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1.
Nutrients ; 13(8)2021 Jul 21.
Article in English | MEDLINE | ID: mdl-34444642

ABSTRACT

Fatty acids play a significant role in maintaining cellular and DNA protection and we previously found an inverse relationship between blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DNA damage. The aim of this study was to explore differences in proteomic profiles, for 117 pro-inflammatory proteins, in two previously defined groups of individuals with different DNA damage and EPA and DHA levels. Healthy children and adolescents (n = 140) aged 9 to 13 years old in an urban area of Brazil were divided by k-means cluster test into two clusters of DNA damage (tail intensity) using the comet assay (cluster 1 = 5.9% ± 1.2 and cluster 2 = 13.8% ± 3.1) in our previous study. The cluster with higher DNA damage and lower levels of DHA (6.2 ± 1.6 mg/dL; 5.4 ± 1.3 mg/dL, p = 0.003) and EPA (0.6 ± 0.2 mg/dL; 0.5 ± 0.1 mg/dL, p < 0.001) presented increased expression of the proteins CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB, which are involved in pro-inflammatory pathways. Our findings support the hypothesis that low levels of n-3 long-chain PUFA may have a less protective role against DNA damage through expression of pro-inflammatory proteins, such as CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB.


Subject(s)
DNA Damage , Docosahexaenoic Acids/blood , Eicosapentaenoic Acid/blood , Fatty Acids, Omega-3/blood , Adolescent , Brazil , Child , Class I Phosphatidylinositol 3-Kinases/blood , Class Ia Phosphatidylinositol 3-Kinase/blood , Cross-Sectional Studies , Cyclin C/blood , Cyclin-Dependent Kinase 8/blood , Female , Humans , Hydrolases/blood , Inflammation/metabolism , Male , Protein Kinase C beta/blood , Proteomics
2.
Mol Neurobiol ; 53(9): 5902-5911, 2016 11.
Article in English | MEDLINE | ID: mdl-26510741

ABSTRACT

Alzheimer's disease (AD) is the most common of the neurodegenerative diseases. Recent diagnostic criteria have defined a preclinical disease phase during which neuropathological substrates are thought to be present in the brain. There is an urgent need to find measurable alterations in this phase as well as a good peripheral biomarker in the blood. We selected a cohort of 100 subjects (controls = 47; preclinical AD = 11; patients with AD = 42) and analyzed whole blood expression of 20 genes by quantitative polymerase chain reaction. The selected genes belonged to calcium signaling, senescence and autophagy, and mitochondria/oxidative stress pathways. Additionally, two genes associated with an increased risk of developing AD (clusterin (CLU) and bridging integrator 1 (BIN1)) were also analyzed. We detected significantly different gene expressions of BECN1 and PRKCB between the control and the AD groups and of CDKN2A between the control and the preclinical AD groups. Notably, these three genes are also considered tumor suppressor (CDKN2A and BECN1) or tumor promoter (PRKCB) genes. Gene-gene expression Pearson correlations were computed separately for controls and patients with AD. The significant correlations (p < 0.001) were represented in a network analysis with Cytoscape tool, which suggested an uncoupling of mitochondria-related genes in AD group. Whole blood is emerging as a valuable tissue in the study of the physiopathology of AD.


Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/genetics , Beclin-1/genetics , Cyclin-Dependent Kinase Inhibitor p18/genetics , Gene Expression Regulation , Genes, Neoplasm , Protein Kinase C beta/genetics , Aged , Beclin-1/blood , Beclin-1/metabolism , Cyclin-Dependent Kinase Inhibitor p16 , Cyclin-Dependent Kinase Inhibitor p18/blood , Cyclin-Dependent Kinase Inhibitor p18/metabolism , Female , Gene Expression Profiling , Gene Regulatory Networks , Humans , Male , Middle Aged , Protein Kinase C beta/blood , Protein Kinase C beta/metabolism
3.
Blood Purif ; 40(3): 260-9, 2015.
Article in English | MEDLINE | ID: mdl-26439941

ABSTRACT

BACKGROUND/AIMS: To evaluate the relationship between plasma hydrogen sulfide (H2S) and cardiovascular risk markers, including pulse pressure (PP), left ventricular mass index (LVMI) and intima-media thickness (IMT), and mortality in chronic hemodialysis (CHD) patients and further investigate the underlying cardiovascular protection mechanism of H2S. METHODS: CHD patients, 113 of them, were studied. Plasma H2S was measured through zinc acetate reaction. cPKCßII membrane translocation and phosphorylation of Akt were detected by western blot. RESULTS: Lower plasma H2S level in CHD patients was predictor of an increased PP, LVMI and IMT. Patients with lower H2S had a lower survival at the end of the study. H2S was an independent predictor of all-cause and cardiovascular mortality when adjusted for other risk factors. CHD patients with lower H2S showed an increase of cPKCßII activation, but phosphorylation of Akt decreased. The level of VCAM-1 and ICAM-1 increased significantly. CONCLUSIONS: Lower plasma H2S in CHD patients is associated with cardiovascular risk factors and mortality, which may be mediated by the cPKCßII/Akt pathway and further VCAM-1/ICAM-1 upregulation.


Subject(s)
Atherosclerosis/blood , Hydrogen Sulfide/blood , Kidney Failure, Chronic/blood , Protein Kinase C beta/blood , Proto-Oncogene Proteins c-akt/blood , Uremia/blood , Adult , Atherosclerosis/complications , Atherosclerosis/mortality , Atherosclerosis/therapy , Biomarkers/blood , Blood Pressure , Carotid Arteries/metabolism , Carotid Arteries/pathology , Carotid Intima-Media Thickness , Female , Gene Expression Regulation , Heart Ventricles/metabolism , Heart Ventricles/pathology , Humans , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/genetics , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/therapy , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Male , Middle Aged , Phosphorylation , Prognosis , Protein Kinase C beta/genetics , Proto-Oncogene Proteins c-akt/genetics , Renal Dialysis , Signal Transduction , Survival Analysis , Uremia/complications , Uremia/mortality , Uremia/therapy , Vascular Cell Adhesion Molecule-1/blood , Vascular Cell Adhesion Molecule-1/genetics
4.
J Thromb Haemost ; 13(8): 1514-20, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25990653

ABSTRACT

BACKGROUND: Enzastaurin is a protein kinase C (PKC)ß inhibitor with antiproliferative and proapoptotic effects that was in clinical development for the treatment of a variety of cancers. However, the primary endpoints in several clinical trials of enzastaurin were not met, and thrombosis was reported as an adverse effect in some trials. While investigating the role of PKC in regulating growth factor release from platelets, we found that, unlike other PKC inhibitors, enzastaurin may potentiate platelet aggregation. OBJECTIVE: To investigate the effects of enzastaurin on platelet aggregation, growth factor secretion from α-granules and cancer cell apoptosis in the presence of platelets. METHODS: Prostacyclin-washed platelets and platelet-rich plasma were isolated from the blood of healthy human volunteers. Platelet light-aggregometry was performed in the presence and absence of enzastaurin and acetylsalicylic acid (ASA). P-selectin was measured by flow cytometry, and vascular endothelial growth factor (VEGF) release was measured by ELISA. A549 lung carcinoma cells were treated with releasates from enzastaurin-titrated platelets. A cell death ELISA was performed to measure A549 apoptosis. RESULTS AND CONCLUSIONS: Enzastaurin (10(-8) -10(-6)  m) potentiated aggregation of prostacyclin-washed platelets and caused an increase in VEGF release from α-granules that, in turn, promoted cancer cell survival. In platelet-rich plasma, 10(-6)  m enzastaurin inhibited platelet aggregation, but not 10(-7)  m enzastaurin, which also failed to suppress VEGF secretion. ASA abrogated enzastaurin-potentiated washed-platelet aggregation and VEGF release. These findings indicate that, at high plasma protein-free drug concentrations, enzastaurin potentiates platelet aggregation and growth factor secretion, an effect that may counteract its anticancer activity. ASA nullifies this effect.


Subject(s)
Antineoplastic Agents/toxicity , Blood Platelets/drug effects , Indoles/toxicity , Platelet Aggregation/drug effects , Protein Kinase Inhibitors/toxicity , Vascular Endothelial Growth Factor A/metabolism , Apoptosis/drug effects , Blood Platelets/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Protein Kinase C beta/antagonists & inhibitors , Protein Kinase C beta/blood , Secretory Vesicles/drug effects , Secretory Vesicles/metabolism , Time Factors
5.
Nat Commun ; 5: 5719, 2014 Dec 12.
Article in English | MEDLINE | ID: mdl-25502755

ABSTRACT

DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.


Subject(s)
Caspases/genetics , DNA Methylation , Diabetes Mellitus, Type 2/genetics , Epigenesis, Genetic , Genetic Loci , Genome, Human , Neoplasm Proteins/genetics , Biomarkers/blood , Case-Control Studies , Caspases/blood , CpG Islands , Diabetes Mellitus, Type 2/blood , Epigenomics , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Insulin/blood , Insulin/genetics , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , Neoplasm Proteins/blood , Nerve Tissue Proteins/blood , Nerve Tissue Proteins/genetics , Promoter Regions, Genetic , Protein Kinase C beta/blood , Protein Kinase C beta/genetics , Receptors, G-Protein-Coupled/blood , Receptors, G-Protein-Coupled/genetics , Taurocholic Acid/blood , Twins, Monozygotic
6.
Mediators Inflamm ; 2013: 510212, 2013.
Article in English | MEDLINE | ID: mdl-23737649

ABSTRACT

Hyperglycemia-induced oxidative stress has been concerned in the development of diabetic nephropathy (DN), which may cause kidney damage associated with inflammation and fibrosis. This study has been conducted to investigate the role of genistein supplementation in an acute DN state. Mice with FBG levels more than 250 mg/dL after alloxan injection (single i.p., 150 mg/kg) were considered as diabetic. Diabetic mice (DM) were further subdivided according to their FBG levels, medium-high FBG (DMMH < 450 mg/dL) and high FBG (DMH; 450 mg/dL) and were administrated by an AIG-93G diet supplemented with different doses of genistein (0, 0.025 or 0.1%). After 2 weeks' treatment, the levels of kidney malondialdehyde (MDA), blood urea nitrogen (BUN), and plasma creatinine and lipid profiles, as well as oxidative stress and inflammation-related markers, were measured (P < 0.05). Genistein supplementation improved levels of FBG in the DMMH groups, but not in the DMH group, regardless of the treatment dose. Moreover, the supplementation attenuated kidney oxidative stress indicated by MDA, BUN, and plasma creatinine. In addition, genistein treatment decreased inflammatory markers such as nuclear factor kappa B (p65), phosphorylated inhibitory kappa B alpha, C-reactive protein, monocyte chemotactic protein-1, cyclooxygenase-2, and tumor necrosis factor-alpha and improved oxidative stress markers (nuclear-related factor E2, heme oxygenase-1, glutathione peroxidase, and superoxide dismutase isoforms) in treatment groups, regardless of the genistein treatment dose. Furthermore, genistein supplementation inhibited the fibrosis-related markers (protein kinase C, protein kinase C-beta II, and transforming growth factor-beta I) in the DN state. However, 0.1% genistein supplementation in diabetes with high FBG levels selectively showed a preventive effect on kidney damage. These results suggest that genistein might be a good protective substance for DN through regulation of oxidative stress and inflammation. In particular, genistein is more efficient in diabetes patients with medium-high blood glucose levels. Finally, it is required to establish the beneficial dosage of genistein according to blood glucose levels.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/drug therapy , Genistein/therapeutic use , Animals , Antioxidants/metabolism , Blood Urea Nitrogen , C-Reactive Protein/metabolism , Chemokine CCL2/blood , Creatinine/blood , Diabetes Mellitus, Experimental/blood , Female , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Lipid Peroxidation , Malondialdehyde/blood , Mice , Mice, Inbred ICR , Oxidative Stress/drug effects , Protein Kinase C/blood , Protein Kinase C beta/blood , Transcription Factor RelA/blood , Tumor Necrosis Factor-alpha/blood
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