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- Ruuth, M., et al.
(författare)
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Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, ismodifiable, and associates with future cardiovascular deaths
- 2018
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 39:27
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Tidskriftsartikel (refereegranskat)abstract
- Aims Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization. Methods and results We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture. Conclusion Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.
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- Jantti, H, et al.
(författare)
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Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:24
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Tidskriftsartikel (refereegranskat)abstract
- The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected PSEN1 ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months. While we did not find significant behavioral changes in younger mice, spatial learning and memory were paradoxically improved in 16-month-old PSEN1 ΔE9 glia-transplanted male mice as compared to age-matched isogenic control-transplanted animals. Memory improvement was associated with lower levels of soluble, but not insoluble, human Aβ42 in the mouse brain. We also found a decreased engraftment of PSEN1 ΔE9 mutant cells in the cingulate cortex and significant transcriptional changes in both human and mouse genes in the hippocampus, including the extracellular matrix-related genes. Overall, the presence of PSEN1 ΔE9 mutant glia exerted a more beneficial effect on aged mouse brain than the isogenic control human cells likely as a combination of several factors.
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- Raty, S., et al.
(författare)
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Resting-state Functional Connectivity After Occipital Stroke
- 2022
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Ingår i: Neurorehabilitation and Neural Repair. - : SAGE Publications. - 1545-9683 .- 1552-6844. ; 36:2, s. 151-163
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Tidskriftsartikel (refereegranskat)abstract
- Background Resting-state functional magnetic resonance imaging (rsfMRI) reflects spontaneous activation of cortical networks. After stroke, these networks reorganize, both due to structural lesion and reorganization of functional connectivity (FC). Objective We studied FC in chronic phase occipital stroke patients with homonymous visual field defects before and after repetitive transorbital alternating current stimulation (rtACS). Methods This spin-off study, embedded in the randomized, sham-controlled REVIS trial, comprised 16 chronic occipital stroke patients with visual field defect and 12 healthy control subjects. The patients underwent rsfMRI at baseline, after two weeks of rtACS or sham treatment, and after two months of treatment-free follow-up, whereas the control subjects were measured once. We used a multivariate regression connectivity model to determine mutual prediction accuracy between 74 cortical regions of interest. Additionally, the model parameters were included into a graph to analyze average path length, centrality eigenvector, centrality degree, and clustering of the network. The patients and controls at baseline and the two treatment groups were compared with multilevel modeling. Results Before treatment, the patients and controls had similar whole-network prediction accuracy and network parameters, whereas centrality eigenvector differed in perilesional regions, indicating local modification in connectivity. In line with behavioral results, neither prediction accuracy nor any network parameter changed systematically as a result of rtACS rehabilitation compared to sham. Conclusions Whole-network FC showed no difference between occipital stroke patients and healthy population, congruent with the peripheral location of the visual network in relation to the high-density cortical core. rtACS treatment in the given setting did not affect FC.
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- Ruuth, Maija, et al.
(författare)
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Overfeeding Saturated Fat Increases LDL (Low-Density Lipoprotein) Aggregation Susceptibility While Overfeeding Unsaturated Fat Decreases Proteoglycan-Binding of Lipoproteins
- 2021
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 41:11, s. 2823-2836
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity.Approach and Results: The participants (36 subjects; age, 48±10 years; body mass index, 30.9±6.2 kg/m2) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL aggregation increased in the saturated fat but not the other groups. This change was associated with increased sphingolipid and saturated triacylglycerols in LDL and in plasma and reduction of clusterin on LDL particles. Proteoglycan binding of plasma lipoproteins decreased in the unsaturated fat group relative to the baseline diet. Lipoprotein properties remained unchanged in the CARB group.CONCLUSIONS: The type of fat during 3 weeks of overfeeding is an important determinant of the characteristics and functional properties of plasma lipoproteins in humans.REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier NCT02133144.
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- Thanikkal, Edvin J., et al.
(författare)
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The Yersinia pseudotuberculosis Cpx envelope stress system contributes to transcriptional activation of rovM
- 2019
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Ingår i: Virulence. - : Taylor & Francis Group. - 2150-5594 .- 2150-5608. ; 10:1, s. 37-57
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Tidskriftsartikel (refereegranskat)abstract
- The Gram-negative enteropathogen Yersinia pseudotuberculosis possesses a number of regulatory systems that detect cell envelope damage caused by noxious extracytoplasmic stresses. The CpxA sensor kinase and CpxR response regulator two-component regulatory system is one such pathway. Active Cpx signalling upregulates various factors designed to repair and restore cell envelope integrity. Concomitantly, this pathway also down-regulates key determinants of virulence. In Yersinia, cpxA deletion accumulates high levels of phosphorylated CpxR (CpxR~P). Accumulated CpxR~P directly repressed rovA expression and this limited expression of virulence-associated processes. A second transcriptional regulator, RovM, also negatively regulates rovA expression in response to nutrient stress. Hence, this study aimed to determine if CpxR~P can influence rovA expression through control of RovM levels. We determined that the active CpxR~P isoform bound to the promoter of rovM and directly induced its expression, which naturally associated with a concurrent reduction in rovA expression. Site-directed mutagenesis of the CpxR~P binding sequence in the rovM promoter region desensitised rovM expression to CpxR~P. These data suggest that accumulated CpxR~P inversely manipulates the levels of two global transcriptional regulators, RovA and RovM, and this would be expected to have considerable influence on Yersinia pathophysiology and metabolism.
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