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- Camacho-Munoz, D., et al.
(author)
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Omega-3 carboxylic acids and fenofibrate differentially alter plasma lipid mediators in patients with non-alcoholic fatty liver disease
- 2021
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In: Faseb Journal. - : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 35:11
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Journal article (peer-reviewed)abstract
- Fibrates and omega-3 polyunsaturated acids are used for the treatment of hypertriglyceridemia but have not demonstrated consistent effects on cardiovascular (CV) risk. In this study, we investigate how these two pharmacological agents influence plasma levels of bioactive lipid mediators, aiming to explore their efficacy beyond that of lipid-lowering agents. Plasma from overweight patients with non-alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia, participating in a randomized placebo-controlled study investigating the effects of 12 weeks treatment with fenofibrate or omega-3 free carboxylic acids (OM-3CA) (200 mg or 4 g per day, respectively), were analyzed for eicosanoids and related PUFA species, N-acylethanolamines (NAE) and ceramides. OM-3CA reduced plasma concentrations of proinflammatory PGE(2), as well as PGE(1), PGD(1) and thromboxane B2 but increased prostacyclin, and eicosapentaenoic acid- and docosahexaenoic acid-derived lipids of lipoxygenase and cytochrome P450 monooxygenase (CYP) (e.g., 17-HDHA, 18-HEPE, 19,20-DiHDPA). Fenofibrate reduced plasma concentrations of vasoactive CYP-derived eicosanoids (DHETs). Although OM-3CA increased plasma levels of the NAE docosahexaenoyl ethanolamine and docosapentaenoyl ethanolamine, and fenofibrate increased palmitoleoyl ethanolamine, the effect of both treatments may have been masked by the placebo (olive oil). Fenofibrate was more efficacious than OM-3CA in significantly reducing plasma ceramides, pro-inflammatory lipids associated with CV disease risk. Neither treatment affected putative lipid species associated with NAFLD. Our results show that OM-3CA and fenofibrate differentially modulate the plasma mediator lipidome, with OM-3CA promoting the formation of lipid mediators with potential effects on chronic inflammation, while fenofibrate mainly reducing ceramides. These findings suggest that both treatments could ameliorate chronic inflammation with possible impact on disease outcomes, independent of triglyceride reduction.
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- Eskilsson, Anna, et al.
(author)
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The generation of immune-induced fever and emotional stress-induced hyperthermia in mice does not involve brown adipose tissue thermogenesis
- 2020
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In: FASEB Journal. - : WILEY. - 0892-6638 .- 1530-6860. ; 34:4, s. 5863-5876
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Journal article (peer-reviewed)abstract
- We examined the role of brown adipose tissue (BAT) for fever and emotional stress-induced hyperthermia. Wild-type and uncoupling protein-1 (UCP-1) knockout mice were injected with lipopolysaccharide intraperitoneally or intravenously, or subjected to cage exchange, and body temperature monitored by telemetry. Both genotypes showed similar febrile responses to immune challenge and both displayed hyperthermia to emotional stress. Neither procedure resulted in the activation of BAT, such as the induction of UCP-1 or peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) mRNA, or reduced BAT weight and triglyceride content. In contrast, in mice injected with a beta (3) agonist, UCP-1 and PGC-1 alpha were strongly induced, and BAT weight and triglyceride content reduced. Both lipopolysaccharide and the beta (3) agonist, and emotional stress, induced UCP-3 mRNA in skeletal muscle. A beta (3) antagonist did not attenuate lipopolysaccharide-induced fever, but augmented body temperature decrease and inhibited BAT activation when mice were exposed to cold. An alpha (1)/alpha (2b) antagonist or a 5HT(1A) agonist, which inhibit vasoconstriction, abolished lipopolysaccharide-induced fever, but had no effect on emotional stress-induced hyperthermia. These findings demonstrate that in mice, UCP-1-mediated BAT thermogenesis does not take part in inflammation-induced fever, which is dependent on peripheral vasoconstriction, nor in stress-induced hyperthermia. However, both phenomena may involve UCP-3-mediated muscle thermogenesis.
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- Fernandez-Gonzalo, Rodrigo, et al.
(author)
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Three months of bed rest induce a residual transcriptomic signature resilient to resistance exercise countermeasures
- 2020
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In: The FASEB Journal. - : WILEY. - 0892-6638 .- 1530-6860. ; 34:6, s. 7958-7969
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Journal article (peer-reviewed)abstract
- This study explored the muscle genome-wide response to long-term unloading (84-day bed rest) in 21 men. We hypothesized that a part of the bed rest-induced gene expression signature would be resilient to a concurrent flywheel resistance exercise (RE) countermeasure. Using DNA microarray technology analyzing 35 345 gene-level probe-sets, we identified 335 annotated probe-sets that were downregulated, and 315 that were upregulated after bed rest (P < .01). Besides a predictable differential expression of genes and pathways related to mitochondria (downregulation; false-discovery rates (FDR) <1E-04), ubiquitin system (upregulation; FDR = 3E-02), and skeletal muscle energy metabolism and structure (downregulation; FDR <= 3E-03), 84-day bed rest also altered circadian rhythm regulation (upregulation; FDR = 3E-02). While most of the bed rest-induced changes were counteracted by RE, 209 transcripts were resilient to the exercise countermeasure. Genes upregulated after bed rest were particularly resistant to training (P < .001 vs downregulated, non-reversed genes). Specifically, "Translation Factors," "Proteasome Degradation," "Cell Cycle," and "Nucleotide Metabolism" pathways were not normalized by RE. This study provides an unbiased high-throughput transcriptomic signature of one of the longest unloading periods in humans to date. Classical disuse-related changes in structural and metabolic genes/pathways were identified, together with a novel upregulation of circadian rhythm transcripts. In the context of previous bed rest campaigns, the latter seemed to be related to the duration of unloading, suggesting the transcriptomic machinery continues to adapt throughout extended disuse periods. Despite that the RE training offset most of the bed rest-induced muscle-phenotypic and transcriptomic alterations, we contend that the human skeletal muscle also displays a residual transcriptomic signature of unloading that is resistant to an established exercise countermeasure.
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- Gupta, G., et al.
(author)
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Cobalt nanoparticles trigger ferroptosis-like cell death (oxytosis) in neuronal cells : Potential implications for neurodegenerative disease
- 2020
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In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 34:4, s. 5262-5281
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Journal article (peer-reviewed)abstract
- The neurotoxicity of hard metal-based nanoparticles (NPs) remains poorly understood. Here, we deployed the human neuroblastoma cell line SH-SY5Y differentiated or not into dopaminergic- and cholinergic-like neurons to study the impact of tungsten carbide (WC) NPs, WC NPs sintered with cobalt (Co), or Co NPs versus soluble CoCl2. Co NPs and Co salt triggered a dose-dependent cytotoxicity with an increase in cytosolic calcium, lipid peroxidation, and depletion of glutathione (GSH). Co NPs and Co salt also suppressed glutathione peroxidase 4 (GPX4) mRNA and protein expression. Co-exposed cells were rescued by N-acetylcysteine (NAC), a precursor of GSH, and partially by liproxstatin-1, an inhibitor of lipid peroxidation. Furthermore, in silico analyses predicted a significant correlation, based on similarities in gene expression profiles, between Co-containing NPs and Parkinson's disease, and changes in the expression of selected genes were validated by RT-PCR. Finally, experiments using primary human dopaminergic neurons demonstrated cytotoxicity and GSH depletion in response to Co NPs and CoCl2 with loss of axonal integrity. Overall, these data point to a marked neurotoxic potential of Co-based but not WC NPs and show that neuronal cell death may occur through a ferroptosis-like mechanism.
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- Hansson, Magnus L., et al.
(author)
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Artificial spider silk supports and guides neurite extension in vitro
- 2021
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In: The FASEB Journal. - : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 35:11
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Journal article (peer-reviewed)abstract
- Surgical intervention with the use of autografts is considered the gold standard to treat peripheral nerve injuries. However, a biomaterial that supports and guides nerve growth would be an attractive alternative to overcome problems with limited availability, morbidity at the site of harvest, and nerve mismatches related to autografts. Native spider silk is a promising material for construction of nerve guidance conduit (NGC), as it enables regeneration of cm-long nerve injuries in sheep, but regulatory requirements for medical devices demand synthetic materials. Here, we use a recombinant spider silk protein (NT2RepCT) and a functionalized variant carrying a peptide derived from vitronectin (VN-NT2RepCT) as substrates for nerve growth support and neurite extension, using a dorsal root ganglion cell line, ND7/23. Two-dimensional coatings were benchmarked against poly-d-lysine and recombinant laminins. Both spider silk coatings performed as the control substrates with regards to proliferation, survival, and neurite growth. Furthermore, NT2RepCT and VN-NT2RepCT spun into continuous fibers in a biomimetic spinning set-up support cell survival, neurite growth, and guidance to an even larger extent than native spider silk. Thus, artificial spider silk is a promising biomaterial for development of NGCs.
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