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- Fagerberg, Björn, 1943, et al.
(författare)
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Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population
- 2005
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 48:9, s. 1716-25
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance. METHODS: A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women). RESULTS: A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: -43% to -30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: -20% to -10%; p<0.0001) and NEFA by 40% (95% CI: -51% to -27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to -24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (-35%; p<0.0001) and plasma glucose concentration (-0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups. CONCLUSIONS/INTERPRETATION: Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.
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- Wicher, K. B., et al.
(författare)
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Deletion of a cytotoxic, N-terminal putative signal peptide results in a significant increase in production yields in Escherichia coli and improved specific activity of Cel12A from Rhodothermus marinus
- 2001
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Ingår i: Applied Microbiology and Biotechnology. - : Springer Science and Business Media LLC. - 0175-7598 .- 1432-0614. ; 55:5, s. 578-584
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Tidskriftsartikel (refereegranskat)abstract
- The thermostable cellulase Cel12A from Rhodothermus marinus was produced at extremely low levels when expressed in Escherichia coli and was cytotoxic to the cells. In addition, severe aggregation occurred when moderately high concentrations of the enzyme were heat-treated at 65°C, the growth optimum of R. marinus. Sequence analysis revealed that the catalytic module of this enzyme is preceded by a typical linker sequence and a highly hydrophobic putative signal peptide. Two deletion mutants lacking this hydrophobic region were cloned and successfully expressed in E. coli. These results indicated that the N-terminal putative signal peptide was responsible for the toxicity of the full-length enzyme in the host organism. This was further corroborated by cloning and expressing the hydrophobic N-terminal domain in E. coli, which resulted in extensive cell lysis. The deletion mutants, made up of either the catalytic module of Cel12A or the catalytic module and the putative linker sequence, were characterised and their properties compared to those of the full-length enzyme. The specific activity of the mutants was approximately threefold higher than that of the full-length enzyme. Both mutant proteins were highly thermostable, with half-lives exceeding 2 h at 90°C and unfolding temperatures up to 103°C.
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- Matosin, N, et al.
(författare)
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Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex
- 2023
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 145:4, s. 439-459
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Tidskriftsartikel (refereegranskat)abstract
- Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.
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- Thorarinsdottir, Kristjana, et al.
(författare)
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Using a Brief Mental Imagery Competing Task to Reduce the Number of Intrusive Memories : Exploratory Case Series With Trauma-Exposed Women
- 2022
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Ingår i: JMIR Formative Research. - : JMIR Publications. - 2561-326X. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Background:Novel interventions should be developed for people who have undergone psychological trauma. In a previous case study, we found that the number of intrusive memories of trauma could be reduced with a novel intervention. The intervention included a brief memory reminder, a visuospatial task and mental rotation, and targeted trauma memory hotspots one at a time in separate sessions.Objective:This case series (N=3) extended the first case study with 3 new cases to determine whether a similar pattern of beneficial results is observed. We explored whether the brief intervention would result in reduced numbers of intrusive memories and whether it would impact symptoms of posttraumatic stress, depression and anxiety, and general functioning. Acceptability of the intervention was also explored.Methods:A total of 3 women completed the study: 2 with posttraumatic stress disorder and other comorbidities and 1 with subthreshold posttraumatic stress disorder. The primary outcome was the change in the number of intrusive memories from the baseline phase to the intervention phase and at the 1-month follow-up, with an assessment of the intrusion frequency at 3 months. Participants monitored the number of intrusive memories in a daily diary for 1 week at baseline, for maximum of 6 weeks during the intervention phase and for 1 week at the 1-month and 3-month follow-ups. The intervention was delivered in person or digitally, with guidance from a clinical psychologist. A repeated AB design was used (A was a preintervention baseline phase and B intervention phase). Intrusions were targeted individually, creating repetitions of an AB design.Results:The total number of intrusive memories was reduced from the baseline to the intervention phase for all participants. The total number for participant 3 (P3) reduced from 38.8 per week during the baseline phase to 18.0 per week in the intervention phase. It was 13 at the 3-month follow-up. The total number for P4 reduced from 10.8 per week at baseline to 4.7 per week in the intervention phase. It was 0 at the 3-month follow-up. The total number for P5 was reduced from 33.7 at baseline to 20.7 per week in the intervention phase. It was 8 at the 3-month follow-up. All participants reported reduction in posttraumatic stress symptoms in the postintervention phase. Depression and anxiety symptoms reduced in 2 of the 3 participants in the postintervention phase. Acceptability was favorable.Conclusions:We observed good compliance with the intervention and intrusive memory diary in all 3 cases. The number of intrusive memories was reduced for all participants during the intervention phase and at the 1-month follow-up, with some improvement in other symptoms and functioning. Further research should explore the remote delivery of the intervention and whether nonspecialists can deliver the intervention effectively.
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