Minerva Medical Research Institute

Helsinki, Finland

Minerva Medical Research Institute

Helsinki, Finland
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Kotronen A.,Minerva Medical Research Institute | Seppanen-Laakso T.,VTT Technical Research Center of Finland | Kiviluoto T.,University of Helsinki | Arola J.,University of Helsinki | And 2 more authors.
Obesity | Year: 2010

Ceramides may mediate saturated fat-induced insulin resistance, but there are no data comparing ceramide concentrations between human tissues. We therefore performed lipidomic analysis of human subcutaneous (SCfat) and intra-abdominal (IAfat) adipose tissue, the liver, and serum in eight subjects. The liver contained (nmol/mg tissue) significantly more ceramides (1.5-3-fold), sphingomyelins (7-8-fold), phosphatidylethanolamines (10-11-fold), lysophosphatidylcholines (7-12-fold), less ether-linked phosphatidylcholines (2-2.5-fold) but similar amounts of diacylglycerols as compared to SCfat and IAfat. The amounts of ceramides and their synthetic precursors, such as palmitic (16:0) free fatty acids and sphingomyelins, differed considerably between the tissues. The liver contained proportionally more palmitic, stearic (18:0), and long polyunsaturated fatty acids than adipose tissues. Stearoyl-CoA desaturase 1 (SCD1) activity reflected by serum, estimated from the 16:1/16:0-ratio, was closely related to that in the liver (r = 0.86, P = 0.024) but not adipose tissues. This was also true for estimated elongase (18:1/16:1, r = 0.89, P = 0.01), and Δ5 (20:4/20:3, r = 0.89, P = 0.012) and Δ6 (18:3n-6/18:2, r = 1.0, P 0.001) desaturase activities. We conclude that the human liver contains higher concentrations of ceramides and saturated free fatty acids than either SCfat or IAfat. © 2010 The Obesity Society.


Bunck M.C.,VU University Amsterdam | Diamant M.,VU University Amsterdam | Eliasson B.,Sahlgrenska University Hospital | Corner A.,University of Helsinki | And 7 more authors.
Diabetes Care | Year: 2010

OBJECTIVE - To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. RESEARCH DESIGN AND METHODS - Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. RESULTS - Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. CONCLUSIONS - Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels. © 2010 by the American Diabetes Association.


Bunck M.C.,VU University Amsterdam | Corner A.,University of Helsinki | Corner A.,Minerva Medical Research Institute | Eliasson B.,Sahlgrenska University Hospital | And 7 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - We previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure. RESEARCH DESIGN AND METHODS - Sixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI). RESULTS - At 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ±0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (27.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the Mvalue by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and 20.99 ± 0.65, respectively; P = 0.028). CONCLUSIONS - EXE and GLAR sustained HbA 1c over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health. © 2011 by the American Diabetes Association.


Romeo S.,University of Cambridge | Romeo S.,University of Cagliari | Huang-Doran I.,University of Cambridge | Baroni M.G.,University of Cagliari | And 3 more authors.
Current Opinion in Lipidology | Year: 2010

Purpose of review: Hepatic steatosis is a leading cause of adult and paediatric liver disease and is inextricably linked to obesity, insulin resistance and cardiovascular disease. Here we summarize our current understanding of the role of the patatin-like phospholipase domain-containing 3 gene (PNPLA3) in hepatic steatosis. Recent findings: Multiple studies have revealed an association between the common I148M variant in PNPLA3 and increased hepatic fat. In the presence of obesity and chronic alcohol intake, the variant is associated with even more striking phenotypes such as hepatitis and cirrhosis, respectively. These findings suggest that genetic variants in PNPLA3 predispose towards hepatic steatosis and, in the context of other environmental stressors, its progression to irreversible liver failure. PNPLA3 is predominantly expressed in human liver and adipose tissue, possesses both lipolytic and lipogenic activity in vitro and localizes to the surface of lipid droplets in heptocytes. The 148M mutant protein has reduced lipolytic activity, with attendant increased cellular triglyceride accumulation. However, the precise physiological role of PNPLA3 remains mysterious. Summary: Recent studies have implicated PNPLA3 in the pathogenesis of hepatic steatosis. Attempts to describe its function in vivo may provide us with both an opportunity to understand and a strategy to overcome this leading cause of human morbidity. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Hyrskyluoto A.,University of Helsinki | Hyrskyluoto A.,Minerva Medical Research Institute | Reijonen S.,University of Helsinki | Kivinen J.,University of Helsinki | And 5 more authors.
Experimental Cell Research | Year: 2012

Increased protein aggregation and altered cell signaling accompany many neurodegenerative diseases including Huntington's disease (HD). Cell stress is counterbalanced by signals mediating cell repair but the identity of these are not fully understood. We show here that the mammalian target of rapamycin (mTOR) pathway is inhibited and cytoprotective autophagy is activated in neuronal PC6.3 cells at 24. h after expression of mutant huntingtin proteins. Tuberous sclerosis complex (TSC) 1/2 interacted with growth arrest and DNA damage protein 34 (GADD34), which caused TSC2 dephosphorylation and induction of autophagy in mutant huntingtin expressing cells. However, GADD34 and autophagy decreased at later time points, after 48. h of transfection with the concomitant increase in mTOR activity. Overexpression of GADD34 counteracted these effects and increased cytoprotective autophagy and cell survival. These results show that GADD34 plays an important role in cell protection in mutant huntingtin expressing cells. Modulation of GADD34 and the TSC pathway may prove useful in counteracting cell degeneration accompanying HD and other neurodegenerative diseases. © 2011 Elsevier Inc.


Cascone A.,University of Helsinki | Bruelle C.,University of Helsinki | Bruelle C.,Minerva Medical Research Institute | Lindholm D.,University of Helsinki | And 3 more authors.
PLoS ONE | Year: 2012

Background: Extensive DNA damage leads to apoptosis. Histones play a central role in DNA damage sensing and may mediate signals of genotoxic damage to cytosolic effectors including mitochondria. Methodology/Principal Findings: We have investigated the effects of histones on mitochondrial function and membrane integrity. We demonstrate that both linker histone H1 and core histones H2A, H2B, H3, and H4 bind strongly to isolated mitochondria. All histones caused a rapid and massive release of the pro-apoptotic intermembrane space proteins cytochrome c and Smac/Diablo, indicating that they permeabilize the outer mitochondrial membrane. In addition, linker histone H1, but not core histones, permeabilized the inner membrane with a collapse of the membrane potential, release of pyridine nucleotides, and mitochondrial fragmentation. Conclusions: We conclude that histones destabilize the mitochondrial membranes, a mechanism that may convey genotoxic signals to mitochondria and promote apoptosis following DNA damage. © 2012 Cascone et al.


Reijonen S.,Minerva Medical Research Institute | Kukkonen J.P.,Minerva Medical Research Institute | Kukkonen J.P.,University of Helsinki | Hyrskyluoto A.,Minerva Medical Research Institute | And 6 more authors.
Cellular and Molecular Life Sciences | Year: 2010

Accumulation of abnormal proteins and endoplasmic reticulum stress accompany neurodegenerative diseases including Huntington's disease. We show that the expression of mutant huntingtin proteins with extended polyglutamine repeats differentially affected endoplasmic reticulum signaling cascades linked to the inositol-requiring enzyme-1 (IRE1) pathway. Thus, the p38 and c-Jun N-terminal kinase pathways were activated, while the levels of the nuclear factor-κB-p65 (NF-κB-p65) protein decreased. Downregulation of NF-κB signaling was linked to decreased antioxidant levels, increased oxidative stress, and enhanced cell death. Concomitantly, calpain was activated, and treatment with calpain inhibitors restored NF-κB-p65 levels and increased cell viability. The calpain regulator, calpastatin, was low in cells expressing mutant huntingtin, and overexpression of calpastatin counteracted the deleterious effects caused by N-terminal mutant huntingtin proteins. These results show that calpastatin and an altered NF-κB-p65 signaling are crucial factors involved in oxidative stress and cell death mediated by mutant huntingtin proteins. © 2010 Springer Basel AG.


Makela J.,Minerva Medical Research Institute | Koivuniemi R.,Minerva Medical Research Institute | Korhonen L.,Minerva Medical Research Institute | Lindholm D.,Minerva Medical Research Institute | Lindholm D.,University of Helsinki
PLoS ONE | Year: 2010

Inflammation is part of many neurological disorders and immune reactions may influence neuronal progenitor cells (NPCs) contributing to the disease process. Our knowledge about the interplay between different cell types in brain inflammation are not fully understood. It is important to know the mechanisms and factors involved in order to enhance regeneration and brain repair. We show here that NPCs express receptors for interferon-γ (IFNγ), and IFNγ activates the signal transducer and activator of transcription (STAT) protein-1. IFNγ reduced cell proliferation in NPCs by upregulation of the cell cycle protein p21 as well as induced cell death of NPCs by activating caspase-3. Studies of putative factors for rescue showed that the neuropeptide, Pituitary adenylate cyclase-activating polypeptide (PACAP) increased cell viability, the levels of p-Bad and reduced caspase-3 activation in the NPCs. Medium from cultured microglia contained IFNγ and decreased the viability of NPCs, whilst blocking with anti-IFNγ antibodies counteracted this effect. The results show that NPCs are negatively influenced by IFNγ whereas PACAP is able to modulate its action. The interplay between IFNγ released from immune cells and PACAP is of importance in brain inflammation and may affect the regeneration and recruitment of NPCs in immune diseases. The observed effects of IFNγ on NPCs deserve to be taken into account in human anti-viral therapies particularly in children with higher rates of brain stem cell proliferation. © 2010 Mäkelä et al.


Lindholm D.,University of Helsinki | Lindholm D.,Minerva Medical Research Institute | Eriksson O.,University of Helsinki | Makela J.,University of Helsinki | And 4 more authors.
Cellular and Molecular Life Sciences | Year: 2012

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that favorably affects mitochondrial function. This concept is supported by an increasing amount of data including studies in PGC-1α gene-deleted mice, suggesting that PGC-1α is a rescue factor capable of boosting cell metabolism and promoting cell survival. However, this view has now been called into question by a recent study showing that adenoassociated virus-mediated PGC-1α overexpression causes overt cell degeneration in dopaminergic neurons. How is this to be understood, and can these seemingly conflicting findings tell us something about the role of PGC-1α in cell stress and in control of neuronal homeostasis? © Springer Basel AG 2012.


Hyrskyluoto A.,University of Helsinki | Hyrskyluoto A.,Minerva Medical Research Institute | Pulli I.,Åbo Akademi University | Tornqvist K.,Minerva Medical Research Institute | And 6 more authors.
Cell Death and Disease | Year: 2013

Alterations in mitochondria and increased oxidative stress are associated with the disease progression in Huntington's disease (HD). Endoplasmic reticulum (ER) stress and oxidative damage are linked through the close communication between the ER and mitochondria. Sigma-1 receptor (Sig-1R) is a chaperone protein in the ER that is involved in ER stress regulation, but little is known about its role in HD or the mechanisms for cell protection. Here we show that the Sig-1R agonist, PRE084 increases cell survival and counteracts the deleterious effects caused by N-terminal mutant huntingtin proteins in neuronal PC6.3 cells. Particularly, PRE084 increased the levels of cellular antioxidants by activating the NF-κB pathway that is compromised by the expression of mutant huntingtin proteins. These results show that the Sig-1R agonist has beneficial effects in models of HD and that compounds affecting the Sig-1R may be promising targets for future drug development in HD. © 2013 Macmillan Publishers Limited. All rights reserved.

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