scholarly journals Prolonged Exposure to Platelet Activating Factor Transforms Breast Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Vaishali Chakravarty ◽  
Libi Anandi ◽  
K. A. Ashiq ◽  
K. Abhijith ◽  
Rintu Umesh ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Second Messengers ◽  
Platelet Activating Factor ◽  
Continuous Exposure ◽  
Oncogenic Signaling ◽  
Epithelial Cancers ◽  
Enhanced Production ◽  
Lipid Species ◽  
Tumor Cell Motility ◽  
Irreversible Effects

Lipid species are known to have various biological functions owing to their structural differences, and each of them possesses a specific role to play depending upon their location and distribution in the cell. Some of these lipids interact with proteins on the cell membrane and acts as second messengers. The level of lipid mediators is generally maintained in the cell by feedback mechanisms; however, their improper degradation or enhanced production leads to their accumulation in the tumor microenvironment and disturbs the homeostasis of the cell. Platelet activating factor (PAF) is a known phospholipid mediator secreted upon immunological challenges by platelets, neutrophils, basophils, and macrophages. PAF, as a potent inflammatory molecule, is well studied, and its role in various cancers and cardiovascular diseases has also been investigated. Interestingly, increased levels of PAF have been found in the blood plasma of smokers, and breast cancer cells have shown the accumulation of PAF in presence of cigarette smoke extract. This accumulation was found to increase tumor cell motility that in turn could promote metastasis. Beyond this, however, the effect of PAF on tumorigenesis has not yet been well explored. Here, we show that the continuous exposure of 3D breast acinar cultures to PAF resulted in the activation of various oncogenic signaling pathways leading to transformation. We also found that the presence of PAF in the micro-environment increased the expression of PAF receptor (PAF-R), which corroborated with the higher expression of PAF-R detected in some epithelial cancers, as per literature. Thus, this study impresses on the fact that the presence of PAF alters the cellular microenvironment and eventually triggers irreversible effects that can cumulatively lead to transformation.

scholarly journals Enhanced Production of Photosynthetic Pigments and Various Metabolites and Lipids in the Cyanobacteria Synechocystis sp. PCC 7338 Culture in the Presence of Exogenous Glucose

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 214
Author(s):  
YuJin Noh ◽  
Hwanhui Lee ◽  
Myeongsun Kim ◽  
Seong-Joo Hong ◽  
Hookeun Lee ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Growth ◽  
Photosynthetic Pigments ◽  
Industrial Applications ◽  
Gas Chromatography Mass Spectrometry ◽  
Enhanced Production ◽  
Exogenous Glucose ◽  
Nanoelectrospray Ionization ◽  
Lipid Species ◽  
Synechocystis Sp

Synechocystis strains are cyanobacteria that can produce useful biomaterials for biofuel and pharmaceutical resources. In this study, the effects of exogenous glucose (5-mM) on cell growth, photosynthetic pigments, metabolites, and lipids in Synechocystis sp. PCC 7338 (referred to as Synechocystis 7338) were investigated. Exogenous glucose increased cell growth on days 9 and 18. The highest production (mg/L) of chlorophyll a (34.66), phycocyanin (84.94), allophycocyanin (34.28), and phycoerythrin (6.90) was observed on day 18 in Synechocystis 7338 culture under 5-mM glucose. Alterations in metabolic and lipidomic profiles under 5-mM glucose were investigated using gas chromatography-mass spectrometry (MS) and nanoelectrospray ionization-MS. The highest production (relative intensity/L) of aspartic acid, glutamic acid, glycerol-3-phosphate, linolenic acid, monogalactosyldiacylglycerol (MGDG) 16:0/18:1, MGDG 16:0/20:2, MGDG 18:1/18:2, neophytadiene, oleic acid, phosphatidylglycerol (PG) 16:0/16:0, and PG 16:0/17:2 was achieved on day 9. The highest production of pyroglutamic acid and sucrose was observed on day 18. We suggest that the addition of exogenous glucose to Synechocystis 7338 culture could be an efficient strategy for improving growth of cells and production of photosynthetic pigments, metabolites, and intact lipid species for industrial applications.

scholarly journals Induction of cytosolic phospholipase A2 activity by phosphatidic acid and diglycerides in permeabilized human neutrophils: interrelationship between phospholipases D and A2

1997 ◽  
Vol 322 (2) ◽  
pp. 353-363 ◽  
Author(s):  
Sue A. BAULDRY ◽  
Rhonda E. WOOTEN
Keyword(s):  
Phosphatidic Acid ◽  
Phospholipase A2 ◽  
Second Messengers ◽  
Platelet Activating Factor ◽  
Human Neutrophils ◽  
Partial Restoration ◽  
Permeabilized Cells ◽  
Cpla2 Activation ◽  
Factor Α ◽  
Cytosolic Pla2

Relationships between phospholipases are poorly understood, but phosphatidic acid (PA) and diglycerides (DGs), produced by phospholipase D (PLD) and phosphatidate phosphohydrolase actions, might function as second messengers coupling cell stimulation to cellular responses. This study investigates the role of PLD-mediated PA and DG formation in inducing phospholipase A2 (PLA2) activity in intact human neutrophils (PMNs) and in PMNs permeabilized with Staphylococcus aureusα-toxin. PMNs were labelled with [3H]arachidonic acid (AA) to assess AA release and metabolism and diacylglycerol formation, or with [3H]1-O-hexadecyl-2-lyso-glycerophosphatidylcholine for the determination of platelet-activating factor (PAF), PA and alkylacylglycerol production. In intact PMNs primed with tumour necrosis factor α before stimulation with N-formyl-Met-Leu-Phe, AA release and metabolism and PAF formation increased in parallel with enhanced PA and DG formation, and inhibition of PA and DG production led to a decrease in both AA release and PAF accumulation. In α-toxin-permeabilized PMNs, AA release and PAF production result from the specific activation of cytosolic PLA2 (cPLA2). In this system, PA and DG formation were always present when cPLA2 activation occurred; blocking PA and DG production inhibited AA release and PAF accumulation. Adding either PA or DG back to permeabilized cells (with endogenous PA and DG formation blocked) led to a partial restoration of AA release and PAF formation; a combination of PA and DGs reconstituted full cPLA2 activity. These results strongly suggest that products of PLD participate in activating cPLA2 in PMNs.

Abstract 458: Obesity-related Alterations in Cardiac Lipid Profile During the Transition to Diastolic Dysfunction

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Vincent G DeMarco ◽  
David A Ford ◽  
Erik Henriksen ◽  
Annayya Aroor ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Diastolic Dysfunction ◽  
Phospholipid Metabolism ◽  
Fatty Acyl ◽  
Acid Oxidation ◽  
Relevant Model ◽  
Insulin Resistant ◽  
Enhanced Production ◽  
Lipid Species ◽  
And Oxidative Stress

Myocardial accumulation of fatty acids and lipid intermediates may contribute to cardiac dysfunction, but the interrelationship between different lipid species to diastolic dysfunction is not clearly understood. Herein, we examined changes in levels and composition of different lipid species during the progression to diastolic dysfunction in a clinically relevant model of obese insulin-resistant db/db mice at 12 and 15 wks of age. Obese db/db mice manifested loss of circadian BP dipping and diastolic dysfunction at 15 wks. Myocardial lipidomic analysis demonstrated elevated ceramides and fatty acids in db/db at 12 wks, but their levels were decreased at 15 wk and this was accompanied by increased fatty acid oxidation and enhanced production of reactive oxygen species. Triacylglyceride and diacylglyceride levels remained elevated at both 12 and 15 wk, but their composition changed to consist of more saturated and less unsaturated fatty acyl at 15 wks of age compared to 12 wk. Dysregulation of phospholipid metabolism persisted at 15 wk in db/db. Changes in triacylglyceride and diacylglyceride composition, phospholipid metabolism, β-oxidation, and oxidative stress that are temporally related to non-dipping of BP and diastolic dysfunction suggest a switch in metabolism of lipid intermediates contributes to the development of diastolic dysfunction in over-nutrition.

Stress and Chronic Effects of Untreated and Treated Bleached Kraft Pulpmill Effluent on the Biochemistry and Stamina of Juvenile Coho Salmon (Oncorhynchus kisutch)

1979 ◽  
Vol 36 (9) ◽  
pp. 1049-1059 ◽  
Author(s):  
Donald J. McLeay ◽  
David A. Brown
Keyword(s):  
Prolonged Exposure ◽  
Coho Salmon ◽  
Oncorhynchus Kisutch ◽  
Effluent Treatment ◽  
Control Fish ◽  
Continuous Exposure ◽  
Stream Channels ◽  
Body Protein ◽  
Glucose Levels ◽  
Treated Effluent

Growth of juvenile coho salmon (Oncorhynchus kisutch) fed a limiting ration (70% of satiation) in experimental stream channels was not altered significantly by prolonged exposure to untreated or laboratory-treated (fermented) bleached kraft pulpmill effluent (BKME), although mean weights for control fish were consistently lower than those for all effluent-exposed groups from 100 to 200 d. Body protein, fat, and moisture content were unaffected by treatment at 30, 90, and 200 d. Fish exposed to all strengths of untreated or treated BKME (i.e. untreated concentrations equivalent by volume to 0.05, 0.1, 0.2, 0.3, and 0.5 of the untreated effluent's 96-h LC50 value; and treated concentrations equivalent by volume to 0.2 and 1.0 LC50) showed significant decreases in serum albumin levels at 30 d, whereas these recovered to control values at 90 and 200 d. The serum electrolytes Na+, K+, and Ca++ were unaffected by treatment at 200 d and not measured for other exposures. Liver and muscle glycogen reserves were decreased significantly by continuous exposure of fish to untreated or treated BKME concentrations for 30 d. These values recovered to control levels at 90 d and were unaffected or depressed at 200 d. Plasma glucose levels at 30 d were elevated significantly in all BKME-exposed groups except those held in the lowest concentration of untreated or treated effluent. Blood sugar values at 90 d were increased only by the highest strength of untreated or treated BKME; whereas at 200 d these values were elevated from control levels in all effluent-exposed groups. Levels of plasma lactic acid were unmeasured at 30 d, increased at 90 d in all BKME-exposed groups except the lowest strength of untreated effluent, and elevated at 200 d in all effluent-exposed groups. The stamina of these fish as determined by critical swimming speeds in freshwater was unaffected by exposure to pulpmill effluent for 90 d and unmeasured for other exposures. Based on the changes in intermediary metabolism for BKME-exposed fish at 30, 90, and 200 d, it was concluded that these fish remained in a state of chronic stress and did not acclimate to prolonged exposure to pulpmill effluent. Treatment of this waste reduced or removed its acute (lethal) toxicity but did not alter the biochemical effects caused by chronic exposure. Key words: stress, growth, proximate analyses, albumin, electrolyte, glycogen, glucose, lactate, critical swimming speed, acclimation

scholarly journals Activation of PAR2 by tissue factor induces the release of the PTEN from MAGI proteins and regulates PTEN and Akt activities

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mohammad A. Mohammad ◽  
John Greenman ◽  
Anthony Maraveyas ◽  
Camille Ettelaie
Keyword(s):  
Tissue Factor ◽  
Phosphatase Activity ◽  
Cell Lines ◽  
Prolonged Exposure ◽  
Term Treatment ◽  
Proximity Ligation Assay ◽  
Continuous Exposure ◽  
Short Term Treatment ◽  
Cellular Survival ◽  
Proximity Ligation

AbstractTissue factor (TF) signalling has been associated with alterations in Akt activity influencing cellular survival and proliferation. TF is also shown to induce signalling through activation of the protease activated receptor (PAR)2. Seven cell lines were exposed to recombinant-TF (rec-TF), or activated using a PAR2-agonist peptide and the phosphorylation state of PTEN, and the activities of PTEN and Akt measured. Furthermore, by measuring the association of PTEN with MAGI proteins a mechanism for the induction of signalling by TF was proposed. Short term treatment of cells resulted in de-phosphorylation of PTEN, increased lipid-phosphatase activity and reduced Akt kinase activity in most of the cell lines examined. In contrast, continuous exposure to rec-TF up to 14 days, resulted in lower PTEN antigen levels, enhanced Akt activity and increased rate of cell proliferation. To explore the mechanism of activation of PTEN by TF, the association of "membrane-associated guanylate kinase-with inverted configuration" (MAGI)1–3 proteins with PTEN was assessed using the proximity ligation assay and by co-immunoprecipitation. The interaction of PTEN with all three MAGI proteins was transiently reduced following PAR2 activation and explains the changes in PTEN activity. Our data is first to show that PAR2 activation directly, or through exposure of cells to TF releases PTEN from MAGI proteins and is concurrent with increases in PTEN phosphatase activity. However, prolonged exposure to TF results in the reduction in PTEN antigen with concurrent increase in Akt activity which may explain the aberrant cell survival, proliferation and invasion associated with TF during chronic diseases.

Changes in Aggressive Interaction in Adjacently Territorial Convict Cichlids (Cichlasoma Nigrofasciatum): a Study of Habituation

Behaviour ◽  
1971 ◽  
Vol 40 (1-2) ◽  
pp. 43-54 ◽  
Author(s):  
Michael J. Herz ◽  
Harman V.S. Peeke ◽  
James E. Gallagher
Keyword(s):  
Ecological Niche ◽  
Prolonged Exposure ◽  
Continuous Exposure ◽  
Aggressive Interaction ◽  
Minute Exposure ◽  
Cichlasoma Nigrofasciatum ◽  
Uniform Pattern ◽  
Convict Cichlids ◽  
Stimulus Source ◽  
Exposure Conditions

AbstractPairs of male Convict Cichlids (Cichlasoma nigrofasciatum) were isolated from each other and then exposed in adjoining territories under one of two exposure conditions, either daily 20 minute exposure for 38-44 days or a massed continuous exposure for 24 or 28 hours. The incidence of biting and the duration of chin display for each fish was recorded. The duration of the chin display described a near uniform pattern of attenuation for both exposure conditions. The waning of the biting response was evident but it was more variable than the chin display. It was concluded that these behaviors both tend to habituate with repeated or constant exposure to the same stimulus source and that prolonged exposure facilitates the habituation of aggressiveness between territorial neighbors, thus promoting peace in a particular ecological niche.

Identification of head and neck cancers (SCCHN) that may respond to dual inhibition of EGFR and HER3 signaling.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5575-5575
Author(s):  
David S. Shames ◽  
Howard Stern ◽  
Kim Walter ◽  
Brittany Jiang ◽  
Ling Fu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Bimodal Distribution ◽  
Autocrine Signaling ◽  
Oncogenic Signaling ◽  
Epithelial Cancers ◽  
Formalin Fixed Paraffin Embedded ◽  
Dual Action ◽  
High Level

5575 Background: Oncogenic signaling through the epidermal growth factor receptor family is one of the most frequent alterations found in human epithelial cancers. These receptor tyrosine kinases mediate their effects via high-level co-expression and homo- and heterodimerization events that drive tumor growth, metastasis, and survival. Extensive preclinical studies suggested that some cell lines depend on oncogenic autocrine signaling through HER3 (Wilson et al.). This phenotype was particularly prominent in cell lines derived from SCCHN and was strongly correlated with high HRG expression. Interestingly, two patients with SCCHN tumors that expressed high levels of HRG in our phase Ia trial (abstract #95245) of MEHD7954A, a dual-action human IgG1 antibody that blocks ligand binding to EGFR and HER3 (Schaefer et al.) had partial responses. To further explore the hypothesis that high-level HRG expression defines a sub-population of SCCHN that may be sensitive to agents targeting HER3, and to identify other potential target indications for the development of MEHD7954A, we evaluated the expression of HRG in large cohorts of multiple solid tumor indications. Methods: HER3 and HRG expression was analyzed by qRT-PCR in 648 formalin-fixed paraffin embedded primary tumor samples from patients with NSCLC, SCCHN, melanoma, CRC and triple-negative breast cancer. Results: SCCHN-derived tumor samples had the highest levels of HRG expression, exhibiting a bimodal distribution in SCCHN – a pattern that is clearly distinct when compared to other tumor types. These data suggest that high HRG levels and potentially HER3-dependent autocrine signaling occur more frequently in SCCHN than in other tumors. Further we investigated whether overexpression of HRG in SCCHN correlated with stage and disease outcome. Updated results from these extended studies will be presented. Conclusions: SCCHN tumors exhibit bimodal expression of HRG, suggesting that HRG expression levels may be useful in identifying a subset of patients most likely to benefit from inhibition of HER3 activity. Antitumor activity in such patients has been observed in a phase I study of MEHD7954A (abstract #95245).

Weekly 20/56 mg/m² carfilzomib, lenalidomide, and dexamethasone until progression in early relapsed refractory multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8041-8041
Author(s):  
Cecile Gruchet ◽  
Valentine Richez ◽  
Stephanie Guidez ◽  
Guillemette Fouquet ◽  
Isabelle Azais ◽  
...  
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Prolonged Exposure ◽  
Safety Concern ◽  
Median Number ◽  
Continuous Exposure ◽  
Similar Data ◽  
Duration Of Treatment ◽  
Safety Issues ◽  
Grade 3

8041 Background: Triplet-based Carfilzomib (K), Lenalidomide and Dexamethasone combination (KRd) has led to approval in early RRMM based on ASPIRE International phase 3 study. However, K was used on a twice a week basis at 27mg/m2 and limited to 18 months exposure. We have reported already that KRd on a weekly basis at 56 mg/m2 was active similar to ASPIRE KRd and safe. We report herein the long-term exposure data on KRd weekly given until progression. We aimed to evaluate the efficacy of KRd given on a prolong duration beyond 18months, and to validate the safety profile of continuous exposure to K. Methods: 28 patients were prospectively recruited. Carfilzomib 20/56mg/m2 was administered on days 1,8,15, Lenalidomide 25mg/day was given 21/28 days and Dexamethasone was administered weekly on 28 days cycles until progression. Results: With a median follow-up at start of KRd of 30 months, 50% of patients relapsed and 39% died. 24/28 patients received 1 prior line of treatment. 8/28 patients are still on treatment with duration > 24 month and 6/28 with duration > 30 months. The median number of cycles was 15. ORR and CBR was 85.7% and 89.3%, whom 46% ≥ CR ; with a median DOR of 13 months and 43% having more than 18 months. 6 patients had negative MRD at 10-6 and normalized PET CT. Median of OS is not reached, and the 30 month-expected OS from the start of KRd was 56%. The median PFS and EFS was at 29 months, and the 30 month-expected PFS and EFS was 45%. PFS and EFS being superimposable speaks to that there was no safety concern related to prolonged exposure to K. Only 4 patients stopped KRd for safety issues. Hematologic and non-hematologic adverse events ≥ grade 3 were reported in 16/28 and 10/28 patients. Adverse events ≥ grade 3 seen in ≥10% of patients were neutropenia, thrombocytopenia, vomiting and pyrexia. Of note, 5 patients (18%) were ≥ 65 years old and showed similar data compared to the cohort. Conclusions: KRd weekly is effective and safe to early in RRMM patients, provides improved safety profile to patients allowing treating patients until progression. Further studies are warranted to confirm this data on a larger early RRMM population and validate the concept of long duration of treatment using Carfilzomib combination.

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