hg. ∑Hg and MeHg were positively and significantly correlated with ww (∑Hg r(2) = 0.18, p = 0.0004, n = 63; MeHg r(2) = 0.42, p = 0.0004, n = 25), but not significantly with δ(13)C nor δ(15)N. Median concentrations of total persistent organic pollutants (POPs) ranged from 9750 to 156,000 ng g(-1) lipid weight, with order of abundance: ∑TOX (chlorobornanes quantified as technical toxaphene) > ∑PCBs > ∑DDTs > ∑chlordanes > ∑mirex compounds > ∑BDEs ∼ ∑chlorobenzenes ∼ octachlorostyrene > α-hexachlorocyclohexane ∼ hexachlorobenzene ∼ pentachloroanisole. Enantioselective accumulation was found for the chiral OCPs o,p'-DDT, cis- and trans-chlordane, nonachlor MC6 and oxychlordane. Lipid-normalized POPs concentrations were elevated in amphipods with lipid percentages ≤10%, suggesting that utilization of lipids resulted in concentration of POPs in the remaining lipid pool. Multidimensional Scaling (MDS) analysis using log-transformed physiological variables and lipid-normalized organochlorine concentrations distinguished amphipods from the central vs western arctic stations. This distinction was also seen for PCB homologues, whereas profiles of other compound classes were more related to specific stations rather than central-west differences.

Design and characterization of Amoitone B-loaded nanostructured lipid carriers for controlled drug release.

PubMed

Luan, Jingjing; Zhang, Dianrui; Hao, Leilei; Li, Caiyun; Qi, Lisi; Guo, Hejian; Liu, Xinquan; Zhang, Qiang

2013-11-01

Amoitone B, a novel compound chemically synthesized as the analogue of cytosporone B, has been proved to own superior affinity with Nur77 than its parent compound and exhibit notable anticancer activity. However, its application is seriously restricted due to the water-insolubility and short biological half-time. The aim of this study was to construct an effective delivery system for Amoitone B to realize sustained release, thus prolong drug circulation time in body and improve the bioavailability. Nanostructured lipid carriers (NLC) act as a new type of colloidal drug delivery system, which offer the advantages of improved drug loading and sustained release. Amoitone B-loaded NLC (AmB-NLC) containing glyceryl monostearate (GMS) and various amounts of medium chain triglycerides (MCT) were successfully prepared by emulsion-evaporation and low temperature-solidification technology with a particle size of about 200 nm and a zeta potential value of about -20 mV. The results of X-ray diffraction and DSC analysis showed amorphous crystalline state of Amoitone B in NLC. Furthermore, the drug entrapment efficacy (EE) was improved compared with solid lipid nanoparticles (SLN). The EE range was from 71.1% to 84.7%, enhanced with the increase of liquid lipid. In vitro drug release studies revealed biphasic drug release patterns with burst release initially and prolonged release afterwards and the release was accelerated with augment of liquid lipid. These results demonstrated that AmB-NLC could be a promising delivery system to control drug release and improve loading capacity, thus prolong drug action time in body and enhance the bioavailability.

Antioxidant properties of the red alga Asparagopsis taxiformis collected on the North West Algerian coast

PubMed Central

Mellouk, Zoheir; Benammar, Ilhem; Krouf, Djamil; Goudjil, Makhlouf; Okbi, Meriem; Malaisse, Willy

2017-01-01

The aim of the present study was to evaluate the total phenolic and lipid content, fatty acids profiles and in vitro antioxidant activities of aqueous and solvent extracts of the red seaweed Asparagopsis taxiformis, through six different investigations. The present study demonstrated that phenol contents (mg gallic acid/g dry weight) were highest in the aqueous and methanolic extracts, followed by the ethanolic, hydroethanolic and hydromethanolic extracts. The lowest phenol contents were identified in the three remaining extracts: Butanolic, petroleum ether and acetone extracts. Furthermore, the total lipid content of the algae powder amounted to 2.85% of dry weight. The fatty acid methyl ester profiles analysed by gas-liquid chromatography represented indicated that fatty acids comprised 91.0±0.3% of total algae lipids. The saturated to unsaturated fatty acid contents amounted to 23.2±0.1 and 67.9±0.4% respectively. C13:0 (tridecanoate), C15:0 (pentadecanoate) and C17:0 (heptadecanoate) represented 47.4% of the total saturated fatty acids. Notably, the two most abundant unsaturated fatty acids, C15:1 (pentadecenoate) and C18:2 (octadecadienoate) represented 13.4 and 11.4% respectively, of the total unsaturated fatty acid content. Furthermore, the results of the antioxidant screening performed at 1.0 mg/ml, revealed that aqueous and methanolic extracts exhibited higher inhibition against superoxide and nitric oxide radicals and excellent radical scavenging activity [with half maximal inhibitory concentration (IC50) values 5.1 and 15.0 µg/ml, respectively], demonstrating improved antioxidant behavior when compared with standard ascorbic acid (which has an IC50 value of 3.7 µg/ml). Scavenging activity of the aqueous and methanolic extracts exhibited a strong peroxidation inhibition against linoleic acid emulsion system at a concentration of 300 µg/ml in comparison to the butylated hydroxyltoluene. Although all the studied extracts exhibited ferric reducing power, the aqueous and methanolic extracts had greater hydrogen donating ability. By contrast, hydromethanolic, ethanolic, hydroethanolic, butanolic, acetone and petroleum ether extracts exhibited weak antioxidant behavior. The antioxidant activity of potent seaweed species identified in the current study means that as well as being used as a functional food, they may be developed as novel pharmaceutical compounds and may be used as anti-ageing agents. PMID:28587401

Design and Characterization of a Multifunctional pH-Triggered Peptide C8 for Selective Anticancer Activity.

PubMed

Lu, Sheng; Bennett, W F Drew; Ding, Yong; Zhang, Lei; Fan, Helen Y; Zhao, Danyang; Zheng, Tao; Ouyang, Ping-Kai; Li, Jason; Wu, Yan; Xu, Wen; Chu, Dafeng; Yuan, Yongfang; Heerklotz, Heiko; Karttunen, Mikko; Chen, P

2015-12-09

Most drug delivery systems have been developed for efficient delivery to tumor sites via targeting and on-demand strategies, but the carriers rarely execute synergistic therapeutic actions. In this work, C8, a cationic, pH-triggered anticancer peptide, is developed by incorporating histidine-mediated pH-sensitivity, amphipathic helix, and amino acid pairing self-assembly design. We designed C8 to function as a pH-responsive nanostructure whose cytotoxicity can be switched on and off by its self-assembly: Noncytotoxic β-sheet fibers at high pH with neutral histidines, and positively charged monomers with membrane lytic activity at low pH. The selective activity of C8, tested for three different cancer cell lines and two noncancerous cell lines, is shown. Based on liposome leakage assays and multiscale computer simulations, its physical mechanisms of pore-forming action and selectivity are proposed, which originate from differences in the lipid composition of the cellular membrane and changes in hydrogen bonding. C8 is then investigated for its potential as a drug carrier. C8 forms a nanocomplex with ellipticine, a nonselective model anticancer drug. It selectively targets cancer cells in a pH-responsive manner, demonstrating enhanced efficacy and selectivity. This study provides a novel powerful strategy for the design and development of multifunctional self-assembling peptides for therapeutic and drug delivery applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antioxidant & anticancer activities of isatin (1H-indole-2,3-dione), isolated from the flowers of Couroupita guianensis Aubl

PubMed Central

Premanathan, Mariappan; Radhakrishnan, Srinivasan; Kulangiappar, Kumarasamy; Singaravelu, Ganesan; Thirumalaiarasu, Velayutham; Sivakumar, Thangavel; Kathiresan, Kandasamy

2012-01-01

Background & objectives: Derivatives of isatin are known to have cytotoxicity against human carcinoma cell lines. This compound therefore, has a potential to be used as a chemotherapeutic agent against cancer. This study was done to investigate the antioxidant and anticancer activities of isatin, extracted from flower of a folklore medicinal plant Couroupita guianensis against human promylocytic leukemia (HL60) cells. Methods: Active fractions demonstrating anticancer and antioxidant activities were isolated from the extracts of shade-dried flowers of C. guianensis by bioassay guided fractionation. The free radical scavenging activity was determined using lipid peroxidation assay. Cytotoxicity against human promylocytic leukemia HL60 cells was determined by MTT assay. Apoptotic activity was analyzed by DNA fragmentation and flowcytometry. Results: Isatin isolated from the active fraction showed antioxidant activity with the EC50 value of 72.80 μg/ml. It also exhibited cytotoxicity against human promylocytic leukemia HL60 cells in dose-dependant manner with the CC50 value of 2.94 μg/ml. The isatin-treated cells underwent apoptosis and DNA fragmentation. Apoptosis was confirmed by the FACS analysis using FITC-annexin V markers. Interpretation & conclusions: Isatin showed antioxidant activity and was cytotoxic to the HL60 cells due to induction of apoptosis. The isatin can be further evaluated to be used as a prophylactic agent to prevent the free radical-induced cancer and as a chemotherapeutic agent to kill the cancer cells. PMID:23287130

Poly(arylene ether)s containing pendent ethynyl groups

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Jensen, Brian J. (Inventor)

1996-01-01

Poly(arylene ether)s containing pendent ethynyl and substituted ethynyl groups and poly(arylene ether) copolymers containing pendent ethynyl and substituted ethynyl groups are readily prepared from bisphenols containing ethynyl and substituted ethynyl groups. The resulting polymers are cured up to 350.degree. C. to provide crosslinked poly(arylene ether)s with good solvent resistance, high strength and modulus.

Poly(arylene ether)s containing pendent ethynyl groups

NASA Technical Reports Server (NTRS)

Hergenrother, Paul M. (Inventor); Jensen, Brian J. (Inventor)

1994-01-01

Poly(arylene ether)s containing pendent ethynyl and substituted ethynyl groups and poly(arylene ether) copolymers containing pendent ethynyl and substituted ethynyl groups are readily prepared from bisphenols containing ethynyl and substituted ethynyl groups. The resulting polymers are cured up to 350 C to provide crosslinked poly(arylene ether)s with good solvent resistance, high strength and modulus.

Remodeling of brain lipidome in methamphetamine-sensitized mice.

PubMed

Jiang, Linhong; Gu, Hui; Lin, Yiyun; Xu, Wei; Zhu, Ruiming; Kong, Jueying; Luo, Li; Long, Hailei; Liu, Bing; Chen, Bo; Zhao, Yinglan; Cen, Xiaobo

2017-09-05

Lipids are predominant components of the brain and key regulators for neural structure and function. The effect of methamphetamine (METH) on behavior, cognition as well as memory has been intensively investigated; however, the impact of METH on brain lipid profiles is largely unknown. Here, we used a global lipidomic approach to investigate brain lipidome of METH-sensitized mice. We found that repeated METH significantly modified the lipidome in the hippocampus, prefrontal cortex (PFC) and striatum. Interestingly, nucleus accumbens showed no obvious alteration in lipidomic profiling. Phospholipid and sphingolipid metabolisms were profoundly modified in the hippocampus of METH-sensitized mice, exhibiting increased phosphatidic acid and ether phosphatidylcholine but decreased lysophosphatidylethanolamine, lactosylceramide and triglycerides. The fatty acyl length of phospholipids and diacylglycerol longer than 40 carbon were clearly decreased in the hippocampus, and that 36 carbon was decreased in the PFC. These results indicate METH can profoundly affect the metabolism of phospholipids, sphingolipids and glycerolipids in the brain. Our findings reveal a link between remodeled brain lipidome and neurobehavior induced by METH. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative studies on extracts from Hericium erinaceus by different polarity reagents to gain higher antioxidant activities.

PubMed

Jiang, Shengjuan; Wang, Yuliang; Zhang, Xiaolong

2016-07-01

Hericium erinaceus (H. erinaceus) is a source of exogenous antioxidants that has been traditionally used in China for the prevention and treatment of oxidative stress-associated disease. In the present study, the bioactive compounds of H. erinaceus were extracted with the following eight representative reagents: n-Hexane, xylene, chloroform, anhydrous ether, ethyl acetate, acetone, anhydrous ethanol and distilled water. The in vitro antioxidant activities were also evaluated. All of the extracted compounds exhibited reducing power and scavenging activity against 1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion free radicals. In addition, the antioxidant capacities varied with the used chemical reagents and exhibited dose-dependent effects. Extracts from anhydrous ethanol, chloroform and acetone were capable of inhibiting lipid peroxidation. The anhydrous ethanol extracts were observed to have significant levels of antioxidant compounds since they had a strong reducing power, high scavenging rates against DPPH and superoxide anion-free radicals (>90%), and high inhibition rates on lipid peroxidation (>60%). The present study will provide reference data for the antioxidant applications of H. erinaceus in pharmaceutical use and disease prevention.

Comparative studies on extracts from Hericium erinaceus by different polarity reagents to gain higher antioxidant activities

PubMed Central

JIANG, SHENGJUAN; WANG, YULIANG; ZHANG, XIAOLONG

2016-01-01

Hericium erinaceus (H. erinaceus) is a source of exogenous antioxidants that has been traditionally used in China for the prevention and treatment of oxidative stress-associated disease. In the present study, the bioactive compounds of H. erinaceus were extracted with the following eight representative reagents: n-Hexane, xylene, chloroform, anhydrous ether, ethyl acetate, acetone, anhydrous ethanol and distilled water. The in vitro antioxidant activities were also evaluated. All of the extracted compounds exhibited reducing power and scavenging activity against 1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion free radicals. In addition, the antioxidant capacities varied with the used chemical reagents and exhibited dose-dependent effects. Extracts from anhydrous ethanol, chloroform and acetone were capable of inhibiting lipid peroxidation. The anhydrous ethanol extracts were observed to have significant levels of antioxidant compounds since they had a strong reducing power, high scavenging rates against DPPH and superoxide anion-free radicals (>90%), and high inhibition rates on lipid peroxidation (>60%). The present study will provide reference data for the antioxidant applications of H. erinaceus in pharmaceutical use and disease prevention. PMID:27347087

Enhanced active liposomal loading of a poorly soluble ionizable drug using supersaturated drug solutions.

PubMed

Modi, Sweta; Xiang, Tian-Xiang; Anderson, Bradley D

2012-09-10

Nanoparticulate drug carriers such as liposomal drug delivery systems are of considerable interest in cancer therapy because of their ability to passively accumulate in solid tumors. For liposomes to have practical utility for antitumor therapy in patients, however, optimization of drug loading, retention, and release kinetics are necessary. Active loading is the preferred method for optimizing loading of ionizable drugs in liposomes as measured by drug-to-lipid ratios, but the extremely low aqueous solubilities of many anticancer drug candidates may limit the external driving force, thus slowing liposomal uptake during active loading. This report demonstrates the advantages of maintaining drug supersaturation during active loading. A novel method was developed for creating and maintaining supersaturation of a poorly soluble camptothecin analogue, AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin), using a low concentration of a cyclodextrin (sulfobutylether-β-cyclodextrin) to inhibit crystallization over a 48 h period. Active loading into liposomes containing high concentrations of entrapped sodium or calcium acetate was monitored using drug solutions at varying degrees of supersaturation. Liposomal uptake rates increased linearly with the degree of supersaturation of drug in the external loading solution. A mathematical model was developed to predict the rate and extent of drug loading versus time, taking into account the chemical equilibria inside and outside of the vesicles and the transport kinetics of various permeable species across the lipid bilayer and the dialysis membrane. Intraliposomal sink conditions were maintained by the high internal pH caused by the efflux of acetic acid and exchange with AR-67, which undergoes lactone ring-opening, ionization, and membrane binding in the interior of the vesicles. The highest drug to lipid ratio achieved was 0.17 from a supersaturated solution at a total drug concentration of 0.6 mg/ml. The rate and extent of loading was similar when a different intraliposomal metal cation (sodium) was used instead of calcium. The proposed method may have general application in overcoming the formulation challenges associated with the liposomal delivery of poorly soluble, ionizable anticancer agents. Copyright © 2012 Elsevier B.V. All rights reserved.

Antioxidant and anti-inflammatory effects of virgin coconut oil supplementation abrogate acute chemotherapy oxidative nephrotoxicity induced by anticancer drug methotrexate in rats.

PubMed

Famurewa, Ademola C; Aja, Patrick M; Maduagwuna, Ekenechukwu K; Ekeleme-Egedigwe, Chima A; Ufebe, Odomero G; Azubuike-Osu, Sharon O

2017-12-01

Methotrexate (MTX) is an efficacious anticancer agent constrained in clinical use due to its toxicity on non-targeted tissue, a considerable source of worry to clinicians. Because the toxicity is associated with oxidative stress and inflammation, the study explored antioxidant and anti-inflammatory effect of virgin coconut oil (VCO) supplementation in nephrotoxicity induced by MTX in rats. Rats were randomized into 4 groups (n=6) as follows: Control group; MTX group injected with single dose of MTX (20mg/kg, ip) on day 14; VCO (5%)+MTX and VCO (15%)+MTX groups were pre-treated with VCO diet and injected with single dose of MTX (20mg/kg, ip) on day 14. After 3 days of MTX injection, serum kidney markers, renal activities of antioxidant enzymes and glutathione (GSH) content were determined. Lipid peroxidation level and inflammatory markers- interleukin-6 (IL-6), nitric oxide (NO) and C-reactive protein (CRP) were estimated in kidney. Histopathological alterations were examined for kidney damage. MTX nephrotoxicity was evidenced by markedly elevated serum renal markers along with significant decreases in renal GSH and activities of antioxidant enzymes confirmed by histopathology. Lipid peroxidation level, IL-6, NO and CRP markedly increased compared to control. VCO supplementation prior to MTX injection attenuated MTX-induced oxidative nephrotoxicity via prominent increases in GSH and antioxidant enzyme activities in a dose-dependent manner. The renal inflammatory markers and MDA depleted considerably compared to MTX control group. Histopathological alterations were mitigated to confirm the biochemical indices. VCO supplementation demonstrates nephroprotective activity by attenuating MTX oxidative nephrotoxicity via antioxidant and anti-inflammatory activities in kidney. Our results suggested that VCO may benefit cancer patients on MTX chemotherapy against kidney injury. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Tumor-targeted polymeric nanostructured lipid carriers with precise ratiometric control over dual-drug loading for combination therapy in non-small-cell lung cancer.

PubMed

Liang, Yan; Tian, Baocheng; Zhang, Jing; Li, Keke; Wang, Lele; Han, Jingtian; Wu, Zimei

2017-01-01

Gemcitabine (GEM) and paclitaxel (PTX) are effective combination anticancer agents against non-small-cell lung cancer (NSCLC). At the present time, a main challenge of combination treatment is the precision of control that will maximize the combined effects. Here, we report a novel method to load GEM (hydrophilic) and PTX (hydrophobic) into simplex tumor-targeted nanostructured lipid carriers (NLCs) for accurate control of the ratio of the two drugs. We covalently preconjugated the dual drugs through a hydrolyzable ester linker to form drug conjugates. N -acetyl-d-glucosamine (NAG) is a glucose receptor-targeting ligand. We added NAG to the formation of NAG-NLCs. In general, synthesis of poly(6- O -methacryloyl-d-galactopyranose)-GEM/PTX (PMAGP-GEM/PTX) conjugates was demonstrated, and NAG-NLCs were prepared using emulsification and solvent evaporation. NAG-NLCs displayed sphericity with an average diameter of 120.3±1.3 nm, a low polydispersity index of 0.233±0.04, and accurate ratiometric control over the two drugs. A cytotoxicity assay showed that the NAG-NLCs had better antitumor activity on NSCLC cells than normal cells. There was an optimal ratio of the two drugs, exhibiting the best cytotoxicity and combinatorial effects among all the formulations we tested. In comparison with both the free-drug combinations and separately nanopackaged drug conjugates, PMAGP-GEM/PTX NAG-NLCs (3:1) exhibited superior synergism. Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis. This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor-targeted combination therapy to achieve maximal anticancer efficacy in NSCLC.

N-Heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold with anticancer and anti-infective dual action.

PubMed

Zablotskaya, Alla; Segal, Izolda; Geronikaki, Athina; Shestakova, Irina; Nikolajeva, Vizma; Makarenkova, Galina

2017-06-01

Pharmacological effects of biologically active "small molecules" can be improved by their targeted modification, which affects drug delivery and interaction with tumor cells and microorganisms. We aimed to evaluate anticancer and antimicrobial activity of lipid-like choline derivatives modified via simultaneous introduction of tetrahydro(iso)quinoline based pharmacophore system at nitrogen atom and long chain alkyl substituent at oxygen atom. Target compounds were synthesized under phase-transfer catalysis conditions followed by quaternization, and evaluated for cytotoxicity and NO-generation ability on HT-1080 and MG-22A tumor cell lines and NIH 3T3 normal mouse fibroblasts, and screened for antimicrobial activity against gram-positive (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis) and fungi (Candida albicans and Aspergillus niger). Inhibitory action of active compounds towards E. coli DNA gyrase was investigated. Target compounds exhibit high selective cytotoxicity (LC 50 <1μg/mL) and NO-induction ability, and reveal strong antimicrobial activity with MIC and MBC/MFC values of 0.5-32μg/mL, predominantly vs. gram-positive bacteria and fungi. Tested substances displayed inhibitory effect towards E. coli DNA gyrase, though less than ciprofloxacin. Tetrahydroisoquinoline derivatives and compounds possessing substituents with chain length of 10 and 11 carbon atoms have highest indices of activities. Lipid-like N-heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold, possessing very high cytotoxicity with attendant strong antimicrobial activity are the leads for developing effective dual action therapeutics. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Ionic channels and nerve membrane lipids. Cholesterol-tetrodotoxin interaction.

PubMed

Villegas, R; Barnola, F V; Camejo, G

1970-04-01

Experiments were carried out to investigate possible interactions of tetrodotoxin (TTX) with lipid molecules isolated from nerve fiber plasma membranes of the squid Dosidicus gigas. TTX has a highly selective ability to block the channel normally used by Na(+) to cross the axolemma during nervous impulse conduction. In order to investigate the interaction each lipid sample was spread on 5 x 10(-7)M TTX and TTX-free 0.15 M NaCl solutions adjusted to pH 7.4 with 7 x 10(-3)M phosphate buffer. The surface pressure-area diagrams of the lipid monolayers revealed that TTX interacts only with cholesterol. The expansion of the cholesterol monolayers at 5 x 10(-7)M TTX was 2 A(2)/molecule at zero pressure for the experiments at 20 degrees C and 2.5 A(2)/molecule for those at 25 degrees C. Similar results were obtained in KCl subphases. The apparent dissociation constant of the cholesterol-TTX complex calculated from dose-response experiments is 2.6 x 10(-7)M. Experiments at pH 10.1 revealed that the zwitter ionic form of TTX is less active. Experiments with cholesterol derivatives (cholesteryl acetate, cholesterol methyl ether, cholestanol, and cholestanyl acetate) indicate that for the interaction with TTX a partial negatively charged group at C-3 and a double bond between C-5 and C-6 on the steroid nucleus are required. Tetrodonic acid, a biologically inactive derivative of TTX, does not interact with cholesterol. The results lead us to propose that cholesterol is part of the Na(+) channel.

Ionic Channels and Nerve Membrane Lipids Cholesterol-tetrodotoxin interaction

PubMed Central

Villegas, Raimundo; Barnola, Flor V.; Camejo, Germáan

1970-01-01

Experiments were carried out to investigate possible interactions of tetrodotoxin (TTX) with lipid molecules isolated from nerve fiber plasma membranes of the squid Dosidicus gigas. TTX has a highly selective ability to block the channel normally used by Na+ to cross the axolemma during nervous impulse conduction. In order to investigate the interaction each lipid sample was spread on 5 x 10-7 M TTX and TTX-free 0.15 M NaCl solutions adjusted to pH 7.4 with 7 x 10-3 M phosphate buffer. The surface pressure-area diagrams of the lipid monolayers revealed that TTX interacts only with cholesterol. The expansion of the cholesterol monolayers at 5 x 10-7 M TTX was 2 A2/molecule at zero pressure for the experiments at 20°C and 2.5 A2/molecule for those at 25°C. Similar results were obtained in KCl subphases. The apparent dissociation constant of the cholesterol-TTX complex calculated from dose-response experiments is 2.6 x 10-7 M. Experiments at pH 10.1 revealed that the zwitter ionic form of TTX is less active. Experiments with cholesterol derivatives (cholesteryl acetate, cholesterol methyl ether, cholestanol, and cholestanyl acetate) indicate that for the interaction with TTX a partial negatively charged group at C-3 and a double bond between C-5 and C-6 on the steroid nucleus are required. Tetrodonic acid, a biologically inactive derivative of TTX, does not interact with cholesterol. The results lead us to propose that cholesterol is part of the Na+ channel. PMID:5435784

Theoretical study of binding and permeation of ether-based polymers through interfaces.

PubMed

Samanta, Susruta; Hezaveh, Samira; Roccatano, Danilo

2013-11-27

We present a molecular dynamics simulation study on the interactions of poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), and their ABA-type block copolymer, poloxamers, at water/n-heptane and 1,2-dimyristoyl-sn-glycero-3-phospatidycholine (DMPC) lipid bilayer/water interfaces. The partition coefficients in water/1-octanol of the linear polyethers up to three monomers were calculated. The partition coefficients evidenced a higher hydrophobicity of the PPO in comparison to PEO. At the water/n-heptane interface, the polymers tend to adopt elongated conformations in agreement with similar experimental ellipsometry studies of different poloxamers. In the case of the poloxamers at the n-heptane/water interface, the stronger preference of the PPO block for the hydrophobic phase resulted in bottle-brush-type polymer conformations. At lipid bilayer/water interface, the PEO polymers, as expected from their hydrophilic nature, are weakly adsorbed on the surface of the lipid bilayer and locate in the water phase close to the headgroups. The free energy barriers of permeation calculated for short polymer chains suggest a thermodynamics propensity for the water phase that increase with the chain length. The lower affinity of PEO for the hydrophobic interior of the lipid bilayer resulted in the spontaneous expulsion within the simulation time. On the contrary, PPO chains and poloxamers have a longer residence time inside the bilayer, and they tend to concentrate in the tail region of the bilayer near the polar headgroups. In addition, polymers with PPO unit length comparable to the thickness of the hydrophobic region of the bilayer tend to span across the bilayer.

Morbidity study of extruder personnel with potential exposure to brominated dioxins and furans. II. Results of clinical laboratory studies.

PubMed

Ott, M G; Zober, A

1996-12-01

To test whether dioxins affect liver and thyroid function, lipid metabolism and glucose or immunological variables, in workers exposed to brominated dioxins and furans. 34 male production employees (29 were extruder operators) and eight technical support personnel were studied, all of whom were potentially exposed to polybrominated dibenzo-p-dioxins (PBDDs) and furans (PBDFs) during production of resins containing polybrominated diphenyl ethers (PBDEs). Controls were from a similar resin producing plant that did not use PBDEs. Blood samples were analysed for tetra, penta, and hexabrominated congeners, but 2,3,7,8-TBDD was the only exposure measure used in the regression analyses. Seven liver function indicators, five measures of blood lipids and glucose, four haematology and blood coagulation measures, and three measures of thyroid function were examined. None of the variables was statistically related to concentration of 2,3,7,8-TBDD in the regression analyses. Cigarette smoking was related to several outcomes at the 0.05 level: aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase (GLDH), erythrocyte sedimentation rate, and white blood cell count. Body mass index was also related to alanine aminotransferase, gamma-glutamyltranspeptidase, cholinesterase, GLDH, cholesterol, triglycerides, high density lipoprotein, low density lipoprotein, and glucose concentrations. No definitive associations between liver, blood lipid, thyroid, or immunological variables and exposure to brominated dioxins or blood lipid concentration of 2,3,7,8-TBDD were found. The study population was small and hence the findings must be interpreted with caution. Nevertheless, these results provide a base for interpreting the results of clinical studies in similarly exposed populations.

Self-assembly of BODIPY based pH-sensitive near-infrared polymeric micelles for drug controlled delivery and fluorescence imaging applications

NASA Astrophysics Data System (ADS)

Liu, Xiaodong; Chen, Bizheng; Li, Xiaojun; Zhang, Lifen; Xu, Yujie; Liu, Zhuang; Cheng, Zhenping; Zhu, Xiulin

2015-10-01

Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (~7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells.Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (~7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells. Electronic supplementary information (ESI) available: GPC, UV/vis, fluorescence, and MTT data of the as-prepared polymers; 1H NMR, 13C NMR, HRMS and FT-IR of organic molecules and polymers. See DOI: 10.1039/c5nr04655f

Preliminary health risk assessment for polybrominated diphenyl ethers and polybrominated dibenzo-p-dioxins/furans in seafood from Guangzhou and Zhoushan, China.

PubMed

Miyake, Yuichi; Jiang, Qinting; Yuan, Wang; Hanari, Nobuyasu; Okazawa, Tsuyoshi; Wyrzykowska, Barbara; So, Man Ka; Lam, Paul K S; Yamashita, Nobuyoshi

2008-01-01

Dietary intake is one of the important routes of human exposure to brominated flame retardants (BFRs) such as polybrominated diphenyl ethers (PBDEs). The use of PBDEs may also result in exposure to polybrominated dibenzo-p-dioxins and dibenzofurans (PBDDs/DFs), as these compounds are impurities in technical mixtures of BFRs and can also be formed unintentionally by the same processes that generate chlorinated dioxins. This study determined the concentrations of polybrominated compounds in common seafood in Guangzhou and Zhoushan, and assessed the health risks of these chemicals via consumption of contaminated seafood. Seafood samples (fish, bivalves, shrimp, crab, and cephalopods) purchased from local markets in 2003 and 2004 were analyzed for PBDEs and PBDDs/DFs. The highest concentration of total PBDEs (46.3 ng g(-1) lipid wt.) was detected in fish from Guangzhou, in which BDEs 47 and 209 were the two predominant congeners. The total daily intakes of PBDEs, PBDDs, and PBDFs were, 946, 6.39, and 6.54 pg kg(-1) body weight (bw) in Guangzhou, and 489, 4.99, and 7.65 pg kg(-1) bw in Zhoushan, respectively. The hazard ratios for PBDDs and PBDFs were both greater than unity, indicating that these compounds may pose some health risks to the local population.

New ether-functionalized ionic liquids for lipase-catalyzed synthesis of biodiesel.

PubMed

Zhao, Hua; Song, Zhiyan; Olubajo, Olarongbe; Cowins, Janet V

2010-09-01

Ionic liquids (ILs) are being explored as solvents for the enzymatic methanolysis of triglycerides. However, most available ILs (especially hydrophobic ones) have poor capability in dissolving lipids, while hydrophilic ILs tend to cause enzyme inactivation. Recently, we synthesized a new type of ether-functionalized ionic liquids (ILs) carrying anions of acetate or formate; they are capable of dissolving a variety of substrates and are also lipase-compatible (Green Chem., 2008, 10, 696-705). In the present study, we carried out the lipase-catalyzed transesterifications of Miglyol oil 812 and soybean oil in these novel ILs. These ILs are capable of dissolving oils at the reaction temperature (50 degrees C); meanwhile, lipases maintained high catalytic activities in these media even in high concentrations of methanol (up to 50% v/v). High conversions of Miglyol oil were observed in mixtures of IL and methanol (70/30, v/v) when the reaction was catalyzed by a variety of lipases and different enzyme preparations (free and immobilized), especially with the use of two alkylammonium ILs 2 and 3. The preliminary study on the transesterification of soybean oil in IL/methanol mixtures further confirms the potential of using oil-dissolving and lipase-stabilizing ILs in the efficient production of biodiesels.

Evaluation of a Fast and Simple Sample Preparation Method for Polybrominated Diphenyl Ether (PBDE) Flame Retardants and Dichlorodiphenyltrichloroethane (DDT) Pesticides in Fish for Analysis by ELISA Compared with GC-MS/MS.

PubMed

Sapozhnikova, Yelena; Simons, Tawana; Lehotay, Steven J

2015-05-13

A simple, fast, and cost-effective sample preparation method, previously developed and validated for the analysis of organic contaminants in fish using low-pressure gas chromatography-tandem mass spectrometry (LPGC-MS/MS), was evaluated for the analysis of polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyltrichloroethane (DDT) pesticides using enzyme-linked immunosorbent assay (ELISA). The sample preparation technique was based on the quick, easy, cheap, rugged, effective, and safe (QuEChERS) approach with filter-vial dispersive solid phase extraction (d-SPE). Incurred PBDEs and DDTs were analyzed in three types of fish with 3-10% lipid content: Pacific croaker, salmon, and National Institute of Standards and Technology (NIST) Standard Reference Material 1947 (Lake Michigan fish tissue). LPGC-MS/MS and ELISA results were in agreement: 108-111 and 65-82% accuracy ELISA versus LPGC-MS/MS results for PBDEs and DDTs, respectively. Similar detection limits were achieved for ELISA and LPGC-MS/MS. Matrix effects (MEs) were significant (e.g., -60%) for PBDE measurement in ELISA, but not a factor in the case of DDT pesticides. This study demonstrated that the sample preparation method can be adopted for semiquantitative screening analysis of fish samples by commercial kits for PBDEs and DDTs.

House crickets can accumulate polybrominated diphenyl ethers (PBDEs) directly from polyurethane foam common in consumer products.

PubMed

Gaylor, Michael O; Harvey, Ellen; Hale, Robert C

2012-02-01

Polybrominated diphenyl ether (PBDE) flame retardants are added at percent levels to many polymers and textiles abundant in human spaces and vehicles, wherein they have been long assumed to be tightly sequestered. However, the mgkg(-1) burdens recently detected in indoor dust testify to substantial releases. The bulk of released PBDEs remain in the terrestrial environment, yet comparatively little research focuses on this compartment. There, insects/arthropods, such as crickets, are the most abundant invertebrate organisms and facilitate the trophic transfer of contaminants by breaking down complex organic matter (including discarded polymers) and serving as food for other organisms. Our experiments revealed that house crickets (Acheta domesticus) provided uncontaminated food and free access to PUF containing Penta-BDE (8.7%drywt) for 28 d accumulated substantial PBDE body burdens. Crickets allowed to depurate gut contents exhibited whole body burdens of up to 13.4 mg kg(-1) lipid ΣPenta-BDE, 1000-fold higher than typically reported in humans. Non-depurated crickets and molted exoskeletons incurred even higher ΣPenta-BDE, up to 80.6 and 63.3 mg kg(-1) lipid, respectively. Congener patterns of whole crickets and molts resembled those of PUF and the commercial Penta-BDE formulation, DE-71, indicative of minimal discrimination or biotransformation. Accumulation factor (AF) calculations were hampered by uncertainties in determining actual PUF ingestion. However, estimated AFs were low, in the range of 10(-4)-10(-3), suggesting that polymer-PBDE interactions limited uptake. Nonetheless, results indicate that substantial PBDE burdens may be incurred by insects in contact with current-use and derelict treated polymers within human spaces and solid waste disposal sites (e.g. landfills, automotive dumps, etc.). Once ingested, even burdens not absorbed across the gut wall may be dispersed within proximate terrestrial food webs via the insect's movements and/or predation. Copyright © 2011 Elsevier Ltd. All rights reserved.

Defined lipid analogues induce transient channels to facilitate drug-membrane traversal and circumvent cancer therapy resistance

PubMed Central

van Hell, Albert J.; Melo, Manuel N.; van Blitterswijk, Wim J.; Gueth, Dayana M.; Braumuller, Tanya M.; Pedrosa, Lilia R. C.; Song, Ji-Ying; Marrink, Siewert J.; Koning, Gerben A.; Jonkers, Jos; Verheij, Marcel

2013-01-01

Design and efficacy of bioactive drugs is restricted by their (in)ability to traverse cellular membranes. Therapy resistance, a major cause of ineffective cancer treatment, is frequently due to suboptimal intracellular accumulation of the drug. We report a molecular mechanism that promotes trans-membrane movement of a stereotypical, widely used anti-cancer agent to counteract resistance. Well-defined lipid analogues adapt to the amphiphilic drug doxorubicin, when co-inserted into the cell membrane, and assemble a transient channel that rapidly facilitates the translocation of the drug onto the intracellular membrane leaflet. Molecular dynamic simulations unveiled the structure and dynamics of membrane channel assembly. We demonstrate that this principle successfully addresses multi-drug resistance of genetically engineered mouse breast cancer models. Our results illuminate the role of the plasma membrane in restricting the efficacy of established therapies and drug resistance - and provide a mechanism to overcome ineffectiveness of existing and candidate drugs. PMID:23739489

Enzymatic synthesis of chlorogenic acid glucoside using dextransucrase and its physical and functional properties.

PubMed

Nam, Seung-Hee; Ko, Jin-A; Jun, Woojin; Wee, Young-Jung; Walsh, Marie K; Yang, Kwang-Yeol; Choi, Jin-Ho; Eun, Jon-Bang; Choi, Jeong; Kim, Young-Min; Han, Songhee; Nguyen, Thi Thanh Hanh; Kim, Doman

2017-12-01

Chlorogenic acid, a major polyphenol in edible plants, possesses strong antioxidant activity, anti-lipid peroxidation and anticancer effects. It used for industrial applications; however, this is limited by its instability to heat or light. In this study, we for the first time synthesized chlorogenic acid glucoside (CHG) via transglycosylation using dextransucrase from Leuconostoc mesenteroides and sucrose. CHG was purified and its structure determined by nuclear magnetic resonance and matrix-associated laser desorption ionization-time-of-flight mass spectroscopy. The production yield of CHG was 44.0% or 141mM, as determined by response surface methodology. CHG possessed a 65% increased water solubility and 2-fold browning resistance while it displayed stronger inhibition of lipid peroxidation and of colon cancer cell growth by MTT assay, compared to chlorogenic acid. Therefore, this study may expand the industrial applications of chlorogenic acid as water-soluble or browning resistant compound (CHG) through enzymatic glycosylation. Copyright © 2017 Elsevier Inc. All rights reserved.

Adipocyte-derived players in hematologic tumors: useful novel targets?

PubMed

Jöhrer, Karin; Ploner, Christian; Thangavadivel, Shanmugapriya; Wuggenig, Philipp; Greil, Richard

2015-01-01

Adipocytes and their products play essential roles in tumor establishment and progression. As the main cellular component of the bone marrow, adipocytes may contribute to the development of hematologic tumors. This review summarizes experimental data on adipocytes and their interaction with various cancer cells. Special focus is set on the interactions of bone marrow adipocytes and normal and transformed cells of the hematopoietic system such as myeloma and leukemia cells. Current in vitro and in vivo data are summarized and the potential of novel therapeutic targets is critically discussed. Targeting lipid metabolism of cancer cells and adipocytes in combination with standard therapeutics might open novel therapeutic avenues in these cancer entities. Adipocyte-derived products such as free fatty acids and specific adipokines such as adiponectin may be vital anti-cancer targets in hematologic malignancies. However, available data on lipid metabolism is currently mostly referring to peripheral fat cell/cancer cell interactions and results need to be evaluated specifically for the bone marrow niche.

Discovery of GPX4 inhibitory peptides from random peptide T7 phage display and subsequent structural analysis.

PubMed

Sakamoto, Kotaro; Sogabe, Satoshi; Kamada, Yusuke; Matsumoto, Shin-Ichi; Kadotani, Akito; Sakamoto, Jun-Ichi; Tani, Akiyoshi

2017-01-08

The phospholipid hydroperoxidase glutathione peroxidase (GPX4) is an enzyme that reduces lipid hydroperoxides in lipid membranes. Recently, GPX4 has been investigated as a target molecule that induces iron-dependent cell death (ferroptosis) selectively in cancer cells that express mutant Ras. GPX4 inhibitors have the potential to become novel anti-cancer drugs. However, there are no druggable pockets for conventional small molecules on the molecular surface of GPX4. To generate GPX4 inhibitors, we examined the use of peptides as an alternative to small molecules. By screening peptide libraries displayed on T7 phages, and analyzing the X-ray crystal structures of the peptides, we successfully identified one peptide that binds to near Sec73 of catalytic site and two peptides that bind to another site on GPX4. To our knowledge, this is the first study reporting GPX4 inhibitory peptides and their structural information. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of thermally oxidized vegetable oils and animal fats on energy and nutrient digestibility in young pigs.

PubMed

Liu, P; Kerr, B J; Chen, C; Weber, T E; Johnston, L J; Shurson, G C

2014-07-01

A total of 108 barrows (6.67 ± 0.03 kg BW) were assigned to 12 dietary treatments in a 4 × 3 factorial design plus a corn-soybean meal control diet to evaluate the effect of lipid source and peroxidation level on DE, ME, and apparent total tract digestibility (ATTD) of DM, GE, ether extract (EE), N, and C in young pigs. Main effects were lipid source (corn oil [CN], canola oil [CA], poultry fat [PF], and tallow [TL]) and peroxidation level (original lipids [OL], slow oxidation [SO] of lipids heated for 72 h at 95°C, or rapid oxidation [RO] of lipids heated for 7 h at 185°C). Pigs were provided ad libitum access to diets for 28 d followed by an 8-d period of controlled feed intake equivalent to 4% BW daily. Diets were formulated based on the ME content of CA with the standardized ileal digestible Lys, Met, Thr, Trp, total Ca, and available P:ME balanced relative to NRC (1998) recommendations. Lipid peroxidation analysis indicated that compared with the OL, SO and RO had a markedly increased concentrations of lipid peroxidation products, and the increase of peroxidation products in CN and CA were greater than those in PF and TL. Addition of lipids to diets increased (P < 0.05) ATTD of EE and tended to improve (P = 0.06) ATTD of GE compared with pigs fed the control diet. Feeding CN or CA increased (P < 0.05) ATTD of DM, GE, EE, N, and C compared with feeding TL, while feeding PF improved (P < 0.05) ATTD of GE and EE and tended to increase (P = 0.06) ATTD of C compared with TL. Pigs fed CN had increased (P = 0.05) percentage N retention than pigs fed TL. No peroxidation level effect or interaction between lipid source and peroxidation level on DE and ME was observed. Lipid source tended (P = 0.08) to affect DE but not ME values of experimental lipids (P > 0.12). Digestible energy values for CA (8,846, 8,682, and 8,668 kcal/kg) and CN (8,867, 8,648, and 8,725 kcal/kg) were about 450 kcal/kg greater than that of TL (8,316, 8,168, and 8,296 kcal/kg), with PF being intermediate (8,519, 8,274, and 8,511 kcal/kg), for OL, SO, and RO lipids, respectively, respectively. In conclusion, lipid source affected ATTD of dietary DM, GE, EE, N, and C, and N retention and tended to influence the DE value of the lipid but did not significantly affect their ME value. Rapid and slow heating of lipids used in this study increased lipid peroxidation products but had no detectable effects on nutrient and energy digestibility as well as DE and ME values of the various lipids.

Cholesterol oxidation in intravenous lipid emulsions: safety of preparations before and after experimental hyperoxia.

PubMed

Scopesi, Fabio; Zunin, Paola; Bellini, Carlo; Sacchi, Renata; Boggia, Raffaella; Evangelisti, Filippo; Serra, Giovanni

2004-01-01

The aim of this preliminary study was to assess the possible presence of cholesterol oxidation products in 2 i.v. lipidic emulsions with different fatty acid compositions (long-chain triglyceride, medium-chain triglyceride-long-chain triglyceride). Because these emulsions are currently used in neonatal parenteral nutrition, their direct venous introduction might be potentially dangerous because of the possible atherogenic role of cholesterol oxidation products. The emulsions were analyzed when bottles were opened (ie, under normal condition of administration) and after a 12-hour direct experimental exposure to air and high (90%) oxygen concentrations. 7-Ketocholesterol and 5alpha-epoxycholesterol were chosen as markers of cholesterol oxidation and detected by gas chromatography-mass spectrometry of their trimethylsilyl ethers. The detected amounts were always very low and in some cases below the detection limit of the analytical method for the 2 cholesterol oxidation products (COPs; 0.1 and 0.3 microg/g of extracted lipids). Immediately after opening the bottles, their concentrations were lower in the emulsions containing the higher amounts of polyunsaturated fatty acids. Experimental hyperoxic exposure generally determined only a mild increase in the content of cholesterol oxidation biomarker, and after exposure to oxygen, the amounts of COPs were slightly higher than after exposure to air. The results of the present study are undoubtedly reassuring for the safety of neonates, although caution is always required when drawing conclusions from in vitro data.

Oxidant and antioxidant status of cadmium administered rats

NASA Astrophysics Data System (ADS)

Toplan, S.; Ozcelik, D.; Dariyerli, N.; Akyolcu, M. C.

2003-05-01

Cadmium is one of the industrial elements that lead environmental pollution. Biological half-life of cadmium is relatively longer, so its clearance from tissue is considerably long. In present study, oxidant stress and antioxidant defense mechanism due to exposure to cadmium in rats wanted to be investigated. For such a purpose adult female wistar albino rats were divided into two as control and experimental groups. During experimental period while both group animals were fed by standard fodder, cadmium added (20 μg Cd/ml as cadmium sulfate) drinking water was given to experimental group for four weeks. At the end of four weeks blood samples were drawn from animals under ether anesthesia. As a Last product of lipid peroxidation malondialdehyde (MDA) level, superoxide dismutas (SOD) activity which is sign of antioxidant defense enzyme activity and glutathione levels (GSH) were measured. Increase in lipid peroxidation has been observed by increased MDA levels in experimental group (p<0.001). SOD enzyme activity was also found to be significantly lower in experimental group (p<0.001). Glutathione level of experimental group found to be decreased according to control group values (p<0.01). As a result of present study it may be concluded that cadmium may lead to increase in lipid peroxidation. On the other hand SOD activity and glutathione levels may also be decreased by effect of cadmium in erythrocytes. So the resultant would be the disturbed antioxidant mechanism

Validation of lipolysis product extraction from aqueous/biological samples, separation and quantification by thin-layer chromatography with flame ionization detection analysis using O-cholesteryl ethylene glycol as a new internal standard.

PubMed

Cavalier, Jean-François; Lafont, Dominique; Boullanger, Paul; Houisse, David; Giallo, Jacqueline; Ballester, Jean-Michel; Carrière, Frédéric

2009-09-11

A general and easily accessible method for the extraction followed by the simultaneous separation and quantitative determination of triacylglycerols, diacylglycerols, monoacylglycerols and free fatty acids has been improved and optimized based on existing protocols using liquid-phase extraction and thin-layer chromatography coupled to flame ionization detection (TLC/FID Iatroscan). After lipid extraction in the presence of a suitable new synthetic internal standard, namely CholE1, a single elution step using n-heptane/diethyl ether/formic acid (55:45:1, v/v/v) was applied. This method was validated in line with international bioanalytical method validation guidelines using two different matrix systems: purified water and human gastro-intestinal fluid. Overall, the assay was found to have high levels of precision with coefficients of variation ranging from 1.48% to 11.0% and accuracy ranging from -13.3% to +5.79% RE. The confidence limits of the lipid mean recovery rates varied between 89.9% and 104%. This method is therefore highly suitable for quantifying the lipolysis products generated in vitro during the hydrolysis of various fats and oils by digestive lipases, as well as those collected from the gastro-intestinal tract in the course of human clinical studies on lipid digestion.

40 CFR 414.70 - Applicability; description of the bulk organic chemicals subcategory.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Monomethyl Ether *Dimer Acids Dioxane Ethane Ethylene Glycol Monophenyl Ether *Ethoxylates, Misc. Ethylene Glycol Dimethyl Ether Ethylene Glycol Monobutyl Ether Ethylene Glycol Monoethyl Ether Ethylene Glycol...

Poly(ethylene oxide monomethyl ether)- block-poly(propylene succinate) Nanoparticles: Synthesis and Characterization, Enzymatic and Cellular Degradation, Micellar Solubilization of Paclitaxel, and in Vitro and in Vivo Evaluation.

PubMed

Jäger, Alessandro; Jäger, Eliézer; Syrová, Zdeňka; Mazel, Tomas; Kováčik, Lubomír; Raška, Ivan; Höcherl, Anita; Kučka, Jan; Konefal, Rafal; Humajova, Jana; Poučková, Pavla; Štěpánek, Petr; Hrubý, Martin

2018-04-11

Polyester-based nanostructures are widely studied as drug-delivery systems due to their biocompatibility and biodegradability. They are already used in the clinic. In this work, we describe a new and simple biodegradable and biocompatible system as the Food and Drug Administration approved polyesters (poly-ε-caprolactone, polylactic acid, and poly(lactic- co-glycolic acid)) for the delivery of the anticancer drug paclitaxel (PTX) as a model drug. A hydrophobic polyester, poly(propylene succinate) (PPS), was prepared from a nontoxic alcohol (propylene glycol) and monomer from the Krebs's cycle (succinic acid) in two steps via esterification and melt polycondensation. Furthermore, their amphiphilic block copolyester, poly(ethylene oxide monomethyl ether)- block-poly(propylene succinate) (mPEO- b-PPS), was prepared by three steps via esterification followed by melt polycondensation and the addition of mPEO to the PPS macromolecules. Analysis of the in vitro cellular behavior of the prepared nanoparticle carriers (NPs) (enzymatic degradation, uptake, localization, and fluorescence resonance energy-transfer pair degradation studies) was performed by fluorescence studies. PTX was loaded to the NPs of variable sizes (30, 70, and 150 nm), and their in vitro release was evaluated in different cell models and compared with commercial PTX formulations. The mPEO- b-PPS copolymer analysis displays glass transition temperature < body temperature < melting temperature, lower toxicity (including the toxicity of their degradation products), drug solubilization efficacy, stability against spontaneous hydrolysis during transport in bloodstream, and simultaneous enzymatic degradability after uptake into the cells. The detailed cytotoxicity in vitro and in vivo tumor efficacy studies have shown the superior efficacy of the NPs compared with PTX and PTX commercial formulations.

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent.

PubMed

Wehbe, Mohamed; Anantha, Malathi; Shi, Minghan; Leung, Ada Wai-Yin; Dragowska, Wieslawa H; Sanche, Léon; Bally, Marcel B

2017-01-01

Copper diethyldithiocarbamate (Cu(DDC) 2 ) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC) 2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC) 2 because of the inherent aqueous insolubility of the complex. Here, we describe an injectable Cu(DDC) 2 formulation prepared through a method that involves synthesis of Cu(DDC) 2 inside the aqueous core of liposomes. Convection-enhanced delivery of a Cu(DDC) 2 formulation prepared using 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol liposomes into a rat model of F98 glioma engendered a 25% increase in median survival time relative to vehicle-treated animals. In a murine subcutaneous MV-4-11 model, treatment resulted in a 45% reduction in tumor burden when compared to controls. Pharmacokinetic studies indicated that the Cu(DDC) 2 was rapidly eliminated after intravenous administration while the liposomes remained in circulation. To test whether liposomal lipid composition could increase Cu(DDC) 2 circulation lifetime, a number of different formulations were evaluated. Studies demonstrated that liposomes composed of DSPC and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-(carboxy[polyethylene glycol]-2000) (95:5) enhanced Cu(DDC) 2 concentrations in the circulation as reflected by a 4.2-fold increase in plasma AUC (0-∞) relative to the DSPC/cholesterol formulation. The anticancer activity of this Cu(DDC) 2 formulation was subsequently evaluated in the MV-4-11 model. At its maximum tolerated dose, this formulation exhibited comparable activity to the DSPC/cholesterol formulation. This is the first report demonstrating the therapeutic effects of an injectable Cu(DDC) 2 formulation in vivo.

Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent

PubMed Central

Wehbe, Mohamed; Anantha, Malathi; Shi, Minghan; Leung, Ada Wai-yin; Dragowska, Wieslawa H; Sanche, Léon; Bally, Marcel B

2017-01-01

Copper diethyldithiocarbamate (Cu(DDC)2) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC)2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC)2 because of the inherent aqueous insolubility of the complex. Here, we describe an injectable Cu(DDC)2 formulation prepared through a method that involves synthesis of Cu(DDC)2 inside the aqueous core of liposomes. Convection-enhanced delivery of a Cu(DDC)2 formulation prepared using 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol liposomes into a rat model of F98 glioma engendered a 25% increase in median survival time relative to vehicle-treated animals. In a murine subcutaneous MV-4–11 model, treatment resulted in a 45% reduction in tumor burden when compared to controls. Pharmacokinetic studies indicated that the Cu(DDC)2 was rapidly eliminated after intravenous administration while the liposomes remained in circulation. To test whether liposomal lipid composition could increase Cu(DDC)2 circulation lifetime, a number of different formulations were evaluated. Studies demonstrated that liposomes composed of DSPC and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-(carboxy[polyethylene glycol]-2000) (95:5) enhanced Cu(DDC)2 concentrations in the circulation as reflected by a 4.2-fold increase in plasma AUC(0−∞) relative to the DSPC/cholesterol formulation. The anticancer activity of this Cu(DDC)2 formulation was subsequently evaluated in the MV-4–11 model. At its maximum tolerated dose, this formulation exhibited comparable activity to the DSPC/cholesterol formulation. This is the first report demonstrating the therapeutic effects of an injectable Cu(DDC)2 formulation in vivo. PMID:28615941

Fermented Moringa oleifera Decreases Hepatic Adiposity and Ameliorates Glucose Intolerance in High-Fat Diet-Induced Obese Mice.

PubMed

Joung, Hyunchae; Kim, Bobae; Park, Hyunjoon; Lee, Kyuyeon; Kim, Hee-Hoon; Sim, Ho-Cheol; Do, Hyun-Jin; Hyun, Chang-Kee; Do, Myoung-Sool

2017-05-01

Metabolic diseases, such as glucose intolerance and nonalcoholic fatty-liver disease (NAFLD), are primary risk factors for life-threatening conditions such as diabetes, heart attack, stroke, and hepatic cancer. Extracts from the tropical tree Moringa oleifera show antidiabetic, antioxidant, anti-inflammatory, and anticancer effects. Fermentation can further improve the safety and nutritional value of certain foods. We investigated the efficacy of fermented M. oleifera extract (FM) against high-fat diet (HFD)-induced glucose intolerance and hepatic lipid accumulation and investigated the underlying mechanisms by analyzing expression of proteins and genes involved in glucose and lipid regulation. C57BL/6 mice were fed with normal chow diet (ND) or HFD supplemented with distilled water (DW, control), nonfermented M. oleifera extract (NFM), or FM for 10 weeks. Although body weights were similar among HFD-fed treatment groups, liver weight was decreased, and glucose tolerance test (GTT) results improved in the FM group compared with DW and NFM groups. Hepatic lipid accumulation was also lower in the FM group, and expressions of genes involved in liver lipid metabolism were upregulated. In addition, HFD-induced endoplasmic reticulum (ER) stress, oxidative stress, and lipotoxicity in quadriceps muscles were decreased by FM. Finally, proinflammatory cytokine mRNA expression was decreased by FM in the liver, epididymal adipose tissue, and quadriceps of HFD-fed mice. FMs may decrease glucose intolerance and NAFLD under HFD-induced obesity by decreasing ER stress, oxidative stress, and inflammation.

Alpha-lipoic acid-stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study.

PubMed

Dhaundiyal, Ankit; Jena, Sunil K; Samal, Sanjaya K; Sonvane, Bhavin; Chand, Mahesh; Sangamwar, Abhay T

2016-12-01

This study was designed to demonstrate the potential of novel α-lipoic acid-stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX). α-lipoic acid-stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification-diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats. Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues. α-lipoic acid-stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects. © 2016 Royal Pharmaceutical Society.

Anti-proliferative activities on HeLa cancer cell line of Thai medicinal plant recipes selected from MANOSROI II database.

PubMed

Manosroi, Jiradej; Boonpisuttinant, Korawinwich; Manosroi, Worapaka; Manosroi, Aranya

2012-07-13

The Thai/Lanna medicinal plant recipe database "MANOSROI II" contained the medicinal plant recipes of all regions in Thailand for the treatment of various diseases including anti-cancer medicinal plant recipes. To investigate anti-proliferative activity on HeLa cell lines of medicinal plant recipes selected from the Thai/Lanna medicinal plant recipe database "MANOSROI II". The forty aqueous extracts of Thai/Lanna medicinal plant recipes selected from the Thai/Lanna medicinal plant recipe database "MANOSROI II" were investigated for anti-proliferative activity on HeLa cell line by SRB assay. The apoptosis induction by caspase-3 activity and MMP-2 inhibition activity by zymography on HeLa cell line of the three selected aqueous extracts, which gave the highest anti-proliferative activity were determined. Phytochemicals and anti-oxidative activities including free radical scavenging activity, inhibition of lipid peroxidation and metal chelating inhibition activities were also investigated. Sixty percentages of the medicinal plant recipes selected from "MANOSROI II" database showed anti-proliferative activity on HeLa cell line. The recipes of N031(Albizia chinensis (Osbeck) Merr, Cassia fistula L., and Dargea volubilis Benth.ex Hook. etc.), N039 (Nymphoides indica L., Peltophorum pterocarpum (DC.), and Polyalthia debilis Finet et Gagnep etc.) and N040 (Nymphoides indica L. Kuntze, Sida rhombifolia L., and Xylinbaria minutiflora Pierre. etc.) gave higher anti-proliferative activity than the standard anti-cancer drug, cisplatin of 1.25, 1.29 and 30.18 times, respectively. The positive relationship between the anti-proliferative activity and the MMP-2 inhibition activity and metal chelating inhibition activity was observed, but no relationship between the anti-proliferative activity and apoptosis induction, free radical scavenging activity and lipid peroxidation inhibition activity. Phytochemicals found in these extracts were alkaloids, flavonoids, tannins and xanthones, but not anthraquinones and carotenoids. The recipe N040 exhibited the highest anti-proliferative and MMP-2 inhibition on HeLa cancer cell line at 30 and threefolds of cisplatin, respectively (p<0.05), while recipe N031 gave the highest caspase-3 activity (1.29-folds over the control) (p<0.05). This study has demonstrated that recipe N040 selected from MANOSROI II database appeared to be a good candidate with high potential for the further development as an anti-cancer agent. Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.

Polymersome Carriers: from Self-Assembly to siRNA and Protein Therapeutics

PubMed Central

Christian, David A.; Cai, Shenshen; Bowen, Diana M.; Kim, Younghoon; Pajerowski, J. David; Discher, Dennis E.

2009-01-01

Polymersomes are polymer-based vesicular shells that form upon hydration of amphiphilic block copolymers. These high molecular weight amphiphiles impart physicochemical properties that allow polymersomes to stably encapsulate or integrate a broad range of active molecules. This robustness together with recently described mechanisms for controlled breakdown of degradable polymersomes as well as escape from endolysosomes suggests that polymersomes might be usefully viewed as having structure/property/function relationships somewhere between lipid vesicles and viral capsids. Here we summarize the assembly and development of controlled release polymersomes to encapsulate therapeutics ranging from small molecule anti-cancer drugs to siRNA and therapeutic proteins. PMID:18977437

RNA-modifying proteins as anticancer drug targets.

PubMed

Boriack-Sjodin, P Ann; Ribich, Scott; Copeland, Robert A

2018-06-01

All major biological macromolecules (DNA, RNA, proteins and lipids) undergo enzyme-catalysed covalent modifications that impact their structure, function and stability. A variety of covalent modifications of RNA have been identified and demonstrated to affect RNA stability and translation to proteins; these mechanisms of translational control have been termed epitranscriptomics. Emerging data suggest that some epitranscriptomic mechanisms are altered in human cancers as well as other human diseases. In this Review, we examine the current understanding of RNA modifications with a focus on mRNA methylation, highlight their possible roles in specific cancer indications and discuss the emerging potential of RNA-modifying proteins as therapeutic targets.

Pharmacophore mapping of arylbenzothiophene derivatives for MCF cell inhibition using classical and 3D space modeling approaches.

PubMed

Mukherjee, Subhendu; Nagar, Shuchi; Mullick, Sanchita; Mukherjee, Arup; Saha, Achintya

2008-01-01

Considering the worth of developing non-steroidal estrogen analogs, the present study explores the pharmacophore features of arylbenzothiophene derivatives for inhibitory activity to MCF-7 cells using classical QSAR and 3D space modeling approaches. The analysis shows that presence of phenolic hydroxyl group and ketonic linkage in the basic side chain of 2-arylbenzothiophene core of raloxifene derivatives are crucial. Additionally piperidine ring connected through ether linkage is favorable for inhibition of breast cancer cell line. These features for inhibitory activity are also highlighted through 3D space modeling approach that explored importance of critical inter features distance among HB-acceptor lipid, hydrophobic and HB-donor features in the arylbenzothiophene scaffold for activity.

Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storage.

PubMed

Seibel, Brad A; Walsh, Patrick J

2002-02-01

Trimethylamine oxide (TMAO) is a common and compatible osmolyte in muscle tissues of marine organisms that is often credited with counteracting protein-destabilizing forces. However, the origin and synthetic pathways of TMAO are actively debated. Here, we examine the distribution of TMAO in marine animals and report a correlation between TMAO and acylglycerol storage. We put forward the hypothesis that TMAO is derived, at least in part, from the hydrolysis of phosphatidylcholine, endogenous or dietary, for storage as diacylglycerol ethers and triacylglycerols. TMAO is synthesized from the trimethylammonium moiety of choline, thus released, and is retained as a compatible solute in concentrations reflecting the amount of lipid stored in the body. A variation on this theme is proposed for sharks.

Application of quality-by-design approach to optimize diallyl disulfide-loaded solid lipid nanoparticles.

PubMed

Talluri, Siddhartha Venkata; Kuppusamy, Gowthamarajan; Karri, Veera Venkata Satyanarayana Reddy; Yamjala, Karthik; Wadhwani, Ashish; Madhunapantula, SubbaRao V; Pindiprolu, Saikiran S S

2017-05-01

The current work was carried out by the principles of quality-by-design approach to develop an optimized solid lipid nanoparticles (SLNs) formulation of diallyl disulfide (DADS) through systematic statistical study. And its antitumor activity of DADS was also evaluated on breast cancer cell lines. To understand the effect of formulation variables (critical parameters) on the responses (critical quality attributes) of SLN, a 3-factor, 3-level Box-Behnken design, was explored to predict the responses such as particle size (Y1) and % entrapment efficiency (EE) (Y2) when concentration of surfactant (X1), amount of lipid (X2), and volume of solvent (X3) were selected as independent variables. Particle size analysis revealed that all the batches were within the nanometer range. DADS was released from the SLN much more rapidly at pH 4.5 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. The cytotoxicity, reactive oxygen species (ROS), determination revealed that the antitumor activity of DADS is enhanced with SLN compared to DADS-free drug, and apoptosis is the mechanism underlying the cytotoxicity. The present study indicated the remarkable potential of DADS-SLN in enhancing the anticancer effect of DADS in breast cancer cells in vitro.

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

PubMed Central

Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk

2014-01-01

Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel. PMID:24531717

Sesamol-loaded solid lipid nanoparticles for treatment of skin cancer.

PubMed

Geetha, T; Kapila, Meenakshi; Prakash, Om; Deol, Parneet Kaur; Kakkar, Vandita; Kaur, Indu Pal

2015-02-01

Abstract Role of reactive oxygen species (ROS) in skin carcinogenesis is well documented. Natural molecules, like sesamol, with marked antioxidant potential can be useful in combating skin cancers. In vitro antiproliferative (using MTT assay) and DNA fragmentation studies in HL 60 cell lines, confirmed the apoptotic nature of sesamol. However, it showed a significant flux across the mice skin upon topical application, such that its local availability in skin is limited. Former is attributed mainly to its properties like small size, low molecular weight (138.28), and a sufficient lipid and water solubility (log P 1.29; solubility 38.8 mg/ml). To achieve its maximum epicutaneous delivery, packaging it into a suitable carrier system is thus indicated. Sesamol-loaded solid lipid nanoparticles (S-SLN) were thus prepared with particle size of 127.9 nm (PI: 0.256) and entrapment efficiency of 88.21%. Topical application of S-SLN in a cream base indicated significant retention in the skin with minimal flux across skin as confirmed by the in-vivo skin retention and ex-vivo skin permeation studies. In vivo anticancer studies performed on TPA-induced and benzo(a)pyrene initiated tumour production (ROS mediated) in mouse epidermis showed the normalization (in histology studies) of skin cancers post their induction, upon treatment with S-SLN.

Isolation and Analysis of Phospholipids in Dairy Foods

PubMed Central

Pimentel, Lígia; Gomes, Ana; Pintado, Manuela

2016-01-01

The lipid fraction of milk is one of the most complex matrixes in foodstuffs due to the presence of a high number of moieties with different physical and chemical properties. Glycerolipids include glycerol and two fatty acids esterified in positions sn-1 and sn-2 with higher concentration of unsaturated fatty acids than in the triglyceride fraction of milk. Sphingolipids consist of a sphingoid base linked to a fatty acid across an amide bond. Their amphiphilic nature makes them suitable to be added into a variety of foods and recent investigations show that phospholipids, mainly phosphatidylserine and sphingomyelin, can exert antimicrobial, antiviral, and anticancer activities as well as positive effects in Alzheimer's disease, stress, and memory decline. Polar lipids can be found as natural constituents in the membranes of all living organisms with soybean and eggs as the principal industrial sources, yet they have low contents in phosphatidylserine and sphingomyelin. Animal products are rich sources of these compounds but since there are legal restrictions to avoid transmission of prions, milk and dairy products are gaining interest as alternative sources. This review summarizes the analysis of polar lipids in dairy products including sample preparation (extraction and fractionation/isolation) and analysis by GC or HPLC and the latest research works using ELSD, CAD, and MS detectors. PMID:27610267

Molecular structure impacts on secondary organic aerosol formation from glycol ethers

NASA Astrophysics Data System (ADS)

Li, Lijie; Cocker, David R.

2018-05-01

Glycol ethers, a class of widely used solvents in consumer products, are often considered exempt as volatile organic compounds based on their vapor pressure or boiling points by regulatory agencies. However, recent studies found that glycol ethers volatilize at ambient conditions nearly as rapidly as the traditional high-volatility solvents indicating the potential of glycol ethers to form secondary organic aerosol (SOA). This is the first work on SOA formation from glycol ethers. The impact of molecular structure, specifically -OH, on SOA formation from glycol ethers and related ethers are investigated in the work. Ethers with and without -OH, with methyl group hindrance on -OH and with -OH at different location are studied in the presence of NOX and under "NOX free" conditions. Photooxidation experiments under different oxidation conditions confirm that the processing of ethers is a combination of carbonyl formation, cyclization and fragmentation. Bulk SOA chemical composition analysis and oxidation products identified in both gas and particle phase suggests that the presence and location of -OH in the carbon bond of ethers determine the occurrence of cyclization mechanism during ether oxidation. The cyclization is proposed as a critical SOA formation mechanism to prevent the formation of volatile compounds from fragmentation during the oxidation of ethers. Glycol ethers with -CH2-O-CH2CH2OH structure is found to readily form cyclization products, especially with the presence of NOx, which is more relevant to urban atmospheric conditions than without NOx. Glycol ethers are evaluated as dominating SOA precursors among all ethers studied. It is estimated that the contribution of glycol ethers to anthropogenic SOA is roughly 1% of the current organic aerosol from mobile sources. The contribution of glycol ethers to anthropogenic SOA is roughly 1% of the current organic aerosol from mobile sources and will play a more important role in future anthropogenic SOA formation.

Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers and esters.

PubMed

Tollefson, Emily J; Hanna, Luke E; Jarvo, Elizabeth R

2015-08-18

This Account presents the development of a suite of stereospecific alkyl-alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal. The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination. Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details. Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative examples of bioactive compounds that we have prepared with high enantioselectivity employing our methods, as well as the discovery of a new anti-cancer agent.

Arginine-Glycine-Aspartic Acid-Modified Lipid-Polymer Hybrid Nanoparticles for Docetaxel Delivery in Glioblastoma Multiforme.

PubMed

Shi, Kairong; Zhou, Jin; Zhang, Qianyu; Gao, Huile; Liu, Yayuan; Zong, Taili; He, Qin

2015-03-01

Hybrid nanoparticles consisting of lipids and the biodegradable polymer, poly (D,L-lactide-co-glycolide) (PLGA), were developed for the targeted delivery of the anticancer drug, docetaxel. Transmission electron microscopic observations confirmed the presence of a lipid coating over the polymeric core. Using coumarin-6 as a fluorescent probe, the uptake efficacy of RGD conjugated lipid coated nanoparticles (RGD-L-P) by C6 cells was increased significantly, compared with that of lipid-polymer hybrid nanoparticles (L-P; 2.5-fold higher) or PLGA-nanoparticles (PLGA-P; 1.76-fold higher). The superior tumor spheroid penetration of RGD-L-P indicated that RGD-L-P could target effectively and specifically to C6 cells overexpressing integrin α(v)β3. The anti-proliferative activity of docetaxel-loaded RGD-L-P against C6 cells was increased 2.69- and 4.13-fold compared with L-P and PLGA-P, respectively. Regarding biodistribution, the strongest brain-localized fluorescence signals were detected in glioblastoma multiforme (GBM)-bearing rats treated with 1,10-Dioctadecyl-3,3,30,30-tetramethylindotricarb-ocyanine iodide (DiR)-loaded RGD-L-P, compared to rats treated with DiR-loaded L-P or PLGA-P. The median survival time of GBM-bearing rats treated with docetaxel-loaded RGD-L-P was 57 days, a fold increase of 1.43, 1.78, 3.35, and 3.56 compared with animals given L-P (P < 0.05), PLGA-P (P < 0.05), Taxotere (P < 0.01) and saline (P < 0.01), respectively. Collectively, these results support RGD-L-P as a promising drug delivery system for the specific targeting and the treatment of GBM.

Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish.

PubMed

Lee, Yeon-Joo; Choi, Hyeon-Son; Seo, Min-Jung; Jeon, Hui-Jeon; Kim, Kui-Jin; Lee, Boo-Yong

2015-08-01

Kaempferol is a flavonoid present in Kaempferia galanga and Opuntia ficus indica var. saboten. Recent studies have suggested that it has anti-oxidant, anti-inflammatory, anti-cancer, and anti-obesity effects. In this study, we focused on the anti-adipogenic effects of kaempferol during adipocyte differentiation. The results showed that kaempferol inhibits lipid accumulation in adipocytes and zebrafish. Oil Red O and Nile Red staining showed that the number of intracellular lipid droplets decreased in adipocytes and zebrafish treated with kaempferol. LPAATθ (lysophosphatidic acid acyltransferase), lipin1, and DGAT1 (triglyceride synthetic enzymes) and FASN and SREBP-1C (fatty acid synthetic proteins) showed decreased expression levels in the presence of kaempferol. In addition, treatment of kaempferol showed an inhibitory activity on cell cycle progression. Kaempferol delayed cell cycle progression from the S to G2/M phase through the regulation of cyclins in a dose-dependent manner. Kaempferol blocked the phosphorylation of AKT (protein kinase B) and mammalian target of rapamycin (mTOR) signaling pathway during the early stages of adipogenesis. In addition, kaempferol down-regulated pro-early adipogenic factors such as CCAAT-enhancer binding proteins β (C/EBPβ), and Krüppel-like factors (KLFs) 4 and 5, while anti-early adipogenic factors, such as KLF2 and pref-1(preadipocyte factor-1), were upregulated. These kaempferol-mediated regulations of early adipogenic factors resulted in the attenuation of late adipogenic factors such as C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ). These results were supported in zebrafish based on the decrease in lipid accumulation and expression of adipogenic factors. Our results indicated that kaempferol might have an anti-obesity effect by regulating lipid metabolism.

Lipid prodrug nanocarriers in cancer therapy.

PubMed

Mura, Simona; Bui, Duc Trung; Couvreur, Patrick; Nicolas, Julien

2015-06-28

Application of nanotechnology in the medical field (i.e., nanomedicine) plays an important role in the development of novel drug delivery methods. Nanoscale drug delivery systems can indeed be customized with specific functionalities in order to improve the efficacy of the treatments. However, despite the progresses of the last decades, nanomedicines still face important obstacles related to: (i) the physico-chemical properties of the drug moieties which may reduce the total amount of loaded drug; (ii) the rapid and uncontrolled release (i.e., burst release) of the encapsulated drug after administration and (iii) the instability of the drug in biological media where a fast transformation into inactive metabolites can occur. As an alternative strategy to alleviate these drawbacks, the prodrug approach has found wide application. The covalent modification of a drug molecule into an inactive precursor from which the drug will be freed after administration offers several benefits such as: (i) a sustained drug release (mediated by chemical or enzymatic hydrolysis of the linkage between the drug-moiety and its promoiety); (ii) an increase of the drug chemical stability and solubility and, (iii) a reduced toxicity before the metabolization occurs. Lipids have been widely used as building blocks for the design of various prodrugs. Interestingly enough, these lipid-derivatized drugs can be delivered through a nanoparticulate form due to their ability to self-assemble and/or to be incorporated into lipid/polymer matrices. Among the several prodrugs developed so far, this review will focus on the main achievements in the field of lipid-based prodrug nanocarriers designed to improve the efficacy of anticancer drugs. Gemcitabine (Pubchem CID: 60750); 5-fluorouracil (Pubchem CID: 3385); Doxorubicin (Pubchem CID: 31703); Docetaxel (Pubchem CID: 148124); Methotrexate (Pubchem CID: 126941); Paclitaxel (Pubchem CID: 36314). Copyright © 2015 Elsevier B.V. All rights reserved.

Isolation and characterization of an ether-type polyurethane-degrading micro-organism and analysis of degradation mechanism by Alternaria sp.

PubMed

Matsumiya, Y; Murata, N; Tanabe, E; Kubota, K; Kubo, M

2010-06-01

To degrade ether-type polyurethane (ether-PUR), ether-PUR-degrading micro-organism was isolated. Moreover, ether-PUR-degrading mechanisms were analysed using model compounds of ether-PUR. A fungus designated as strain PURDK2, capable of changing the configuration of ether-PUR, has been isolated. This isolated fungus was identified as Alternaria sp. Using a scanning electron microscope, the grid structure of ether-PUR was shown to be melted and disrupted by the fungus. The degradation of ether-PUR by the fungus was analysed, and the ether-PUR was degraded by the fungus by about 27.5%. To analyse the urethane-bond degradation by the fungus, a degraded product of ethylphenylcarbamate was analysed using GC/MS. Aniline and ethanol were detected by degradation with the supernatant, indicating that the fungus secreted urethane-bond-degrading enzyme(s). PURDK2 also degraded urea bonds when diphenylmethane-4,4'-dibutylurea was used as a substrate. The enzyme(s) from PURDK2 degraded urethane and urea bonds to convert the high molecular weight structure of ether-PUR to small molecules; and then the fungus seems to use the small molecules as an energy source. Ether-PUR-degrading fungus, strain PURDK2, was isolated, and the urethane- and urea-bonds-degrading enzymes from strain PURDK2 could contribute to the material recycling of ether-PUR.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

Phillips Petroleum Co. is poised to license its high conversion process to produce fuel ethers for blending in reformulated gasolines. The technology has been proven in a Phillips semiworks at Bartlesville, Okla. The process can produce methyl tertiary butyl ether, ethyl tertiary butyl ether, tertiary amyl methyl ether, or tertiary amyl ethyl ether with typical refinery process equipment and techniques. Phillips said it can achieve conversion levels of 92-99%, depending on the ether. The ether produced is determined by which hydrocarbon fraction is used for feedstock and which alcohol is chosen for reaction. The process is described.

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin.

PubMed

Shukla, Mahendra; Jaiswal, Swati; Sharma, Abhisheak; Srivastava, Pradeep Kumar; Arya, Abhishek; Dwivedi, Anil Kumar; Lal, Jawahar

2017-05-01

Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability. In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin. As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague-Dawley rats, the optimized SNEDDS of curcumin-phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS. The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.

A new route to synthesize aryl acetates from carbonylation of aryl methyl ethers

PubMed Central

Yang, Youdi; Li, Shaopeng; Han, Buxing

2018-01-01

Ether bond activation is very interesting because the synthesis of many valuable compounds involves conversion of ethers. Moreover, C–O bond cleavage is also very important for the transformation of biomass, especially lignin, which abundantly contains ether bonds. Developing efficient methods to activate aromatic ether bonds has attracted much attention. However, this is a challenge because of the inertness of aryl ether bonds. We proposed a new route to activate aryl methyl ether bonds and synthesize aryl acetates by carbonylation of aryl methyl ethers. The reaction could proceed over RhCl3 in the presence of LiI and LiBF4, and moderate to high yields of aryl acetates could be obtained from transformation of various aryl methyl ethers with different substituents. It was found that LiBF4 could assist LiI to cleave aryl methyl ether bonds effectively. The reaction mechanism was proposed by a combination of experimental and theoretical studies. PMID:29795781

Hybrid lipid-based nanostructures

NASA Astrophysics Data System (ADS)

Dayani, Yasaman

Biological membranes serve several important roles, such as structural support of cells and organelles, regulation of ionic and molecular transport, barriers to non-mediated transport, contact between cells within tissues, and accommodation of membrane proteins. Membrane proteins and other vital biomolecules incorporated into the membrane need a lipid membrane to function. Due to importance of lipid bilayers and their vital function in governing many processes in the cell, the development of various models as artificial lipid membranes that can mimic cell membranes has become a subject of great interest. Using different models of artificial lipid membranes, such as liposomes, planar lipid bilayers and supported or tethered lipid bilayers, we are able to study many biophysical processes in biological membranes. The ability of different molecules to interact with and change the structure of lipid membranes can be also investigated in artificial lipid membranes. An important application of lipid bilayer-containing interfaces is characterization of novel membrane proteins for high throughput drug screening studies to investigate receptor-drug interactions and develop biosensor systems. Membrane proteins need a lipid bilayer environment to preserve their stability and functionality. Fabrication of materials that can interact with biomolecules like proteins necessitates the use of lipid bilayers as a mimic of cell membranes. The objective of this research is to develop novel hybrid lipid-based nanostructures mimicking biological membranes. Toward this aim, two hybrid biocompatible structures are introduced: lipid bilayer-coated multi-walled carbon nanotubes (MWCNTs) and hydrogel-anchored liposomes with double-stranded DNA anchors. These structures have potential applications in biosensing, drug targeting, drug delivery, and biophysical studies of cell membranes. In the first developed nanostructure, lipid molecules are covalently attached to the surfaces of MWCNTs, and then, using a sonication process, a uniform lipid bilayer that supports the incorporation of membrane proteins is formed. These bilayer-coated carbon nanotubes are highly dispersible and stable in aqueous solution, and they can be used in development of various biosensors and energy producing devices. In the other hybrid nanostructure, the lipid bilayer of a liposome is covalently anchored to a biocompatible poly(ethylene) glycol (PEG) hydrogel core using double-stranded DNA (dsDNA) linkers. Release studies shows that nano-size hydrogel-anchored liposomes are exceptionally stable, and they can be used as biomimetic model membranes that mimic the connectivity between the cytoskeleton and the plasma membrane. After lipid bilayer removal, dsDNA linkers can provide programmable nanogels decorated with oligonucleotides with potential sites for further molecular assembly. These stable nanostructures can be useful for oligonucleotide and drug delivery applications. The developed hydrogel-anchored liposomes are exploited for encapsulation and intracellular delivery of therapeutic peptide. Peptides with anti-cancer properties are successfully encapsulated in hydrogel core of pH-sensitive liposomes during rehydration process. Liposomes release their cargo at acidic pH. Confocal microscopy confirms the intracellular delivery of liposomes through an endocytotic pathway.

Catalytic oxidation of dimethyl ether

DOEpatents

Zelenay, Piotr; Wu, Gang; Johnston, Christina M.; Li, Qing

2016-05-10

A composition for oxidizing dimethyl ether includes an alloy supported on carbon, the alloy being of platinum, ruthenium, and palladium. A process for oxidizing dimethyl ether involves exposing dimethyl ether to a carbon-supported alloy of platinum, ruthenium, and palladium under conditions sufficient to electrochemically oxidize the dimethyl ether.

Potential Anticancer Properties of Grape Antioxidants

PubMed Central

Zhou, Kequan; Raffoul, Julian J.

2012-01-01

Dietary intake of foods rich in antioxidant properties is suggested to be cancer protective. Foods rich in antioxidant properties include grape (Vitis vinifera), one of the world's largest fruit crops and most commonly consumed fruits in the world. The composition and cancer-protective effects of major phenolic antioxidants in grape skin and seed extracts are discussed in this review. Grape skin and seed extracts exert strong free radical scavenging and chelating activities and inhibit lipid oxidation in various food and cell models in vitro. The use of grape antioxidants are promising against a broad range of cancer cells by targeting epidermal growth factor receptor (EGFR) and its downstream pathways, inhibiting over-expression of COX-2 and prostaglandin E2 receptors, or modifying estrogen receptor pathways, resulting in cell cycle arrest and apoptosis. Interestingly, some of these activities were also demonstrated in animal models. However, in vivo studies have demonstrated inconsistent antioxidant efficacy. Nonetheless, a growing body of evidence from human clinical trials has demonstrated that consumption of grape, wine and grape juice exerts many health-promoting and possible anti-cancer effects. Thus, grape skin and seed extracts have great potential in cancer prevention and further investigation into this exciting field is warranted. PMID:22919383

Molecular modeling of transmembrane delivery of paclitaxel by shock waves with nanobubbles

NASA Astrophysics Data System (ADS)

Lu, Xue-mei; Yuan, Bing; Zhang, Xian-ren; Yang, Kai; Ma, Yu-qiang

2017-01-01

The development of advanced delivery strategies for anticancer drugs that can permeate through cellular membranes is urgently required for biomedical applications. In this work, we investigated the dynamic transmembrane behavior of paclitaxel (PTX), a powerful anticancer drug, under the combined impact of shock waves and nanobubbles, by using atomistic molecular dynamics simulations. Our simulations show that the PTX molecule experiences complicated motion modes during the action process with the membrane, as a consequence of its interplay with the lipid bilayer and water, under the joint effect of the shock wave and nanobubble. Moreover, it was found that the transmembrane movement of PTX is closely associated with the conformation changes of PTX, as well as the structural changes of the membrane (e.g., compression and poration in membrane). The nanobubble collapse induced by the shock wave, the proper PTX location with respect to the nanobubble, and a suitable nanobubble size and shock impulse are all necessary for the delivery of PTX into the cell. This work provides a molecular understanding of the interaction mechanism between drug molecules and cell membranes under the influence of shock waves and nanobubbles, and paves the way for exploiting targeted drug delivery systems that combine nanobubbles and ultrasound.

Liposomal nanomedicines.

PubMed

Fenske, David B; Cullis, Pieter R

2008-01-01

Liposomal nanoparticles (LNs) encapsulating therapeutic agents, or liposomal nanomedicines, represent an advanced class of drug delivery systems, with several formulations presently on the market and many more in clinical trials. Over the past 20 years, a variety of techniques have been developed for encapsulating both conventional drugs (such as anticancer drugs and antibiotics) and the new genetic drugs (plasmid DNA containing therapeutic genes, antisense oligonucleotides and small interfering RNA) within LNs. If the LNs possess certain properties, they tend to accumulate at sites of disease, such as tumours, where the endothelial layer is 'leaky' and allows extravasation of particles with small diameters. These properties include a diameter centred on 100 nm, a high drug-to-lipid ratio, excellent retention of the encapsulated drug, and a long (> 6 h) circulation lifetime. These properties permit the LNs to protect their contents during circulation, prevent contact with healthy tissues, and accumulate at sites of disease. The authors discuss recent advances in this field involving conventional anticancer drugs, as well as applications involving gene delivery, stimulation of the immune system and silencing of unwanted gene expression. Liposomal nanomedicines have the potential to offer new treatments in such areas as cancer therapy, vaccine development and cholesterol management.

Shotgun ecotoxicoproteomics of Daphnia pulex: biochemical effects of the anticancer drug tamoxifen.

PubMed

Borgatta, Myriam; Hernandez, Céline; Decosterd, Laurent Arthur; Chèvre, Nathalie; Waridel, Patrice

2015-01-02

Among pollutants released into the environment by human activities, residues of pharmaceuticals are an increasing matter of concern because of their potential impact on ecosystems. The aim of this study was to analyze differences of protein expression resulting from acute (2 days) and middle-term (7 days) exposure of aquatic microcrustacean Daphnia pulex to the anticancer drug tamoxifen. Using a liquid chromatography-mass spectrometry shotgun approach, about 4000 proteins could be identified, providing the largest proteomics data set of D. pulex published up to now. Considering both time points and tested concentrations, 189 proteins showed a significant fold change. The identity of regulated proteins suggested a decrease in translation, an increase in protein degradation and changes in carbohydrate and lipid metabolism as the major effects of the drug. Besides these impacted processes, which reflect a general stress response of the organism, some other regulated proteins play a role in Daphnia reproduction. These latter results are in accordance with our previous observations of the impact of tamoxifen on D. pulex reproduction and illustrate the potential of ecotoxicoproteomics to unravel links between xenobiotic effects at the biochemical and organismal levels. Data are available via ProteomeXchange with identifier PXD001257.

Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update

PubMed Central

Khan, Fazlullah; Niaz, Kamal; Maqbool, Faheem; Ismail Hassan, Fatima; Abdollahi, Mohammad; Nagulapalli Venkata, Kalyan C.; Nabavi, Seyed Mohammad; Bishayee, Anupam

2016-01-01

Quercetin, a medicinally important member of the flavonoid family, is one of the most prominent dietary antioxidants. It is present in a variety of foods—including fruits, vegetables, tea, wine, as well as other dietary supplements—and is responsible for various health benefits. Numerous pharmacological effects of quercetin include protection against diseases, such as osteoporosis, certain forms of malignant tumors, and pulmonary and cardiovascular disorders. Quercetin has the special ability of scavenging highly reactive species, such as hydrogen peroxide, superoxide anion, and hydroxyl radicals. These oxygen radicals are called reactive oxygen species, which can cause oxidative damage to cellular components, such as proteins, lipids, and deoxyribonucleic acid. Various oxygen radicals play important roles in pathophysiological and degenerative processes, such as aging. Subsequently, several studies have been performed to evaluate possible advantageous health effects of quercetin and to collect scientific evidence for these beneficial health claims. These studies also gather data in order to evaluate the exact mechanism(s) of action and toxicological effects of quercetin. The purpose of this review is to present and critically analyze molecular pathways underlying the anticancer effects of quercetin. Current limitations and future directions of research on this bioactive dietary polyphenol are also critically discussed. PMID:27589790

Determining the fatty acid composition in plasma and tissues as fatty acid methyl esters using gas chromatography – a comparison of different derivatization and extraction procedures.

PubMed

Ostermann, Annika I; Müller, Maike; Willenberg, Ina; Schebb, Nils Helge

2014-12-01

Analysis of the fatty acid (FA) composition in biological samples is commonly carried out using gas liquid chromatography (GC) after transesterification to volatile FA methyl esters (FAME). We compared the efficacy of six frequently used protocols for derivatization of different lipid classes as well as for plasma and tissue samples. Transesterification with trimethylsulfonium hydroxide (TMSH) led to insufficient derivatization efficacies for polyunsaturated FAs (PUFA, <50%). Derivatization in presence of potassium hydroxide (KOH) failed at derivatizing free FAs (FFAs). Boron trifluoride (BF3) 7% in hexane/MeOH (1:1) was insufficient for the transesterification of cholesterol ester (CE) as well as triacylglycerols (TGs). In contrast, methanolic hydrochloric acid (HCl) as well as a combination of BF3 with methanolic sodium hydroxide (NaOH+BF3) were suitable for the derivatization of FFAs, polar lipids, TGs, and CEs (derivatization rate >80% for all tested lipids). Regarding plasma samples, all methods led to an overall similar relative FA pattern. However, significant differences were observed, for example, for the relative amount of EPA+DHA (n3-index). Absolute FA plasma concentrations differed considerably among the methods, with low yields for KOH and BF3. We also demonstrate that lipid extraction with tert-butyl methyl ether/methanol (MTBE/MeOH) is as efficient as the classical method according to Bligh and Dyer, making it possible to replace (environmentally) toxic chloroform.We conclude that HCl-catalyzed derivatization in combination with MeOH/MTBE extraction is the most appropriate among the methods tested for the analysis of FA concentrations and FA pattern in small biological samples. A detailed protocol for the analysis of plasma and tissues is included in this article.

Morbidity study of extruder personnel with potential exposure to brominated dioxins and furans. II. Results of clinical laboratory studies.

PubMed Central

Ott, M G; Zober, A

1996-01-01

OBJECTIVE: To test whether dioxins affect liver and thyroid function, lipid metabolism and glucose or immunological variables, in workers exposed to brominated dioxins and furans. METHODS: 34 male production employees (29 were extruder operators) and eight technical support personnel were studied, all of whom were potentially exposed to polybrominated dibenzo-p-dioxins (PBDDs) and furans (PBDFs) during production of resins containing polybrominated diphenyl ethers (PBDEs). Controls were from a similar resin producing plant that did not use PBDEs. Blood samples were analysed for tetra, penta, and hexabrominated congeners, but 2,3,7,8-TBDD was the only exposure measure used in the regression analyses. Seven liver function indicators, five measures of blood lipids and glucose, four haematology and blood coagulation measures, and three measures of thyroid function were examined. RESULTS: None of the variables was statistically related to concentration of 2,3,7,8-TBDD in the regression analyses. Cigarette smoking was related to several outcomes at the 0.05 level: aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase (GLDH), erythrocyte sedimentation rate, and white blood cell count. Body mass index was also related to alanine aminotransferase, gamma-glutamyltranspeptidase, cholinesterase, GLDH, cholesterol, triglycerides, high density lipoprotein, low density lipoprotein, and glucose concentrations. No definitive associations between liver, blood lipid, thyroid, or immunological variables and exposure to brominated dioxins or blood lipid concentration of 2,3,7,8-TBDD were found. CONCLUSIONS: The study population was small and hence the findings must be interpreted with caution. Nevertheless, these results provide a base for interpreting the results of clinical studies in similarly exposed populations. PMID:8994404

Palladium-Catalyzed Reductive Insertion of Alcohols into Aryl Ether Bonds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Meng; Gutiérrez, Oliver Y.; Camaioni, Donald M.

Pd/C catalyzes C-O bond cleavage of aryl ethers (diphenyl ether and cyclohexyl phenyl ether) by methanol in H2. The aromatic C-O bond is cleaved by reductive methanolysis, which is initiated by Pd-catalyzed partial hydrogenation of one phenyl ring to form an enol ether. The enol ether reacts rapidly with methanol to form a ketal, which generates methoxycyclohexene by eliminating phenol or an alkanol. Subsequent hydrogenation leads to methoxycyclohexane.

Blechnum Orientale Linn - a fern with potential as antioxidant, anticancer and antibacterial agent

PubMed Central

2010-01-01

Background Blechnum orientale Linn. (Blechnaceae) is used ethnomedicinally for the treatment of various skin diseases, stomach pain, urinary bladder complaints and sterilization of women. The aim of the study was to evaluate antioxidant, anticancer and antibacterial activity of five solvent fractions obtained from the methanol extract of the leaves of Blechnum orientale Linn. Methods Five solvent fractions were obtained from the methanol extract of B. orientale through successive partitioning with petroleum ether, chloroform, ethyl acetate, butanol and water. Total phenolic content was assessed using Folin-Ciocalteu's method. The antioxidant activity was determined by measuring the scavenging activity of DPPH radicals. Cytotoxic activity was tested against four cancer cell lines and a non-malignant cell using MTT assay. Antibacterial activity was assessed using the disc diffusion and broth microdilution assays. Standard phytochemical screening tests for saponins, tannins, terpenoids, flavonoids and alkaloids were also conducted. Results The ethyl acetate, butanol and water fractions possessed strong radical scavenging activity (IC50 8.6-13.0 μg/ml) and cytotoxic activity towards human colon cancer cell HT-29 (IC50 27.5-42.8 μg/ml). The three extracts were also effective against all Gram-positive bacteria tested: Bacillus cereus, Micrococcus luteus, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and Stapylococcus epidermidis(minimum inhibitory concentration MIC 15.6-250 μg/ml; minimum bactericidal concentration MBC 15.6-250 μg/ml). Phytochemical analysis revealed the presence of flavonoids, terpenoids and tannins. Ethyl acetate and butanol fractions showed highest total phenolic content (675-804 mg gallic acid equivalent/g). Conclusions The results indicate that this fern is a potential candidate to be used as an antioxidant agent, for colon cancer therapy and for treatment of MRSA infections and other MSSA/Gram-positive bacterial infectious diseases. PMID:20429956

A green analytical chemistry approach for lipid extraction: computation methods in the selection of green solvents as alternative to hexane.

PubMed

Cascant, Mari Merce; Breil, Cassandra; Garrigues, Salvador; de la Guardia, Miguel; Fabiano-Tixier, Anne Silvie; Chemat, Farid

2017-05-01

There is a great interest in finding alternatives and green solvents in extraction processes to replace petroleum based solvents. In order to investigate these possibilities, computational methods, as Hansen solubility parameters (HSP) and conductor-like screening model for real solvent (COSMO-RS), were used in this work to predict the solvation power of a series of solvents in salmon fish lipids. Additionally, experimental studies were used to evaluate the performance in lipids extraction using 2-methyltetrahydrofurane, cyclopentyl methyl ether, dimethyl carbonate, isopropanol, ethanol, ethyl acetate, p-cymene and d-limonene compared with hexane. Lipid classes of extracts were obtained by using high performance thin-layer chromatography (HPTLC), whereas gas chromatography with a flame ionization detector (GC/FID) technique was employed to obtain fatty acid profiles. Some differences between theoretical and experimental results were observed, especially regarding the behavior of p-cymene and d-limonene, which separate from the predicted capability. Results obtained from HPTLC indicated that p-cymene and d-limonene extract triglycerides (TAGs) and diglycerides (DAGs) at levels of 73 and 19%, respectively, whereas the other studied extracts contain between 75 and 76% of TAGs and between 16 and 17% of DAGs. Fatty acid profiles, obtained by using GC-FID, indicated that saturated fatty acids (SFAs) between 19.5 and 19.9% of extracted oil, monounsaturated fatty acids (MUFAs) in the range between 43.5 and 44.9%, and PUFAs between 31.2 and 34.6% were extracted. p-Cymene and limonene extracts contained lower percentages than the other studied solvents of some PUFAs due probably to the fact that these unsaturated fatty acids are more susceptible to oxidative degradation than MUFAs. Ethyl acetate has been found to be the best alternative solvent to hexane for the extraction of salmon oil lipids. Graphical Abstract ᅟ.

Ion channels in artificial bolaamphiphile membranes deposited on sensor chips: optical detection in an ion-channel-based biosensor

NASA Astrophysics Data System (ADS)

Schalkhammer, Thomas G. M.; Weiss-Wichert, Christof; Smetazko, Michaela M.; Valina-Saba, Miriam

1997-06-01

Signal amplification using labels should be replaced by a technique monitoring the biochemical binding event directly. The use of a ligand coupled to an artificial gated membrane ion channel is a new promising strategy. Binding of protein- or DNA/RNA-analytes at ligand modified peptide channels results in an on/off-response of the channel current due to channel closure or distortion. The sensor consists of stable transmembrane channels with a ligand bound covalently at the peptide channel entrance, a sensor chip with a photostructurized hydrophobic polymer frame, a hydrophilic ion conducting membrane support, a lipid membrane incorporating the engineered ion channels, and a current amplifier or a sensitive fluorescence monitor. Detection of channel opening or closure can ether be obtained by directly monitoring membrane conductivity or a transient change of pH or ion concentration within the membrane compartment. This change can be induced by electrochemical or optical means and its decay is directly correlated to the permeability of the membrane. The ion concentration in the sub membrane compartment was monitored by incorporation of fluorescent indicator dyes. To obtain the stable sensor membrane the lipid layer had to be attached on a support and the floating of the second lipid membrane on top of the first one had to be prevented. Both problems do not occur using our new circular C44-C76 bolaamphiphilic lipids consisting of a long hydrophobic core region and two hydrophilic heads. Use of maleic ester-head groups enabled us to easily modify the lipids with amines, thioles, alcohols, phosphates, boronic acid as well as fluorescent dyes. The properties of these membranes were studied using LB and fluorescence techniques. Based on this detection principle miniaturized sensor chips with significantly enhanced sensitivity and large multi analyte arrays are under construction.

RATE CONSTANTS FOR THE REACTIONS OF OH RADICALS AND CL ATOMS WITH DI-N-PROPYL ETHER AND DI-N-BUTYL ETHER AND THEIR DEUTERATED ANALOGS. (R825252)

EPA Science Inventory

Using relative rate methods, rate constants for the gas-phase reactions of OH radicals and Cl atoms with di-n-propyl ether, di-n-propyl ether-d₁₄, di-n-butyl ether and di-n-butyl ether-d₁₈ have been measured at 296 ? 2 K and atmos...

NIOSH Manual of Analytical Methods (third edition). Fourth supplement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1990-08-15

The NIOSH Manual of Analytical Methods, 3rd edition, was updated for the following chemicals: allyl-glycidyl-ether, 2-aminopyridine, aspartame, bromine, chlorine, n-butylamine, n-butyl-glycidyl-ether, carbon-dioxide, carbon-monoxide, chlorinated-camphene, chloroacetaldehyde, p-chlorophenol, crotonaldehyde, 1,1-dimethylhydrazine, dinitro-o-cresol, ethyl-acetate, ethyl-formate, ethylenimine, sodium-fluoride, hydrogen-fluoride, cryolite, sodium-hexafluoroaluminate, formic-acid, hexachlorobutadiene, hydrogen-cyanide, hydrogen-sulfide, isopropyl-acetate, isopropyl-ether, isopropyl-glycidyl-ether, lead, lead-oxide, maleic-anhydride, methyl-acetate, methyl-acrylate, methyl-tert-butyl ether, methyl-cellosolve-acetate, methylcyclohexanol, 4,4'-methylenedianiline, monomethylaniline, monomethylhydrazine, nitric-oxide, p-nitroaniline, phenyl-ether, phenyl-ether-biphenyl mixture, phenyl-glycidyl-ether, phenylhydrazine, phosphine, ronnel, sulfuryl-fluoride, talc, tributyl-phosphate, 1,1,2-trichloro-1,2,2-trifluoroethane, trimellitic-anhydride, triorthocresyl-phosphate, triphenyl-phosphate, and vinyl-acetate.

Micro- and nanofabrication methods for ion channel reconstitution in bilayer lipid membranes

NASA Astrophysics Data System (ADS)

Tadaki, Daisuke; Yamaura, Daichi; Arata, Kohei; Ohori, Takeshi; Ma, Teng; Yamamoto, Hideaki; Niwano, Michio; Hirano-Iwata, Ayumi

2018-03-01

The self-assembled bilayer lipid membrane (BLM) forms the basic structure of the cell membrane and serves as a major barrier against ion movement. Ion channel proteins function as gated pores that permit ion permeation across the BLM. The reconstitution of ion channel proteins in artificially formed BLMs represents a well-defined system for investigating channel functions and screening drug effects on ion channels. In this review, we will discuss our recent microfabrication approaches to the formation of stable BLMs containing ion channel proteins as a potential platform for next-generation drug screening systems. BLMs formed in a microaperture having a tapered edge exhibited highly stable properties, such as a lifetime of ∼65 h and tolerance to solution changes even after the incorporation of the human ether-a-go-go-related gene (hERG) channel. We also explore a new method of efficiently incorporating human ion channels into BLMs by centrifugation. Our approaches to the formation of stable BLMs and efficient channel incorporation markedly improve the experimental efficiency of BLM reconstitution systems, leading to the realization of a BLM-based high-throughput platform for functional assays of various ion channels.

Characterization of Fatty Acids in Crenarchaeota by GC-MS and NMR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamerly, Timothy; Tripet, Brian; Wurch, Louie

Lipids composed of condensed isoprenyl units connected to glycerol backbones by ether linkages are a distinguishing feature of Archaea. Data suggesting that fatty acids with linear hydrocarbon chains are present in some Archaea have been available for decades. However, lack of genomic and biochemical evidence for the metabolic machinery required to synthesize and degrade fatty acids has left the field unclear on this potentially significant biochemical aspect. Because lipids are energy currency and cell signaling molecules, their presence in Archaea is significant for understanding archaeal biology. A recent large-scale bioinformatics analysis reignited the debate as to the importance of fattymore » acids in Archaea by presenting genetic evidence for the presence of enzymes required for anabolic and catabolic fatty acid metabolism across the archaeal domain. Here, we present direct biochemical evidence from gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy for the presence of fatty acids in two members of the Crenarchaeota,Sulfolobus solfataricusandIgnicoccus hospitalis. Lastly, this is the first report providing biochemical data for the existence of fatty acids in these Crenarchaeota, opening new discussions on energy balance and the potential for the discovery of new thermostable enzymes for industry.« less

Influence of inhalation anesthetics on ion transport across a planar bilayer lipid membrane.

PubMed

Hichiri, Kei; Shirai, Osamu; Kano, Kenji

2012-01-01

Ion transport from one aqueous phase (W1) to another (W2) across a planar bilayer lipid membrane (BLM) in the presence of inhalation anesthetics was electrochemically investigated. In the absence of inhalation anesthetics in the BLM system, no ion transport current flowed between W1 and W2 across the BLM. When inhalation anesthetics such as halothane, chloroform, diethyl ether and trichloroethylene were added to the two aqueous phases or the BLM, the ion transport current quite clearly appeared. When the ratio of the concentration of KCl or NaCl in W1 to that in W2 was varied, the zero current potential across the BLM was shifted. By considering the magnitude of the potential shift, we concluded that the ion transport current can be predominantly ascribed to the transport of Cl(-) across the BLM. Since the dielectric constants of these anesthetics are larger than that of the inner hydrophobic domain of the BLM, the concentration of hydrophilic electrolyte ions in the BLM increases with the increase in the dielectric constant of the inner hydrophobic domain caused by addition of these anesthetics. These situations lead to an increase in the ion permeability coefficient.

Characterization of Fatty Acids in Crenarchaeota by GC-MS and NMR

PubMed Central

Hamerly, Timothy; Tripet, Brian; Wurch, Louie; Hettich, Robert L.; Podar, Mircea; Bothner, Brian; Copié, Valérie

2015-01-01

Lipids composed of condensed isoprenyl units connected to glycerol backbones by ether linkages are a distinguishing feature of Archaea. Data suggesting that fatty acids with linear hydrocarbon chains are present in some Archaea have been available for decades. However, lack of genomic and biochemical evidence for the metabolic machinery required to synthesize and degrade fatty acids has left the field unclear on this potentially significant biochemical aspect. Because lipids are energy currency and cell signaling molecules, their presence in Archaea is significant for understanding archaeal biology. A recent large-scale bioinformatics analysis reignited the debate as to the importance of fatty acids in Archaea by presenting genetic evidence for the presence of enzymes required for anabolic and catabolic fatty acid metabolism across the archaeal domain. Here, we present direct biochemical evidence from gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy for the presence of fatty acids in two members of the Crenarchaeota, Sulfolobus solfataricus and Ignicoccus hospitalis. This is the first report providing biochemical data for the existence of fatty acids in these Crenarchaeota, opening new discussions on energy balance and the potential for the discovery of new thermostable enzymes for industry. PMID:26880868

Characterization of Fatty Acids in Crenarchaeota by GC-MS and NMR

DOE PAGES

Hamerly, Timothy; Tripet, Brian; Wurch, Louie; ...

2015-01-01

Lipids composed of condensed isoprenyl units connected to glycerol backbones by ether linkages are a distinguishing feature of Archaea. Data suggesting that fatty acids with linear hydrocarbon chains are present in some Archaea have been available for decades. However, lack of genomic and biochemical evidence for the metabolic machinery required to synthesize and degrade fatty acids has left the field unclear on this potentially significant biochemical aspect. Because lipids are energy currency and cell signaling molecules, their presence in Archaea is significant for understanding archaeal biology. A recent large-scale bioinformatics analysis reignited the debate as to the importance of fattymore » acids in Archaea by presenting genetic evidence for the presence of enzymes required for anabolic and catabolic fatty acid metabolism across the archaeal domain. Here, we present direct biochemical evidence from gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy for the presence of fatty acids in two members of the Crenarchaeota,Sulfolobus solfataricusandIgnicoccus hospitalis. Lastly, this is the first report providing biochemical data for the existence of fatty acids in these Crenarchaeota, opening new discussions on energy balance and the potential for the discovery of new thermostable enzymes for industry.« less

Radionuclide-binding compound, a radionuclide delivery system, a method of making a radium complexing compound, a method of extracting a radionuclide, and a method of delivering a radionuclide

DOEpatents

Fisher, Darrell R.; Wai, Chien M.; Chen, Xiaoyuan

2000-01-01

The invention pertains to compounds which specifically bind radionuclides, and to methods of making radionuclide complexing compounds. In one aspect, the invention includes a radionuclide delivery system comprising: a) a calix[n]arene-crown-[m]-ether compound, wherein n is an integer greater than 3, and wherein m is an integer greater than 3, the calix[n]arene-crown-[m]-ether compound comprising at least two ionizable groups; and b) an antibody attached to the calix[n]arene-crown-[m]-ether compound. In another aspect, the invention includes a method of making a radium complexing compound, comprising: a) providing a calix[n]arene compound, wherein n is an integer greater than 3, the calix[n]arene compound comprising n phenolic hydroxyl groups; b) providing a crown ether precursor, the crown ether precursor comprising a pair of tosylated ends; c) reacting the pair of tosylated ends with a pair of the phenolic hydroxyl groups to convert said pair of phenolic hydroxyl groups to ether linkages, the ether linkages connecting the crown ether precursor to the calix[n]arene to form a calix[n]arene-crown-[m]-ether compound, wherein m is an integer greater than 3; d) converting remaining phenolic hydroxyl groups to esters; e) converting the esters to acids, the acids being proximate a crown-[m]-ether portion of the calix[n]arene-crown-[m]-ether compound; and f) providing a Ra.sup.2+ ion within the crown-[m]-ether portion of the calix[n]arene-crown-[m]-ether compound.

Transgenic rice plants expressing a Bacillus subtilis protoporphyrinogen oxidase gene are resistant to diphenyl ether herbicide oxyfluorfen.

PubMed

Lee, H J; Lee, S B; Chung, J S; Han, S U; Han, O; Guh, J O; Jeon, J S; An, G; Back, K

2000-06-01

Protoporphyrinogen oxidase (Protox), the penultimate step enzyme of the branch point for the biosynthetic pathway of Chl and hemes, is the target site of action of diphenyl ether (DPE) herbicides. However, Bacillus subtilis Protox is known to be resistant to the herbicides. In order to develop the herbicide-resistant plants, the transgenic rice plants were generated via expression of B. subtilis Protox gene under ubiquitin promoter targeted to the cytoplasm or to the plastid using Agrobacterium-mediated gene transformation. The integration and expression of the transgene were investigated at T0 generation by DNA and RNA blots. Most transgenic rice plants revealed one copy transgene insertion into the rice genome, but some with 3 copies. The expression levels of B. subtilis Protox mRNA appeared to correlate with the copy number. Furthermore, the plastidal transgenic lines exhibited much higher expression of the Protox mRNA than the cytoplasmic transgenic lines. The transgenic plants expressing the B. subtilis Protox gene at T0 generation were found to be resistant to oxyfluorfen when judged by cellular damage with respect to cellular leakage, Chl loss, and lipid peroxidation. The transgenic rice plants targeted to the plastid exhibited higher resistance to the herbicide than the transgenic plants targeted to the cytoplasm. In addition, possible resistance mechanisms in the transgenic plants to DPE herbicides are discussed.

Brominated flame retardants (BFRs) in breast milk and associated health risks to nursing infants in Northern Tanzania.

PubMed

Müller, M H B; Polder, A; Brynildsrud, O B; Lie, E; Løken, K B; Manyilizu, W B; Mdegela, R H; Mokiti, F; Murtadha, M; Nonga, H E; Skaare, J U; Lyche, J L

2016-01-01

The main aim of this study was to assess brominated flame retardants (BFRs) in breast milk in the Northern parts of Tanzania. Ninety-five colostrum samples from healthy, primiparous mothers at Mount Meru Regional Referral Hospital (MMRRH), Arusha Tanzania, were analyzed for polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), hexabromobenzene (HBB), (2,3-dibromopropyl) (2,4,6-tribromophenyl) ether (DPTE), pentabromoethylbenzene (PBEB) and 2,3,4,5,6-pentabromotoluene (PBT). The Ʃ7PBDE (BDE 28, 47, 99, 100, 153, 154, 183) ranged from below level of detection (

Validation of the analytical method for the simultaneous determination of selected polybrominated diphenyl ethers, polychlorinated biphenyls and organochlorine pesticides in human blood serum by gas chromatography with microelectron capture detector.

PubMed

Matuszak, Małgorzata; Minorczyk, Maria; Góralczyk, Katarzyna; Hernik, Agnieszka; Struciński, Paweł; Liszewska, Monika; Czaja, Katarzyna; Korcz, Wojciech; Łyczewska, Monika; Ludwicki, Jan K

2016-01-01

Polybrominated diphenyl ethers (PBDEs) as other persistent organic pollutants like polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) pose a significant hazard to human health, mainly due to interference with the endocrine system and carcinogenetic effects. Humans are exposed to these substances mainly through a food of animal origin. These pollutants are globally detected in human matrices which requires to dispose reliable and simple analytical method that would enable further studies to assess the exposure of specific human populations to these compounds. The purpose of this study was to modify and validate of the analytical procedure for the simultaneous determination of selected PBDEs, PCBs and OCPs in human blood serum samples. The analytical measurement was performed by GC-µECD following preparation of serum samples (denaturation, multiple extraction, lipid removal). Identity of the compounds was confirmed by GC-MS. The method was characterised by the appropriate linearity, good repeatability (CV below 20%). The recoveries ranged from 52.9 to 125.0% depending on compound and level of fortification. The limit of quantification was set at 0.03 ng mL(-1) of serum. The modified analytical method proved to be suitable for the simultaneous determination of selected PBDEs, PCBs and OCPs in human blood serum by GC-µECD with good precision.

Synthesis of Alkyl-Glycerolipids Standards for Gas Chromatography Analysis: Application for Chimera and Shark Liver Oils

PubMed Central

Pinault, Michelle; Guimaraes, Cyrille; Couthon, Hélène; Thibonnet, Jérôme; Fontaine, Delphine; Chantôme, Aurélie; Chevalier, Stephan; Jaffrès, Paul-Alain; Vandier, Christophe

2018-01-01

Natural O-alkyl-glycerolipids, also known as alkyl-ether-lipids (AEL), feature a long fatty alkyl chain linked to the glycerol unit by an ether bond. AEL are ubiquitously found in different tissues but, are abundant in shark liver oil, breast milk, red blood cells, blood plasma, and bone marrow. Only a few AEL are commercially available, while many others with saturated or mono-unsaturated alkyl chains of variable length are not available. These compounds are, however, necessary as standards for analytical methods. Here, we investigated different reported procedures and we adapted some of them to prepare a series of 1-O-alkyl-glycerols featuring mainly saturated alkyl chains of various lengths (14:0, 16:0, 17:0, 19:0, 20:0, 22:0) and two monounsaturated chains (16:1, 18:1). All of these standards were fully characterized by NMR and GC-MS. Finally, we used these standards to identify the AEL subtypes in shark and chimera liver oils. The distribution of the identified AEL were: 14:0 (20–24%), 16:0 (42–54%) and 18:1 (6–16%) and, to a lesser extent, (0.2–2%) for each of the following: 16:1, 17:0, 18:0, and 20:0. These standards open the possibilities to identify AEL subtypes in tumours and compare their composition to those of non-tumour tissues. PMID:29570630

Polybrominated biphenyl ethers in breast milk and infant formula from Shanghai, China: temporal trends, daily intake, and risk assessment.

PubMed

Zhang, Xiaolan; Zhang, Kaiqiong; Yang, Dan; Ma, Li; Lei, Bingli; Zhang, Xinyu; Zhou, Jing; Fang, Xiangming; Yu, Yingxin

2014-11-01

To investigate the temporal trend of polybrominated diphenyl ethers (PBDEs) in breast milk and assess the risks to breast- and formula-fed infants, breast milk and infant formula samples were collected from Shanghai, China. The PBDE concentrations decreased from 14.8 to 4.85 pmol/g lipid weight during 2006-2012, with a rate of decrease by half approximately every four years. Although there were no significant correlations between the total PBDEs in breast milk and age, parity, and pre-pregnant BMI of mothers, there were significant differences between primiparous and multiparous mothers for tri- to hepta-BDEs. PBDEs in breast milk were much higher than those in infant formula (equivalent to 91.9 vs. 5.25 pg/mL). Among the different brand infant formulas, there were no significant differences in their PBDE concentrations. The estimated daily intake of PBDEs by breast- and formula-fed infants suggested that breast-fed infants are exposed to much more PBDEs than formula-fed ones (12.9 vs. 0.72 ng/kg-bw/day). However, the hazard quotient values were much smaller than one, indicating that the ingested PBDEs did not exert obvious adverse effects on both breast- and formula-fed infants considering non-carcinogenic effect endpoint. This is the first report on temporal trend of PBDEs in breast milk from China. Copyright © 2014 Elsevier B.V. All rights reserved.

Hepatoprotective potential of ether insoluble phenolic components of n-butanol fraction (EPC-BF) of flaxseed against CCl(4) -induced liver damage in rats.

PubMed

Kasote, D M; Badhe, Y S; Zanwar, A A; Hegde, M V; Deshmukh, K K

2012-07-01

to investigate the hepatoprotective potential of ether insoluble phenolic components of n-butanol fraction (EPC-BF) of flaxseed against CCl(4) -induced liver damage in rats. Hepatotoxicity was induced to Wistar rats by administration of 0.2% CCl(4) in olive oil (8 mL/kg, i.p.) on the seventh day of treatment. Hepatoprotective potential of EPC-BF at doses, 250 and 500 mg/kg, p.o. was assessed through biochemical and histological parameters. EPC-BF and silymarin pretreated animal groups showed significantly decreased activities of Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and level of total bilirubin, elevated by CCl(4) intoxication. Hepatic lipid peroxidation elevated by CCl(4) intoxication were also found to be alleviated at almost normal level in the EPC-BF and silymarin pretreated groups. Histological studies supported the biochemical findings and treatment of EPC-BF at doses 250 and 500 mg/kg, p.o. was found to be effective in restoring CCl(4) -induced hepatic damage. However, EPC-BF did not show dose-dependent hepatoprotective potential. EPC-BF depicted maximum protection against CCl(4) -induced hepatic damage at lower dose 250 mg/kg than higher dose (500 mg/ kg). EPC-BF possesses the significant hepatoprotective activity against CCl(4) induced liver damage, which could be mediated through increase in antioxidant defenses.

A Comparative Study on Selective PPAR Modulators through Quantitative Structure-activity Relationship, Pharmacophore and Docking Analyses.

PubMed

Nandy, Ashis; Roy, Kunal; Saha, Achintya

2018-01-01

Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involved in metabolism of fats and glucose. In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi-cheminformatics studies have been performed. In silico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structure-activity relationship (QSAR), pharmacophore mapping and docking studies. It is observed that the presence of an amide fragment (-CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and selective PPARγ modulation. Negative ionizable features (i.e. polar fragments) must be present in PPARδ and α modulators, but a hydrophobic feature is the prime requirement for PPARγ modulation. Here, the essential structural features have been explored for selective modulation of each subtype of PPAR in order to design new modulators with improved activity/selectivity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Vapor intrusion risk of fuel ether oxygenates methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME) and ethyl tert-butyl ether (ETBE): A modeling study.

PubMed

Ma, Jie; Xiong, Desen; Li, Haiyan; Ding, Yi; Xia, Xiangcheng; Yang, Yongqi

2017-06-15

Vapor intrusion of synthetic fuel additives represents a critical yet still neglected problem at sites contaminated by petroleum fuel releases. This study used an advanced numerical model to investigate the vapor intrusion potential of fuel ether oxygenates methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), and ethyl tert-butyl ether (ETBE). Simulated indoor air concentration of these compounds can exceed USEPA indoor air screening level for MTBE (110μg/m 3 ). Our results also reveal that MTBE has much higher chance to cause vapor intrusion problems than TAME and ETBE. This study supports the statements made by USEPA in the Petroleum Vapor Intrusion (PVI) Guidance that the vertical screening criteria for petroleum hydrocarbons may not provide sufficient protectiveness for fuel additives, and ether oxygenates in particular. In addition to adverse impacts on human health, ether oxygenate vapor intrusion may also cause aesthetic problems (i.e., odour and flavour). Overall, this study points out that ether oxygenates can cause vapor intrusion problems. We recommend that USEPA consider including the field measurement data of synthetic fuel additives in the existing PVI database and possibly revising the PVI Guidance as necessary. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro growth inhibition and cytotoxicity of Euphorbia caducifolia against four human cancer cell lines and its phytochemical characterisation.

PubMed

Bano, Shaista; Siddiqui, Bina Shaheen; Farooq, Ahsana Dar; Begum, Sabira; Siddiqui, Faheema; Kashif, Muhammad; Azhar, Mudassar

2017-12-01

Several Euphorbia species have been used in folklore as cancer remedies, however, scientific studies on the cytotoxicity (in vitro studies) of Euphorbia caducifolia are lacking. In present study, anticancer potential of E. caducifolia aerial parts ethanol extract and its fractions were evaluated against human lung (NCI-H460), breast (MCF-7), prostate (PC-3) and cervical (HeLa) cancer cell lines, using sulphorhodamine-B in vitro cytotoxicity (in vitro studies) assay. The ethanol extract demonstrated growth inhibitory effect against all aforementioned cancer cell lines with IC 50 , 19-135 μg/mL and LC 50 , ~220 μg/mL, and its petroleum ether fraction obtained on bioactivity guided fraction showed highest activity with IC 50 , 28-70 μg/mL and LC 50 , 71 μg/mL against NCI-H460 and MCF-7 cell lines. Its phytochemicals were analysed by gas chromatography-mass spectrometry (GC-MS). The present study provides scientific justification for its traditional use against cancer.

Design and preliminary structure-activity relationship of redox-silent semisynthetic tocotrienol analogues as inhibitors for breast cancer proliferation and invasion.

PubMed

Elnagar, Ahmed Y; Wali, Vikram B; Sylvester, Paul W; El Sayed, Khalid A

2010-01-15

Vitamin E (VE) is a generic term that represents a family of compounds composed of various tocopherol and tocotrienol isoforms. Tocotrienols display potent anti-angiogenic and antiproliferative activities. Redox-silent tocotrienol analogues also display potent anticancer activity. The ultimate objective of this study was to develop semisynthetically C-6-modified redox-silent tocotrienol analogues with enhanced antiproliferative and anti-invasive activities as compared to their parent compound. Examples of these are carbamate and ether analogues of alpha-, gamma-, and delta-tocotrienols (1-3). Various aliphatic, olefinic, and aromatic substituents were used. Steric limitation, electrostatic, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) properties were varied at this position and the biological activities of these derivatives were tested. Three-dimensional quantitative structure-activity relationship (3D QSAR) studies were performed using Comparative Molecular Field (CoMFA) and Comparative Molecular Similarity Indices Analyses (CoMSIA) to better understand the structural basis for biological activity and guide the future design of more potent VE analogues. Copyright 2009 Elsevier Ltd. All rights reserved.

Trehalose Polyphleates, External Cell Wall Lipids in Mycobacterium abscessus, Are Associated with the Formation of Clumps with Cording Morphology, Which Have Been Associated with Virulence

PubMed Central

Llorens-Fons, Marta; Pérez-Trujillo, Míriam; Julián, Esther; Brambilla, Cecilia; Alcaide, Fernando; Byrd, Thomas F.; Luquin, Marina

2017-01-01

Mycobacterium abscessus is a reemerging pathogen that causes pulmonary diseases similar to tuberculosis, which is caused by Mycobacterium tuberculosis. When grown in agar medium, M. abscessus strains generate rough (R) or smooth colonies (S). R morphotypes are more virulent than S morphotypes. In searching for the virulence factors responsible for this difference, R morphotypes have been found to form large aggregates (clumps) that, after being phagocytozed, result in macrophage death. Furthermore, the aggregates released to the extracellular space by damaged macrophages grow, forming unphagocytosable structures that resemble cords. In contrast, bacilli of the S morphotype, which do not form aggregates, do not damage macrophages after phagocytosis and do not form cords. Cording has also been related to the virulence of M. tuberculosis. In this species, the presence of mycolic acids and surface-exposed cell wall lipids has been correlated with the formation of cords. The objective of this work was to study the roles of the surface-exposed cell wall lipids and mycolic acids in the formation of cords in M. abscessus. A comparative study of the pattern and structure of mycolic acids was performed on R (cording) and S (non-cording) morphotypes derived from the same parent strains, and no differences were observed between morphotypes. Furthermore, cords formed by R morphotypes were disrupted with petroleum ether (PE), and the extracted lipids were analyzed by thin layer chromatography, nuclear magnetic resonance spectroscopy and mass spectrometry. Substantial amounts of trehalose polyphleates (TPP) were recovered as major lipids from PE extracts, and images obtained by transmission electron microscopy suggested that these lipids are localized to the external surfaces of cords and R bacilli. The structure of M. abscessus TPP was revealed to be similar to those previously described in Mycobacterium smegmatis. Although the exact role of TPP is unknown, our results demonstrated that TPP are not toxic by themselves and have a function in the formation of clumps and cords in M. abscessus, thus playing an important role in the pathogenesis of this species. PMID:28790995

Neural defects and cardiac arrhythmia in fish larvae following embryonic exposure to 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47).

PubMed

Lema, Sean C; Schultz, Irvin R; Scholz, Nathaniel L; Incardona, John P; Swanson, Penny

2007-05-31

Polybrominated diphenyl ethers (PBDEs) are added to plastics, polyurethane foam, and textiles as a flame retardant. While PBDEs play a key role in reducing loss of human life and property from fires, these flame retardants have become pervasive organic contaminants in the environment and in the tissues of fish, birds, marine mammals, and humans. Levels of PBDEs in wildlife and humans continue to rise, raising concerns about potential ecological and health risks associated with exposure to these chemicals. Nevertheless, there is little currently known about the toxicological effects of PBDE exposure. Here, we examined the developmental toxicity of the PBDE congener 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47) using the zebrafish (Danio rerio) as an ontogenetic model. Zebrafish embryos were exposed continuously to dissolved phase PBDE 47 (100-5000 microg/l) beginning 3-5 h post-fertilization (hpf). Fish treated with the highest concentrations of PBDE 47 delayed hatching, had reduced growth post-hatching, and displayed an abnormal dorsal curvature of the body with flexion at the hindbrain. By 96h post-fertilization larvae exposed to PBDE 47 had significant tachycardia, which progressed into atrioventricular block arrhythmias. Microinjection of fluorescent dye into the hindbrain ventricle revealed that cerebrospinal fluid in the neural tube and brain ventricles flowed more slowly in fish larvae exposed to PBDE 47, a likely etiology for the dorsal curvature. Similar, though much less pronounced, developmental toxicity also occurred in larvae exposed to PBDE 47 only for a 20h period during early embryogenesis (3-23 hpf), suggesting that PBDEs incorporated in lipid of the egg are bioavailable and cause toxicity later in life. Taken together, this work indicates that exposure to PBDE 47 can cause morphological abnormalities, impair cardiovascular function and cerebrospinal fluid flow, and provides a tractable starting point for using the zebrafish model to explore molecular mechanisms of PBDE toxicity.

"One-shot" analysis of polybrominated diphenyl ethers and their hydroxylated and methoxylated analogs in human breast milk and serum using gas chromatography-tandem mass spectrometry.

PubMed

Butryn, Deena M; Gross, Michael S; Chi, Lai-Har; Schecter, Arnold; Olson, James R; Aga, Diana S

2015-09-10

The presence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-BDE) and methoxylated (MeO-BDE) analogs in humans is an area of high interest to scientists and the public due to their neurotoxic and endocrine disrupting effects. Consequently, there is a rise in the investigation of the occurrence of these three classes of compounds together in environmental matrices and in humans in order to understand their bioaccumulation patterns. Analysis of PBDEs, OH-BDEs, and MeO-BDEs using liquid chromatography-mass spectrometry (LC-MS) can be accomplished simultaneously, but detection limits for PBDEs and MeO-BDEs in LC-MS is insufficient for trace level quantification. Therefore, fractionation steps of the phenolic (OH-BDEs) and neutral (PBDEs and MeO-BDEs) compounds during sample preparation are typically performed so that different analytical techniques can be used to achieve the needed sensitivities. However, this approach involves multiple injections, ultimately increasing analysis time. In this study, an analytical method was developed for a "one-shot" analysis of 12 PBDEs, 12 OH-BDEs, and 13 MeO-BDEs using gas chromatography with tandem mass spectrometry (GC-MS/MS). This overall method includes simultaneous extraction of all analytes via pressurized liquid extraction followed by lipid removal steps to reduce matrix interferences. The OH-BDEs were derivatized using N-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide (TBDMS-MTFA), producing OH-TBDMS derivatives that can be analyzed together with PBDEs and MeO-BDEs by GC-MS/MS in "one shot" within a 25-min run time. The overall recoveries were generally higher than 65%, and the limits of detection ranged from 2 to 14 pg in both breast milk and serum matrices. The applicability of the method was successfully validated on four paired human breast milk and serum samples. The mean concentrations of total PBDEs, OH-BDEs, and MeO-BDEs in breast milk were 59, 2.2, and 0.57 ng g(-1) lipid, respectively. In serum, the mean total concentrations were 79, 38, and 0.96 ng g(-1) lipid, respectively, exhibiting different distribution profiles from the levels detected in breast milk. This "one-shot" GC-MS/MS method will prove useful and cost-effective in large-scale studies needed to further understand the partitioning behavior, and ultimately the adverse health effects, of these important classes of brominated flame retardants in humans. Copyright © 2015 Elsevier B.V. All rights reserved.

Enhanced electrochemical sensing of leukemia cells using drug/lipid co-immobilized on the conducting polymer layer.

PubMed

Gurudatt, N G; Naveen, M Halappa; Ban, Changill; Shim, Yoon-Bo

2016-12-15

Electrochemical biosensors using five anticancer drug and lipid molecules attached on the conducting polymer layer to obtain the orientation of drug molecules toward cancer cells, were evaluated as sensing materials and their performances were compared. Conjugation of the drug molecules with a lipid, phosphatidylcholine (PC) has enhanced the sensitivity towards leukemia cells and differentiates cancer cells from normal cells. The composition of each layer of sensor probe was confirmed by electrochemical and surface characterization experiments. Both impedance spectroscopy and voltammetry show the enhanced interaction of leukemia cells using the drug/lipid modified sensor probe. As the number of leukemia cells increased, the charge transfer resistance (Rct) in impedance spectra increased and the amine oxidation peak current of drug molecules in voltammograms decreased at around 0.7-1.0V. Of test drug molecules, raltitrexed (Rtx) showed the best performance for the cancer cells detection. Cancer and normal cell lines from different origins were examined to evaluate the degree of expression of folate receptors (FR) on cells surface, where cervical HeLa cell line was found to be shown the highest expression of the receptor. Impedance and chronoamperometric experiments for leukemia cell line (Jurkat E6-1) showed linear dynamic ranges of 1.0×10(3)-2.5×10(5) cells/mL and 1.0×10(3)-8.0×10(3) cells/mL with detection limits of 68±5 cells/mL and 21±3 cells/mL, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Boundary lubrication, thermal and oxidative stability of a fluorinated polyether and a perfluoropolyether triazine

NASA Technical Reports Server (NTRS)

Jones, W. R., Jr.; Snyder, C. E., Jr.

1979-01-01

Boundary lubricating characteristics, thermal stability, and oxidation-corrosion stability were determined for a fluorinated polyether and a perfluoropolyether triazine. A ball-on-disk apparatus, a tensimeter, and oxidation-corrosion apparatus were used. Results were compared to data for a polyphenyl ether and a C-ether. The polyether and triazine yielded better boundary lubricating characteristics than either the polyphenyl ether or C-ether. The polyphenyl ether had the greatest thermal stability (443 C) while the other fluids had stabilities in the range 389 to 397 C. Oxidation-corrosion results indicated the following order of stabilities: perfluoropolyether trizine greater than polyphenyl ether greater than C-ether greater than fluorinated polyether.

Sinterable Ceramic Powders from Laser-Heated Gases.

DTIC Science & Technology

1988-02-01

ether . carboxylic acid. and aldehyde clases: water is also included.Acrigto William and Goodman.’ a single crystalline sili- The single-crstalline...represent commonly available organic families, Including aliphatic and aromatic hydrocarbons, chlorides, ethers , ketones , esters, alcohols, aldehydes...Hydrocarbons Ketone Amine Chlorides Low-alcohols 8f . Ether Ester - _Aldehyde Ether Ketones High-alcohols 04 Carboxylic Ester I acid Ether o . Nitrile

N-alpha-Cocoyl-L-arginine ethyl ester, DL-pyroglutamic acid salt, as an inactivator of hepatitis B surface antigen.

PubMed Central

Sugimoto, Y; Toyoshima, S

1979-01-01

N-alpha-Cocoyl-L-arginine ethyl ester, DL-pyroglutamic acid salt (CAE), exhibited a strong inactivating effect on hepatitis B surface antigen. Concentrations of CAE required for 50 and 100% inactivation of the antigen were 0.01 to 0.025% and 0.025 to 0.05% respectively. CAE completely inactivated hepatitis B surface antigen at the lowest concentration compared with various compounds including about 500 amino acid derivatives, sodium hypochlorite, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, and some detergents. Furthermore, CAE inactivated vaccinia virus, herpes simplex virus, and influenza virus, whereas poliovirus was not inactivated at all. The results suggest that the inactivating effects of CAE are related to interaction with lipid-containing viral envelopes. PMID:228595

Fisetin induces Sirt1 expression while inhibiting early adipogenesis in 3T3-L1 cells.

PubMed

Kim, Sang Chon; Kim, Yoo Hoon; Son, Sung Wook; Moon, Eun-Yi; Pyo, Suhkneung; Um, Sung Hee

2015-11-27

Fisetin (3,7,3',4'-tetrahydroxyflavone) is a naturally found flavonol in many fruits and vegetables and is known to have anti-aging, anti-cancer and anti-viral effects. However, the effects of fisetin on early adipocyte differentiation and the epigenetic regulator controlling adipogenic transcription factors remain unclear. Here, we show that fisetin inhibits lipid accumulation and suppresses the expression of PPARγ in 3T3-L1 cells. Fisetin suppressed early stages of preadipocyte differentiation, and induced expression of Sirt1. Depletion of Sirt1 abolished the inhibitory effects of fisetin on intracellular lipid accumulation and on PPARγ expression. Mechanistically, fisetin facilitated Sirt1-mediated deacetylation of PPARγ and FoxO1, and enhanced the association of Sirt1 with the PPARγ promoter, leading to suppression of PPARγ transcriptional activity, thereby repressing adipogenesis. Lowering Sirt1 levels reversed the effects of fisetin on deacetylation of PPARγ and increased PPARγ transactivation. Collectively, our results suggest the effects of fisetin in increasing Sirt1 expression and in epigenetic control of early adipogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

Surface modification of solid lipid nanoparticles for oral delivery of curcumin: Improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake.

PubMed

Baek, Jong-Suep; Cho, Cheong-Weon

2017-08-01

Curcumin has been reported to exhibit potent anticancer effects. However, poor solubility, bioavailability and stability of curcumin limit its in vivo efficacy for the cancer treatment. Solid lipid nanoparticles (SLN) are a promising delivery system for the enhancement of bioavailability of hydrophobic drugs. However, burst release of drug from SLN in acidic environment limits its usage as oral delivery system. Hence, we prepared N-carboxymethyl chitosan (NCC) coated curcumin-loaded SLN (NCC-SLN) to inhibit the rapid release of curcumin in acidic environment and enhance the bioavailability. The NCC-SLN exhibited suppressed burst release in simulated gastric fluid while sustained release was observed in simulated intestinal fluid. Furthermore, NCC-SLN exhibited increased cytotoxicity and cellular uptake on MCF-7 cells. The lymphatic uptake and oral bioavailability of NCC-SLN were found to be 6.3-fold and 9.5-fold higher than that of curcumin solution, respectively. These results suggest that NCC-SLN could be an efficient oral delivery system for curcumin. Copyright © 2017 Elsevier B.V. All rights reserved.

Research on the effect of formononetin on photodynamic therapy in K562 cells.

PubMed

Sun, Dan; Lu, Yao; Zhang, Su-Juan; Wang, Kai-Ge; Sun, Zhe

2017-10-01

At the present time, many cancer patients combine some forms of complementary and alternative medicine therapies with their conventional therapies. The most common choice of these therapies is the use of antioxidants. Formononetin is presented in different foods. It has a variety of biological activities including antioxidant and anti-cancer properties. On account of its antioxidant activity, formononetin might protect cancer cells from free radical damage in photodynamic therapy (PDT) during which reactive oxygen species (ROS) production was stimulated leading to irreversible tumor cell injury. In this study, the influence of formononetin on K562 cells in PDT was demonstrated. The results showed that formononetin supplementation alone did not affect the lipid peroxidation, DNA damage and apoptosis in K562 cells. It increases the lipid peroxidation, DNA damage and apoptosis in K562 cells induced by PDT. The singlet oxygen quencher sodium azide suppresses the apoptosis induced by PDT with formononetin. In conclusion, formononetin consumption during PDT increases the effectiveness of cancer therapy on malignant cells. The effect of antioxidants on PDT maybe was determined by its sensitization ability to singlet oxygen.

Interaction of 3‧,4‧,6‧-trimyristoyl-uridine derivative as potential anticancer drug with phospholipids of tumorigenic and non-tumorigenic cells

NASA Astrophysics Data System (ADS)

Salis, Luiz Fernando Grosso; Jaroque, Guilherme Nuñez; Escobar, Jhon Fernando Berrío; Giordani, Cristiano; Martinez, Alejandro Martinez; Fernández, Diana Margarita Márquez; Castelli, Francesco; Sarpietro, Maria Grazia; Caseli, Luciano

2017-12-01

Investigating the mechanism of action of drugs whose pharmaceutical activity is associated with cell membranes is fundamental to comprehending the biochemical and biophysical processes that occur on membrane surfaces. In this work, we investigated the interaction of an ester-type derivative of uridine, 3‧,4‧,6‧-trimyristoyl uridine, with models for cell membranes formed by lipid monolayers at the air-water interface. For that, selected lipids have been chosen in order to mimic tumorigenic and non-tumorigenic cells. For mixed monolayers with 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-dihexadecanoyl-sn-glycero-3-phospho-L-serine (DPPS), the surface pressure-area isotherms exhibited a noticeable shift to lower areas in relation to the areas predicted for ideal mixtures, indicating a condensation of the monolayer structure. Changes in the viscoelastic properties of the interfacial film could be inferred by analyzing the compressibility modulus of the monolayer. Structural and morphological changes were also evidenced by using vibrational spectroscopy and Brewster angle microscopy, respectively, with distinctive effects on DPPC and DPPS. As conclusion we can state that the lipid composition of the monolayer modulates the interaction with this lipophilic drug, which may have important implications in understanding how this drug acts on specific sites of the cellular membrane.

Accumulation of arachidonic acid-containing phosphatidylinositol at the outer edge of colorectal cancer

PubMed Central

Hiraide, Takanori; Ikegami, Koji; Sakaguchi, Takanori; Morita, Yoshifumi; Hayasaka, Takahiro; Masaki, Noritaka; Waki, Michihiko; Sugiyama, Eiji; Shinriki, Satoru; Takeda, Makoto; Shibasaki, Yasushi; Miyazaki, Shinichiro; Kikuchi, Hirotoshi; Okuyama, Hiroaki; Inoue, Masahiro; Setou, Mitsutoshi; Konno, Hiroyuki

2016-01-01

Accumulating evidence indicates that cancer cells show specific alterations in phospholipid metabolism that contribute to tumour progression in several types of cancer, including colorectal cancer. Questions still remain as to what lipids characterize the outer edge of cancer tissues and whether those cancer outer edge-specific lipid compositions emerge autonomously in cancer cells. Cancer tissue-originated spheroids (CTOSs) that are composed of pure primary cancer cells have been developed. In this study, we aimed to seek out the cancer cell-autonomous acquisition of cancer outer edge-characterizing lipids in colorectal cancer by analysing phospholipids in CTOSs derived from colorectal cancer patients with matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS). A signal at m/z 885.5 in negative ion mode was detected specifically at the surface regions. The signal was identified as an arachidonic acid (AA)-containing phosphatidylinositol (PI), PI(18:0/20:4), by tandem mass spectrometry analysis. Quantitative analysis revealed that the amount of PI(18:0/20:4) in the surface region of CTOSs was two-fold higher than that in the medial region. Finally, PI(18:0/20:4) was enriched at the cancer cells/stromal interface in colorectal cancer patients. These data imply a possible importance of AA-containing PI for colorectal cancer progression, and suggest cells expressing AA-containing PI as potential targets for anti-cancer therapy. PMID:27435310

Oral and intraperitoneal administration of quercetin decreased lymphocyte DNA damage and plasma lipid peroxidation induced by TSA in vivo.

PubMed

Chan, Shu-Ting; Lin, Yi-Chin; Chuang, Cheng-Hung; Shiau, Rong-Jen; Liao, Jiunn-Wang; Yeh, Shu-Lan

2014-01-01

Our previous study showed that quercetin enhances the anticancer effect of trichostatin A (TSA) in xenograft mice given quercetin intraperitoneally (10 mg/kg, 3 times/week). Herein, we investigate whether quercetin administered orally exerts such an effect and prevents the cytotoxic side effects of TSA. We found that quercetin given orally (20 and 100 mg/kg, 3 times/week) failed to enhance the antitumor effect of TSA although it increased the total quercetin concentration more than quercetin administered intraperitoneally in the plasma. The compound quercetin-3-glucuronide (Q3G) increased the most. However, quercetin administered intraperitoneally increased the total quercetin level in tumor tissues more than oral quercetin. Oral and intraperitoneal administration of quercetin similarly decreased lymphocyte DNA damage and plasma lipid peroxidation level induced by TSA. Furthermore, we found that the enhancing effect of Q3G on the antitumor effect of TSA and the incorporation of Q3G was less than that of quercetin in A549 cells. However, we found that A549 cells possessed the ability to convert Q3G to quercetin. In conclusion, different from quercetin administered intraperitoneally, quercetin administered orally failed to enhance the antitumor effect of TSA because of its metabolic conversion. However, it prevented TSA-induced DNA damage and lipid peroxidation.

Oral and Intraperitoneal Administration of Quercetin Decreased Lymphocyte DNA Damage and Plasma Lipid Peroxidation Induced by TSA In Vivo

PubMed Central

Chan, Shu-Ting; Shiau, Rong-Jen; Liao, Jiunn-Wang; Yeh, Shu-Lan

2014-01-01

Our previous study showed that quercetin enhances the anticancer effect of trichostatin A (TSA) in xenograft mice given quercetin intraperitoneally (10 mg/kg, 3 times/week). Herein, we investigate whether quercetin administered orally exerts such an effect and prevents the cytotoxic side effects of TSA. We found that quercetin given orally (20 and 100 mg/kg, 3 times/week) failed to enhance the antitumor effect of TSA although it increased the total quercetin concentration more than quercetin administered intraperitoneally in the plasma. The compound quercetin-3-glucuronide (Q3G) increased the most. However, quercetin administered intraperitoneally increased the total quercetin level in tumor tissues more than oral quercetin. Oral and intraperitoneal administration of quercetin similarly decreased lymphocyte DNA damage and plasma lipid peroxidation level induced by TSA. Furthermore, we found that the enhancing effect of Q3G on the antitumor effect of TSA and the incorporation of Q3G was less than that of quercetin in A549 cells. However, we found that A549 cells possessed the ability to convert Q3G to quercetin. In conclusion, different from quercetin administered intraperitoneally, quercetin administered orally failed to enhance the antitumor effect of TSA because of its metabolic conversion. However, it prevented TSA-induced DNA damage and lipid peroxidation. PMID:24868531