| 1. |
- Battistella, Roberta, et al.
(författare)
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Not All Lectins Are Equally Suitable for Labeling Rodent Vasculature
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 22:21
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Tidskriftsartikel (refereegranskat)abstract
- The vascular system is vital for all tissues and the interest in its visualization spans many fields. A number of different plant-derived lectins are used for detection of vasculature; however, studies performing direct comparison of the labeling efficacy of different lectins and techniques are lacking. In this study, we compared the labeling efficacy of three lectins: Griffonia simplicifolia isolectin B4 (IB4); wheat germ agglutinin (WGA), and Lycopersicon esculentum agglutinin (LEA). The LEA lectin was identified as being far superior to the IB4 and WGA lectins in histological labeling of blood vessels in brain sections. A similar signal-to-noise ratio was achieved with high concentrations of the WGA lectin injected during intracardial perfusion. Lectins were also suitable for labeling vasculature in other tissues, including spinal cord, dura mater, heart, skeletal muscle, kidney, and liver tissues. In uninjured tissues, the LEA lectin was as accurate as the Tie2-eGFP reporter mice and GLUT-1 immunohistochemistry for labeling the cerebral vasculature, validating its specificity and sensitivity. However, in pathological situations, e.g., in stroke, the sensitivity of the LEA lectin decreases dramatically, limiting its applicability in such studies. This work can be used for selecting the type of lectin and labeling method for various tissues.
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| 2. |
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| 3. |
- Don-Doncow, Nicholas, et al.
(författare)
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Simvastatin therapy attenuates memory deficits that associate with brain monocyte infiltration in chronic hypercholesterolemia
- 2021
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Ingår i: npj Aging and Mechanisms of Disease. - : Springer Science and Business Media LLC. - 2056-3973. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.
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| 4. |
- Don-Doncow, Nicholas, et al.
(författare)
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T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis.
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 20:3, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated elevated circulating T-lymphocyte populations and target organ damage spurred the interest to understanding mechanisms leading to inflammation-associated brain damage during hypertension. The present study describes sphingosine-1-phosphate (S1P) as major contributor to T-cell chemotaxis to the brain during hypertension-associated neuro-inflammation and cognitive impairment. Using Western blotting, flow cytometry and mass spectrometry approaches, we show that hypertension stimulates a sphingosine kinase 1 (SphK1)-dependent increase of cerebral S1P concentrations in a mouse model of angiotensin II (AngII)-induced hypertension. The development of a distinct S1P gradient between circulating blood and brain tissue associates to elevated CD3+ T-cell numbers in the brain. Inhibition of S1P1-guided T-cell chemotaxis with the S1P receptor modulator FTY720 protects from augmentation of brain CD3 expression and the development of memory deficits in hypertensive WT mice. In conclusion, our data highlight a new approach to the understanding of hypertension-associated inflammation in degenerative processes of the brain during disease progression.
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| 5. |
- Don-Doncow, Nicholas, et al.
(författare)
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The emerging alliance of sphingosine-1-phosphate signaling and immune cells: from basic mechanisms to implications in hypertension.
- 2019
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 176:12, s. 1989-2001
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Forskningsöversikt (refereegranskat)abstract
- The immune system plays a considerable role in hypertension. In particular, T-lymphocytes are recognized as important players in its pathogenesis. Despite substantial experimental efforts, the molecular mechanisms underlying the nature of T-cell activation contributing to an onset of hypertension or disease perpetuation are still elusive. Amongst other cell types, lymphocytes express distinct profiles of GPCRs for sphingosine-1-phosphate (S1P) – a bioactive phospholipid that is involved in many critical cell processes and most importantly majorly regulates T-cell development, lymphocyte recirculation, tissue-homing patterns and chemotactic responses. Recent findings have revealed a key role for S1P chemotaxis and T-cell mobilization for the onset of experimental hypertension, and elevated circulating S1P levels have been linked to several inflammation-associated diseases including hypertension in patients. In this article, we review the recent progress towards understanding how S1P and its receptors regulate immune cell trafficking and function and its potential relevance for the pathophysiology of hypertension. Linked Articles: This article is part of a themed section on Immune Targets in Hypertension.
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| 6. |
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| 7. |
- Ekroos, Johan, et al.
(författare)
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Declines amongst breeding Eider Somateria mollissima numbers in the Baltic/Wadden Sea flyway
- 2012
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Ingår i: Ornis Fennica. - 0030-5685. ; 89:2, s. 81-90
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Tidskriftsartikel (refereegranskat)abstract
- We report on the status of the Baltic/Wadden Sea flyway Eider population based on trends in breeding and wintering numbers throughout the region, supplemented by changes in the sex ratio and proportion of young Eiders as monitored in the Danish hunting bag. At the flyway scale, total numbers of breeding pairs decreased by 48% during 2000-2009, after relatively stable breeding numbers in 1991-2000. The majority of the population nest in Finland and Sweden, where the number of breeding pairs has halved over the same period. After initial declines in winter numbers between 1991 and 2000, during 2000-2009, national wintering numbers increased in the Baltic Sea, but decreased in the Wadden Sea. The annual proportion of adult females in the Danish hunting bag data decreased from ca. 45% (1982) to ca. 25% (2009) and simultaneously the proportion of first-winter birds fell from ca. 70% to ca. 30%, indicating dramatic structural changes in the Danish wintering numbers. These results suggest that the total flyway population will experience further declines, unless productivity increases and the factors responsible for decreasing adult female survival are identified and ameliorated. We discuss potential population drivers and present some recommendations for improved flyway-level monitoring and management of Eiders.
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| 8. |
- Jujic, Amra, et al.
(författare)
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Plasma Galectin-4 Levels Are Increased after Stroke in Mice and Humans
- 2023
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Ingår i: International Journal of Molecular Sciences. - 1661-6596 .- 1422-0067. ; 24:12
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies have associated plasma galectin-4 (Gal-4) levels with prevalent and incident diabetes, and with an increased risk of coronary artery disease. To date, data regarding possible associations between plasma Gal-4 and stroke are lacking. Using linear and logistic regression analyses, we tested Gal-4 association with prevalent stroke in a population-based cohort. Additionally, in mice fed a high-fat diet (HFD), we investigated whether plasma Gal-4 increases in response to ischemic stroke. Plasma Gal-4 was higher in subjects with prevalent ischemic stroke, and was associated with prevalent ischemic stroke (odds ratio 1.52; 95% confidence interval 1.01-2.30; p = 0.048) adjusted for age, sex, and covariates of cardiometabolic health. Plasma Gal-4 increased after experimental stroke in both controls and HFD-fed mice. HFD exposure was devoid of impact on Gal-4 levels. This study demonstrates higher plasma Gal-4 levels in both experimental stroke and in humans that experienced ischemic stroke.
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| 9. |
- Jujic, Amra, et al.
(författare)
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Plasma S1P (Sphingosine-1-Phosphate) Links to Hypertension and Biomarkers of Inflammation and Cardiovascular Disease : Findings From a Translational Investigation
- 2021
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Ingår i: Hypertension. - 1524-4563. ; 78:1, s. 195-209
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Tidskriftsartikel (refereegranskat)abstract
- S1P (Sphingosine-1-phosphate) is an important regulator of immune cell trafficking and vascular dysfunction contributing to the development and progression of overt hypertension. Although targeting S1P signaling revealed therapeutic potential in different experimental hypertension studies, validations of S1P-blood pressure (BP) associations in humans are lacking. In a translational approach, we explored the associations between plasma S1P and BP in a family based study cohort (MOS [Malmö Offspring Study]; N=1046) and in a longitudinally conducted murine hypertension cohort. In MOS, linear multivariate regression analyses showed that plasma S1P associates with increased systolic BP (β=1.06, P=0.015). Study subjects with systolic BP ≥140 mm Hg presented with significantly higher S1P plasma concentrations compared with subjects with BP <120 mm Hg independent of age and sex. The S1P-BP association was validated in a murine model where plasma S1P increased with systolic BP (r=0.7018, R2=0.4925; P<0.0001). In a subsample of MOS (N=444), proteomic profiling for markers of inflammation, metabolism, and cardiovascular disease using Proximity Extension Assays revealed multiple significant S1P associations, some of them with marked sex-specificity. In vitro and ex vivo validation of identified S1P associations disclosed augmented expression of different vascular dysfunction and inflammation markers in response to S1P. Our translational findings show a link between plasma S1P and systolic BP as well as several inflammation and cardiovascular disease markers and suggest S1P's biomarker potential. This encourages further studies to investigate its predictive capacity for hypertensive disease or the therapeutic potential of its signaling axis.
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| 10. |
- Lidington, Darcy, et al.
(författare)
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CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage
- 2019
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Ingår i: JACC: Basic to Translational Science. - : Elsevier BV. - 2452-302X. ; 4:8, s. 940-958
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations in cerebral artery CFTR expression, vascular reactivity, and cerebral perfusion, without affecting systemic hemodynamic parameters. This normalization correlates with reduced neuronal injury. Therefore, CFTR therapeutics have emerged as valuable clinical tools to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury.
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