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Chi Hang Tse, Jeffrey Comer, Yi Wang, Christophe Chipot
Prediction of membrane permeability to small molecules represents an important aspect of drug discovery. First-principle calculations of this quantity require an accurate description of both the thermodynamics and kinetics that underlie translocation of the permeant across the lipid bilayer. In this contribution, the membrane permeability to three drugs, or drug-like molecules, namely, 9-anthroic acid (ANA), 2',3'-dideoxyadenosine (DDA) and hydrocortisone (HYL) are estimated in a pure 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and in a POPC:cholesterol (2:1) mixture...
May 17, 2018: Journal of Chemical Theory and Computation
Derya Meral, Davide Provasi, Diego Prada-Gracia, Jan Möller, Kristen Marino, Martin J Lohse, Marta Filizola
Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer...
May 16, 2018: Scientific Reports
Victoria E Palau, Kanishka Chakraborty, Daniel Wann, Janet Lightner, Keely Hilton, Marianne Brannon, William Stone, Koyamangalath Krishnan
BACKGROUND: Ceramide synthesis and metabolism is a promising target in cancer drug development. γ-tocotrienol (GT3), a member of the vitamin E family, orchestrates multiple effects that ensure the induction of apoptosis in both, wild-type and RAS-mutated pancreatic cancer cells. Here, we investigated whether these effects involve changes in ceramide synthesis and transport. METHODS: The effects of GT3 on the synthesis of ceramide via the de novo pathway, and the hydrolysis of sphingomyelin were analyzed by the expression levels of the enzymes serine palmitoyl transferase, ceramide synthase-6, and dihydroceramide desaturase, and acid sphingomyelinase in wild-type RAS BxPC3, and RAS-mutated MIA PaCa-2 and Panc 1 pancreatic cancer cells...
May 16, 2018: BMC Cancer
Ryan J H West, Laura Briggs, Maria Perona Fjeldstad, Richard R Ribchester, Sean T Sweeney
Sphingolipids are found in abundance at synapses and have been implicated in regulation of synapse structure, function and degeneration. Their precise role in these processes, however, remains obscure. Serine Palmitoyl-transferase (SPT) is the first enzymatic step for synthesis of sphingolipids. Analysis of the Drosophila larval neuromuscular junction revealed mutations in the SPT enzyme subunit, lace/SPTLC2 resulted in deficits in synaptic structure and function. Although neuromuscular junction (NMJ) length is normal in lace mutants, the number of boutons per NMJ is reduced to ∼50% of the wild type number...
May 15, 2018: Journal of Comparative Neurology
Yan Li, Shuang Liu, Elizabeth Yihui Ng, Rong Li, Anders Poulsen, Jeffrey Hill, Ajaybabu V Pobatti, Alvin W Hung, Wanjin Hong, Thomas H Keller, CongBao Kang
The oncoprotein YAP requires the TEAD family of transcription factors for the upregulation of genes important for cell proliferation. Disrupting YAP-TEAD interaction is an attractive strategy for cancer therapy. Targeting TEADs using small molecules that either bind to the YAP-binding pocket or the palmitate-binding pocket is proposed to the disrupt YAP-TEAD interaction. There is a need for methodologies to facilitate robust and reliable identification of compounds that occupy either YAP-binding pocket or palmitate-binding pocket...
May 14, 2018: Biochemical Journal
Zhishi Yang, Wenhao Qin, Yao Chen, Bo Yuan, Xiaoling Song, Bibo Wang, Feng Shen, Jing Fu, Hongyang Wang
Cholesterol plays a vital role in modulating the action of membrane proteins critical to cellular function. The effect of serum cholesterol on the prognosis of hepatocellular carcinoma (HCC) patients remains uncertain. Here, we report that high levels of cholesterol predict good survival and low disease recurrence after surgery. Cholesterol could significantly suppress migration and invasion of HCC cells and restrain metastasis of HCC in mice. High levels of cholesterol promoted CD44 translocation into lipid rafts and attenuated CD44-Ezrin binding, which are crucial for cell migration and cancer metastasis...
May 7, 2018: Cancer Letters
Guoren Huang, Jinli Xue, Xiangjun Sun, Jing Wang, Yilin Wang, Thomas T Y Wang, LucyYu Liangli
This study investigated whether and how 3-chloro-1,2-propanediol (3-MCPD) fatty acid esters, a group of food contaminants formed during processing, might inhibit the immune system through suppressing T lymphocyte activation for the first time. Three 3-MCPD esters including 1-palmitoyl-3-chloropropanediol (1-pal), 2-palmitoyl-3-chloropropanediol (2-pal), and1,2-dipalmitoyl-3-chloropropanediol (dipal) were selected as the probe compounds to test the possible effects of fatty acid structure on their potential immune inhibitory effect...
May 4, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Soohyung Park, Wonpil Im
We have devised a practical simulation protocol for quantitative characterization of cholesterol (Chol) partitioning between bilayers with different lipid types. The simulation model contains two patches of laterally contacting lipid bilayers, where the host lipids of each bilayer are allowed to self-adjust their packing. For two combinations of bilayers with different lipid types, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the simulation model has been verified by self-adjusted lipid packing in each bilayer, convergence of Chol partitioning between different Chol initial distributions, and relative diffusion coefficients consistent to those from experiments...
May 7, 2018: Journal of Chemical Theory and Computation
Sang Joon Won, Brent R Martin
S-palmitoylation is required for membrane anchoring, proper trafficking, and the normal function of hundreds of integral and peripheral membrane proteins. Previous bioorthogonal pulse-chase proteomics analyses identified Ras family GTPases, polarity proteins, and G proteins as rapidly cycling S-palmitoylated proteins sensitive to depalmitoylase inhibition, yet the breadth of enzyme regulated dynamic S-palmitoylation largely remains a mystery. Here we present a pulsed bioorthogonal S-palmitoylation assay for temporal analysis of S-palmitoylation dynamics...
May 7, 2018: ACS Chemical Biology
Stephen R Wassall, Xiaoling Leng, Samuel W Canner, Edward Ross Pennington, Jacob J Kinnun, Andres T Cavazos, Sahil Dadoo, Dylan Johnson, Frederick A Heberle, John Katsaras, Saame Raza Shaikh
Docosahexaenoic acid (DHA, 22:6) is an n-3 polyunsaturated fatty acid (n-3 PUFA) that influences immunological, metabolic, and neurological responses through complex mechanisms. One structural mechanism by which DHA exerts its biological effects is through its ability to modify the physical organization of plasma membrane signaling assemblies known as sphingomyelin/cholesterol (SM/chol)-enriched lipid rafts. Here we studied how DHA acyl chains esterified in the sn-2 position of phosphatidylcholine (PC) regulate the formation of raft and non-raft domains in mixtures with SM and chol on differing size scales...
May 3, 2018: Biochimica et Biophysica Acta
Zheqiong Tan, Lanbo Xiao, Min Tang, Fang Bai, Jiangjiang Li, Liling Li, Feng Shi, Namei Li, Yueshuo Li, Qianqian Du, Jingchen Lu, Xinxian Weng, Wei Yi, Hanwen Zhang, Jia Fan, Jian Zhou, Qiang Gao, José N Onuchic, Ann M Bode, Xiangjian Luo, Ya Cao
Nasopharyngeal carcinoma (NPC) has a particularly high prevalence in southern China, southeastern Asia and northern Africa. Radiation resistance remains a serious obstacle to successful treatment in NPC. This study aimed to explore the metabolic feature of radiation-resistant NPC cells and identify new molecular-targeted agents to improve the therapeutic effects of radiotherapy in NPC. Methods : Radiation-responsive and radiation-resistant NPC cells were used as the model system in vitro and in vivo . Metabolomics approach was used to illustrate the global metabolic changes...
2018: Theranostics
Robert A Olek, Sylwester Kujach, Ewa Ziemann, Wieslaw Ziolkowski, Piotr Waz, Radoslaw Laskowski
Purpose: The aim of this study was to compare the effect of applying two different rest recovery times in a 10-s sprint interval training session on aerobic and anaerobic capacities as well as skeletal muscle enzyme activities. Methods: Fourteen physically active but not highly trained male subjects (mean maximal oxygen uptake 50.5 ± 1.0 mlO2 ·kg-1 ·min-1 ) participated in the study. The training protocol involved a series of 10-s sprints separated by either 1-min (SIT10:1) or 4-min (SIT10:4) of recovery...
2018: Frontiers in Physiology
Pratibha Kumari, Supreet Kaur, Shobha Sharma, Hemant K Kashyap
Modulation of lipid membrane properties due to the permeation of amphiphiles is an important biological process pertaining to many applications in the field of pharmaceutics, toxicology, and biotechnology. Sphingolipids are both structural and functional lipids that constitute an important component of mechanically stable and chemically resistant outer leaflets of plasma membranes. Here, we present an atomistic molecular dynamics simulation study to appreciate the concentration-dependent effects of small amphiphilic molecules, such as ethanol, acetone, and dimethyl sulfoxide (DMSO), on the structure and stability of a fully hydrated homogeneous N-palmitoyl-sphingomyelin (PSM) bilayer...
April 28, 2018: Journal of Chemical Physics
Lisa M Galli, Frederick Santana, Chantilly Apollon, Linda A Szabo, Keri Ngo, Laura W Burrus
Paracrine Wnt signals are critical regulators of cell proliferation, specification, and differentiation during embryogenesis. Consistent with the discovery that Wnt ligands are post-translationally modified with palmitoleate (a 16 carbon mono-unsaturated fatty acid), our studies show that the vast majority of bioavailable chick WNT1 (cWNT1) produced in stably transfected L cells is cell-associated. Thus, it seems unlikely that the WNT1 signal is propagated by diffusion alone. Unfortunately, the production and transport of vertebrate Wnt proteins has been exceedingly difficult to study as few antibodies are able to detect endogenous Wnt proteins and fixation is known to disrupt the architecture of cells and tissues...
April 28, 2018: Developmental Biology
Esteban N Lorenzón, Thatyane M Nobre, Luciano Caseli, Eduardo M Cilli, Gabriel C A da Hora, Thereza A Soares, Osvaldo N Oliveira
Antimicrobial peptides (AMPs) are alternatives to conventional antibiotics against multi-drug resistant bacteria with low potential for developing microbial resistance. The design of such molecules requires understanding of the mechanisms of action, particularly the interaction with bacteria cell membranes. In this work, we determine the mechanism responsible for the higher activity against Escherichia coli of the C-terminal lysine dimer of magainin 2, (MG2)2 K, in comparison to the monomeric peptide magainin 2 (MG2)...
April 20, 2018: Colloids and Surfaces. B, Biointerfaces
Lei Zhao, Chang Zhang, Xiaoxiao Luo, Pei Wang, Wei Zhou, Shan Zhong, Yunxia Xie, Yibo Jiang, Ping Yang, Renkuang Tang, Qin Pan, Andrew R Hall, Tu Vinh Luong, Jiangao Fan, Zac Varghese, John F Moorhead, Massimo Pinzani, Yaxi Chen, Xiong Z Ruan
BACKGROUND AND AIMS: Fatty acid translocase CD36 (CD36) is a membrane protein with multiple immuno-metabolic functions. Palmitoylation has been suggested to regulate the distribution and functions of CD36, but little is known about its significance in NASH. METHODS: Human liver tissue samples were obtained from patients undergoing liver biopsy for diagnostic purposes. CD36 knockout mice were injected with lentivirus vectors to express wild type CD36 and palmitoylation sites mutated CD36 in the livers...
April 26, 2018: Journal of Hepatology
Renata Tiemi Okuro, Mariana Nascimento Machado, Natália Vasconcelos Casquilho, Alcendino Jardim-Neto, Alysson Roncally-Carvalho, Georgia Correa Atella, Walter Araujo Zin
AIM: This study assessed pulmonary outcomes generated by inhibiting key enzymes of sphingolipid metabolism pathways related to ceramide synthesis in a murine model of lung injury induced by lipopolysaccharide (LPS). METHODS: C57BL/6 male adult mice received LPS intratracheally and the expressions of acid sphingomyelinase (ASM), neutral sphingomyelinase (NSM), serine palmitoyl transferase (SPT) and dihydroceramide synthase (DS) were assessed at 2, 4, 6, 12 and 24 h after LPS instillation in lung homogenate (n = 30)...
April 24, 2018: Pulmonary Pharmacology & Therapeutics
Hussein Sultan, Juan Wu, Takumi Kumai, Andres M Salazar, Esteban Celis
Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical approach to treat cancer. We have previously described a peptide vaccination strategy that generates vast numbers of endogenous tumor-reactive CTLs after two sequential immunizations (prime-boost) using poly-ICLC adjuvant, which stimulates endosomal toll-like receptor 3 (TLR3) and cytoplasmic melanoma differentiation antigen 5 (MDA5). Dendritic cells (DCs) play an important role not only in antigen presentation but are critical in generating costimulatory cytokines that promote CTL expansion...
April 25, 2018: Cancer Immunology, Immunotherapy: CII
Xubo Lin, Alemayehu A Gorfe, Ilya Levental
Cellular membranes are laterally organized into domains of distinct structures and compositions by the differential interaction affinities between various membrane lipids and proteins. A prominent example of such structures are lipid rafts, which are ordered, tightly packed domains that have been widely implicated in cellular processes. The functionality of raft domains is driven by their selective recruitment of specific membrane proteins to regulate their interactions and functions; however, there have been few general insights into the factors that determine the partitioning of membrane proteins between coexisting liquid domains...
April 24, 2018: Biophysical Journal
Thais A Enoki, Frederick A Heberle, Gerald W Feigenson
Biomembranes with as few as three lipid components can form coexisting liquid-disordered (Ld) and liquid-ordered (Lo) phases. In the coexistence region of Ld and Lo phases, the lipid mixtures 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/chol or brain sphingomyelin (bSM)/DOPC/chol form micron-scale domains that are easily visualized with light microscopy. Although large domains are not observed in the mixtures DSPC/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/chol and bSM/POPC/chol, lateral heterogeneity is nevertheless detected using techniques with nanometer-scale spatial resolution...
April 24, 2018: Biophysical Journal
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