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13 results on '"SECRETORY PHOSPHOLIPASE A(2)"'

1. Regulation and Function of Epithelial Secreted Phospholipase A2 Group X in Asthma

Author

Hallstrand, Teal S, Lai, Ying, Altemeier, William A, Appel, Cara L, Johnson, Brian, Frevert, Charles W, Hudkins, Kelly L, Bollinger, James G, Woodruff, Prescott G, Hyde, Dallas M, Henderson, William R, and Gelb, Michael H

Subjects
Lung, Clinical Research, Asthma, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Adolescent, Adult, Animals, Asthma, Exercise-Induced, Bronchial Hyperreactivity, Enzyme-Linked Immunosorbent Assay, Epithelial Cells, Female, Gene Expression, Group X Phospholipases A2, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Real-Time Polymerase Chain Reaction, Young Adult, airway hyperresponsiveness, asthma, eicosanoid, epithelial cell, secretory phospholipase A(2), Medical and Health Sciences, Respiratory System
Abstract

RationaleIndirect airway hyperresponsiveness (AHR) is a fundamental feature of asthma that is manifest as exercise-induced bronchoconstriction (EIB). Secreted phospholipase A2 group X (sPLA2-X) plays a key role in regulating eicosanoid formation and the development of inflammation and AHR in murine models.ObjectivesWe sought to examine sPLA2-X in the airway epithelium and airway wall of patients with asthma, the relationship to AHR in humans, and the regulation and function of sPLA2-X within the epithelium.MethodsWe precisely phenotyped 34 patients with asthma (19 with and 15 without EIB) and 10 normal control subjects to examine in vivo differences in epithelial gene expression, quantitative morphometry of endobronchial biopsies, and levels of secreted protein. The regulation of sPLA2-X gene (PLA2G10) expression was examined in primary airway epithelial cell cultures. The function of epithelial sPLA2-X in eicosanoid formation was examined using PLA2 inhibitors and murine tracheal epithelial cells with Pla2g10 deletion.Measurements and main resultsWe found that sPLA2-X protein is increased in the airways of patients with asthma and that epithelial-derived sPLA2-X may be increased in association with indirect AHR. The expression of sPLA2-X increases during in vitro epithelial differentiation; is regulated by inflammatory signals including tumor necrosis factor, IL-13, and IL-17; and is both secreted from the epithelium and directly participates in the release of arachidonic acid by epithelial cells.ConclusionsThese data reveal a relationship between epithelial-derived sPLA2-X and indirect AHR in asthma and that sPLA2-X serves as an epithelial regulator of inflammatory eicosanoid formation. Therapies targeting epithelial sPLA2-X may be useful in asthma.

Published
2013

2. Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.

Author

Holmes, Michael V, Simon, Tabassome, Exeter, Holly J, Folkersen, Lasse, Asselbergs, Folkert W, Guardiola, Montse, Cooper, Jackie A, Palmen, Jutta, Hubacek, Jaroslav A, Carruthers, Kathryn F, Horne, Benjamin D, Brunisholz, Kimberly D, Mega, Jessica L, van Iperen, Erik P A, Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J W, Hovingh, G Kees, and Dehghan, Abbas

Abstract

Objectives: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.Background: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.Methods: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.Results: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.Conclusions: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. [ABSTRACT FROM AUTHOR]

Published
2013
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3. rHDL administration increases reverse cholesterol transport in mice, but is not additive on top of ezetimibe or cholestyramine treatment

Author

Uwe J. F. Tietge, Cyrille Maugeais, Jean-Luc Mary, Denise Blum, Wijtske Annema, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)

Subjects
Very low-density lipoprotein, DEFICIENT MICE, chemistry.chemical_compound, Feces, Mice, PLAQUE STABILIZATION, ABSORPTION, Cholesterol absorption inhibitor, Chemistry, Anticholesteremic Agents, Reverse cholesterol transport, Drug Synergism, RANDOMIZED CONTROLLED-TRIAL, CORONARY ATHEROSCLEROSIS, Sterols, Cholesterol, Liver, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, medicine.drug, EXPRESSION, medicine.medical_specialty, HDL, medicine.drug_class, Cholestyramine Resin, Models, Biological, ATHEROSCLEROSIS REGRESSION, Bile Acids and Salts, SECRETORY PHOSPHOLIPASE A(2), Ezetimibe, Bile acid sequestrant, Internal medicine, medicine, Animals, Triglycerides, Cholestyramine, Apolipoprotein A-I, APOLIPOPROTEIN-A-I, Macrophages, Cholesterol, HDL, Biological Transport, Sterol, Mice, Inbred C57BL, Sterol excretion, Endocrinology, Intestinal Absorption, Azetidines
Abstract

Objective: Promoting reverse cholesterol transport (RCT) is a major atheroprotective property of HDL. The present study explored the effect of stimulating the first step of RCT (cholesterol efflux from macrophages) alone or in combination with stimulating the last step of RCT (fecal sterol excretion).Methods and results: Reconstituted HDL (rHDL) was injected into wild-type mice either with or without administration of the cholesterol absorption inhibitor ezetimibe or the bile acid sequestrant cholestyramine. Single dose administration of rHDL (100 mg apoA-I/kg) resulted in an early (4 h) increase in plasma free cholesterol levels (p Conclusion: These data demonstrate that increasing the first step of RCT by rHDL administration results in transient cholesterol mobilization from macrophages to plasma. This effect is not further enhanced by stimulating the last step of RCT, fecal sterol excretion. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Published
2013

4. Secretory phospholipase A2 responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo

Author

Ole L. Nielsen, Thomas Lars Andresen, Anders Elias Hansen, Andreas Kjaer, Gael Clergeaud, Houman Pourhassan, Ladan Parhamifar, and Ragnhild Garborg Østrem

Subjects
0301 basic medicine, Cancer therapy, Pharmaceutical Science, Pharmacology, Biology, Secretory phospholipase A(2), 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, SDG 3 - Good Health and Well-being, In vivo, Membrane fluidity, Liposome, Liposomal Oxaliplatin, Cholesterol, Triggered release, In vitro, Oxaliplatin, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Drug delivery, Growth inhibition
Abstract

The clinical use of liposomal drug delivery vehicles is often hindered by insufficient drug release. Here we present the rational design of liposomes optimized for secretory phospholipase A2 (sPLA2) triggered drug release, and test their utility in vitro and in vivo. We hypothesized that by adjusting the level of cholesterol in anionic, unsaturated liposomes we could tune the enzyme specificity based on membrane fluidity, thus obtaining liposomes with an improved therapeutic outcome and reduced side effects. Cholesterol is generally important as a component in the membranes of liposome drug delivery systems due to its stabilizing effects in vivo. The incorporation of cholesterol in sPLA2 sensitive liposomes has not previously been possible due to reduced sPLA2 activity. However, in the present work we solved this challenge by optimizing membrane fluidity. In vitro release studies revealed enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA2 secreting mammary carcinoma cell line MT-3. Three days after first treatment all mice having received the novel sPLA2 sensitive liposome formulation were euthanized due to severe systemic toxicity. Thus the present study demonstrates that great caution should be implemented when utilizing sPLA2 sensitive liposomes and that the real utility can only be disclosed in vivo. The present studies have clinical implications, as sPLA2 sensitive formulations are currently undergoing clinical trials (LiPlaCis®).

Published
2017
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5. Secretory phospholipase A2 responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo

Author

Østrem, Ragnhild Garborg, Parhamifar, Ladan, Pourhassan, Houman, Clergeaud Veiga, Gael, Nielsen, Ole L., Kjær, Andreas, Hansen, Anders Elias, Andresen, Thomas Lars, Østrem, Ragnhild Garborg, Parhamifar, Ladan, Pourhassan, Houman, Clergeaud Veiga, Gael, Nielsen, Ole L., Kjær, Andreas, Hansen, Anders Elias, and Andresen, Thomas Lars

Abstract

The clinical use of liposomal drug delivery vehicles is often hindered by insufficient drug release. Here we present the rational design of liposomes optimized for secretory phospholipase A2 (sPLA2) triggered drug release, and test their utility in vitro and in vivo. We hypothesized that by adjusting the level of cholesterol in anionic, unsaturated liposomes we could tune the enzyme specificity based on membrane fluidity, thus obtaining liposomes with an improved therapeutic outcome and reduced side effects. Cholesterol is generally important as a component in the membranes of liposome drug delivery systems due to its stabilizing effects in vivo. The incorporation of cholesterol in sPLA2 sensitive liposomes has not previously been possible due to reduced sPLA2 activity. However, in the present work we solved this challenge by optimizing membrane fluidity. In vitro release studies revealed enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA2 secreting mammary carcinoma cell line MT-3. Three days after first treatment all mice having received the novel sPLA2 sensitive liposome formulation were euthanized due to severe systemic toxicity. Thus the present study demonstrates that great caution should be implemented when utilizing sPLA2 sensitive liposomes and that the real utility can only be disclosed in vivo. The present studies have clinical implications, as sPLA2 sensitive formulations are currently undergoing clinical trials (LiPlaCis®).

Published
2017

6. Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress

Author

Theo J.C. Van Berkel, Domenico Praticò, Miranda Van Eck, Colin D. Funk, Tao Ding, Uwe J.F. Tietge, Reeni B. Hildebrand, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)

Subjects
RECEPTOR-DEFICIENT MICE, medicine.disease_cause, Biochemistry, DISEASE, Mice, chemistry.chemical_compound, Endocrinology, Receptor, IN-VIVO, Bone Marrow Transplantation, Foam cell, TRANSGENIC MICE, hypercholesterolemia, Malondialdehyde, Low-density lipoprotein, secretory phospholipase A2, lipids (amino acids, peptides, and proteins), medicine.symptom, medicine.medical_specialty, Lipoproteins, LOW-DENSITY-LIPOPROTEIN, Mice, Transgenic, Inflammation, QD415-436, GENE FAMILY, Biology, secretory phospholipase A(2), Group II Phospholipases A2, Phospholipases A, HUMAN AORTIC PROTEOGLYCANS, In vivo, Internal medicine, medicine, Animals, Humans, cardiovascular diseases, PLASMA-LEVELS, Cholesterol, Macrophages, nutritional and metabolic diseases, Cell Biology, Atherosclerosis, lipoxygenase, Oxidative Stress, Phospholipases A2, Receptors, LDL, chemistry, inflammation, Oxidative stress, Foam Cells
Abstract

Group IIA secretory phospholipase A2 (sPLA2) is an acute-phase protein mediating decreased plasma HDL cholesterol and increased atherosclerosis. This study investigated the impact of macrophage-specific sPLA2 overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA2 transgenic mice have 2.5 times increased rates of LDL oxidation (thiobarbituric acid-reactive substances formation) in vitro (59 +/- 5 vs. 24 +/- 4 nmol malondialdehyde/mg protein; P0.001) dependent on functional 12/15-lipoxygenase (12/15-LO). Low density lipoprotein receptor-deficient (LDLR-/-) mice were transplanted with bone marrow from either sPLA2 transgenic mice (sPLA2--LDLR-/-; n = 19) or wild-type C57BL/6 littermates (C57 BL/6--LDLR-/-; n = 19) and maintained for 8 weeks on chow and then for 9 weeks on a Western-type diet. Plasma sPLA2 activity and plasma lipoprotein profiles were not significantly different between sPLA2--LDLR-/- and C57BL/6--LDLR-/- mice. Aortic root atherosclerosis was increased by 57% in sPLA2--LDLR-/- mice compared with C57BL/6--LDLR-/- controls (P0.05). Foam cell formation in vitro and in vivo was increased significantly. Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF2alpha-VI and aortic levels of 12/15-LO reaction products were each significantly higher (P0.001) in sPLA2--LDLR-/- compared with C57BL/6--LDLR-/- mice, indicating significantly increased in vivo oxidative stress in sPLA2--LDLR-/-. These data demonstrate that macrophage-specific overexpression of human sPLA2 increases atherogenesis by directly modulating foam cell formation and in vivo oxidative stress without any effect on systemic sPLA2 activity and lipoprotein metabolism.

Published
2005
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7. Colorectal adenoma risk is modified by the interplay between polymorphisms in arachidonic acid pathway genes and fish consumption

Author

Christine L.E. Siezen, Astrid I.M. van Leeuwen, Nicolien R. Kram, Manon E.M. Luken, Henk J. van Kranen, and Ellen Kampman

Subjects
Cancer Research, Candidate gene, Nutrition and Disease, Aetiology, screening and detection [ONCOL 5], dietary n-3, Voeding en Ziekte, Genotype, Determinants in Health and Disease [EBP 1], ppar-gamma, Netherlands, Arachidonic Acid, Fishes, General Medicine, Middle Aged, cyclooxygenase-2, Colorectal Neoplasms, Adenoma, Adult, medicine.medical_specialty, Adolescent, Single-nucleotide polymorphism, Colorectal adenoma, Biology, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], Translational research [ONCOL 3], Interventional oncology [UMCN 1.5], Internal medicine, expression, medicine, SNP, Animals, Humans, cancer, Genetic Predisposition to Disease, Aged, VLAG, locus, Hereditary cancer and cancer-related syndromes [ONCOL 1], Haplotype, Case-control study, Membrane Proteins, medicine.disease, neoplasia susceptibility variants, Diet, PPAR gamma, activated-receptor-delta, Endocrinology, Haplotypes, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Case-Control Studies, secretory phospholipase a(2), polyunsaturated fatty-acids
Abstract

Item does not contain fulltext Associations between polymorphisms in genes (SNPs) involved in the arachidonic acid (AA) pathway and colorectal adenomas have been investigated in a Dutch case control study including 384 cases and 403 polyp-free controls. Twenty-one polymorphisms in seven candidate genes were studied and a potential modifying effect of fish consumption was considered. A protective effect on colorectal adenomas was found for the CT genotype of SNP H477H in PPARgamma and the GC genotype of SNP V102V in COX-2 (OR 0.63, 95% CI 0.45-0.89 and OR 0.65, 95% CI 0.46-0.92, respectively) compared with the homozygous major genotypes. An increase in adenoma risk was observed for the TC genotype of SNP c.2242T-->C in COX-2 (OR 1.47, 95% CI 1.07-2.00) compared with the TT genotype. Analysis with estimated haplotypes confirmed these associations and revealed three additional associations with COX-2, sPLA(2) and 15LOX haplotypes. Fish consumption modified the associations with COX-2 and PPARdelta genotypes. For SNP c.-789C-->T in PPARdelta the major genotype showed a decrease in adenoma risk for those in the highest tertile of fish consumption (T3), as compared with the lowest tertile (T1) (OR 0.65, 95% CI 0.41-1.02). Protective effects were also observed for SNPs V102V and c.2242T-->C in COX-2 and high fish intake. The interaction between fish consumption and c.2242T-->C was statistically significant, with an OR for the TT genotype and high fish consumption of 0.52 (95% CI 0.27-1.01) as compared with low fish intake. These results indicate that SNPs in genes involved in the AA pathway are associated with colorectal adenoma risk. Some of these associations are modified by fish consumption.

Published
2005
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8. Reduced complement activation during cardiopulmonary bypass does not affect the postoperative acute phase response

Author

van den Goor, J., Nieuwland, R., van den Brink, A., van Oeveren, W., Rutten, 27818, Tijssen, J., Eijsman, L., Rutten, P, Faculteit Medische Wetenschappen/UMCG, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Laboratory for Experimental Clinical Chemistry, and Cardiology

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, Surface Properties, SURGERY, coronary artery bypass grafting, HEPARIN-COATED CIRCUITS, Phospholipases A, BIOCOMPATIBILITY, law.invention, EXTRACORPOREAL CIRCUIT, Intraoperative Period, SECRETORY PHOSPHOLIPASE A(2), Coated Materials, Biocompatible, law, acute phase response, Cardiopulmonary bypass, Medicine, Humans, Derivation, Postoperative Period, Prospective Studies, Coronary Artery Bypass, Acute-Phase Reaction, Pancreatic elastase, Complement Activation, Aged, biology, Pancreatic Elastase, business.industry, Elastase, C-reactive protein, INFLAMMATORY RESPONSE, Acute-phase protein, General Medicine, Perioperative, Middle Aged, C-REACTIVE PROTEIN, Phospholipases A2, surgical procedures, operative, Trillium, Anesthesia, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, cardiopulmonary bypass, Perfusion
Abstract

Objective: In the present study the relationship was evaluated between perioperative inflammation and the postoperative acute phase response in patients undergoing elective coronary artery bypass grafting (CABG) assisted by cardiopulmonary bypass (CPB). CPB circuits contained either non-coated- (UMS), Carmeda(R)- (BPS) or Trillium(R)-coated oxygenators (BAS). Methods: Prospectively, 71 CABG patients were randomly allocated to one of the oxygenator groups (UMS: n = 25, BPS: n = 25 and BAS: n = 2 1). Terminal complement complexes (TCC) and elastase were determined in plasma samples collected before, during and after bypass. Secretory phospholipase A(2) (sPLA(2)) and C-reactive protein (CRP) were determined before and after bypass. Results: Demographic, CPB and clinical outcome data were similar for the three groups. TCC and elastase increased during CPB, and decreased thereafter. Significant differences between the groups were present in the levels of TCC at the end of CPB (P = 0.002) and at the first (P = 0.012) and second (P

Published
2004

9. Low-penetrance genes and their involvement in colorectal cancer susceptibility

Subjects
GLUTATHIONE-S-TRANSFERASE, FRAGMENT LENGTH POLYMORPHISM, SECRETORY PHOSPHOLIPASE A(2), FAMILIAL ADENOMATOUS POLYPOSIS, ALPHA PROMOTER POLYMORPHISM, METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM, HETEROCYCLIC AMINE CARCINOGENS, ARYLAMINE-N-ACETYLTRANSFERASE, NONPOLYPOSIS COLON-CANCER, TUMOR-NECROSIS-FACTOR
Abstract

This report focuses on low-penetrance genes that are associated with colorectal adenoma and/or cancer or that are in strong linkage disequilibrium with colorectal adenoma and/or cancer causing variants. A pooled analysis was performed for 30 polymorphisms in 20 different genes that have been reported in more than one colorectal adenoma or cancer study. An association with colorectal cancer was found for seven polymorphisms in seven genes reported in more than one study; no associations were found with colorectal adenoma. Four of the polymorphisms exhibited an increased colorectal cancer risk [GSTT1, NAT2 (phenotype), HRAS1, and ALDH2]. Two others [MTHFR, Tp53 (intron 3)] exhibited a decreased risk. For the tumor necrosis factor (TNF)a polymorphism of the TNF-alpha gene, one allele was associated with an increased risk (a2 allele) and two other TNFa alleles with decreased risks (a5 and a13 allele). No association with colorectal adenoma and/or cancer was detected for 23 other polymorphisms in 15 genes. However, of all 30 polymorphisms, only three pooled analyses had sufficiently large samples to confirm (MTHFR) or to exclude (GSTM1 and NAT2 genotype) the association with a P

Published
2002

10. ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma

Author

Thomas Gautier, Daniel J. Rader, Jan Freark de Boer, Wijtske Annema, Arne Dikkers, Patrick C.N. Rensen, Uwe J. F. Tietge, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)

Subjects
Apolipoprotein E, CD36 Antigens, RECEPTOR-DEFICIENT MICE, Apolipoprotein E3, ATP-binding cassette transporter A1, Biochemistry, chemistry.chemical_compound, Endocrinology, High-density lipoprotein, Biliary Tract, Research Articles, apolipoprotein E, biology, REDUCES ATHEROSCLEROSIS, Reverse cholesterol transport, MACROPHAGE-SPECIFIC EXPRESSION, Cholesterol, high density lipoprotein, lipids (amino acids, peptides, and proteins), medicine.drug, ATP Binding Cassette Transporter 1, medicine.medical_specialty, mice, cholesteryl ester transfer protein, LDL-RECEPTOR, Probucol, bile, probucol, QD415-436, macrophage, liver, GENE-TRANSFER, SECRETORY PHOSPHOLIPASE A(2), Internal medicine, Cholesterylester transfer protein, medicine, Animals, Humans, Particle Size, APOLIPOPROTEIN-E DEFICIENCY, Macrophages, Cholesterol, HDL, Biological Transport, Cell Biology, Sterol, reverse cholesterol transport, Mice, Inbred C57BL, ENDOTHELIAL LIPASE, chemistry, feces, B TYPE-I, ABCA1, biology.protein, Hepatocytes, ATP-Binding Cassette Transporters, atherosclerosis, HIGH-DENSITY-LIPOPROTEIN, metabolism
Abstract

ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirus-mediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased (P

Published
2012

11. Low-penetrance genes and their involvement in colorectal cancer susceptibility

Author

de Jong, MM, Nolte, IM, te Meerman, Gerard J., van der Graaf, WTA, de Vries, EGE, Sijmons, RH, Hofstra, RMW, Kleibeuker, JH, Life Course Epidemiology (LCE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
GLUTATHIONE-S-TRANSFERASE, FRAGMENT LENGTH POLYMORPHISM, SECRETORY PHOSPHOLIPASE A(2), FAMILIAL ADENOMATOUS POLYPOSIS, ALPHA PROMOTER POLYMORPHISM, METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM, HETEROCYCLIC AMINE CARCINOGENS, ARYLAMINE-N-ACETYLTRANSFERASE, NONPOLYPOSIS COLON-CANCER, TUMOR-NECROSIS-FACTOR
Abstract

This report focuses on low-penetrance genes that are associated with colorectal adenoma and/or cancer or that are in strong linkage disequilibrium with colorectal adenoma and/or cancer causing variants. A pooled analysis was performed for 30 polymorphisms in 20 different genes that have been reported in more than one colorectal adenoma or cancer study. An association with colorectal cancer was found for seven polymorphisms in seven genes reported in more than one study; no associations were found with colorectal adenoma. Four of the polymorphisms exhibited an increased colorectal cancer risk [GSTT1, NAT2 (phenotype), HRAS1, and ALDH2]. Two others [MTHFR, Tp53 (intron 3)] exhibited a decreased risk. For the tumor necrosis factor (TNF)a polymorphism of the TNF-alpha gene, one allele was associated with an increased risk (a2 allele) and two other TNFa alleles with decreased risks (a5 and a13 allele). No association with colorectal adenoma and/or cancer was detected for 23 other polymorphisms in 15 genes. However, of all 30 polymorphisms, only three pooled analyses had sufficiently large samples to confirm (MTHFR) or to exclude (GSTM1 and NAT2 genotype) the association with a P

Published
2002

12. Secretory expression of a phospholipase A2 from Lactobacillus casei DSM20011 in Kluyveromyces lactis.

Author

Wang H, Zhang L, and Shi G

Subjects
Culture Media metabolism, Electrophoresis, Polyacrylamide Gel, Galactose metabolism, Gene Dosage, Gene Expression, Hydrogen-Ion Concentration, Kluyveromyces genetics, Lacticaseibacillus casei genetics, Mating Factor, Molecular Weight, Peptides genetics, Peptides metabolism, Phospholipases A2 chemistry, Phospholipases A2 genetics, Promoter Regions, Genetic, Real-Time Polymerase Chain Reaction, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Temperature, Kluyveromyces metabolism, Lacticaseibacillus casei enzymology, Phospholipases A2 biosynthesis, Phospholipases A2 metabolism
Abstract

The pla2 gene encoding a phospholipase A2 (EC 3.1.1.4) of Lactobacillus casei DSM20011 was cloned and expressed in the yeast Kluyveromyces lactis GG799 successfully for the first time. The structural pla2 gene fused in frame with the K. lactis secretion signal α-mating factor was integrated into the LAC4 locus and expressed under the control of the LAC4 promoter. sPLA2 activity was detected in the culture supernatant during shake flask culture of K. lactis/pKLAC1-pla2. In comparison with the control strain K. lactis/pKLAC1, SDS-PAGE analysis revealed a 17-kDa recombinant protein band in K. lactis/pKLAC1-pla2, which was consistent with the predicted molecular weight of the mature protein. Real-time quantitative PCR analysis indicated that the copy number of the integrated pla2 gene ranged from 2 to 6 and positively correlated with sPLA2 activity. When the inducer galactose was used as the carbon source, the sPLA2 activity in the culture supernatant of the recombinant that harbored six pla2 gene copies reached 1.96 ± 0.15 U/mL. The influence of the culture composition and conditions on the recombinant sPLA2 activity in shake flask culture were also studied. When the recombinant was cultured at 30°C in a YPD medium culture volume of 70 mL in a 250-mL shake flask with an initial pH of 7.0, the sPLA2 activity reached 2.16 ± 0.18 U/mL., (Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Published
2015
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13. C-type lectin-like domain and fibronectin-like type II domain of phospholipase A(2) receptor 1 modulate binding and migratory responses to collagen.

Author

Takahashi S, Watanabe K, Watanabe Y, Fujioka D, Nakamura T, Nakamura K, Obata JE, and Kugiyama K

Subjects
Animals, Binding Sites, Fibronectins metabolism, HEK293 Cells, Humans, Lectins, C-Type metabolism, Mice, Mutation, Protein Structure, Tertiary, Receptors, Phospholipase A2 chemistry, Collagen metabolism, Receptors, Phospholipase A2 genetics, Receptors, Phospholipase A2 metabolism
Abstract

Phospholipase A2 receptor 1 (PLA2R) mediates collagen-dependent migration. The mechanisms by which PLA2R interacts with collagen remain unclear. We produced HEK293 cells expressing full-length wild-type PLA2R or a truncated PLA2R that lacks fibronectin-like type II (FNII) domains or several regions of C-type lectin-like domain (CTLD). We show that the CTLD1-2 as well as the FNII domain of PLA2R are responsible for binding to collagen and for collagen-dependent migration. Thus, multiple regions and domains of the extracellular portion of PLA2R participate in the responses to collagen. These data suggest a potentially new mechanism for PLA2R-mediated biological response beyond that of a receptor for secretory PLA2., (Copyright © 2015. Published by Elsevier B.V.)

Published
2015
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