Lipid Content Of Cell Membranes Research Articles

Significant Increase in Oxidative Stress Indices in Erythrocyte Membranes of Obese Patients with Metabolically-Associated Fatty Liver Disease.

Metabolic dysfunction-associated hepatic steatosis (MAFLD) indicates the metabolic risk associated with hepatic steatosis, overweight and obesity, and clinical evidence of metabolic dysregulation. Since MAFLD is one of the diseases that show a high frequency of alterations in the lipid content of cell membranes, the aim of this study was to evaluate the indices of oxidative damage of erythrocyte membranes in overweight and obese MAFLD subjects. The study was conducted on serum samples and red blood cell membranes of overweight and obese MAFLD subjects. For each patient, biochemical measurements and lipidomic analyses of erythrocytes membranes were performed. Significant differences in fatty acid profiles of RBC membranes were found between overweight and obese patients. In particular, the Peroxidation Index (PI) was higher in the erythrocyte membranes of obese subjects than in overweight subjects. The same behavior was observed for Unsaturation Index (UI) and Free Radical Stress Index (Free RSI), supporting the fact that the systemic increase in oxidative stress was associated with obesity. The study shows that there is a different susceptibility to erythrocyte membrane peroxidation for overweight and obese subjects, and the increased values of oxidative stress indices observed in the erythrocyte membranes of obese patients with MAFLD may be a possible indicator of pro-oxidative events occurring in obesity-related diseases.

Abstract 2581: Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway

Abstract Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes. We are interested in understanding the influence of diet on PC prevention and have studied the effects of polyunsaturated fatty acids (PUFAs) in the progression of the disease both in vitro (via PC cell lines) and in vivo (via EL-KrasG12D and p48Cre/LSL-KrasG12D mouse models that recapitulate IPMN- and PanIN-like lesions, respectively). Our data demonstrate that dietary PUFAs are incorporated into plasma membrane phospholipids (PL) affecting signal transduction, particularly PI3K/AKT signaling, supporting the emergence of membrane-targeted therapies. We evaluated the effects of diets supplemented with omega-3 (ω-3) or omega-6 (ω-6) PUFAs on neoplastic lesion development. This work supports that ω-3 reduces while ω-6 accelerates lesion penetrance, tumor formation and proliferation associated with changes in pAKT. These results were also recapitulated in vitro to confirm that reduced activity of the PI3K/AKT pathway when incubated with Docosahexaenoic Acid (DHA), the primary component of the ω-3 enriched diet. This effect was abrogated by over-activation of the pathway when dosed with the main component of the ω-6 enriched diet, Linoleic Acid (LA). Since PI3K depends on its binding to PIP2 in the membrane for its activity, we next aimed to study if PUFAs were altering PL composition. By using IF and stably-transfected PC cells with a fluorescent translocation biosensor to monitor PIP2 and PIP3 lipids in the membrane, we discovered an effect of exogenous fatty acids expressed as a ratio of PIP2 to PIP3 in the plasma membrane. Enriched areas of membrane GFP staining (or PIP3) were observed in LA-treated Panc-1 cells. DHA treatment prevented PIP3 localization in the membrane of tumor cells, keeping the GFP signal diffuse in the cytoplasm. Using the PIP2 biosensor we sought to study the affinity of PI3K for PIP2 depending on the incorporation of DHA or LA in PIP2. DHA treatment reduced PI3K interaction (not total PI3K) with PIP2 resulting in lower levels of PIP3 in the membrane and reduced pAKT activation. Our results are encouraging because these PUFAs impinge on AKT, a downstream target of Kras which serves as a logical alternative to the elusive therapies for Kras and often toxic effects of PI3K/AKT pathway inhibition. Citation Format: Carolina Torres, Georgina Mancinelli, Emily Chen, Jose Cordoba-Chacon, Danielle Pins, Ronald McKinney, Sara Saeed, Karla Castellanos, Giulia Orsi, Megha Singhal, Sam Grimaldo, Poorna Chandra Rao Yalagala, Papasani Subbaiah, Cecilia Leal, Paul Grippo. Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2581.

Peroxisomal Dysfunction in Neurological Diseases and Brain Aging.

Peroxisomes exist in most cells, where they participate in lipid metabolism, as well as scavenging the reactive oxygen species (ROS) that are produced as by-products of their metabolic functions. In certain tissues such as the liver and kidneys, peroxisomes have more specific roles, such as bile acid synthesis in the liver and steroidogenesis in the adrenal glands. In the brain, peroxisomes are critically involved in creating and maintaining the lipid content of cell membranes and the myelin sheath, highlighting their importance in the central nervous system (CNS). This review summarizes the peroxisomal lifecycle, then examines the literature that establishes a link between peroxisomal dysfunction, cellular aging, and age-related disorders that affect the CNS. This review also discusses the gap of knowledge in research on peroxisomes in the CNS.

Abstract CT067: 2-hydroxyoleic acid (2-OHOA), a novel activator of sphingomyelin synthase with antitumor activity in refractory glioblastoma: results of the first-in-human dose-escalation (DE) study in patients with advanced solid tumors (AST) and refractory gliomas/glioblastomas

Abstract Background: 2-OHOA, is a synthetic hydroxylated lipid that activates sphingomyelin synthase and regulates the lipid content of cell membranes resulting in translocation of Ras to the cytoplasm and inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. 2-OHOA causes autophagic cell death of glioma cell lines in vitro, and reduces tumor growth in numerous xenograft mice models including glioblastoma (GBM), prostate, leukemia, breast and colon cancer. It also crosses the blood brain barrier. This first-in-human trial was designed to determine the safety, tolerability, and recommended phase 2 dose (RP2D), alongside the pharmacokinetic (PK), pharmacodynamic (PD) and anti-tumor profile of 2-OHOA. Methods: Eligible pts with AST or GIII/IV gliomas/glioblastomas received 2-OHOA as a daily PO suspension in 21 day cycles using a 3+3 DE design. Adverse events (AE) were assessed by CTCAEv4; Tumor response was assessed every 2 cycles using RECIST 1.1/RANO criteria. Results: 32 pts were enrolled on the DE stage. 28 pts were evaluable for safety (13 gliomas and 15 AST). Pts were treated with doses from 500mg-16g/day in 7 cohorts. Drug-related AEs >Grade 3 of nausea, vomiting and diarrhea (n = 6) were seen at high doses. DLTs were diarrhea (n = 3) and vomiting (n = 1) at 12 and 16g/day. Extent of exposure (AUC) was generally proportional to the dose. The PK profile showed dose accumulation from 8g/day. Average t1/2 ranged from 1-2h to 8-12h with longer half-lives seen at higher doses Steady state was reached with 12 and 16g/day. 4 pts had clinical benefit for >6mo, 25% of refractory GBM patients treated (3/12) had objective responses by RANO criteria : 1 partial response (PR) and 2 stable disease (SD). The GBM pt with confirmed PR was treated at 1g/daily for 41 cycles and continues on treatment; the other 2 GBM pts were treated at 12g/day and had SD for 9 cycles. Conclusions: The MTD and RP2D of 2-OHOA is 12g/daily. Clinical benefit was observed in 4 pts including durable responses in 25% of advanced treatment-refractory GBM pts treated. Recruitment is ongoing including an expansion cohort for advanced gliomas/glioblastomas. Clinical trial information: NCT01792310 Citation Format: Juanita S. Lopez, Mariane Fontes, Niamh Coleman, Analia Azaro, Yvette Drew, Pablo Escriba, Xavier Busquets, Gareth Veal, Vicenc Tur, Antoine Perier, Elisabet Sicart, Rhoda Molife, Ruth Plummer, Jordi Rodon. 2-hydroxyoleic acid (2-OHOA), a novel activator of sphingomyelin synthase with antitumor activity in refractory glioblastoma: results of the first-in-human dose-escalation (DE) study in patients with advanced solid tumors (AST) and refractory gliomas/glioblastomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT067.

A first-in-human dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of oral 2-hydroxyoleic acid (2-OHOA) in adult patients (pt) with advanced solid tumors including grade III/IV glioblastoma multiforme (GBM).

2513 Background: 2-OHOA, is a synthetic hydroxylated lipid that activates sphingomyelin synthase (SGMS) and regulates the lipid content of cell membranes resulting in translocation of Ras to the cy...

Aliiglaciecola coringensis sp. nov., isolated from a water sample collected from mangrove forest in Coringa, Andhra Pradesh, India.

A Gram-negative, rod shaped, motile, aerobic bacterium, designated as strain AK49(T) was isolated from a water sample from a mangrove forest in Coringa village, Andhra Pradesh, India. Strain AK49(T) was observed to form yellow coloured, smooth, circular, convex colonies on marine agar, with entire margins. Cells of strain AK49(T) are 0.5-1.0 µm wide and 1.5-3.5 µm long. Growth was observed at 25-37 °C (optimum 30 °C), 2-6 % NaCl (optimum 2 %) and pH 6-8 (optimum 7). Phylogenetic analysis based on 16S rRNA gene sequences showed that the strain AK49(T) is closely related to two species recently reclassified as members of the genus Aliiglaciecola: Aliiglaciecola lipolytica JCM 15139(T) (sequence similarity 95.43 %) and Aliiglaciecola litoralis JCM 15896(T) (sequence similarity 96.91 %). The major cellular fatty acids of strain AK49(T) were found to include C16:0, C18:1ω7c and summed feature 3 (C16:1ω7c/C15:0 iso-2-OH). The polar lipid content of cell membrane was found to include phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminolipid, an unidentified lipid and an unidentified glycolipid. The genomic DNA G+C content of strain AK49(T) was determined to be 41.9 mol%. Based on the taxonomic methods, including chemotaxonomic, phenotypic and phylogenetic approaches, strain AK49(T) is described here as a novel species belonging to the genus Aliiglaciecola, for which the name Aliiglaciecola coringensis sp. nov. is proposed. The type strain of Aliiglaciecola coringensis sp. nov. is AK49(T) (=MTCC 12003(T )= JCM19197(T)).

Erythrocyte cation transport systems and membrane lipids in insulin-dependent diabetes.

The relationship between erythrocyte cation transport systems and membrane and plasma lipids was examined in normal men and patients with insulin-dependent diabetes mellitus (IDDM). Different measurements of erythrocyte transport systems were obtained in patients with IDDM and in age- and weight-matched healthy men: Na+:Li+ countertransport activity or Li(+)-stimulated Na+ efflux, Na+:K+ cotransport activity or bumetanide-sensitive Na+ efflux, Na+:K+ pump activity or ouabain-sensitive Na+ efflux, and the ouabain- and bumetanide-resistant Na+ and K+ fluxes or the ground membrane permeability for Na+ and K+ as well as the intraerythrocyte Na+, K+, and Mg2+ concentrations. Plasma cholesterol, triglycerides, phospholipids, low- and high- density lipoprotein cholesterol, and erythrocyte membrane cholesterol and phospholipid content were obtained from the fasting subjects. The patients with IDDM had an elevated (P < .05 or less) erythrocyte Na+:Li+ countertransport activity, ground membrane leak for K+, intraerythrocyte K+ concentration, and erythrocyte membrane cholesterol content, but a lower red blood cell phospholipid content. In single regression analysis, the erythrocyte Na+:Li+ countertransport, Na+:K+ cotransport, and Na+:K+ pump activity and ground membrane leak for Na+ and K+ were inversely related to the red blood cell membrane lipid content. Our data in patients with IDDM show that a decreased erythrocyte membrane lipid content was accompanied by a higher erythrocyte Na+:Li+ countertransport, Na+:K+ cotransport, and Na+:K+ pump activity.