| 1. |
- Addinsall, Alex B., et al.
(författare)
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Ruxolitinib Prevents Ventilator Induced Diaphragm Dysfunction
- 2022
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Ingår i: The FASEB Journal. - : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 36:S1
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Tidskriftsartikel (refereegranskat)abstract
- Mechanical ventilation (MV), however brief results in the loss of diaphragm muscle mass and strength, termed ventilator induced diaphragm dysfunction (VIDD). VIDD increases dependence, complicates and prolongs weaning and significantly increases discharge mortality rate and health care costs worldwide. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway was recently identified as an important signalling pathway implicated in VIDD, upregulated in the diaphragm following MV and limb muslces during critical care. Regulation of STAT3 is imperritve to skeletal muscle mass and function, as STAT3 is required in proper muscle growth and regeneration, while chronic activation of STAT3 is implicated in muscle dysfunction. As JAK/STAT pathway inhibition can restrict the development of chronic muscle wasting conditons, this study aimed to explore the therapeutic potential of Ruxolitinib, an approved JAK1/2 inhibitor for myelofibrosis, for treatment of CIM. We hypothesised Ruxolitinib would reduce loss of muscle mass and function associated with VIDD. Here, rats were subjected to five days controlled MV (CMV) with and without daily Ruxolitinib gavage. Five-days CMV significantly reduced diaphragm muscle size and impaired specific force, which was associated with 2-fold upregulation of P-STAT3, disrupted mitochondrial structure and respiratory function. Expression of the motor protein myosin was not affected, however CMV may alter myosin function through deamidation post translational modification. Ruxolitinib increases five-day survival rate, restored P-STAT3 expression and preserved diaphragm muscle size and specific force. These functional improvements were associated with improved mitochondrial structure, augmented mitochondrial respiratory function and reversal or augmentation of myosin deamidations. These results provide evidence of the preclinical potential of repurposing Ruxolitinib for the treatment of VIDD.
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| 2. |
- Aguado, T, et al.
(författare)
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The endocannabinoid system drives neural progenitor proliferation
- 2005
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 19:9, s. 1704-1704
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of multipotent neural progenitor (NP) cells has provided strong support for the existence of neurogenesis in the adult brain. However, the signals controlling NP proliferation remain elusive. Endocannabinoids, the endogenous counterparts of marijuana-derived cannabinoids, act as neuromodulators via presynaptic CB1 receptors and also control neural cell death and survival. Here we show that progenitor cells express a functional endocannabinoid system that actively regulates cell proliferation both in vitro and in vivo. Specifically, NPs produce endocannabinoids and express the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase ( FAAH). CB1 receptor activation promotes cell proliferation and neurosphere generation, an action that is abrogated in CB1-deficient NPs. Accordingly, proliferation of hippocampal NPs is increased in FAAH-deficient mice. Our results demonstrate that endocannabinoids constitute a new group of signaling cues that regulate NP proliferation and thus open novel therapeutic avenues for manipulation of NP cell fate in the adult brain.
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| 3. |
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| 4. |
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| 5. |
- Alkhori, Liza, et al.
(författare)
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The corepressor Atrophin specifies odorant receptor expression in Drosophila
- 2014
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Ingår i: The FASEB Journal. - : Federation of American Societies for Experimental Biology. - 0892-6638 .- 1530-6860. ; 28:3, s. 1355-1364
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Tidskriftsartikel (refereegranskat)abstract
- In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.
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| 6. |
- Almuzzaini, Bader, et al.
(författare)
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In beta-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects
- 2016
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 30:8, s. 2860-2873
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Tidskriftsartikel (refereegranskat)abstract
- Actin and nuclear myosin 1 (NM1) are regulators of transcription and chromatin organization. Using a genome-wide approach, we report here that beta-actin binds intergenic and genic regions across the mammalian genome, associated with both protein-coding and rRNA genes. Within the rDNA, the distribution of beta-actin correlated with NM1 and the other subunits of the B-WICH complex, WSTF and SNF2h. In beta-actin(-/-) mouse embryonic fibroblasts (MEFs), we found that rRNA synthesis levels decreased concomitantly with drops in RNA polymerase I (Pol I) and NM1 occupancies across the rRNA gene. Reintroduction of wild-type beta-actin, in contrast to mutated forms with polymerization defects, efficiently rescued rRNA synthesis underscoring the direct role for a polymerization-competent form of beta-actin in Pol I transcription. The rRNA synthesis defects in the beta-actin(-/-) MEFs are a consequence of epigenetic reprogramming with up-regulation of the repressive mark H3K4me1 (mono-methylation of lys4 on histone H3) and enhanced chromatin compaction at promoter-proximal enhancer (T0 sequence), which disturb binding of the transcription factor TTF1. We propose a novel genome-wide mechanism where the polymerase-associated beta-actin synergizes with NM1 to coordinate permissive chromatin with Pol I transcription, cell growth, and proliferation.
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| 7. |
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| 8. |
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| 9. |
- Alvarado-Kristensson, Maria, et al.
(författare)
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p38 Mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis.
- 2002
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 16:1, s. 31-129
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil apoptosis is essential for resolution of inflammatory reactions. Here, we studied the role of two apoptosis/survival-associated protein kinases in this process. We discovered a previously undetected early and transient inhibition of the activity of p38 mitogen-activated protein kinase (p38 MAPK) during both spontaneous and Fas-induced apoptosis. Pharmacological inhibition of this enzyme augmented the activation of caspases and the apoptotic response, which suggests that the p38 MAPK signals survival in neutrophils. Our finding that caspase-3 activity was initiated during the transient inhibition of p38 MAPK suggests that apoptosis is initiated during this inhibition. Furthermore, such transient inhibition was counteracted by granulocyte-macrophage colony-stimulating factor, which elicits survival. We also found that neither this inhibition of p38 MAPK nor the spontaneous apoptotic response depended on Fas. Instead, the early inhibition of p38 MAPK concurred with a Fas-induced activation of phosphatidylinositol 3-kinase, inhibition of which reduced apoptosis. Thus, the Fas-induced augmentation of spontaneous apoptosis can be explained by its activation of phosphatidylinositol 3-kinase. We conclude that p38 MAPK activity represents a survival signal that is inactivated transiently during both spontaneous and Fas-induced apoptosis, whereas Fas-induced phosphatidylinositol 3-kinase activity is a proapoptotic signal in isolated human neutrophils.
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| 10. |
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| 11. |
- Ameye, L, et al.
(författare)
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Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis
- 2002
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 16:7, s. 673-680
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Tidskriftsartikel (refereegranskat)abstract
- Small leucine-rich proteoglycans (SLRPs) regulate extracellular matrix organization, a process essential in development, tissue repair, and metastasis. In vivo interactions of biglycan and fibromodulin, two SLRPs highly expressed in tendons and bones, were investigated by generating biglycan/fibromodulin double-deficient mice. Here we show that collagen fibrils in tendons from mice deficient in biglycan and/or fibromodulin are structurally and mechanically altered resulting in unstable joints. As a result, the mice develop successively and progressively 1) gait impairment, 2) ectopic tendon ossification, and 3) severe premature osteoarthritis. Forced use of the joints increases ectopic ossification and osteoarthritis in the double-deficient mice, further indicating that structurally weak tendons cause the phenotype. The study shows that mutations in SLRPs may predispose to osteoarthritis and offers a valuable and unique animal model for spontaneous osteoarthritis characterized by early onset and a rapid progression of the disease.
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| 12. |
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| 13. |
- Amrutkar, Manoj, et al.
(författare)
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Protein kinase STK25 regulates hepatic lipid partitioning and progression of liver steatosis and NASH
- 2015
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Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:4, s. 1564-1576
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease, and 10% to 20% of NAFLD patients progress to nonalcoholic steatohepatitis (NASH). The molecular pathways controlling progression to NAFLD/NASH remain poorly understood. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of whole-body insulin and glucose homeostasis. This study investigates the role of STK25 in liver lipid accumulation and NASH. Stk25 transgenic mice challenged with a high-fat diet displayed a dramatic increase in liver steatosis and hepatic insulin resistance compared to wild-type siblings. Focal fibrosis, hepatocellular damage, and inflammation were readily seen in transgenic but not wild-type livers. Transgenic livers displayed reduced beta-oxidation and triacylglycerol secretion, while lipid uptake and synthesis remained unchanged. STK25 was associated with lipid droplets, colocalizing with the main hepatic lipid droplet-coating protein adipose differentiation-related protein, the level of which was increased 3.8 +/- 0.7-fold in transgenic livers (P < 0.01), while a key hepatic lipase, adipose triacylglycerol lipase, was translocated from the lipid droplets surface to the cytoplasm, providing the likely mechanism underlying the effect of STK25. In summary, STK25 is a lipid droplet-associated protein that promotes NAFLD through control of lipid release from the droplets for beta-oxidation and triacylglycerol secretion. STK25 also drives pathogenesis of NASH.
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| 14. |
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| 15. |
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| 16. |
- Apró, William, et al.
(författare)
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Is leucine induced p70S6 kinase phosphorylation following resistance exercise dependent on elevated phenylalanine levels in human skeletal muscle?
- 2010
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 24, s. lb273-
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate the specific role ofleucine in the stimulation of the mammalian target of rapamycinsignalling pathway. Six male subjects performed four heavyresistance exercise sessions, each separated by approximately oneweek. Subjects were randomly supplemented with one of fourdrinks: placebo (flavored water), leucine or essential amino acids(EAA) with and without leucine. Immediately following eachexercise session, four subjects were infused with a flooding dose ofL-[2H5] phenylalanine (Inf) while two subjects served as controls(Ctrl). Muscle biopsies were taken before and one hour afterexercise. In the Ctrl group, resistance exercise resulted in asubstantial increase (45-fold) in p70 kinase phosphorylationwhen all EAA were ingested, whereas ingestion of leucine alonehad no greater effect than that of placebo. In the Inf group,however, ingestion of leucine alone and EAA increased p70phosphorylation to a similar extent (35-fold). The divergentsignalling response in the two groups suggests that leucine alone isinsufficient to increase p70phosphorylation. Indeed, in the Infgroup, there was a strong correlation (r=0.91) betweenp70 phosphorylation and the product of muscle leucine andphenylalanine levels. These results suggest that the stimulatoryeffect of leucine on p70 phosphorylation is dependent onelevated muscle phenylalanine levels. Supported by the SwedishNational Centre for Research in Sports
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| 17. |
- Apró, William, et al.
(författare)
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Leucine does not affect mechanistic target of rapamycin complex 1 assembly but is required for maximal ribosomal protein s6 kinase 1 activity in human skeletal muscle following resistance exercise
- 2015
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:10, s. 4358-4373
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Tidskriftsartikel (refereegranskat)abstract
- We examined how the stimulatory effect of leucine on the mechanistic target of rapamycin complex 1 (mTORC1) pathway is affected by the presence of the remaining essential amino acids (EAAs). Nine male subjects performed resistance exercise on 4 occasions and were randomly supplied EAAs with leucine, EAAs without leucine (EAA-Leu), leucine alone, or flavored water (placebo; control). Muscle biopsies were taken from the vastus lateralis before and 60 and 90 min after exercise. Biopsies were analyzed for protein phosphorylation, kinase activity, protein-protein interactions, amino acid concentrations, and tracer incorporation. Leucine alone stimulated ribosomal protein s6 kinase 1 (S6K1) phosphorylation similar to 280% more than placebo and EAA-Leu after exercise. Moreover, this response was enhanced by 60-75% after intake of EAAs compared with that of leucine alone (P < 0.05). Kinase activity of S6K1 reflected that of S6K1 phosphorylation; 60 min after exercise, the activity was elevated 3.3- and 4.2-fold with intake of leucine alone and with EAAs, respectively (P < 0.05). The interaction between mammalian target of rapamycin and regulatory-associated protein of mammalian target of rapamycin was unaltered in response to both resistance exercise and amino acid provision. Leucine alone stimulates mTORC1 signaling, although this response is enhanced by other EAAs and does not appear to be caused by alterations inmTORC1 assembly.
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| 18. |
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| 19. |
- Ashmore, T, et al.
(författare)
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Suppression of erythropoiesis by dietary nitrate
- 2015
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 29:3, s. 1102-1112
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Tidskriftsartikel (refereegranskat)
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| 20. |
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| 21. |
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| 22. |
- Barnes, Brian R, et al.
(författare)
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5'-AMP-activated protein kinase regulates skeletal muscle glycogen content and ergogenics
- 2005
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 19:7, s. 773-779
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Tidskriftsartikel (refereegranskat)abstract
- 5'-AMP-activated protein kinase (AMPK) activity is increased during exercise in an intensity- and glycogen-dependent manner. We previously reported that a mutation in the AMPK3 subunit (Prkag3225Q) increases AMPK activity and skeletal muscle glycogen content. Transfection experiments revealed the R225Q mutation is associated with high basal AMPK activity and diminished AMP dependence. Thus, the R225Q mutation can be considered a loss-of-function mutation that abolished allosteric regulation by AMP/ATP, causing increased basal AMPK activity. We used AMPK3 transgenic (Tg-Prkag3225Q) and knockout (Prkag3-/-) mice to determine the relationship between AMPK activity, glycogen content, and ergogenics (ability to perform work) in isolated extensor digitorum longus skeletal muscle after contractions induced by electrical stimulation. Contraction-induced AMPK activity was inversely coupled to glycogen content in wild-type and Tg-Prkag3225Q mice, but not in Prkag3-/- mice, highlighting a partial feedback control of glycogen on contraction-induced AMPK activity in the presence of a functional AMPK3 isoform. Skeletal muscle glycogen content was positively correlated to work performance, regardless of genotype. Thus, chronic activation of AMPK by the Prkag3225Q mutation directly influences skeletal muscle ergogenics by enhancing glycogen content. In conclusion, functional studies of the AMPK3 isoform further support the close connection between glycogen content and exercise performance in skeletal muscle.
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| 23. |
- Benedict, Christian, et al.
(författare)
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Enhancing influence of intranasal interleukin-6 on slow-wave activity and memory consolidation during sleep
- 2009
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Ingår i: The FASEB Journal. - : FASEB. - 0892-6638 .- 1530-6860. ; 23:10, s. 3629-3636
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Tidskriftsartikel (refereegranskat)abstract
- The cytokine IL-6 has been considered to exert neuromodulating influences on the brain, with promoting influences on sleep. Sleep enhances the consolidation of memories, and, in particular, late nocturnal sleep also represents a period of enhanced IL-6 signaling, due to a distinctly enhanced availability of soluble IL-6 receptors during this period, enabling trans-signaling of IL-6 to neurons. Thus, a contribution of IL-6 to sleep-dependent memory consolidation is hypothesized. To test this hypothesis, we compared effects of intranasally administered IL-6 (vs. placebo) on sleep-dependent consolidation of declarative (neutral and emotional texts, 2-dimensional object location) and procedural (finger sequence tapping) memories in 17 healthy young men. IL-6 distinctly improved the sleep-related consolidation of emotional text material (P<0.03), which benefits mostly from sleep in the second night-half, in which rapid eye movement sleep (REM) dominates the non-REM-REM sleep cycle. During this second night-half, the amount of electroencephalogram slow-wave activity (0.5-4 Hz) distinctly increased after IL-6 (P<0.01). Other types of memory were not affected. The ability of IL-6 to enhance sleep-associated emotional memory consolidation highlights an example of a functional interaction between the central nervous and immune system.
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| 24. |
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| 25. |
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| 26. |
- Benrick, Anna, 1979, et al.
(författare)
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Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture
- 2017
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Ingår i: Faseb Journal. - : Federation of American Societies for Experimental Biology. - 0892-6638 .- 1530-6860. ; 31:8, s. 3288-3297
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Tidskriftsartikel (refereegranskat)abstract
- A single bout of low-frequency electroacupuncture (EA) causing muscle contractions increases whole-body glucose uptake in insulin-resistant rats. We explored the underlying mechanism of this finding and whether it can be translated into clinical settings. Changes in glucose infusion rate (GIR) were measured by euglycemic-hyperinsulinemic clamp during and after 45 min of low-frequency EA in 21 overweight/obese women with polycystic ovary syndrome (PCOS) and 21 controls matched for age, weight, and body mass index (experiment 1) and in rats receiving autonomic receptor blockers (experiment 2). GIR was higher after EA in controls and women with PCOS. Plasma serotonin levels and homovanillic acid, markers of vagal activity, decreased in both controls and patients with PCOS. Adipose tissue expression of pro-nerve growth factor (proNGF) decreased, and the mature NGF/proNGF ratio increased after EA in PCOS, but not in controls, suggesting increased sympathetic-driven adipose tissue metabolism. Administration of alpha-/beta-adrenergic receptor blockers in rats blocked the increase in GIR in response to EA. Muscarinic and dopamine receptor antagonist also blocked the response but with slower onset. In conclusion, a single bout of EA increases whole-body glucose uptake by activation of the sympathetic and partly the parasympathetic nervous systems, which could have important clinical implications for the treatment of insulin resistance.
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| 27. |
- Berghard, Anna, et al.
(författare)
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Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons
- 2012
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Ingår i: The FASEB Journal. - : Federation of American Society of Experimental Biology (FASEB). - 0892-6638 .- 1530-6860. ; 26:8, s. 3464-3472
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Tidskriftsartikel (refereegranskat)abstract
- Inactivation of the LIM-homeodomain 2 gene (Lhx2) results in a severe defect in specification of olfactory sensory neurons (OSNs). However, the ramifications of lack of Lhx2-dependent OSN specification for formation of the primary olfactory pathway have not been addressed, since mutant mice die in utero. We have analyzed prenatal and postnatal consequences of conditionally inactivating Lhx2 selectively in OSNs. A cell-autonomous effect is that OSN axons cannot innervate their target, the olfactory bulb. Moreover, the lack of Lhx2 in OSNs causes unpredicted, non-cell-autonomous phenotypes. First, the olfactory bulb shows pronounced hypoplasia in adults, and the data suggest that innervation by correctly specified OSNs is necessary for adult bulb size and organization. Second, absence of an olfactory nerve in the conditional mutant reveals that the vomeronasal nerve is dependent on olfactory nerve formation. Third, the lack of a proper vomeronasal nerve prevents migration of gonadotropin-releasing hormone (GnRH) cells the whole distance to their final positions in the hypothalamus during embryo development. As adults, the conditional mutants do not pass puberty, and these findings support the view of an exclusive nasal origin of GnRH neurons in the mouse. Thus, Lhx2 in OSNs is required for functional development of three separate systems.—Berghard, A., Hägglund, A.-C., Bohm, S., and Carlsson, L. Lhx2-dependent specification of olfactory sensory neurons is required for successful integration of olfactory, vomeronasal, and GnRH neurons.
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| 28. |
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| 29. |
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| 30. |
- Bett, Cyrus, et al.
(författare)
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Structure of the beta 2-alpha 2 loop and interspecies prion transmission
- 2012
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Ingår i: The FASEB Journal. - : Federation of American Society of Experimental Biology (FASEB). - 0892-6638 .- 1530-6860. ; 26:7, s. 2868-2876
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Tidskriftsartikel (refereegranskat)abstract
- Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The beta 2-alpha 2 loop region of endogenous prion protein, PrPC, has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar beta 2-alpha 2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the beta 2-alpha 2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered beta 2-alpha 2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrPC from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.
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| 31. |
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| 32. |
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| 33. |
- Björkgren, Ida, et al.
(författare)
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Imbalanced lipid homeostasis in the conditional Dicer1 knockout mouse epididymis causes instability of the sperm membrane.
- 2015
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 29:2, s. 433-442
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Tidskriftsartikel (refereegranskat)abstract
- During epididymal sperm maturation, the lipid content of the sperm membrane is modified, which facilitates sperm motility and fertility. However, little is known about the mechanisms regulating the maturation process. By generating a conditional knockout (cKO) of Dicer1 in the proximal part of the mouse epididymis, we studied the role of RNA interference in epididymal functions. The Dicer1 cKO epididymis displayed an altered lipid homeostasis associated with a 0.6-fold reduction in the expression of the gene elongation of very long chain fatty acids-like 2, an enzyme needed for production of long-chain polyunsaturated fatty acids (PUFAs). Furthermore, the expression of several factors involved in cholesterol synthesis was up-regulated. Accordingly, the Dicer1 cKO sperm membrane showed a 0.7-fold decrease in long-chain PUFAs, whereas the amount of cholesterol in acrosome-reacted sperm displayed a 1.7-fold increase. The increased cholesterol:PUFA ratio of the sperm membrane caused breakage of the neck and acrosome region and immotility of sperm. Dicer1 cKO mice sperm also displayed reduced ability to bind to and fertilize the oocyte in vitro. This study thus shows that Dicer1 is critical for lipid synthesis in the epididymis, which directly affects sperm membrane integrity and male fertility.-Björkgren, I., Gylling, H., Turunen, H., Huhtaniemi, I., Strauss, L., Poutanen, M., Sipilä, P. Imbalanced lipid homeostasis in the conditional Dicer1 knockout mouse epididymis causes instability of the sperm membrane.
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| 34. |
- Bondia-Pons, Isabel, et al.
(författare)
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Metabolome and fecal microbiota in monozygotic twin pairs discordant for weight : a Big Mac challenge
- 2014
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 28:9, s. 4169-4179
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Tidskriftsartikel (refereegranskat)abstract
- Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels.
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| 35. |
- Bondjers, Cecilia, 1974, et al.
(författare)
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Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes.
- 2006
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Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 20:10, s. 1703-5
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Tidskriftsartikel (refereegranskat)abstract
- Normal blood microvessels are lined by pericytes, which contribute to microvessel development and stability through mechanisms that are poorly understood. Pericyte deficiency has been implicated in the pathogenesis of microvascular abnormalities associated with diabetes and tumors. However, the unambiguous identification of pericytes is still a problem because of cellular heterogeneity and few available molecular markers. Here we describe an approach to identify pericyte markers based on transcription profiling of pericyte-deficient brain microvessels isolated from platelet-derived growth factor (PDGF-B)-/- and PDGF beta receptor (PDGFRbeta)-/- mouse mutants. The approach was validated by the identification of known pericyte markers among the most down-regulated genes in PDGF-B-/- and PDGFRbeta-/- microvessels. Of candidates for novel pericyte markers, we selected ATP-sensitive potassium-channel Kir6.1 (also known as Kcnj8) and sulfonylurea receptor 2, (SUR2, also known as Abcc9), both part of the same channel complex, as well as delta homologue 1 (DLK1) for in situ hybridization, which demonstrated their specific expression in brain pericytes of mouse embryos. We also show that Kir6.1 is highly expressed in pericytes in brain but undetectable in pericytes in skin and heart. The three new brain pericyte markers are signaling molecules implicated in ion transport and intercellular signaling, potentially opening new windows on pericyte function in brain microvessels.
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| 36. |
- Botchkarev, V A, et al.
(författare)
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Noggin is required for induction of the hair follicle growth phase in postnatal skin.
- 2001
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 15:12, s. 2205-14
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Tidskriftsartikel (refereegranskat)abstract
- During postnatal development, the hair follicle (HF) shows cyclic activity with periods of relative resting, active growth (anagen), and regression. We demonstrate that similar to the HF induction in embryonic skin, initiation of a new hair growth phase in postnatal skin requires neutralization of the inhibitory activity of bone morphogenetic protein 4 (BMP4) by the BMP antagonist noggin. In the resting HF, BMP4 mRNA predominates over noggin in the epithelium and mesenchyme, and the BMP receptor IA is prominently expressed in the follicular germ. Anagen development is accompanied by down-regulation of the BMP4 and increased noggin mRNA in the HF. Furthermore, administration of noggin protein induces new hair growth phase in postnatal telogen skin in vivo. In contrast, BMP4 induces selective arrest of anagen development in the non-tylotrich (secondary) HF. As a hair growth inducer, noggin increases Shh mRNA in the HF whereas BMP4 down-regulates Shh. This suggests that modulation of BMP4 signaling by noggin is essential for hair growth phase induction in postnatal skin and that the hair growth-inducing effect of noggin is mediated, at least in part, by Shh.
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| 37. |
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| 38. |
- Bratengeier, Cornelia, et al.
(författare)
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High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cells
- 2020
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Ingår i: The FASEB Journal. - : FEDERATION AMER SOC EXP BIOL. - 0892-6638 .- 1530-6860. ; 34:3, s. 3755-3772
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Tidskriftsartikel (refereegranskat)abstract
- To date, it is unclear how fluid dynamics stimulate mechanosensory cells to induce an osteoprotective or osteodestructive response. We investigated how murine hematopoietic progenitor cells respond to 2 minutes of dynamic fluid flow stimulation with a precisely controlled sequence of fluid shear stresses. The response was quantified by measuring extracellular adenosine triphosphate (ATP), immunocytochemistry of Piezo1, and sarcoplasmic/endoplasmic Ca2+ reticulum ATPase 2 (SERCA2), and by the ability of soluble factors produced by mechanically stimulated cells to modulate osteoclast differentiation. We rejected our initial hypothesis that peak wall shear stress rate determines the response of hematopoietic progenitor cells to dynamic fluid shear stress, as it had only a minor correlation with the abovementioned parameters. Low stimulus amplitudes corresponded to activation of Piezo1, SERCA2, low concentrations of extracellular ATP, and inhibition of osteoclastogenesis and resorption area, while high amplitudes generally corresponded to osteodestructive responses. At a given amplitude (3 Pa) and waveform (square), the duration of individual stimuli (duty cycle) showed a strong correlation with the release of ATP and osteoclast number and resorption area. Collectively, our data suggest that hematopoietic progenitor cells respond in a viscoelastic manner to loading, since a combination of high shear stress amplitude and prolonged duty cycle is needed to trigger an osteodestructive response. Plain Language Summary In case of painful joints or missing teeth, the current intervention is to replace them with an implant to keep a high-quality lifestyle. When exercising or chewing, the cells in the bone around the implant experience mechanical loading. This loading generally supports bone formation to strengthen the bone and prevent breaking, but can also stimulate bone loss when the mechanical loading becomes too high around orthopedic and dental implants. We still do not fully understand how cells in the bone can distinguish between mechanical loading that strengthens or weakens the bone. We cultured cells derived from the bone marrow in the laboratory to test whether the bone loss response depends on (i) how fast a mechanical load is applied (rate), (ii) how intense the mechanical load is (amplitude), or (iii) how long each individual loading stimulus is applied (duration). We mimicked mechanical loading as it occurs in the body, by applying very precisely controlled flow of fluid over the cells. We found that a mechanosensitive receptor Piezo1 was activated by a low amplitude stimulus, which usually strengthens the bone. The potential inhibitor of Piezo1, namely SERCA2, was only activated by a low amplitude stimulus. This happened regardless of the rate of application. At a constant high amplitude, a longer duration of the stimulus enhanced the bone-weakening response. Based on these results we deduce that a high loading amplitude tends to be bone weakening, and the longer this high amplitude persists, the worse it is for the bone.
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| 39. |
- Bratengeier, Cornelia, et al.
(författare)
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Mechanical loading intensities affect the release of extracellular vesicles from mouse bone marrow-derived hematopoietic progenitor cells and change their osteoclast-modulating effect
- 2024
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Ingår i: The FASEB Journal. - : WILEY. - 0892-6638 .- 1530-6860. ; 38:1
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Tidskriftsartikel (refereegranskat)abstract
- Low-intensity loading maintains or increases bone mass, whereas lack of mechanical loading and high-intensity loading decreases bone mass, possibly via the release of extracellular vesicles by mechanosensitive bone cells. How different loading intensities alter the biological effect of these vesicles is not fully understood. Dynamic fluid shear stress at low intensity (0.7 +/- 0.3 Pa, 5 Hz) or high intensity (2.9 +/- 0.2 Pa, 1 Hz) was used on mouse hematopoietic progenitor cells for 2 min in the presence or absence of chemical compounds that inhibit release or biogenesis of extracellular vesicles. We used a Receptor activator of nuclear factor kappa-Beta ligand-induced osteoclastogenesis assay to evaluate the biological effect of different fractions of extracellular vesicles obtained through centrifugation of medium from hematopoietic stem cells. Osteoclast formation was reduced by microvesicles (10 000x g) obtained after low-intensity loading and induced by exosomes (100 000x g) obtained after high-intensity loading. These osteoclast-modulating effects could be diminished or eliminated by depletion of extracellular vesicles from the conditioned medium, inhibition of general extracellular vesicle release, inhibition of microvesicle biogenesis (low intensity), inhibition of ESCRT-independent exosome biogenesis (high intensity), as well as by inhibition of dynamin-dependent vesicle uptake in osteoclast progenitor cells. Taken together, the intensity of mechanical loading affects the release of extracellular vesicles and change their osteoclast-modulating effect. The intensity of mechanical loading strongly affects bone remodeling by either formation of bone or resorption of bone. Low-intensity loading on bone cells releases microvesicles that reduce formation of bone-resorbing osteoclasts, while high-intensity loading on bone cells releases exosomes that induce formation of bone-resorbing osteoclasts. The graphical abstract was created with image
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| 41. |
- Bruton, Joseph D., et al.
(författare)
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Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion
- 2003
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 17:2, s. 301-303
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Tidskriftsartikel (refereegranskat)abstract
- The ryanodine (RY) receptors in beta-cells amplify signals by Ca2+-induced Ca2+ release (CICR). The role of CICR in insulin secretion remains unclear in spite of the fact that caffeine is known to stimulate secretion. This effect of caffeine is attributed solely to the inhibition of cAMP-phosphodiesterases (cAMP-PDEs). We demonstrate that stimulation of insulin secretion by caffeine is due to a sensitization of the RY receptors. The dose-response relationship of caffeine-induced inhibition of cAMP-PDEs was not correlated with the stimulation of insulin secretion. Sensitization of the RY receptors stimulated insulin secretion in a context-dependent manner, that is, only in the presence of a high concentration of glucose. This effect of caffeine depended on an increase in [Ca2+]i. Confocal images of beta-cells demonstrated an increase in [Ca2+]i induced by caffeine but not by forskolin. 9-Methyl-7-bromoeudistomin D (MBED), which sensitizes RY receptors, did not inhibit cAMP-PDEs, but it stimulated secretion in a glucose-dependent manner. The stimulation of secretion by caffeine and MBED involved both the first and the second phases of secretion. We conclude that the RY receptors of beta-cells mediate a distinct glucose-dependent signal for insulin secretion and may be a target for developing drugs that will stimulate insulin secretion only in a glucose-dependent manner.
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| 42. |
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| 43. |
- Camacho-Munoz, D., et al.
(författare)
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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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Ingår i: Faseb Journal. - : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 35:11
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Tidskriftsartikel (refereegranskat)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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| 44. |
- Cansby, Emmelie, 1984, et al.
(författare)
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Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.
- 2013
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 27:9, s. 3660-3671
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Tidskriftsartikel (refereegranskat)abstract
- Partial depletion of serine/threonine protein kinase 25 (STK25), a member of the Ste20 superfamily of kinases, increases lipid oxidation and glucose uptake in rodent myoblasts. Here we show that transgenic mice overexpressing STK25, when challenged with a high-fat diet, develop reduced glucose tolerance and insulin sensitivity compared to wild-type siblings, as evidenced by impairment in glucose and insulin tolerance tests as well as in euglycemic-hyperinsulinemic clamp studies. The fasting plasma insulin concentration was elevated in Stk25 transgenic mice compared to wild-type littermates (4.9±0.8 vs. 2.6±0.4 ng/ml after 17 wk on high-fat diet, P<0.05). Overexpression of STK25 decreased energy expenditure during the dark phase of observation (P<0.05), despite increased spontaneous activity. The oxidative capacity of skeletal muscle of transgenic carriers was reduced, as evidenced by altered expression of Cpt1, Acox1, and ACC. Hepatic triglycerides and glycogen were elevated (1.6- and 1.4-fold, respectively; P<0.05) and expression of key enzymes regulating lipogenesis (Fasn), glycogen synthesis (Gck), and gluconeogenesis (G6pc, Fbp1) was increased in the liver of the transgenic mice. Our findings suggest that overexpression of STK25 in conditions of excess dietary fuels associates with a shift in the metabolic balance in peripheral tissues from lipid oxidation to storage, leading to a systemic insulin resistance.-Cansby, E., Amrutkar, M., Mannerås Holm, L., Nerstedt, A., Reyahi, A., Stenfeldt, E., Borén, J., Carlsson, P., Smith, U., Zierath, J.R., Mahlapuu, M. Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.
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| 45. |
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| 46. |
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| 47. |
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| 48. |
- Carvalho, Eugénia, 1967, et al.
(författare)
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Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM.
- 1999
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Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 0892-6638 .- 1530-6860. ; 13:15, s. 2173-8
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Tidskriftsartikel (refereegranskat)abstract
- We examined the gene and protein expression of IRS 1 (insulin receptor substrate 1) in adipocytes from two groups of healthy individuals with an increased propensity for non-insulin-dependent diabetes mellitus (NIDDM): those with two first-degree relatives with diabetes and another group with massive obesity. A low expression of IRS 1 (
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| 49. |
- Cébe-Suarez, Stéphanie, et al.
(författare)
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Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR
- 2008
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 22:8, s. 3078-3086
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factors (VEGFs) interact with the receptor tyrosine kinases (RTKs) VEGFR-1, -2, and -3; neuropilins (NRPs); and heparan sulfate (HS) proteoglycans. VEGF RTKs signal to downstream targets upon ligand-induced tyrosine phosphorylation, while NRPs and HS act as coreceptors that lack enzymatic activity yet modulate signal output by VEGF RTKs. VEGFs exist in various isoforms with distinct receptor specificity and biological activity. Here, a series of mammalian VEGF-A splice variants and orf virus VEGF-Es, as well as chimeric and mutant VEGF variants, were characterized to determine the motifs required for binding to NRP-1 in the absence (VEGF-E) or presence (VEGF-A(165)) of an HS-binding sequence. We identified the carboxyterminal peptides RPPR and DKPRR as the NRP-1 binding motifs of VEGF-E and VEGF-A, respectively. RPPR had significantly higher affinity for NRP-1 than DKPRR. VEGFs containing an RPPR motif promoted HS-independent coreceptor complex assembly between VEGFR-2 and NRP-1, independent of whether these receptors were expressed on the same or separate cells grown in cocultures. Functional studies showed that stable coreceptor assembly by VEGF correlated with its ability to promote vessel formation in an embryoid body angiogenesis assay.
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