| 21. |
- Agardh, Carl-David, et al.
(författare)
-
Plasma high density lipoproteins and lipolytic enzyme activities in diabetic patients
- 1983
-
Ingår i: Acta Medica Scandinavica. - 0001-6101. ; 213:2, s. 123-128
-
Tidskriftsartikel (refereegranskat)abstract
- Eighty diabetic patients, consecutively selected from an out-patient clinic, were studied with regard to plasma lipoprotein levels, especially HDL. Patients treated with sulphonylureas had 24% lower HDL cholesterol concentrations (p less than 0.01) but only about 7% lower apo AI levels (n.s.) than those on insulin treatment. This difference could at least partly be explained by differences in age and type of diabetes. There was no relationship between the degree of diabetic control, as measured by fasting blood glucose levels, and HDL levels. In two subgroups of insulin-treated diabetics, selected to represent extremely low and high HDL levels (range 0.5-0.8 and 1.8-2.0 mmol/l, respectively) but matched with regard to age, duration of diabetes, insulin dosage and diabetic control, the activities of lipoprotein lipase and hepatic lipase in postheparin plasma were also recorded. The high HDL group had significantly higher lipoprotein lipase activities (p less than 0.01) and significantly lower hepatic lipase activities (p less than 0.05) than the low HDL group, supporting the hypothetical roles of these enzymes in HDL metabolism, and offering a tentative mechanism behind the large variability of HDL levels in diabetics.
|
|
| 22. |
- Agardh, Carl-David, et al.
(författare)
-
Plasma lipids and plasma lipoproteins in diabetics with and without proliferative retinopathy
- 1988
-
Ingår i: Acta Medica Scandinavica. - 0001-6101. ; 223:2, s. 165-169
-
Tidskriftsartikel (refereegranskat)abstract
- The single most important factor related to the development of diabetic retinopathy is the duration of diabetes. Little is known about the underlying mechanisms, but many factors have been suggested to be involved, among them derangements in plasma lipids and plasma lipoproteins. In the present study we examined the relation between plasma lipids, plasma lipoproteins, and the duration of diabetes in Type I diabetics with and without proliferative retinopathy. The duration of diabetes in the two groups was 12.2 +/- 2.8 and 21.5 +/- 9.0 years, respectively (mean +/- SD; p less than 0.01). Except for moderately low HDL levels, plasma lipid and lipoprotein concentrations were normal in both groups of patients. The levels of lipids and lipoproteins did not correlate with the duration of diabetes. Furthermore, no differences were seen between patients with and without proliferative retinopathy. Thus, the present study does not indicate that plasma lipids and plasma lipoproteins play any major role in the development of diabetic proliferative retinopathy.
|
|
| 23. |
|
|
| 24. |
- Agardh, Carl-David, et al.
(författare)
-
The effects of tolbutamide on lipoproteins, lipoprotein lipase and hormone-sensitive lipase
- 1999
-
Ingår i: Diabetes Research and Clinical Practice. - 1872-8227. ; 46:2, s. 99-108
-
Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetic patients are at increased risk to develop atherosclerotic vascular disease. These patients are often treated with sulphonylurea derivatives, and it has been suggested that this treatment might contribute to the increased atherosclerotic process. The aim of the present study was therefore to investigate whether tolbutamide influences lipid metabolism in such a way that the atherosclerotic process may be promoted. Addition of tolbutamide (5-500 mg/l) to isolated rat fat adipocytes inhibited the lipoprotein lipase (LPL) activity in a dose-dependent manner to levels about 50% of those registered in the absence of tolbutamide. This effect was due to inhibition of the activation of the enzyme in the tissue and not to interference with the interaction of enzyme with its substrate. Addition of tolbutamide (500 mg/l) also inhibited noradrenaline (100 nM) and isoprenaline (40 nM)-induced lipolysis by 48.1 +/- 7.4% (mean +/- S.E.M.) and 47.3 +/- 5.5%, respectively. The decreased lipolysis in tolbutamide preincubated adipocytes was shown to be the result of an inhibition of the phosphorylation of hormone sensitive lipase (HSL). Three months of tolbutamide treatment (0.5 g t.i.d.) in diet treated type 2 diabetic patients did not influence the plasma concentrations of cholesterol, triglycerides, LDL cholesterol, HDL cholesterol as well as HDL triglycerides and HDL phospholipids, and there were no differences compared to placebo treated patients. There was a tendency towards a decrement in the elimination rate of exogenous triglycerides in the tolbutamide group (P = 0.0801). No differences between the groups and no treatment effects were seen on LPL and hepatic lipase activities. In conclusion, our in vitro data show that tolbutamide has dual effects on lipid transport, with impairment of the LPL system, which would tend to decrease plasma lipoproteins by reducing hepatic production of lipoproteins. In vivo, these two effects seem to balance each other and plasma lipoprotein levels remain unaffected.
|
|
| 25. |
- Agardh, Carl-David, et al.
(författare)
-
The influence of treatment with estrogens and estramustine phosphate on platelet aggregation and plasma lipoproteins in non-disseminated prostatic carcinoma
- 1984
-
Ingår i: Journal of Urology. - 1527-3792. ; 132:5, s. 1021-1024
-
Tidskriftsartikel (refereegranskat)abstract
- The treatment of prostatic carcinoma with estrogens is associated with an increased risk of cardiovascular as well as thromboembolic complications. In the present study, patients harboring highly or moderately differentiated prostatic carcinoma without signs of metastases were treated with either polyestradiolphosphate + etinylestradiol, estramustine phosphate or given no treatment. Subsequently, these patients were investigated regarding factors (platelet aggregation, plasma and platelet phospholipid composition and lipoprotein patterns) that might contribute to increased thrombogenesis and cardiovascular risk. The results indicate the presence of increased in vitro platelet aggregation in patients treated with polyestradiolphosphate + etinylestradiol compared to those treated with estramustine phosphate or given no treatment. A possible relationship between the availability of arachidonic acid in platelet membrane phospholipids and in vitro platelet aggregation is suggested. On the other hand the alterations in plasma lipoproteins observed during treatment are generally considered positive from an atherogenic point of view and do not seem relevant to the elevated incidence of cardiovascular disease in these patients.
|
|
| 26. |
- Agnoletti, Davide, et al.
(författare)
-
Microbiota, Diet, Oral Health and Vascular Aging
- 2024. - 2
-
Ingår i: Early Vascular Aging (EVA) : New Directions in Cardiovascular Protection - 2nd Edition - New Directions in Cardiovascular Protection - 2nd Edition. - 9780443155123
-
Bokkapitel (refereegranskat)
|
|
| 27. |
- Aguilar-Calvo, Patricia, et al.
(författare)
-
Generation of novel neuroinvasive prions following intravenous challenge
- 2018
-
Ingår i: Brain Pathology. - : WILEY. - 1015-6305 .- 1750-3639. ; 28:6, s. 999-1011
-
Tidskriftsartikel (refereegranskat)abstract
- Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.
|
|
| 28. |
- Aguilar-Calvo, Patricia, et al.
(författare)
-
Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection
- 2023
-
Ingår i: PLoS Pathogens. - : PUBLIC LIBRARY SCIENCE. - 1553-7366 .- 1553-7374. ; 19:9
-
Tidskriftsartikel (refereegranskat)abstract
- Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase), from neurons or astrocytes, we then investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, only affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance. Prions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain of affected individuals triggering neuronal loss and neuroinflammation, yet the molecules that facilitate prion protein aggregation are largely unknown. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated, neuron-derived HS, and infect mice with different prions strains. We find that mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to controls. We also found that recombinant prion protein was efficiently transported within the interstitial fluid of mice having poorly sulfated HS, suggesting more efficient clearance from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates a specific HS biosynthetic enzyme to target to enhance protein clearance.
|
|
| 29. |
- Aguilar-Calvo, Patricia, et al.
(författare)
-
Post-translational modifications in PrP expand the conformational diversity of prions in vivo
- 2017
-
Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Misfolded prion protein aggregates (PrPSc) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-beta, tau, alpha-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)anchorless prion protein, PrPC, together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how posttranslational modifications impact the aggregated prion protein properties and disease phenotype. Four GPI-anchorless prion strains caused a nearly identical clinical and pathological disease phenotype, yet maintained their structural diversity in the anchorless state. HXMS studies revealed that GPIanchorless PrPSc is characterized by substantially higher protection against hydrogen/deuterium exchange in the C-terminal region near the N-glycan sites, suggesting this region had become more ordered in the anchorless state. For one strain, passage of GPI-anchorless prions into wild type mice led to the emergence of a novel strain with a unique biochemical and phenotypic signature. For the new strain, histidine hydrogen-deuterium mass spectrometry revealed altered packing arrangements of beta-sheets that encompass residues 139 and 186 of PrPSc. These findings show how variation in posttranslational modifications may explain the emergence of new protein conformations in vivo and also provide a basis for understanding how the misfolded protein structure impacts the disease.
|
|
| 30. |
- Aguilar-Calvo, Patricia, et al.
(författare)
-
Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions
- 2020
-
Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 139:3, s. 527-546
-
Tidskriftsartikel (refereegranskat)abstract
- Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1(+/-)) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.
|
|
