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1.
Eur J Pharm Biopharm ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521716

RESUMO

Novel treatment methods for obesity are urgently needed due to the increasing global severity of the problem. Gastrointestinal hormones, such as GLP-1 and PYY, are secreted by the enteroendocrine cells, playing a critical role in regulating food intake. Digested nutrients trigger the secretion of these hormones, which have a very short half-life. α-Linolenic acid (αLA) has been shown to stimulate GLP-1 secretion, however, chemical instability and fast uptake in the small intestine hinder its use in body weight management. We developed a novel delivery system based on inorganic mesoporous particles for αLA to increase secretion of gastrointestinal peptides. αLA was loaded to thermally hydrocarbonized porous silicon particles (THCPSi). 47.9 ± 3.84% and 30.7 ± 2.86% of αLA was released during 6 h from 3.0% and 9.2% loading degree (w/w) samples in vitro, respectively. Native αLA (50 µM) significantly increased GLP-1 secretion from enteroendocrine STC-1 and GLUTag cell lines. αLA loaded THCPSi significantly and dose dependently stimulated GLP-1 secretion from STC-1 cells, whereas empty particles did not. We demonstrated in vitro that THCPSi particles have the potential to be used as a controlled delivery system for nutrients such as αLA, increasing GLP-1 secretion. Our results justify further in vivo investigations.

2.
Sci Rep ; 9(1): 11209, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371751

RESUMO

The dietary lignan metabolite, enterolactone, has been suggested to have anti-cancer functions, and high serum enterolactone concentrations have been associated with decreased risk of breast and prostate cancers. We hypothesized that serum enterolactone concentrations as a marker of plant-based foods are associated with decreased risk in colorectal cancer (CRC). We measured serum enterolactone glucuronide and sulfate concentrations by liquid chromatography-tandem mass spectrometry in 115 CRC patients and 76 sex- and age-matched controls and analyzed the results with respect to tumor parameters, clinical parameters, and systemic inflammatory markers. Patients with colon cancer had significant lower serum enterolactone glucuronide and sulfate concentrations than controls (glucuronide: median 3.14 nM vs. 6.32 nM, P < 0.001; sulfate: median 0.13 nM vs. 0.17 nM, P = 0.002), whereas rectal cancer patients had similar enterolactone levels as controls (glucuronide: median 5.39 nM vs. 6.32 nM, P = 0.357; sulfate: median 0.19 nM vs. 0.17 nM, P = 0.452). High serum enterolactone concentrations were associated with low tumor grade, high serum creatinine levels, and concomitant diabetes. In summary, our results suggest that serum enterolactone concentrations are decreased in colon but not in rectal cancer. Further investigations are required to assess whether this reflects an altered lignan metabolism by the colon microbiome.

3.
Clin Epigenetics ; 11(1): 97, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262328

RESUMO

BACKGROUND: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. METHODS: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring. RESULTS: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10-7) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes. CONCLUSIONS: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

5.
J Med Genet ; 56(9): 607-616, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31217265

RESUMO

BACKGROUND: Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood. OBJECTIVE: To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns. METHODS: Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels. RESULTS: We identified seven novel and six previously reported genetic associations (p<3.1×10-9). Three loci were associated with soluble vascular cell adhesion molecule-1 (sVCAM-1) level, one of which was the ABO locus that has been previously associated with soluble E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) levels. Our findings suggest that the blood type B associates primarily with sVCAM-1 level, while the A1 subtype shows a robust effect on sE-selectin and sICAM-1 levels. The genotypes in the ABO locus associating with higher soluble adhesion molecule levels tend to associate with lower circulating cholesterol levels and lower cardiovascular disease risk. CONCLUSION: The present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels in the ABO locus and that elevated soluble adhesion molecule levels per se may not increase risk for cardiovascular disease.

6.
Nutrients ; 11(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151163

RESUMO

INTRODUCTION: Vitamin D deficiency has been linked to the increased risk of several chronic diseases, especially in people living in the Northern Latitudes. The aim of this study was to assess the vitamin D status in older subjects born in 1945 in Northern Finland (latitude 65°North), and to examine its associations to components of metabolic syndrome (MetS). METHODS: In this cross-sectional study, we invited 904 subjects born in 1945 from the Oulu region (Oulu45 cohort), out of an original cohort of 1332 subjects. In the cohort, plasma 25 hydroxyvitamin D (25OHD) levels were determined by an enzyme immunoassay of 263 men and 373 women, with a mean age baseline of 69±0.5 years old. We assessed the participants' usage of vitamin D supplements, as well as their lifestyle factors, using a questionnaire. RESULTS: Nearly 80% of the subjects had low vitamin D levels [either vitamin D deficient (<50 nmol/L) or insufficient (50 - 75 nmol/L)], and only 20% of the participants had sufficient vitamin D levels (>75 nmol/L) (based on the American Endocrine Society guidelines). The low vitamin D status was associated with a high prevalence of MetS; a significantly higher number of subjects with MetS (41%) had low vitamin D levels in comparison to the non-MetS subjects (38%) (p ≤ 0.05). The subjects under vitamin D supplementation had a significantly lower incidence of MetS (42.6% vs 57.4%) and its components in comparison to the non-supplemented subjects (p ≤ 0.05). CONCLUSIONS: Low vitamin D levels are a risk factor for MetS amongst other lifestyle factors, such as dietary habits and physical inactivity, among older subjects in the Northern Latitudes (65°North). Optimal supplementation of vitamin D, along with rich dietary sources of vitamin D, are highly recommended for older subjects as a means to positively affect, e.g., hypertension, insulin resistance, and obesity, as components of the MetS.

7.
J Transl Med ; 17(1): 199, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196200

RESUMO

BACKGROUND: Platelets not only contribute to hemostasis but also to the regulation of inflammatory reactions and cancer pathogenesis. We hypothesized that blood platelet count would be associated with systemic inflammation, the densities of tumor infiltrating immune cells, and survival in colorectal cancer (CRC), and these relationships could be altered by aspirin use. METHODS: We measured blood platelet count in a cohort of 356 CRC patients and analyzed its relationships with tumor and patient characteristics including aspirin use, markers of systemic inflammation (modified Glasgow Prognostic Score, mGPS; serum levels of CRP, albumin, and 13 cytokines), blood hemoglobin levels, five types of tumor infiltrating immune cells (CD3, CD8, FoxP3, Neutrophil elastase, mast cell tryptase), and survival. RESULTS: Platelet count inversely correlated with blood hemoglobin levels (p < 0.001) and positively correlated with serum levels of CRP and multiple cytokines including IL-1RA, IL-4, IL-6, IL-7, IL-8, IL-12, IFNγ, and PDGF-BB (p < 0.001 for all), while aspirin use was not associated with the levels of systemic inflammatory markers. High platelet count was also associated with high mGPS (p < 0.001) but did not show statistically significant multivariable adjusted associations with the densities of tumor infiltrating immune cells. Higher platelet counts were observed in higher tumor stage (p < 0.001), but platelet count or aspirin use were not associated with patient survival. CONCLUSIONS: High platelet count is associated with systemic inflammation in CRC. This study could not demonstrate statistically significant associations between platelet count, aspirin use, and the densities of tumor infiltrating immune cells.

9.
Mol Nutr Food Res ; : e1801405, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964598

RESUMO

SCOPE: To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with metabolic syndrome. METHODS AND RESULTS: Subjects with metabolic syndrome undergo a 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average habitual Nordic diet served as control (SYSDIET study). Altogether, 68 participants are included. PBMCs are obtained before and after intervention and total RNA is subjected to global transcriptome analysis. 1302 probe sets are differentially expressed between the diet groups (p-value < 0.05). Twenty-five of these are significantly regulated (FDR q-value < 0.25) and are mainly involved in mitochondrial function, cell growth, and cell adhesion. The list of 1302 regulated probe sets is subjected to functional analyses. Pathways and processes involved in the mitochondrial electron transport chain, immune response, and cell cycle are downregulated in the healthy Nordic diet group. In addition, gene transcripts with common motifs for 42 transcription factors, including NFR1, NFR2, and NF-κB, are downregulated in the healthy Nordic diet group. CONCLUSION: These results suggest that benefits of a healthy diet may be mediated by improved mitochondrial function and reduced inflammation.

10.
Am J Hypertens ; 32(6): 538-546, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-30984970

RESUMO

BACKGROUND: Exaggerated sympathetic cardiovascular (CV) reactivity to stress associates with elevated risk for clinical and preclinical end points of CV disease. It would be useful to identify these individuals, preferably from feasible measurements commonly used in health care. Our study examined the association between home blood pressure (BP) variability and cardiac workload response to whole-body cold exposure. METHODS: Seventy-five men (55-65 years, 46 hypertensive) measured BP at home twice in the morning and evening for a week. We computed systolic home BP variability as SD of daily means and divided the subjects into groups demonstrating either high or low BP variability. They were exposed to whole-body cold exposure (-10 °C, wind 3 m/second, 15 minutes, winter clothes, standing). BP and heart rate were measured at 3-minute intervals during, and 15 minutes before and after the exposure. Rate-pressure product (RPP) was calculated to represent cardiac workload. RESULTS: Subjects with high systolic home BP variability demonstrated a greater RPP increase in cold conditions compared to those with low BP variability [mean change from baseline (95% CI): 1,850 (1,450 to 2,250) bpm × mm Hg vs. 930 (610, 1,250) bpm × mm Hg, P < 0.01]. This was related to the augmented systolic BP change [31(28, 35) mm Hg vs. 23(20, 26) mm Hg, P < 0.01]. Home BP variability correlated with cold-related RPP (rS = 0.34, P = 0.003) and systolic BP (rS = 0.38, P < 0.001) responses. CONCLUSIONS: Moderate whole-body cold exposure increased BP and cardiac workload more among those with higher systolic home BP variability, independently of home BP level. Elevated home BP variability may indicate augmented sympathetically mediated vascular reactivity for environmental stressors. PUBLIC TRIALS REGISTRY NUMBER: Trial Number NCT02007031.

11.
iScience ; 13: 284-304, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875610

RESUMO

The circadian clock and the hypoxia-signaling pathway are regulated by an integrated interplay of positive and negative feedback limbs that incorporate energy homeostasis and carcinogenesis. We show that the negative circadian regulator CRY1 is also a negative regulator of hypoxia-inducible factor (HIF). Mechanistically, CRY1 interacts with the basic-helix-loop-helix domain of HIF-1α via its tail region. Subsequently, CRY1 reduces HIF-1α half-life and binding of HIFs to target gene promoters. This appeared to be CRY1 specific because genetic disruption of CRY1, but not CRY2, affected the hypoxia response. Furthermore, CRY1 deficiency could induce cellular HIF levels, proliferation, and migration, which could be reversed by CRISPR/Cas9- or short hairpin RNA-mediated HIF knockout. Altogether, our study provides a mechanistic explanation for genetic association studies linking a disruption of the circadian clock with hypoxia-associated processes such as carcinogenesis.

12.
J Nutr ; 149(3): 422-431, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30759235

RESUMO

BACKGROUND: Postprandial lipemia is a risk factor for cardiovascular disease. Dairy products differ in nutrient content and food matrix, and little is known about how different dairy products affect postprandial triglyceride (TG) concentrations. OBJECTIVE: We investigated the effect of meals with similar amounts of fat from different dairy products on postprandial TG concentrations over 6 h in healthy adults. METHODS: A randomized controlled cross-over study was performed on 47 subjects (30% men), with median (25th-75th percentile) age of 32 (25-46) y and body mass index of 23.6 (21.0-25.8) kg/m2. Meals included 1 of butter, cheese, whipped cream, or sour cream, corresponding to 45 g of fat (approximately 60 energy%). Serum concentrations of TGs (primary outcome), and total cholesterol (TC), low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), insulin, glucose, non-esterified fatty acids, and plasma glucose-dependent insulinotropic polypeptide (secondary outcomes) were measured before the meal and 2, 4, and 6 h postprandially. Incremental AUC (iAUC) was calculated for the responses, and data were analyzed using a linear mixed model. RESULTS: Sour cream induced a 61% larger TG-iAUC0-6 h compared to whipped cream (P < 0.001), a 53% larger TG-iAUC0-6 h compared to butter (P < 0.001), and a 23% larger TG-iAUC0-6 h compared to cheese (P = 0.05). No differences in TG-iAUC0-6 h between the other meals were observed. Intake of sour cream induced a larger HDL cholesterol-iAUC0-6 h compared to cheese (P = 0.01). Intake of cheese induced a 124% larger insulin iAUC0-6 h compared to butter (P = 0.006). No other meal effects were observed. CONCLUSIONS: High-fat meals containing similar amount of fat from different dairy products induce different postprandial effects on serum TGs, HDL cholesterol, and insulin in healthy adults. The potential mechanisms and clinical impact of our findings remain to be further elucidated. The study was registered at www.clinicaltrials.gov as NCT02836106.

13.
Psychiatry Res ; 272: 326-333, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30597385

RESUMO

Associations between adverse childhood experiences (ACEs) and cholesterol in depressed patients are unclear. Therefore, we compared 78 adult outpatients with major depressive disorder (MDD) with (n = 24) or without (n = 54) experiences of physical violence in childhood. Background data were collected with questionnaires, and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured from fasting blood samples. Patients with a history of childhood physical violence had lower levels of TC than the control group. No differences were observed in HDL-C, LDL-C, or low-grade inflammation levels between the two groups. In multivariate models, decreased levels of TC were associated with childhood physical violence, and these associations remained significant after adjustments for age, gender, lifestyle, metabolic condition, socioeconomic situation, psychiatric status, suicidality, low-grade inflammation, the chronicity of depression, medications used and somatic diseases. At the 8-month follow-up, the results were essentially the same when the Trauma and Distress Scale (TADS) was used as the measure of ACEs. The specific mechanisms underlying cholesterol alterations associated with ACEs are a topic for future studies. Better understanding of these mechanisms might lead to possible new interventions in the prevention of adverse health effects resulting from ACEs.


Assuntos
Experiências Adversas da Infância/tendências , Colesterol/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/psicologia , Pacientes Ambulatoriais/psicologia , Abuso Físico/psicologia , Adulto , Biomarcadores/sangue , Criança , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Transtorno Depressivo Maior/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Br J Cancer ; 120(2): 238-246, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30563990

RESUMO

BACKGROUND: Cancer cachexia is a complex wasting syndrome affecting patients with advanced cancer, with systemic inflammation as a key component in pathogenesis. Protein degradation and release of amino acids (AAs) in skeletal muscle are stimulated in cachexia. Here, we define factors contributing to serum AA levels in colorectal cancer (CRC). METHODS: Serum levels of nine AAs were characterised in 336 CRC patients and their relationships with 20 markers of systemic inflammatory reaction, clinicopathological features of cancers and patient survival were analysed. RESULTS: Low serum glutamine and histidine levels and high phenylalanine levels associated with indicators of systemic inflammation, including high modified Glasgow Prognostic Score, high blood neutrophil/lymphocyte ratio and high serum levels of CRP, IL-6 and IL-8. Low levels of serum glutamine, histidine, alanine and high glycine levels also associated with advanced cancer stage and with poor cancer-specific survival in univariate analysis. CONCLUSIONS: In CRC, serum AA levels are associated with systemic inflammation and disease stage. These findings may reflect muscle catabolism induced by systemic inflammation in CRC.


Assuntos
Aminoácidos/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Citocinas/sangue , Inflamação/sangue , Idoso , Aminoácidos/classificação , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Inflamação/complicações , Inflamação/patologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutrófilos/patologia , Prognóstico
15.
Acta Anaesthesiol Scand ; 63(1): 69-73, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30079511

RESUMO

BACKGROUND: A high prevalence of delirium is observed in sepsis, yet specific markers for this brain dysfunction in sedated patients are still lacking. Cytoplasmic low molecular weight calcium-binding protein, S-100ß, is a commonly used nonspecific marker for brain injury. Here, we evaluated whether delirium is associated with increases in S-100ß levels. METHODS: This observational study included 22 patients with septic shock. Delirium was assessed by CAM-ICU and blood samples were obtained to measure inflammatory (CRP, PCT, IL-6, IL-17, TNF-α) and cerebral biomarkers (S-100ß, NSE, HAB42, SUBP). Patients were categorized according to the presence of delirium. RESULTS: Delirium was present in 10/22 of the patients (45.5%). Serum S-100ß levels were above the laboratory cutoff value of 0.15 µg/L in 13/22 (59.1%) of the patients. The odds ratio for risk of developing delirium in cases with an S-100ß >0.15 µg/L was 18.0 (95%CI, 1.7-196.3, P = 0.011). Patients with delirium had higher plasma levels of IL-6 compared to those without; 138.3 pg/mL [28.0-296.7] vs 53.6 pg/mL [109.3-505, P = 0.050]. There was a positive correlation between S100 ß and IL-6 levels (r = 0.489, P = 0.021). Delirium patients had higher SOFA scores; 10 [5-9] vs 7[8-10.5], P = 0.036. CONCLUSIONS: Delirium in septic shock was associated with an elevated protein S-100ß when using a laboratory cutoff value of 0.15 µg/L and with more severe organ dysfunction during the ICU stay.

16.
J Agric Food Chem ; 67(4): 1104-1114, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30592221

RESUMO

Insoluble residue (INS) is a lignin-rich fraction of brewer's spent grain (BSG) that also contains ß-glucan and arabinoxylan, the major constituents of dietary fiber. We investigated the effects of INS in diet-induced obese mice in terms of lipid metabolism and metabolic diseases. Male mice (C57bl6) were fed a high-fat diet (HFD), a HFD + 20% INS, a HFD + 20% cellulose (CEL), a HFD with a combination of 20% INS-CEL (1:1), or a control diet for 14 weeks. Insulin and glucose tolerance tests were performed after 12 weeks. Fasting plasma lipids, bile acid, and fecal bile acid were measured after 14 weeks of feeding, and tissues were collected for gene expression analysis. Body weight gain was significantly reduced with all fibers, but only INS and INS-CEL decreased fasting plasma low-density lipoprotein cholesterol and total cholesterol compared to HFD. CEL and INS-CEL significantly improved insulin resistance. Fecal bile acids were significantly increased by all fibers, but there was no change in plasma bile acid. Clostridium leptum was increased with all fibers, but universal bacterial diversity was only with INS and INS-CEL. In addition, INS significantly increased the abundance of Bacteriodes, while CEL decreased Atopobium and Lactobacillus. INS feeding significantly upregulated various genes of cholesterol and bile acid metabolism, such as Srebp2, Hmgcr, Ldlr, Cyp7a1, Pparα, Fxr, and Pxr, in the liver. INS, INS-CEL, and CEL significantly attenuated liver steatosis. Our results suggest that INS from BSG induced beneficial systemic changes in mice via gut microbiota, bile acids, and gene expression in the liver.


Assuntos
Anticolesterolemiantes/metabolismo , Grão Comestível/metabolismo , Hipercolesterolemia/metabolismo , Lignina/metabolismo , Resíduos/análise , Animais , Anticolesterolemiantes/isolamento & purificação , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Fibras na Dieta/análise , Fibras na Dieta/metabolismo , Microbioma Gastrointestinal , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/microbiologia , Hipercolesterolemia/fisiopatologia , Lignina/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Ganho de Peso
18.
Acta Physiol (Oxf) ; : e13221, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30468571

RESUMO

Each year we are reminded of our body clocks with the change in "daylight saving times". At those times we are forcefully reminded of our bodily clocks and need to plan our daily schedules more carefully. In contrast, we like to deny our clocks becoming a 24/7 type, since we are "homo sapiens" (Latin - "wise man") as Carl Linnaeus, also known after his ennoblement as Carl von Linné, described us in his biological classification. This article is protected by copyright. All rights reserved.

20.
Peptides ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30312641
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