AA amyloid in human food chain is a possible biohazard
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ABSTRACT:
SUBMITTER: Rising A
PROVIDER: S-EPMC8548551 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: Amyloid A (AA) amyloidosis is found in humans and non-human primates, but quantifying disease risk prior to clinical symptoms is challenging. We applied machine learning to identify the best predictors of amyloidosis in rhesus macaques from available clinical and pathology records. To explore potential biomarkers, we also assessed whether changes in circulating serum amyloid A (SAA) or lipoprotein profiles accompany the disease. Methods: We conducted a retrospective study using 86 cases and 163 controls matched for age and sex. We performed data reduction on 62 clinical, pathological and demographic variables, and applied multivariate modelling and model selection with cross-validation. To test the performance of our final model, we applied it to a replication cohort of 2,775 macaques. Results: The strongest predictors of disease were colitis, gastrointestinal adenocarcinoma, endometriosis, arthritis, trauma, diarrhoea and number of pregnancies. Sensitivity and specificity of the risk model were predicted to be 82%, and were assessed at 79 and 72%, respectively. Total, low density lipoprotein and high density lipoprotein cholesterol levels were significantly lower, and SAA levels and triglyceride-to-HDL ratios were significantly higher in cases versus controls. Conclusion: Machine learning is a powerful approach to identifying macaques at risk of AA amyloidosis, which is accompanied by increased circulating SAA and altered lipoprotein profiles.
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Project description:Component specific responses of the microbiomes to common chemical stressors in the human food chain
| PRJEB72104 | ENA
Project description:Systemic AA amyloidosis is a debilitating protein misfolding disease in humans and animals. In humans, it occurs in two variants that are called 'vascular' and 'glomerular', depending on the main amyloid deposition site in the kidneys. Using cryo electron microscopy, we here show the amyloid fibril structure underlying the vascular disease variant. Fibrils purified from the tissue of such patients are mainly left-hand twisted and contain two non-equal stacks of fibril proteins. They contrast in these properties to the fibrils from the glomerular disease variant which are right-hand twisted and consist of two structurally equal stacks of fibril proteins. Our data demonstrate that the different disease variants in systemic AA amyloidosis are associated with different fibril morphologies.
| S-EPMC9700864 | biostudies-literature
Project description:Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant ?6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 ?M, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.
| S-EPMC4579077 | biostudies-literature
Project description: Not available
| EMPIAR-11342 | biostudies-other
Project description:Amyloid deposition and neighboring tissue responses remain poorly understood. Twenty percent of patients with systemic light-chain amyloidosis (AL) have interstitial marrow amyloid containing clonal Ig light-chain fibrils and apolipoprotein chaperone proteins. We compared CD138-depleted aspirate mononuclear cells (MNC) from marrows of AL patients with (+MA) and without (-MA) interstitial amyloid by gene expression profiling (GEP) and single-cell RNA-sequencing (scRNA seq). GEP showed no differential expression of genes for proteolytic enzymes or apolipoproteins between the groups but +MA cases had significantly up-regulated erythroid genes involved in oxygen transport, including transmembrane and coiled-coil domain family 2 (TMCC2). In +MA marrows at the single-cell level, CD14+ monocytes were increased by 22%, granulocyte-monocyte progenitors decreased by 66%, and erythroid-megakaryocyte progenitors and early and late erythroid progenitors increased up to five-fold. Gene enrichment studies showed that in +MA marrows pathways for TNFα signaling, immune activation, monocyte hypoxia and erythropoiesis were significantly enriched. We also compared peripheral blood and marrow plasma by immunoprecipitation and immunoblot with respect to apolipoproteins and light chains in complex with the erythroid protein TMCC2, and by ELISA for marrow apolipoprotein E and J levels. Apolipoprotein J is strongly associated with light chains in blood and E is not, while in +MA marrow plasma J and E are strongly present in association with light chains. There is also significantly more apolipoprotein E and J in +MA marrow plasma. In summary, marrows with interstitial amyloid provide opportunities to study amyloid’s impact on cellular and regenerative activity and chaperone involvement in amyloid formation.
2023-12-01 | GSE239717 | GEO
Project description:Oligomerization of human islet amyloid polypeptide (IAPP) has been increasingly considered a pathogenic process in type II diabetes. Here structural features of the IAPP monomer have been probed using a combination of ion mobility mass spectrometry (IMS-MS) and all-atom replica exchange molecular dynamics (REMD) simulations. Three distinct conformational families of human IAPP monomer are observed in IMS experiments, and two of them are identified as dehydrated solution structures on the basis of our simulation results: one is an extended beta-hairpin structural family, and the second is a compact helix-coil structural family. The extended beta-hairpin family is topologically similar to the peptide conformation in the solid-state NMR fibril structure published by Tycko and co-workers. It is absent in both experiments and simulations performed on the non-amyloidogenic rat IAPP, suggesting it may play an important role in the fibrillation pathway of human IAPP. In addition, pH dependence studies show that the relative abundance of the beta-hairpin structural family is significantly enhanced at pH 8.0. This observation is consistent with the increased rate of fibrillation at high pH in vitro and offers a possible explanation of the pH dependent fibrillation in vivo. This paper, to the best of our knowledge, presents the first experimental evidence of a significant population of beta-hairpin conformers for the IAPP peptide. It is consistent with a previous suggestion in the literature that beta-sheet-rich oligomers are assembled from ordered beta-hairpins rather than from coiled structures.
| S-EPMC2810149 | biostudies-literature
Project description:AA-amyloidosis is a disease characterized by abnormal deposition of serum A amyloid (SAA) peptide along with other components in various organs. The disease is a complication of inflammatory conditions that cause persistent high levels of the acute phase reactant SAA in plasma. In experimental animal models, the deposited amyloid is resolved when the inflammation is stopped, suggesting that there is an efficient clearance mechanism for the amyloid. As heparan sulfate (HS) is one of the major components in the amyloid, its metabolism is expected to affect the pathology of AA amyloidosis. In this study, we investigated the effect of heparanase, a HS degradation enzyme, in resolution of the AA amyloid. The transgenic mice deficient in heparanase (Hpa-KO) produced a similar level of SAA in plasma as the wildtype control (Ctr) mice upon induction by injection of AEF (amyloid enhancing factor) and inflammatory stimuli. The induction resulted in formation of SAA amyloid 7-days post treatment in the spleen that displayed a comparable degree of amyloid load in both groups. The amyloid became significantly less in the Hpa-KO spleen than in the Ctr spleen 10-days post treatment, and was completely resolved in the Hpa-KO spleen on day 21 post induction, while a substantial amount was still detected in the Ctr spleen. The rapid clearance of the amyloid in the Hpa-KO mice can be ascribed to upregulated matrix metalloproteases (MMPs) that are believed to contribute to degradation of the protein components in the AA amyloid. The results indicate that both heparanase and MMPs play important parts in the pathological process of AA amyloidosis.
| S-EPMC3393718 | biostudies-literature
Project description:PURPOSE:I-labeled human serum amyloid P component (SAP) is used clinically only in the UK for imaging visceral amyloidosis to assist with diagnosis, disease staging, and monitoring response to therapy. We compare a new amyloid-reactive probe, peptide p5, with SAP for imaging amyloidosis. PROCEDURES:Dual-energy SPECT/CT images were acquired of (125)I-labeled SAP and (99m)Tc-labeled p5 in mice with systemic AA amyloidosis (n?=?3). Twelve organs and tissues were harvested for radiotracer biodistribution assessment and for micro-autoradiographic analysis. RESULTS:I-SAP and (99m)Tc-p5 localized equivalently in amyloid deposits in liver (?10% injected dose (ID)/g) whereas (125)I-SAP was twofold higher in the spleen (?20% ID/g; (99m)Tc-p5, ?10% ID/g). In contrast, (99m)Tc-p5 was bound to pancreatic and intestinal amyloid approximately fivefold more efficiently as evidenced in biodistribution data. CONCLUSIONS:Radiolabeled p5 is an effective amyloid-imaging radiotracer as compared to SAP in the murine model of amyloidosis and may be rapidly translated for imaging patients with visceral amyloidosis in the USA.
| S-EPMC3664664 | biostudies-literature