Effects ofin vivoconditions on amyloid aggregation

2019 ◽  
Vol 48 (14) ◽  
pp. 3946-3996 ◽  
Author(s):  
Michael C. Owen ◽  
David Gnutt ◽  
Mimi Gao ◽  
Sebastian K. T. S. Wärmländer ◽  
Jüri Jarvet ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Amyloid Aggregation ◽  
Comprehensive Overview ◽  
Grand Challenges ◽  
Biophysical Chemistry

One of the grand challenges of biophysical chemistry is to understand the principles that govern protein aggregation leading to amyloid fibrils, which is a highly complex and sensitive process. This review provides a comprehensive overview of how amyloid aggregation is affected by the variousin vivoconstituents and conditions.

scholarly journals Lysozyme Fibrils Alter the Mechanism of Insulin Amyloid Aggregation

2021 ◽  
Vol 22 (4) ◽  
pp. 1775
Author(s):  
Mantas Ziaunys ◽  
Andrius Sakalauskas ◽  
Tomas Sneideris ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Protein Aggregates ◽  
Amyloid Aggregation ◽  
Amyloid Aggregates ◽  
Affected Tissue ◽  
New Ideas

Protein aggregation into amyloid fibrils is linked to multiple disorders. The understanding of how natively non-harmful proteins convert to these highly cytotoxic amyloid aggregates is still not sufficient, with new ideas and hypotheses being presented each year. Recently it has been shown that more than one type of protein aggregates may co-exist in the affected tissue of patients suffering from amyloid-related disorders, sparking the idea that amyloid aggregates formed by one protein may induce another protein’s fibrillization. In this work, we examine the effect that lysozyme fibrils have on insulin amyloid aggregation. We show that not only do lysozyme fibrils affect insulin nucleation, but they also alter the mechanism of its aggregation.

An Aβ42 variant that inhibits intra- and extracellular amyloid aggregation and enhances cell viability

2018 ◽  
Vol 475 (19) ◽  
pp. 3087-3103 ◽  
Author(s):  
Ofek Oren ◽  
Victor Banerjee ◽  
Ran Taube ◽  
Niv Papo
Keyword(s):  
Amyloid Fibrils ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Peptide ◽  
Cell Cytotoxicity ◽  
Amyloid Aggregation ◽  
Molar Ratios

Aggregation and accumulation of the 42-residue amyloid β peptide (Aβ42) in the extracellular matrix and within neuronal cells is considered a major cause of neuronal cell cytotoxicity and death in Alzheimer's disease (AD) patients. Therefore, molecules that bind to Aβ42 and prevent its aggregation are therapeutically promising as AD treatment. Here, we show that a non-self-aggregating Aβ42 variant carrying two surface mutations, F19S and L34P (Aβ42DM), inhibits wild-type Aβ42 aggregation and significantly reduces Aβ42-mediated cell cytotoxicity. In addition, Aβ42DM inhibits the uptake and internalization of extracellularly added pre-formed Aβ42 aggregates into cells. This was the case in both neuronal and non-neuronal cells co-expressing Aβ42 and Aβ42DM or following pre-treatment of cells with extracellular soluble forms of the two peptides, even at high Aβ42 to Aβ42DM molar ratios. In cells, Aβ42DM associates with Aβ42, while in vitro, the two soluble recombinant peptides exhibit nano-molar binding affinity. Importantly, Aβ42DM potently suppresses Aβ42 amyloid aggregation in vitro, as demonstrated by thioflavin T fluorescence and transmission electron microscopy for detecting amyloid fibrils. Overall, we present a new approach for inhibiting Aβ42 fibril formation both within and outside cells. Accordingly, Aβ42DM should be evaluated in vivo for potential use as a therapeutic lead for treating AD.

scholarly journals Methylene blue inhibits nucleation and elongation of SOD1 amyloid fibrils

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9719
Author(s):  
Greta Musteikyte ◽  
Mantas Ziaunys ◽  
Vytautas Smirnovas
Keyword(s):  
Methylene Blue ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Late Onset ◽  
Amyloid Aggregation ◽  
Amyloidogenic Proteins ◽  
Lateral Sclerosis

Protein aggregation into highly-structured amyloid fibrils is linked to several neurodegenerative diseases. Such fibril formation by superoxide dismutase I (SOD1) is considered to be related to amyotrophic lateral sclerosis, a late-onset and fatal disorder. Despite much effort and the discovery of numerous anti-amyloid compounds, no effective cure or treatment is currently available. Methylene blue (MB), a phenothiazine dye, has been shown to modulate the aggregation of multiple amyloidogenic proteins. In this work we show its ability to inhibit both the spontaneous amyloid aggregation of SOD1 as well as elongation of preformed fibrils.

scholarly journals Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Aida Attar ◽  
Farid Rahimi ◽  
Gal Bitan
Keyword(s):  
Protein Aggregation ◽  
Drug Targets ◽  
Amyloid Fibrils ◽  
Specific Binding ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Amyloid Protein ◽  
Islet Amyloid

AbstractAbnormal protein folding and self-assembly causes over 30 cureless human diseases for which no disease-modifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies — the green-tea derivative (−)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01’s effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.

An Ultra-Structural Study of Human Melanoma in Vivo and Vitro

1976 ◽  
Vol 34 ◽  
pp. 258-259
Author(s):  
James R. Gaylor ◽  
Fredda Schafer ◽  
Robert E. Nordquist
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Protein Aggregation ◽  
Structural Study ◽  
Human Melanoma ◽  
Protein Matrix ◽  
Early Form ◽  
Endoplasmic Reticulum Protein ◽  
Mitochondrial Origin

Several theories on the origin of the melanosome exist. These include the Golgi origin theory, in which a tyrosinase-rich protein is "packaged" by the Golgi apparatus, thus forming the early form of the melanosome. A second theory postulates a mitochondrial origin of melanosomes. Its author contends that the melanosome is a modified mitochondria which acquires melanin during its development. A third theory states that a pre-melanosome is formed in the smooth or rough endoplasmic reticulum. Protein aggregation is suggested by one author as a possible source of the melanosome. This fourth theory postulates that the melanosome originates when the protein products of several genetic loci aggregate in the cytoplasm of the melanocyte. It is this protein matrix on which the melanin is deposited. It was with these theories in mind that this project was undertaken.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
Author(s):  
Hongyu Tao ◽  
Ling Zuo ◽  
Huanli Xu ◽  
Cong Li ◽  
Gan Qiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cdk Inhibitors ◽  
Comprehensive Overview ◽  
P53 Expression ◽  
Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

scholarly journals Nature Exposure and Its Effects on Immune System Functioning: A Systematic Review

2021 ◽  
Vol 18 (4) ◽  
pp. 1416
Author(s):  
Liisa Andersen ◽  
Sus Sola Corazon ◽  
Ulrika Karlsson Stigsdotter
Keyword(s):  
Systematic Review ◽  
Natural Killer Cell Activity ◽  
Public Health Practice ◽  
Killer Cell ◽  
Cell Activity ◽  
Natural Environments ◽  
Comprehensive Overview ◽  
Potential Health ◽  
Positive Effects

Given the drastic changes in our lifestyles and ecosystems worldwide, the potential health effects of natural environments have grown into a highly pervasive topic. Recent scientific findings suggest beneficial effects from nature exposure on human immune responses. This review aims at providing a comprehensive overview of literature published on immunomodulatory effects of nature exposure by inhalation of natural substances. A systematic database search was performed in SCOPUS and PubMed. The quality and potential bias of included studies (n = 33) were assessed by applying the EPHPP (Effective Public Health Practice Project) tool for human studies and the ARRIVE (Animal Research: Reporting of In Vivo Experiments) and SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation) tools for animal studies. The synthesis of reviewed studies points to positive effects of nature exposure on immunological health parameters; such as anti-inflammatory, anti-allergic, anti-asthmatic effects or increased NK (natural killer) cell activity. Decreased expression of pro-inflammatory molecules, infiltration of leukocytes and release of cytotoxic mediators are outcomes that may serve as a baseline for further studies. However, partially weak study designs evoked uncertainties about outcome reproducibility and key questions remain open concerning effect sizes, duration of exposure and contributions of specific vegetation or ecosystem types.

scholarly journals Drug Delivery by Ultrasound-Responsive Nanocarriers for Cancer Treatment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1135
Author(s):  
Kristin Entzian ◽  
Achim Aigner
Keyword(s):  
Drug Delivery ◽  
Biological Effects ◽  
Invasive Technique ◽  
Stimuli Responsive ◽  
Comprehensive Overview ◽  
Drug Concentrations ◽  
Therapeutic Outcomes ◽  
Cost Efficient ◽  
Safety Considerations

Conventional cancer chemotherapies often exhibit insufficient therapeutic outcomes and dose-limiting toxicity. Therefore, there is a need for novel therapeutics and formulations with higher efficacy, improved safety, and more favorable toxicological profiles. This has promoted the development of nanomedicines, including systems for drug delivery, but also for imaging and diagnostics. Nanoparticles loaded with drugs can be designed to overcome several biological barriers to improving efficiency and reducing toxicity. In addition, stimuli-responsive nanocarriers are able to release their payload on demand at the tumor tissue site, preventing premature drug loss. This review focuses on ultrasound-triggered drug delivery by nanocarriers as a versatile, cost-efficient, non-invasive technique for improving tissue specificity and tissue penetration, and for achieving high drug concentrations at their intended site of action. It highlights aspects relevant for ultrasound-mediated drug delivery, including ultrasound parameters and resulting biological effects. Then, concepts in ultrasound-mediated drug delivery are introduced and a comprehensive overview of several types of nanoparticles used for this purpose is given. This includes an in-depth compilation of the literature on the various in vivo ultrasound-responsive drug delivery systems. Finally, toxicological and safety considerations regarding ultrasound-mediated drug delivery with nanocarriers are discussed.

scholarly journals Valorization of Apple Peels through the Study of the Effects on the Amyloid Aggregation Process of κ-Casein

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2371
Author(s):  
Valeria Guarrasi ◽  
Giacoma Cinzia Rappa ◽  
Maria Assunta Costa ◽  
Fabio Librizzi ◽  
Marco Raimondo ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Environmental Sustainability ◽  
Bovine Milk ◽  
Amyloid Formation ◽  
Aggregation Process ◽  
Amyloid Aggregation ◽  
Social Challenges ◽  
Force Microscopy ◽  
Atomic Force ◽  
Apple Peels

Waste valorization represents one of the main social challenges when promoting a circular economy and environmental sustainability. Here, we evaluated the effect of the polyphenols extracted from apple peels, normally disposed of as waste, on the amyloid aggregation process of κ-casein from bovine milk, a well-used amyloidogenic model system. The effect of the apple peel extract on protein aggregation was examined using a thioflavin T fluorescence assay, Congo red binding assay, circular dichroism, light scattering, and atomic force microscopy. We found that the phenolic extract from the peel of apples of the cultivar “Fuji”, cultivated in Sicily (Caltavuturo, Italy), inhibited κ-casein fibril formation in a dose-dependent way. In particular, we found that the extract significantly reduced the protein aggregation rate and inhibited the secondary structure reorganization that accompanies κ-casein amyloid formation. Protein-aggregated species resulting from the incubation of κ-casein in the presence of polyphenols under amyloid aggregation conditions were reduced in number and different in morphology.

scholarly journals Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils

2021 ◽  
Vol 22 (10) ◽  
pp. 5075
Author(s):  
Mantas Ziaunys ◽  
Andrius Sakalauskas ◽  
Kamile Mikalauskaite ◽  
Ruta Snieckute ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Prion Protein ◽  
Amyloid Fibrils ◽  
Prion Diseases ◽  
Morphological Properties ◽  
Large Sample Size ◽  
Structural Variations ◽  
Temperature Dependent ◽  
Protein Fibrils ◽  
Propagation Properties

Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein forms multiple, conformationally and morphologically distinct structures. Considering that such structural variations can greatly complicate the search for potential antiamyloid compounds, either by having specific propagation properties or stability, it is important to better understand this aggregation event. We have recently reported the ability of prion protein fibrils to obtain at least two distinct conformations under identical conditions, which raised the question if this occurrence is tied to only certain environmental conditions. In this work, we examined a large sample size of prion protein aggregation reactions under a range of temperatures and analyzed the resulting fibril dye-binding, secondary structure and morphological properties. We show that all temperature conditions lead to the formation of more than one fibril type and that this variability may depend on the state of the initial prion protein molecules.

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