| 1. |
- Blomgren, Bo, et al.
(författare)
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A novel method for quantification of the folding of elastic laminae in elastic arteries
- 2008
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Ingår i: Micron. - : Elsevier BV. - 0968-4328 .- 1878-4291. ; 39:5, s. 623-630
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Forskningsöversikt (refereegranskat)abstract
- A transgenic mouse overexpressing the human form of semicarbazide-sensitive amine oxidase (SSAO) is known to have an abnormal structure of the elastic laminae and the elastic fibres in the aorta. Compared to the non-transgenic littermates, the elastic laminae are less folded. In order to quantify the undulation of this structure, an image analysis program that identified the elastic laminae was developed. The program measures the area fraction in different sectors from a plane parallel to the aorta wall. Images were taken from unstained aorta specimens where the elastic laminae were visualised with phase contrast microscopy. A contextual operation of the images produced a local orientation estimation for every linear structure. The image was then thresholded in eight sectors from 0 degrees to 180 degrees, with different orientation angles. The results show that the area fraction of the elastic laminae was significantly lower for the transgenic mouse in all sectors measured except for two. At 0-25 degrees, no difference was seen. In the sector at 160-180 degrees, parallel to the aorta wall, the area fraction of elastic laminae was instead significantly higher in the transgenic mouse. A novel method is presented, developed for detection and quantification of pathological changes in the elastic laminae in the aorta wall. The method gave reliable results and is considered to be a useful tool for morphometric studies of aorta with this kind of altered morphology concerning the elastic laminae. When compared with tangent count, the control group had a significantly larger mean curvature.
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| 2. |
- Comasco, Erika, et al.
(författare)
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The clock gene PER2 and sleep problems : association with alcohol consumption among Swedish adolescents
- 2010
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 115:1, s. 41-48
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. Previous studies have separately examined the effects of mutations in the clock gene PER2 on alcohol consumption and sleep problems. Here we hypothesized that an allelic variation in the PER2 gene is associated with alcohol consumption in interaction with sleep problems among adolescents. METHODS: The Survey of Adolescent Life and Health in Västmanland 2006, a Swedish county, including 1254 students 17-18 years old, was used as a population-representative sample of adolescents. We investigated the PER2 Single Nucleotide polymorphism (SNP) 10870 (A/G) in the cohort together with an assessment of alcohol consumption according to the AUDIT-C questionnaire, and sleep problems using a survey consisting of 18 items. Furthermore, we carried out an exploratory analysis on the PER2 Single Nucleotide Polymorphism 10870 polymorphism in a group of severely alcoholic females. RESULTS: We found a significant association of the SNP 10870 in adolescent boys, where the genotype AA, in the presence of several and frequent sleep problems, was associated with increased alcohol consumption. Among adolescent girls, only sleep problems were related to alcohol consumption. A non-significant trend was observed among the severely alcoholic females, with the G allele being over-represented in the severely alcoholic females group in comparision to the control females. CONCLUSION: These results indicate that PER2 gene variation is associated with alcohol consumption in interaction with sleep problems among Swedish adolescent boys.
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| 3. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 4. |
- Göktürk, Camilla, et al.
(författare)
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Semicarbazide-sensitive amine oxidase in transgenic mice with diabetes
- 2004
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 325:3, s. 1013-1020
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Tidskriftsartikel (refereegranskat)abstract
- Semicarbazide-sensitive amine oxidase (SSAO) activity in plasma is increased in diabetes, and in particular, in diabetic patients with vascular complications. It has been speculated that SSAO is involved in the development of such complications due to the production of cytotoxic compounds. In this work, we have induced diabetes in a previously described mouse-model, overexpressing SSAO in smooth muscle cells. SSAO activity was estimated as well as expression of the endogenous mouse gene and human transgene using real-time PCR. Diabetes induced an increase in SSAO activity in serum, kidney, and adipose tissue of transgenic animals. An inverse correlation between SSAO activity and mouse SSAO mRNA levels was observed in transgenic animals with diabetes. These results further support the suggestion of a negative feedback control of the SSAO gene expression. The increased SSAO activity in diabetes is most likely dependent on post-transcriptional modifications or activation of existing inactive enzyme molecules.
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| 5. |
- Göktürk, Camilla, 1967-
(författare)
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Semicarbazide-sensitive Amine Oxidase (SSAO) – Regulation and Involvement in Blood Vessel Damage with Special Regard to Diabetes : A Study on Mice Overexpressing Human SSAO
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6) belongs to a family of copper-containing amine oxidases. SSAO exists as a membrane bound protein in endothelial-, smooth muscle-, and adipose cells as well as soluble in plasma. SSAO catalyses oxidative deamination of primary monoamines, which results in the production of corresponding aldehydes, hydrogen peroxide and ammonia. These compounds are very reactive and potentially cytotoxic, and are able to induce vascular damage if produced in high levels. Patients with diabetes mellitus, and with diabetic complications in particular, have a higher SSAO activity in plasma compared to healthy controls. It has therefore been speculated that high SSAO activity is involved in the development of vascular complications associated with diabetes. The aim of this thesis is to investigate the importance of SSAO in the development of disorders of a vascular origin. We have studied the transcriptional regulation of the SSAO gene, by inducing diabetes in NMRI and in transgenic mice, overexpressing the human form of SSAO in smooth muscle cells. We found that the increase in SSAO activity in diabetes is accompanied by reduced mRNA levels of the endogenous mouse gene, suggesting a negative feedback on the transcription of the SSAO gene. In addition, the transgenic mice exhibited an abnormal phenotype in the elastic tissue of aorta and renal artery. These mice have a lower mean artery pressure and an elevated pulse pressure. These results indicate that high SSAO activity in smooth muscle cells is associated with a change in the morphology of large arteries. This is likely contributing to the development of vascular complications in diabetes.
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| 8. |
- Nordquist, Niklas, et al.
(författare)
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The Transcription Factor TFAP2B Is Associated With Insulin Resistance and Adiposity in Healthy Adolescents
- 2009
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Ingår i: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 17:9, s. 1762-1767
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance and central adiposity are strong risk indicators for type 2 diabetes and coronary heart disease. An important role for adipose tissue in the etiology and progression of these conditions has recently become more evident. A transcription factor, TFAP2B, has been shown to participate in the regulation of adipocyte metabolism, by facilitating glucose uptake and lipid accumulation, while simultaneously reducing insulin sensitivity, and recently a direct function for TFAP2B as an inhibitor of adiponectin expression was observed. In this study, we have investigated how insulin resistance, plasma adiponectin, and central adiposity, in a normal population of adolescents, are affected by genetic variability in TFAP2B. Our results show that both insulin sensitivity, as measured from levels of fasting glucose and insulin, and central adiposity, estimated by subscapular skinfold thickness, were significantly associated to genetic variability in TFAP2B. This association was restricted to males only, where carriers of the 4-repeat allele of intron 2 had higher insulin sensitivity and lower subscapular skinfold thickness. Levels of adiponectin did not show any association to the TFAP2B polymorphism, but was negatively correlated to central adiposity in females. These results suggest that reduction of TFAP2B expression could have a protective effect against future risk of complications associated with decreased insulin sensitivity and central adiposity, such as type 2 diabetes and coronary heart disease.
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| 9. |
- Nordquist, Niklas, et al.
(författare)
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Transcription factor AP2 beta involved in severe female alcoholism
- 2009
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1305:Supplement 11, s. S20-S26
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Tidskriftsartikel (refereegranskat)abstract
- Susceptibility to alcoholism and antisocial behavior exhibits an evident link to monoaminergic neurotransmission. The serotonin system in particular, which is associated with regulation of mood and behavior, has an influence on personality characters that are firmly connected to risk of developing alcoholism and antisocial behavior, such as impulsiveness, and aggression. The transcription factor TFAP2b has repeatedly been shown to be involved in monoaminergic transmission, likely due to a regulatory effect on genes that are fundamental to this system, e.g. monoamine oxidase type A, and the serotonin transporter. Recent research has identified a functional polymorphism in the gene encoding TFAP2B that regulates its level of expression. In the present study we have compared a sample of female alcoholics (n = 107), sentenced to institutional care for their severe addiction, contrasted against a control sample of adolescent females (n = 875). The results showed that parental alcohol misuse was significantly more common among the alcoholic females, and also that parental alcohol misuse was associated with a reduction in age of alcohol debut. We also addressed the question of whether a functional TFAP2b polymorphism was associated with alcoholism. Results showed that the high-functioning allele was significantly more common among the female alcoholics, compared to the non-alcoholic controls. Furthermore, the results also indicated that psychosocial factors, in terms of parental alcohol misuse, depression or psychiatric disorder, had an influence on the association. It was observed that the genetic association was restricted to the subset of cases that had not experienced these negative psychosocial factors.
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