A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Biochemical Journal, Journal Year: 2022, Volume and Issue: 479(4), P. 537 - 559

Published: Feb. 23, 2022

Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype COVID-19), is a relatively frequent consequence SARS-CoV-2 infection, in which symptoms such breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions the blood coagulation system) persist long after initial infection. It bears similarities other post-viral syndromes, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this separate disease entity, refer it under broad terminology ‘COVID’, although its demographics are quite different from those acute COVID-19. A few years ago, we discovered that fibrinogen can clot into an anomalous ‘amyloid’ form fibrin (like β-rich amyloids prions) resistant proteolysis (fibrinolysis). The result, strongly manifested platelet-poor plasma (PPP) individuals with Long COVID, extensive amyloid microclots persist, entrap proteins, may lead production various autoantibodies. These more-or-less easily measured PPP stain thioflavin T simple fluorescence microscope. Although multifarious, here argue ability these (fibrinaloids) block up capillaries, thus limit passage red cells hence O2 exchange, actually underpin majority symptoms. Consistent this, preliminary report, has been shown suitable closely monitored ‘triple’ anticoagulant therapy leads removal also removes Fibrin represent novel potentially important target for both understanding treatment related disorders.

Language: Английский

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Mechanochemistry: New Tools to Navigate the Uncharted Territory of “Impossible” Reactions

ChemSusChem, Journal Year: 2022, Volume and Issue: 15(17)

Published: July 21, 2022

Mechanochemical transformations have made chemists enter unknown territories, forcing a different chemistry perspective. While questioning or revisiting familiar concepts belonging to solution chemistry, mechanochemistry has broken new ground, especially in the panorama of organic synthesis. Not only does it foster "thinking outside box", but also opened reaction paths, allowing overcome weaknesses traditional exactly where use well-established solution-based methodologies rules out progress. In this Review, reader is introduced an intriguing research subject not yet fully explored and waiting for improved understanding. Indeed, study mainly focused on that, although impossible solution, become possible under mechanochemical processing conditions, simultaneously entailing innovation expanding chemical space.

Language: Английский

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Dynamic intracellular exchange of nanomaterials’ protein corona perturbs proteostasis and remodels cell metabolism

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(23)

Published: June 2, 2022

Significance This study analyzed the dynamic protein corona on surface of nanoparticles as they traversed from blood to cell lysosomes and escaped cytoplasm in target cells. We found with proteomic analysis an abundance chaperone glycolysis coronal proteins (i.e., heat shock cognate 70, 90, pyruvate kinase M2 [PKM2]) after escape cytosol. Alterations (e.g., PKM2 binding) induced proteostasis collapse, which subsequently led elevated chaperone-mediated autophagy (CMA) activity As is a key molecule metabolism, we also revealed that depletion was causative CMA-induced metabolism disruption lipid metabolism.

Language: Английский

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Orchestration of selective autophagy by cargo receptors

Current Biology, Journal Year: 2022, Volume and Issue: 32(24), P. R1357 - R1371

Published: Dec. 1, 2022

Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for degradation such cargo This is achieved by sequestration within double-membrane vesicles termed autophagosomes, which form de novo around subsequently deliver their content to lysosomes degradation. The importance selective exemplified various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia. It has become evident that receptors are acting as Swiss army knives recognizing cargo, orchestrating recruitment machinery autophagosome biogenesis, closely aligning membrane cargo. Furthermore, sequester ubiquitinated proteins into larger condensates upstream induction. Here, we review recent insights mechanisms action focusing on roles sequestosome-like misfolded, mitochondria. We also highlight at steps function result accumulation harmful material how knowledge may guide design future therapies.

Language: Английский

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Plant Protein Amyloid Fibrils for Multifunctional Sustainable Materials

Advanced Sustainable Systems, Journal Year: 2023, Volume and Issue: 7(4)

Published: Jan. 12, 2023

Abstract Artificial functional materials based on amyloid fibrils are proven to be a promising strategy toward materials. However, scaling‐up applications present sustainability concerns, as animal proteins the main sources for fabricating fibrils. Plant‐protein‐based fibrils, more sustainable alternative proteins, attracting increasing interests building blocks in Herein, 11 different from wide range of plants evaluated, and comprehensive analysis seven species plant including kidney bean, black cowpea, mung chickpea, lentil, pumpkin seed, with an excellent ability form is presented. A universal diversity protein extraction fibrillization applied. Flexible persistence length ≈100 nm rigid several micrometers discovered 7S/8S 11S subunits dominated protein, respectively. Structural evolution β‐sheet content these proteinaceous assemblies characterized by thioflavin T (ThT) intensity, circular dichroism (CD) spectra, attenuated total reflectance‐Fourier transform infrared (ATR‐FTIR) typical angle X‐ray scattering (WAXS) spectra. Finally, their multifunctional further explored that amyloids demonstrate performance renewable degradable bioplastics, water purification membranes heavy metal removal.

Language: Английский

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Food amyloid fibrils are safe nutrition ingredients based on in-vitro and in-vivo assessment

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 26, 2023

Food protein amyloid fibrils have superior technological, nutritional, sensorial, and physical properties compared to native monomers, but there is as yet insufficient understanding of their digestive fate safety for wide consumption. By combining SDS-PAGE, ELISA, fluorescence, AFM, MALDI-MS, CD, microfluidics, SAXS techniques the characterization β-lactoglobulin lysozyme subjected in-vitro gastrointestinal digestion, here we show that either no noticeable conformational differences exist between aggregates monomer counterparts after digestion process (as in β-lactoglobulin), or are digested significantly better than monomers lysozyme). Moreover, exposure human cell lines in-vivo studies with C. elegans mouse models, indicate present observable cytotoxicity, physiological abnormalities health-span, nor accumulation fibril-induced plaques brain other organs. These extensive together suggest food amyloids at least equally safe those obtained from corresponding pointing potential ingredients nutrition.

Language: Английский

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Endothelial leakiness elicited by amyloid protein aggregation

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 19, 2024

Abstract Alzheimer’s disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding AD pathophysiology implicates aggregation amyloid beta (Aβ) as causative to neurodegeneration, with tauopathies, apolipoprotein E and neuroinflammation considered other culprits. Curiously, vascular endothelial barrier dysfunction strongly associated Aβ deposition 80-90% subjects also experience cerebral angiopathy. Here we show protein-induced leakiness (APEL) in human microvascular monolayers well mouse vasculature. Using signaling pathway assays discrete molecular dynamics, revealed that angiopathy first arose from disruption (VE)-cadherin junctions exposed nanoparticulates oligomers seeds, preceding earlier implicated proinflammatory pro-oxidative stressors leakiness. These findings were analogous nanomaterials-induced (NanoEL), phenomenon nanomedicine depicting paracellular transport anionic inorganic nanoparticles As APEL occurred vitro seeds alpha synuclein, this study proposes paradigm for elucidating permeation, systemic spread, cross-seeding proteins underlie pathogeneses Parkinson’s disease.

Language: Английский

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Peptide hydrogen-bonded organic frameworks

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(8), P. 3640 - 3655

Published: Jan. 1, 2024

This tutorial review discusses the design principles, implications, and future challenges associated with peptide-based hydrogen-bonded porous frameworks (P-HPFs).

Language: Английский

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Nanomaterials for the treatment and diagnosis of Alzheimer's disease: An overview

NanoImpact, Journal Year: 2020, Volume and Issue: 20, P. 100251 - 100251

Published: Aug. 31, 2020

Language: Английский

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In situ architecture of neuronal α-Synuclein inclusions

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: April 14, 2021

Abstract The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly fibrils, but recent reports pointed intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) image neuronal in situ at resolution. We show that seeded by aggregates produced recombinantly or purified from patient brain fibrils crisscrossing a variety cellular organelles. Using gold-labeled seeds, find aggregate seeding is predominantly mediated small which cytoplasmic grow unidirectionally. Detailed analysis membrane interactions revealed do not contact directly, and does drive clustering. Altogether, conclusively demonstrate intermixed with membranous organelles, illuminate mechanism interaction.

Language: Английский

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