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- Yang, L., et al.
(författare)
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Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell-fibronectinadhesion of colon cancer cells
- 2010
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Ingår i: Oncogene. - : Nature publishing group. - 0950-9232 .- 1476-5594. ; 29:4, s. 516-526
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Tidskriftsartikel (refereegranskat)abstract
- The role of peroxisome proliferator-activated receptor-/ (PPAR-/) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR- expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR- expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR- may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly PPAR- seems to have a more important role in poorly metastatic cells than in highly metastatic ones.
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| 2. |
- Adamsson, Viola, et al.
(författare)
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Effects of a healthy Nordic diet on cardiovascular risk factors in hypercholesterolaemic subjects : a randomized controlled trial (NORDIET)
- 2011
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Ingår i: Journal of Internal Medicine. - Oxford : Wiley. - 0954-6820 .- 1365-2796. ; 269:2, s. 150-159
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this study was to investigate the effects of a healthy Nordic diet (ND) on cardiovascular risk factors. Design and subjects. In a randomized controlled trial (NORDIET) conducted in Sweden, 88 mildly hypercholesterolaemic subjects were randomly assigned to an ad libitum ND or control diet (subjects' usual Western diet) for 6 weeks. Participants in the ND group were provided with all meals and foods. Primary outcome measurements were low-density lipoprotein (LDL) cholesterol, and secondary outcomes were blood pressure (BP) and insulin sensitivity (fasting insulin and homeostatic model assessment-insulin resistance). The ND was rich in high-fibre plant foods, fruits, berries, vegetables, whole grains, rapeseed oil, nuts, fish and low-fat milk products, but low in salt, added sugars and saturated fats. Results. The ND contained 27%, 52%, 19% and 2% of energy from fat, carbohydrate, protein and alcohol, respectively. In total, 86 of 88 subjects randomly assigned to diet completed the study. Compared with controls, there was a decrease in plasma cholesterol (-16%, P < 0.001), LDL cholesterol (-21%, P < 0.001), high-density lipoprotein (HDL) cholesterol (-5%, P < 0.01), LDL/HDL (-14%, P < 0.01) and apolipoprotein (apo)B/apoA1 (-1%, P < 0.05) in the ND group. The ND reduced insulin (-9%, P = 0.01) and systolic BP by -6.6 +/- 13.2 mmHg (-5%, P < 0.05) compared with the control diet. Despite the ad libitum nature of the ND, body weight decreased after 6 weeks in the ND compared with the control group (-4%, P < 0.001). After adjustment for weight change, the significant differences between groups remained for blood lipids, but not for insulin sensitivity or BP. There were no significant differences in diastolic BP or triglyceride or glucose concentrations. Conclusions. A healthy ND improves blood lipid profile and insulin sensitivity and lowers blood pressure at clinically relevant levels in hypercholesterolaemic subjects.
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| 6. |
- Steensland, P., et al.
(författare)
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The Monoamine Stabilizer (-)-OSU6162 Attenuates Voluntary Ethanol Intake and Ethanol-Induced Dopamine Output in Nucleus Accumbens
- 2012
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 72:10, s. 823-831
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Tidskriftsartikel (refereegranskat)abstract
- Background: New medications for alcohol use disorder (AUD) are needed. Long-term alcohol consumption leads to a dysregulated dopamine system. A novel approach to normalize these dysregulations might be treatment with "monoamine stabilizers," a novel class of compounds characterized by the ability to either suppress, stimulate, or not influence dopamine activity depending on the prevailing dopaminergic tone. Methods: The effects of the monoamine stabilizer (-)-OSU6162 (OSU6162) on voluntary ethanol intake and ethanol withdrawal symptoms were evaluated in rats voluntarily consuming ethanol for at least 3 months before testing. Furthermore, effects of OSU6162 on ethanol seeking behavior were evaluated with the progressive ratio and cue-induced reinstatement paradigms. Finally, the interaction of OSU6162 with ethanol on dopamine output and metabolism was studied with microdialysis. Results: The OSU6162 attenuated several ethanol-mediated behaviors, including voluntary ethanol consumption, ethanol withdrawal symptoms, operant ethanol self-administration under progressive ratio schedule, and cue-induced reinstatement of ethanol seeking in rats that had voluntarily consumed ethanol for at least 3 months before treatment. In addition, OSU6162 blunted ethanol-induced dopamine output in nucleus accumbens of ethanol-naive rats. Conclusions: These results highlight the ability of OSU6162 to stabilize dopamine activity depending on the prevailing dopaminergic tone and indicate that OSU6162 might decrease ethanol intake by attenuating the acute rewarding properties of ethanol. In addition, OSU6162 might have potential to prevent relapse triggered by alcohol craving, alcohol related cues, and or an urge to relieve abstinence symptoms. The present study is to our knowledge the first indicating that OSU6162 might serve as a novel medication for AUD.
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| 8. |
- Sällman Almén, Markus, et al.
(författare)
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Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children.
- 2013
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 37:3, s. 424-431
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Tidskriftsartikel (refereegranskat)abstract
- Background:The Fat mass and obesity-associated gene (FTO) was the first gene reliably associated with body mass index in genome-wide association studies on a population level. At present, the genetic variations within the FTO gene are still the common variants that have the largest influence on body mass index.Methods:In the current study, we amplified the entire FTO gene, in total 412 Kbp, in over 200 long-range PCR fragments from each individual, from 524 severely obese and 527 lean Swedish children, and sequenced the products as two DNA pools using massive parallel sequencing (SOLiD).Results:The sequencing achieved very high coverage (median 18 000 reads) and we detected and estimated allele frequencies for 705 single nucleotide polymorphisms (SNPs) (19 novel) and 40 indels (24 novel) using a sophisticated statistical approach to remove false-positive SNPs. We identified 19 obesity-associated SNPs within intron one of the FTO gene, and validated our findings with genotyping. Ten of the validated obesity-associated SNPs have a stronger obesity association (P<0.007) than the commonly studied rs9939609 SNP (P<0.012).Conclusions:This study provides a comprehensive obesity-associated variation map of FTO, identifies novel lead SNPs and evaluates putative causative variants. We conclude that intron one is the only region within the FTO gene associated with obesity, and finally, we establish next generation sequencing of pooled DNA as a powerful method to investigate genetic association with complex diseases and traits.
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| 9. |
- Zheleznyakova, Galina Y., et al.
(författare)
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Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:9, s. 988-993
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Tidskriftsartikel (refereegranskat)abstract
- Spinal muscular atrophy (SMA) is a monogenic disorder that is subdivided into four different types and caused by survival motor neuron gene 1 (SMN1) deletion. Discordant cases of SMA suggest that there exist additional severity modifying factors, apart from the SMN2 gene copy number. Here we performed the first genome-wide methylation profiling of SMA patients and healthy individuals to study the association of DNA methylation status with the severity of the SMA phenotype. We identified strong significant differences in methylation level between SMA patients and healthy controls in CpG sites close to the genes CHML, ARHGAP22, CYTSB, CDK2AP1 and SLC23A2. Interestingly, the CHML and ARHGAP22 genes are associated with the activity of Rab and Rho GTPases, which are important regulators of vesicle formation, actin dynamics, axonogenesis, processes that could be critical for SMA development. We suggest that epigenetic modifications may influence the severity of SMA and that these novel genetic positions could prove to be valuable biomarkers for the understanding of SMA pathogenesis.
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