| 1. |
- Azhar, Salman, et al.
(författare)
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Novel ABCA1 peptide agonists with antidiabetic action
- 2019
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 480, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Previously, apoE-derived ABCA1 agonist peptides have been shown to possess anti-atherosclerotic and possibly antidiabetic properties. Here we assessed the in vitro and in vivo actions of a second generation of ABCA1 peptide agonists, CS6253 and T6991-2, on glucose homeostasis. The results show that these two peptides improve glucose tolerance in a prediabetic diet-induced obesity mouse model by enhancing insulin secretion. It was further demonstrated that T6991-2 also improved glucose tolerance in leptin-deficient (ob/ob) mice. CS6253 increased insulin secretion both under basal conditions and in response to high glucose stimulation in pancreatic INS-1 β-cells rendered leptin receptor deficient with specific siRNA. Additional in vitro cell studies suggest that the CS6253 agonist attenuates hepatic gluconeogenesis and glucose transport. It also potentiates insulin-stimulated glucose uptake and utilization. These observed anti-diabetic actions suggest additional benefits of the CS6253 and T6991-2 ABCA1 peptide agonists for cardiovascular disease beyond their direct anti-atherosclerosis properties previously described.
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| 2. |
- Backe, Marie Balslev, et al.
(författare)
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Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function
- 2018
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 460, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptional changes control β-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects β cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate β-cell fate in response to inflammatory stress.Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced β-cell destruction. Inhibition of KDM6 demethylases using the selective inhibitor GSK-J4 protected insulin-producing cells and human and mouse islets from cytokine-induced apoptosis by blunting nuclear factor (NF)-κB signaling and endoplasmic reticulum (ER) stress response gene expression. GSK-J4 furthermore increased expression of insulin gene and glucose-stimulated insulin secretion. Expression of genes regulating purinergic and cytokine ligand-receptor interactions was downregulated following GSK-J4 exposure, while expression of genes involved in cell maintenance and survival was upregulated. These data suggest that KDMs are important regulators of inflammation-induced β-cell dysfunction and death.
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| 3. |
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| 4. |
- Bjorkgren, I., et al.
(författare)
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Targeted inactivation of the mouse epididymal beta-defensin 41 alters sperm flagellar beat pattern and zona pellucida binding
- 2016
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 427:C, s. 143-154
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Tidskriftsartikel (refereegranskat)abstract
- During epididymal maturation, sperm acquire the ability to swim progressively by interacting with proteins secreted by the epididymal epithelium. Beta-defensin proteins, expressed in the epididymis, continue to regulate sperm motility during capacitation and hyperactivation in the female reproductive tract. We characterized the mouse beta-defensin 41 (DEFB41), by generating a mouse model with iCre recombinase inserted into the first exon of the gene. The homozygous Defb41(iCre/iCre) knock-in mice lacked Defb41 expression and displayed iCre recombinase activity in the principal cells of the proximal epididymis. Heterozygous Defb41(iCre/+) mice can be used to generate epididymis specific conditional knock-out mouse models. Homozygous Defb41(iCre/iCre) sperm displayed a defect in sperm motility with the flagella primarily bending in the pro-hook conformation while capacitated wild-type sperm more often displayed the anti-hook conformation. This led to a reduced straight line motility of Defb41(iCre/liCre) sperm and weaker binding to the oocyte. Thus, DEFB41 is required for proper sperm maturation.
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| 5. |
- Björklund, Peyman, et al.
(författare)
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Epigenetics of pheochromocytoma and paraganglioma
- 2018
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Ingår i: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 469, s. 92-97
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising in the medullae of the adrenal glands or in paraganglia. The knowledge of the tumor biology of these lesions has increased dramatically during the past two decades and more than a dozen recurrently mutated genes have been identified. Different clusters have been described that share epigenetic signatures. Mutations in the succinate dehydrogenase complex subunit genes play a pivotal role in reprogramming the epigenetic state of these tumors by inhibiting epigenetic regulators such as TET enzymes and histone demethylases. Another subgroup of tumors carries hypomethylated genomes, and overexpression of several microRNAs has been described. While much remains to be investigated regarding the epigenetics of PPGLs, it is clear that it plays an important role in PPGL biology.
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| 6. |
- Bugliani, Marco, et al.
(författare)
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DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes
- 2018
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 473, s. 186-193
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Tidskriftsartikel (refereegranskat)abstract
- It has been reported that the incretin system, including regulated GLP-1 secretion and locally expressed DPP-4, is present in pancreatic islets. In this study we comprehensively evaluated the expression and role of DPP-4 in islet alpha and beta cells from non-diabetic (ND) and type 2 diabetic (T2D) individuals, including the effects of its inhibition on beta cell function and survival. Isolated islets were prepared from 25 ND and 18 T2D organ donors; studies were also performed with the human insulin-producing EndoC-βH1 cells. Morphological (including confocal microscopy), ultrastructural (electron microscopy, EM), functional (glucose-stimulated insulin secretion), survival (EM and nuclear dyes) and molecular (RNAseq, qPCR and western blot) studies were performed under several different experimental conditions. DPP-4 co-localized with glucagon and was also expressed in human islet insulin-containing cells. Furthermore, DPP-4 was expressed in EndoC-βH1 cells. The proportions of DPP-4 positive alpha and beta cells and DPP-4 gene expression were significantly lower in T2D islets. A DPP-4 inhibitor protected ND human beta cells and EndoC-βH1 cells against cytokine-induced toxicity, which was at least in part independent from GLP1 and associated with reduced NFKB1 expression. Finally, DPP-4 inhibition augmented glucose-stimulated insulin secretion, reduced apoptosis and improved ultrastructure in T2D beta cells. These results demonstrate the presence of DPP-4 in human islet alpha and beta cells, with reduced expression in T2D islets, and show that DPP-4 inhibition has beneficial effects on human ND and T2D beta cells. This suggests that DPP-4, besides playing a role in incretin effects, directly affects beta cell function and survival.
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| 7. |
- Chowdhury, Azazul Islam, et al.
(författare)
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GLP-1 analogue recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS2
- 2017
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207 .- 1872-8057. ; 439:C, s. 194-202
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Tidskriftsartikel (refereegranskat)abstract
- Elevated circulating palmitate levels have been connected with type 2 diabetes mellitus. GLP-1 has favorable effects on beta-cells function. The aim was to identify mechanisms for decreased GSIS after long-term palmitate exposure and restoration by GLP-1 by analyzing changes in G-protein coupled receptor (GPCR) pathway signaling. Insulin secretory response to 20 mM glucose was attenuated after 7 days in islets exposed to palmitate but inclusion of exendin-4 restored secretion. Palmitate treatment altered genes of several GPCR signaling pathways including inflammatory pathways with up-regulated IL-1B, SOCS1 and SOCS2 transcript levels. Protein level of SOCS2 was also up-regulated by palmitate and accompanied by down-regulation of pAkt(T308), which was restored by exendin-4 treatment. When SOCS2 was knocked down, palmitate-induced clown-regulation of IRS-1 and pAkt(T308) was prevented and GSIS, proinsulin to insulin ratio and apoptosis was restored. Long-term palmitate treatment up regulates SOCS2 and reduces PI3K activity, thereby impairing GSIS. GLP-1 reverts the palmitate-induced effects.
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| 8. |
- Christakoudi, Sofia, et al.
(författare)
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Steroid regulation : An overlooked aspect of tolerance and chronic rejection in kidney transplantation
- 2018
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Ingår i: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 473, s. 205-216
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Tidskriftsartikel (refereegranskat)abstract
- Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n= 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.
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| 9. |
- Drzazga, Anna, et al.
(författare)
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Lysophosphatidylcholine and its phosphorothioate analogues potentiate insulin secretion via GPR40 (FFAR1), GPR55 and GPR119 receptors in a different manner
- 2018
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Ingår i: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 472, s. 117-125
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Tidskriftsartikel (refereegranskat)abstract
- Lysophosphatidylcholine (LPC) is an endogenous ligand for GPR119 receptor, mediating glucose-stimulated insulin secretion (GSIS). We demonstrate that LPC facilitates GSIS in MINE pancreatic beta-cell line and murine islets of Langerhans by recognizing not only GPR119 but also GPR40 (free fatty acid receptor 1) and GPR55 activated by lysophosphatidylinositol. Natural LPCs are unstable when administered in vivo limiting their therapeutic value and therefore, we present phosphorothioate LPC analogues with increased stability. All the modified LPCs under study (12:0,14:0,16:0,18:0, and 18:1) significantly enhanced GSIS. The 16:0 sulfur analogue was the most potent, evoking 2-fold accentuated GSIS compared to the native counterpart. Interestingly, LPC analogues evoked GPR40-, GPR55-and GPR119 dependent [Ca2+](i), signaling, but did not stimulate cAMP accumulation as in the case of unmodified molecules. Thus, introduction of a phosphorothioate function not only increases LPC stability but also modulates affinity towards receptor targets and evokes different signaling pathways.
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| 10. |
- Eliasson, Lena
(författare)
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The small RNA miR-375 - a pancreatic islet abundant miRNA with multiple roles in endocrine beta cell function
- 2017
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 456, s. 95-101
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of diabetes is complex and recent research put focus on the pancreatic islets of Langerhans and the insulin-secreting beta cells as central in the development of the disease. MicroRNAs (miRNAs), the small non-coding RNAs regulating post-transcriptional gene expression, are significant regulators of beta cell function. One of the most abundant miRNAs in the islets is miR-375. This review focus on the role of miR-375 in beta cell function, including effects in development and differentiation, proliferation and regulation of insulin secretion. It also discusses the regulation of miR-375 expression, miR-375 as a potential circulating biomarker in type 1 and type 2 diabetes, and the need for the beta cell to keep expression of miR-375 within optimal levels. The summed picture of miR-375 is a miRNA with multiple functions with importance in the formation of beta cell identity, control of beta cell mass and regulation of insulin secretion.
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