| 11. |
- de Jong, Jasper M. A., et al.
(författare)
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Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
- 2019
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:8, s. 830-843
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Tidskriftsartikel (refereegranskat)abstract
- Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 degrees C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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| 12. |
- Diederichsen, Soren Z., et al.
(författare)
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Impact of fasting glucose on electrocardiographic left ventricular hypertrophy in an elderly general population
- 2015
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Ingår i: Blood Pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 24:3, s. 164-173
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To evaluate relationships between fasting plasma glucose (FPG), other cardiovascular risk markers and left ventricular hypertrophy (LVH) as detected by electrocardiography. Methods. Subjects were selected randomly from groups defi ned by FPG. Traditional risk markers were assessed. LVH was defi ned by either Cornell voltage -duration product (CP) or Sokolow -Lyon voltage combination (SL), and univariate and multivariable regressions were performed in search of explanatory factors for the presence of LVH and the values of CP and SL. Results. Of the 1759 subjects included, 1007 had a history of cardiovascular disease and/or medical treatment, while 752 subjects appeared to be healthy. We found an independent association between FPG and LVH (odds ratio 1.152, p = 0.042] as well as continuous CP (beta = 0.126, p = 0.007) in healthy men. As expected, we found an association between systolic blood pressure and LVH (odds ratio 1.020, p < 0.001) among healthy subjects, but only in subjects with FPG < 6 mmol/l (p = 0.04 for interaction). Conclusions. We found an independent association between FPG and LVH in healthy men, and no potentiating effect by FPG on the impact of hypertension.
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| 13. |
- Ejlertsen, Bent, et al.
(författare)
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Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer
- 2006
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Ingår i: J Clin Oncol. - : American Society of Clinical Oncology (ASCO). - 1527-7755. ; 24:31, s. 4956-4962
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Tidskriftsartikel (refereegranskat)abstract
- To compare the efficacy of ovarian ablation versus chemotherapy in early breast cancer patients with hormone receptor–positive disease. Patients and Methods We conducted an open, randomized, multicenter trial including premenopausal breast cancer patients with hormone receptor–positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more. Patients were randomly assigned to ovarian ablation by irradiation or to nine courses of chemotherapy with intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) administered every 3 weeks. Results Between 1990 and May 1998, 762 patients were randomly assigned, and the present analysis is based on 358 first events. After a median follow-up time of 8.5 years, the unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22). After a median follow-up time of 10.5 years, overall survival (OS) was similar in the two groups, with a hazard ratio of 1.11 (95% CI, 0.88 to 1.42) for the ovarian ablation group compared with the CMF group. Conclusion In this study, ablation of ovarian function in premenopausal women with hormone receptor–positive breast cancer had a similar effect to CMF on disease-free and OS. No significant interactions were demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.
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| 14. |
- Eltschkner, Sandra, et al.
(författare)
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The structure of songbird MHC class I reveals antigen binding that is flexible at the N-terminus and static at the C-terminus
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Long-distance migratory animals such as birds and bats have evolved to withstand selection imposed by pathogens across the globe, and pathogen richness is known to be particularly high in tropical regions. Immune genes, so-called Major Histocompatibility Complex (MHC) genes, are highly duplicated in songbirds compared to other vertebrates, and this high MHC diversity has been hypothesised to result in a unique adaptive immunity. To understand the rationale behind the evolution of the high MHC genetic diversity in songbirds, we determined the structural properties of an MHC class I protein, Acar3, from a long-distance migratory songbird, the great reed warbler Acrocephalus arundinaceus (in short: Acar). The structure of Acar3 was studied in complex with pathogen-derived antigens and shows an overall antigen presentation similar to human MHC class I. However, the peptides bound to Acar3 display an unusual conformation: Whereas the N-terminal ends of the peptides display enhanced flexibility, the conformation of their C-terminal halves is rather static. This uncommon peptide-binding mode in Acar3 is facilitated by a central Arg residue within the peptide-binding groove that fixes the backbone of the peptide at its central position, and potentially permits successful interactions between MHC class I and innate immune receptors. Our study highlights the importance of investigating the immune system of wild animals, such as birds and bats, to uncover unique immune mechanisms which may neither exist in humans nor in model organisms.
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| 15. |
- Hildenbrand, Anna, et al.
(författare)
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Aquaporin 1 is expressed in the human endometrium during normal cycle and increases after mifepristone treatment.
- 2008
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Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 22:1, s. 49-53
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporin-1 (AQP1) is involved in the angiogenesis and structural modifications of microvessels and possibly also in the pathogenesis of idiopathic menhorrhagia, where a reduced AQP1 expression is seen in the endometrium. Mifepristone treatment induces reduced menstrual bleeding and amenorrhea and also has a direct effect on endometrial arterioles. Administered with gestagen-only contraceptive methods, antiprogestins improve the bleeding pattern. The objective of this study was to evaluate the AQP1 expression in endometrial blood vessels during normal cycle and after mifepristone treatment. Localization and expression of AQP1 was determined using immunohistochemistry and reverse transcriptase chain reaction (RT-PCR) in 43 biopsies from human endometrium taken during a normal cycle and after mifepristone treatment. AQP1 expression in human endometrial vessels is not cycle dependent and is stronger in capillaries and arteries than in veins. After mifepristone treatment the staining intensity was increased, but not the number of stained vessels. The presence of AQP1 was also confirmed using RT-PCR. The changes in AQP1 expression could contribute to the reduced bleeding seen following mifepristone treatment and could be an effect of either antagonizing progesterone or cortisol.
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| 16. |
- Holm, Anne I. S., et al.
(författare)
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Synchrotron Radiation Circular Dichroism of Various G-Guadruplex Structures
- 2010
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Ingår i: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 93:5, s. 429-433
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Tidskriftsartikel (refereegranskat)abstract
- Here we report synchrotron radiation circular dichroism spectra of various G-quadruplexes from 179 to 350 nm, and a number of bands in the vacuum ultraviolet (VUV) are reported for the first time. For a tetramolecular parallel structure, the strongest band in the spectrum is a negative band in the VUV at 182 nm; for a bimolecular antiparallel structure with diagonal loops, a new strong positive band is found at 190 nm; for a bimolecular parallel structure with edgewise loops, a strong positive band at 189 nm is observed; and for a self-folded chair-type structure, the strongest band in the spectrum is a positive band at 187 nm. For the tetramolecular parallel structure, the CD signals at all wavelengths are dominated by contributions from quartets of G bases, and the signal strength is approximately proportional to the number of quartets. Our experiments on well-characterized G-quadruplex structures lead us to question past attributions of CD signals to helix handedness and G quartet polarity. Although differences can be observed in the VUV region for the various quadruplex types, there do not appear to be clear-cut spectral features that can be used to identify specific topological features. It is suggested that this is because a dominant positive band in the VUV seen near 190 nm in all quadruplex structures is due to intrastrand guanine guanine base stacking. However, our spectra can serve as reference spectra for the G-quadruplex structures investigated and, not least, to benchmark theoretical calculations and empirical models.
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| 17. |
- Holm, Paetur M., et al.
(författare)
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Effects of neuromuscular control and strengthening exercises on MRI-measured thigh tissue composition and muscle properties in people with knee osteoarthritis - an exploratory secondary analysis from a randomized controlled trial
- 2024
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Ingår i: SEMINARS IN ARTHRITIS AND RHEUMATISM. - 0049-0172 .- 1532-866X. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the effects of adding strength training to neuromuscular control exercises on thigh tissue composition and muscle properties in people with radiographic -symptomatic knee osteoarthritis (KOA). Methods: In this exploratory secondary analysis of a randomized controlled trial, using a complete -case approach, participants performed 12 weeks of twice -weekly neuromuscular control exercise and patient education (NEMEX, n = 34) or NEMEX plus quadriceps strength training (NEMEX+ST, n = 29). Outcomes were MRImeasured inter- and intramuscular adipose tissue (InterMAT, IntraMAT), quadriceps muscle cross-sectional area (CSA), knee -extensor strength, specific strength (strength/lean CSA) and 30 s chair -stands. Betweengroup effects were compared using a mixed model analysis of variance. Results: At 12 weeks, responses to NEMEX+ST overlapped with NEMEX for all outcomes. Both groups reduced InterMAT (NEMEX+ST=25 %, NEMEX=21 %); between -group difference: 0.8cm2 (95 % CI: -0.1, 1.7). NEMEX+ST decreased IntraMAT (2 %) and NEMEX increased IntraMAT (4 %); between -group difference 0.1 %-points (-0.3, 0.5). Both groups increased quadriceps CSA and lean CSA (CSA minus IntraMAT), improved knee -extensor strength and specific strength, and improved chair -stand performance with a trend towards greater effects in NEMEX+ST. Conclusion: Adding strength training to 12 weeks of neuromuscular control exercises provided largely similar effects to neuromuscular control exercises alone in decreasing InterMAT and IntraMAT, in improving kneeextensor strength, CSA and in improving performance -based function in KOA persons, with a trend towards greater effects with additional strength training. Notably, both groups substantially reduced InterMAT and improved specific strength (an index of muscle quality). Our hypothesis -generating work warrants exploration of the roles played by InterMAT and IntraMAT in exercise effects in KOA.
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| 18. |
- Huber, Vincent J., et al.
(författare)
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Aquaporins : Chemical inhibition by small molecules
- 2016
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Ingår i: Aquaporins in Health and Disease : New Molecular Targets for Drug Discovery - New Molecular Targets for Drug Discovery. - 9781498707831 - 9781498707848 ; , s. 249-271
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Bokkapitel (refereegranskat)abstract
- The human genome encodes 13 aquaporin isoforms with characteristic substrate specificity that are expressed at specific locations throughout the body. Of these isoforms, AQPs 1-4 serve important functions in renal water reabsorption. Consequently, specific AQP inhibitors have been proposed as 'aquaretics', a new class of drugs suitable to induce diuresis without concomitant salt wasting. Furthermore, animal experiments suggested that AQP4 inhibitors could be useful to treat some forms of brain edema. Other proposed applications for AQP inhibitors involve amongst others treatment of diabetes, inflammatory skin diseases and cancer. However, few of these putative applications have been critically evaluated against current forms of therapy. Furthermore, development of AQP inhibitors remains difficult and despite numerous efforts during at least the last 15 years very few AQP inhibitors have been described. Moreover, none of the hitherto described substances have been developed to a level where meaningful verification of proposed AQP drug targets in preclinical or clinical settings was possible. Nonetheless, encouraging progress towards development of such substances has been made during recent years. Novel cell-based assays facilitate high throughput screening of chemical compound libraries for hit discovery. AQP 3D structures have been solved for 10 isoforms, which can support rapidly evolving computational hit discovery methods, as well as hit to lead programs. In this chapter, we will provide a critical review of current evidence supporting relevance of AQPs as drug targets, describe current methods for AQP inhibitor discovery and will try to highlight challenges that remain before successful AQP inhibitor development.
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| 19. |
- Jelen, Sabina, et al.
(författare)
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AQP9 Expression in Glioblastoma Multiforme Tumors Is Limited to a Small Population of Astrocytic Cells and CD15(+)/CalB(+) Leukocytes
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporin-9 (AQP9) is a membrane protein channel that is permeable to a range of small solutes, including glycerol, urea and nucleobases. Expression of AQP9 in normal brain is limited, while widespread AQP9 expression has previously been reported in human glioblastoma. However, the specific cellular expression of AQP9 in glioblastoma remains unclear. In this study, we have examined microarrays to corroborate AQP9 mRNA expression in glioma. These analyses suggested that AQP9 mRNA expression in glioblastoma is primarily explained by tumor infiltration with AQP9 expressing leukocytes. Immunolabeling confirmed that within tumor regions, AQP9 was expressed in CD15(+) and Calgranulin B+ leukocytes, but also in larger cells that morphologically resembled glioma cells. Specificity of immunoreagents was tested in recombinant cell lines, leukocyte preparations, and sections of normal human brain and liver tissue. Apparent AQP9(+) glioma cells were frequently observed in proximity to blood vessels, where brain tumor stem cells have been observed previously. A fraction of these larger AQP9 expressing cells co-expressed the differentiated astrocyte marker GFAP. AQP9 expressing glioma cells were negative for the brain tumor stem cell marker CD15, but were observed in proximity to CD15(+) glioma cells. AQP9 expression may therefore require signals of the perivascular tumor environment or alternatively it may be restricted to a population of glioma stem cell early progenitor cells.
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| 20. |
- Jelen, Sabina, et al.
(författare)
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Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in Mice
- 2011
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 286:52, s. 44319-44325
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Tidskriftsartikel (refereegranskat)abstract
- It has been hypothesized that aquaporin-9 (AQP9) is part of the unknown route of hepatocyte glycerol uptake. In a previous study, leptin receptor-deficient wild-type mice became diabetic and suffered from fasting hyperglycemia whereas isogenic AQP9(-/-) knock-out mice remained normoglycemic. The reason for this improvement in AQP9(-/-) mice was not established before. Here, we show increased glucose output (by 123% +/- 36% S. E.) in primary hepatocyte culture when 0.5 mM extracellular glycerol was added. This increase depended on AQP9 because it was absent in AQP9(-/-) cells. Likewise, the increase was abolished by 25 mu M HTS13286 (IC(50) similar to 2 mu M), a novel AQP9 inhibitor, which we identified in a small molecule library screen. Similarly, AQP9 deletion or chemical inhibition eliminated glycerol-enhanced glucose output in perfused liver preparations. The following control experiments suggested inhibitor specificity to AQP9: (i) HTS13286 affected solute permeability in cell lines expressing AQP9, but not in cell lines expressing AQPs 3, 7, or 8. (ii) HTS13286 did not influence lactate-and pyruvate-dependent hepatocyte glucose output. (iii) HTS13286 did not affect glycerol kinase activity. Our experiments establish AQP9 as the primary route of hepatocyte glycerol uptake for gluconeogenesis and thereby explain the previously observed, alleviated diabetes in leptin receptor-deficient AQP9(-/-) mice.
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