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This study performed molecular dynamics simulation for the full-length human IAPP using the polarized protein-specific charges and calculated the electrostatic interaction energy for amyloid oligomers.
discrete molecule dynamics simulations were used to investigate the oligomerization of full-length hIAPP.
Our results also reveal the ability of EGCG or EGCG:Zn(II) to efficiently suppress IAPP's cellular toxicity. We believe that the reported results could be useful to develop strategies to trap IAPP intermediates for further biophysical and structural studies, and also to devise approaches to abolish amyloid aggregation and cellular toxicity.
Study revealed that the conserved HIF1alpha/PFKFB3 signaling pathway is activated by IAPP misfolded protein-driven stress in pancreatic beta-cells to trigger an adaptive protective metabolic response that slows beta-cell death at the expense of beta-cell function. This signaling pathway is activated in beta-cells in humans with type 2 diabetes providing a basis for slow beta-cell loss.
Levels of retinal islet amyloid polypeptide (IAPP) are altered in Alzheimer's disease patients and correlate with vascular changes and hippocampal IAPP levels.
This study was planned to test whether follicular fluid (FF) levels of patatin-like phospholipase domain containing 3-gene (PNPLA3:adiponutrin), preptin, kisspeptin, and amylin change in polycystic ovarian syndrome.
research provides a new outlook for the design of oxidovanadium complexes as effective inhibitors of hIAPP against T2DM.
Human amylin is one of the peptides forming fibrils in beta-sheet conformation finally leading to amyloid formation. In contrast to rodent amylin, human amylin is prone to form amyloidogenic aggregates, proposed to play a role in the pathogenesis of Type 2 Diabetes by impairing beta-cell functionality.
suggests a novel regulatory pathway in beta-cells involving proteasome, FOXA2, and IAPP, which can be possibly targeted to regulate hIAPP levels and islet amyloidosis in type 2 diabetes
In this work, the decisive roles of peptide structures on amyloid self-assembly and morphological diversity were investigated by the design of eight amyloidogenic peptides derived from islet amyloid polypeptide.
The molecular dynamics simulations also demonstrate that the beta-sheet intermediates induce more perturbation on the membrane than the alpha-helical and disordered states and thus pose higher disruption ability.
these findings highlighted a novel role of sub-toxic concentrations of human amylin in promoting the secretion of proteic factors by endothelial cells (HspB5 and VEGF) that support the survival and proliferation of neuron-like cells.
Mass spectrometry has been applied to determine the deamidation sites and the aggregation region of the deamidated human islet amyloid polypeptide (hIAPP). Mutant hIAPP with iso-aspartic residue mutations at possible deamidation sites showed very different fibril formation behaviour, which correlates with the observed deamidation-induced acceleration of hIAPP aggregation.
this paper shows that human amylin induces CD4+Foxp3+ regulatory T cells and decrease in the incidence of diabetes in nod mice
In conclusion, IAPP/amylin directly interacts with NLRP3 to activate NLRP3 inflammasome, and this interaction could be an attractive drug target to avoid inflammation and beta-cell death during therapy for diabetes, although there are mechanisms in NLRP3 inflammasome and diabetes pathology in human tissues that still require elucidation.
These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca(2+) dysregulation in pre-diabetes.
down-regulation of IAPP expression induces the death of human annulus fibrosus cells via mitochondrial and death receptor pathways, potentially offering a novel therapeutic target for the treatment of intervertebral disc degeneration.
This study highlights that with positional scanning of the split-tetracysteine motif (Cys-Cys), the fluorogenic probe fluorescein arsenical hairpin detection method offers unique time-dependent conformational insights on the proteospecies assembled throughout the amyloidogenic pathway of IAPP.
Bri2 BRICHOS domain is a potent inhibitor of IAPP fibril formation.IAPP colocalizes with Bri2 both intracellularly and in islet amyloid deposits.
Insulin resistance in rheumatoid arthritis does not appear to be mediated by amylin. This would imply that the mechanisms associated with IR in RA patients differ from those at work in type 2 diabetes.
These data provide for the first time evidences for the toxic nature of oligomeric assemblies of murine amylin and its existence in wild-type, non-transgenic mice.
n T2 mice, the mRNA expression of Retn showed a moderate up-regulation (fold change=8.32; p=0.0019) in the adipose tissues. Iapp expression was also significantly up-regulated (fold change=9.78; p=0.012). Moreover, a 6.36-fold up-regulation for Drd5 was observed in the adipose tissues of T2 mice
Data suggest that hybrid insulin peptides (HIPs), formed in insulin-secreting-cells by fusion of insulin C-peptide fragments to peptide fragments of chromogranin A or islet amyloid polypeptide, and reactivity of CD4+-T-lymphocytes to HIPs may act as biomarkers of autoimmunity in type 1 diabetes.
Circulating aggregated amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca(2+) cycling do not require diabetic remodeling of the myocardium.
Results suggest that amylin directly acts, through a p-ERK-mediated process, on POMC neurons to enhance arcuate nucleus-paraventricular nucleus alphaMSH pathway development.
These data suggest participation by both soluble and fibrillar aggregates in IAPP-induced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction.
Hypothalamic amylin is transcriptionally regulated by leptin, that it can act directly on ObRb neurons in concert with leptin, and that it regulates feeding.
Matrix Metalloproteinase-9 Protects Islets from Amyloid-induced Toxicity.
Data indicate that T-cell receptors that react to chromogranin A (ChgA) and islet amyloid polypeptide precursor (IAPP) autoantigens were impaired when the thymic stromal cells lacked thymus-specific serine protease (TSSP).
Study the physiologic actions of IAPP on pancreatic beta cells, which secrete this peptide together with insulin upon glucose stimulation. Explore the signaling pathways and mitogenic actions of IAPP on beta cells.
deletion of the DeltaN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the beta cells of the pancreas
The stability, conformational dynamics and association force of different single-layer models of the full-length wild-type and glycine mutants of amylin, were investigated.
studies have identified a novel TXNIP/miR-124a/FoxA2/IAPP signaling cascade linking the critical beta-cell signaling pathways of TXNIP and IAPP
MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP.
Data suggest that amylin and leptin play additive roles in regulating energy homeostasis via activation of overlapping signalling pathways; mechanisms may be different in hypothalamus, muscle, and liver and in cases of endoplasmic reticulum stress.
These findings point to a potential for Drosophila melanogaster to serve as a model system for studies of hproIAPP and hIAPP expression with subsequent aggregation and developed pathology.
MCP-1 induces amylin expression through ERK1/2/JNK-AP1 and NF-kappaB related signaling pathways independent of CCR2. Amylin upregulation by MCP-1 may contribute to elevation of plasma amylin in obesity and insulin resistance
This study demonstrated that amylin inactivation leads to a low bone mass due to an increase in bone resorption whereas bone formation is unaffected.
Fatty acids differently regulate amylin and insulin expression and induce both amylin and insulin release
Amylin/leptin's marked weight- and fat-reducing effects are due to activation of intrinsic synergistic neuronal signaling pathways.
Bovine amylin differs from the human peptide at 10 positions and is one of the most divergent among known amylin sequences. Bovine amylin oligomerizes but is not toxic to cultured beta-cells and it is considerably less amyloidogenic than the human polypeptide and is only a low-potency agonist at human amylin-responsive receptors.
Data indicated that a novel stable dimer was observed in pIAPP(20-29) solution, whereas hIAPP(20-29) exists mostly as monomers and trimers.
Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism.
Islet amyloid polypeptide (diabetes-associated peptide; amylin)
, diabetes-associated peptide
, insulinoma amyloid peptide
, islet amyloid polypeptide
, amyloid protein