skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


  • NSF Public Access
  • Search Results
  • Chaperone Activity and Protective Effect against Aβ-Induced Cytotoxicity of Artocarpus camansi Blanco and Amaranthus dubius Mart. ex Thell Seed Protein Extracts
Title: Chaperone Activity and Protective Effect against Aβ-Induced Cytotoxicity of Artocarpus camansi Blanco and Amaranthus dubius Mart. ex Thell Seed Protein Extracts
Alzheimer’s disease (AD) is the most common type of dementia and is listed as the sixth-leading cause of death in the United States. Recent findings have linked AD to the aggregation of amyloid beta peptides (Aβ), a proteolytic fragment of 39–43 amino acid residues derived from the amyloid precursor protein. AD has no cure; thus, new therapies to stop the progression of this deadly disease are constantly being searched for. In recent years, chaperone-based medications from medicinal plants have gained significant interest as an anti-AD therapy. Chaperones are responsible for maintaining the three-dimensional shape of proteins and play an important role against neurotoxicity induced by the aggregation of misfolded proteins. Therefore, we hypothesized that proteins extracted from the seeds of Artocarpus camansi Blanco (A. camansi) and Amaranthus dubius Mart. ex Thell (A. dubius) could possess chaperone activity and consequently may exhibit a protective effect against Aβ1–40-induced cytotoxicity. To test this hypothesis, the chaperone activity of these protein extracts was measured using the enzymatic reaction of citrate synthase (CS) under stress conditions. Then, their ability to inhibit the aggregation of Aβ1–40 using a thioflavin T (ThT) fluorescence assay and DLS measurements was determined. Finally, the neuroprotective effect against Aβ1–40 in SH-SY5Y neuroblastoma cells was evaluated. Our results demonstrated that A. camansi and A. dubius protein extracts exhibited chaperone activity and inhibited Aβ1–40 fibril formation, with A. dubius showing the highest chaperone activity and inhibition at the concentration assessed. Additionally, both protein extracts showed neuroprotective effects against Aβ1–40-induced toxicity. Overall, our data demonstrated that the plant-based proteins studied in this research work can effectively overcome one of the most important characteristics of AD.  more » « less
Award ID(s):
2114401
PAR ID:
10472894
Author(s) / Creator(s):
; ;
Publisher / Repository:
MDPI
Date Published:
Journal Name:
Pharmaceuticals
Volume:
16
Issue:
6
ISSN:
1424-8247
Page Range / eLocation ID:
1-16
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; (, Cells)
    Alzheimer’s disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aβ in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aβ1-40 and Aβ1-42 in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aβ1-40 and Aβ1-42 are differently accumulated in cardiomyocytes and coronary endothelial cells. Aβ1-42 had more adverse effects than Aβ1-40 on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aβ1-42. Mitochondrial dysfunction induced by Aβ was associated with apoptosis of the cells. The effects of Aβ1-42 on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aβ1-40 and Aβ1-42 significantly increased Ca2+ -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aβ on cell survival and mitochondria function in cardiac cells. 
    more » « less
  2. ; ; ; ; ; ; (, Chemical Science)
    Amyloid aggregation and microbial infection are considered as pathological risk factors for developing amyloid diseases, including Alzheimer's disease (AD), type II diabetes (T2D), Parkinson's disease (PD), and medullary thyroid carcinoma (MTC). Due to the multifactorial nature of amyloid diseases, single-target drugs and treatments have mostly failed to inhibit amyloid aggregation and microbial infection simultaneously, thus leading to marginal benefits for amyloid inhibition and medical treatments. Herein, we proposed and demonstrated a new “anti-amyloid and antimicrobial hypothesis” to discover two host-defense antimicrobial peptides of α-defensins containing β-rich structures (human neutrophil peptide of HNP-1 and rabbit neutrophil peptide of NP-3A), which have demonstrated multi-target, sequence-independent functions to (i) prevent the aggregation and misfolding of different amyloid proteins of amyloid-β (Aβ, associated with AD), human islet amyloid polypeptide (hIAPP, associated with T2D), and human calcitonin (hCT, associated with MTC) at sub-stoichiometric concentrations, (ii) reduce amyloid-induced cell toxicity, and (iii) retain their original antimicrobial activity upon the formation of complexes with amyloid peptides. Further structural analysis showed that the sequence-independent amyloid inhibition function of α-defensins mainly stems from their cross-interactions with amyloid proteins via β-structure interactions. The discovery of antimicrobial peptides containing β-structures to inhibit both microbial infection and amyloid aggregation greatly expands the new therapeutic potential of antimicrobial peptides as multi-target amyloid inhibitors for better understanding pathological causes and treatments of amyloid diseases. 
    more » « less
  3. ; ; ; (, Advanced Biology)
    Neurodegenerative diseases and cancers are considered to be two families of diseases caused by completely opposite cell-death mechanisms: the former caused by premature cell death, with the latter due to the increased resistance to cell death. Growing epidemiologic evidence appear to suggest an inverse correlation between neurodegenerative diseases and cancers. However, pathological links, particularly from a protein-cell interaction perspective, between these two families of diseases remains to be proven. Here, a fundamental study investigates the effects of three amyloid proteins of Aβ (associated with AD), hIAPP (associated with T2D), and hCT (associated with MTC) on pancreatic cancer (PANC-1) cells. Collective results demonstrate a general inhibitory activity of all of three amyloid proteins on cancer cell proliferation, but inhibition efficiencies are strongly dependent on amyloid sequence (Aβ, hIAPP, hCT), concentration (IC25, IC50, IC75), and aggregation states (monomers, oligomers). Amyloid proteins exhibit two pathways against cancer cells: amyloid monomer-induced ROS production to inhibit cell growth and amyloid oligomer-induced membrane disruption to kill cells. Collectively, the results demonstrate a general inhibition function of amyloid proteins to induce cancer cell death by preventing cell proliferation, suppressing cell migration, promoting reactive oxygen species production, and disrupting cell membranes. 
    more » « less
  4. ; ; ; (, Sensors & Diagnostics)
    Misfolding and aggregation of amyloid peptides are critical pathological events in numerous protein misfolding diseases (PMDs), such as Alzheimer's disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). While developing effective amyloid detectors and inhibitors to probe and prevent amyloid aggregation is a crucial diagnostic and therapeutic strategy for treating debilitating diseases, it is important to recognize that amyloid detection and amyloid prevention are two distinct strategies for developing pharmaceutical drugs. Here, we reported novel fluorescent BO21 as a versatile “dual-function, multi-target” amyloid probe and inhibitor for detecting and preventing amyloid aggregates of different sequences (Aβ, hIAPP, or hCT) and sizes (monomers, oligomers, or fibrils). As an amyloid probe, BO21 demonstrated a higher sensitivity and binding affinity to oligomeric and fibrillar amyloids compared to ThT, resulting in up to 18–39 fold fluorescence enhancements. As an amyloid inhibitor, BO21 also demonstrated its strong amyloid inhibition property by effectively preventing amyloid aggregation, disaggregating preformed amyloid fibrils, and reducing amyloid-induced cytotoxicity. The findings of this study offer a new perspective for the discovery of dual-functional amyloid probes and inhibitors, which have the potential to greatly expand the diagnostic and therapeutic treatments available for PMDs. 
    more » « less
  5. ; ; (, ACS Chemical Neuroscience)
    Amyloids and antimicrobial peptides have traditionally been recognized as distinct families with separate biological functions and targets. However, certain amyloids and antimicrobial peptides share structural and functional characteristics that contribute to the development of neurodegenerative diseases. Specifically, the aggregation of amyloid-β (Aβ) and microbial infections are interconnected pathological factors in Alzheimer’s disease (AD). In this study, we propose and demonstrate a novel repurposing strategy for an antimicrobial peptide of protegrin-1 (PG-1), which exhibits the ability to simultaneously prevent Aβ aggregation and microbial infection both in vitro and in vivo. Through a comprehensive analysis using protein, cell, and worm assays, we uncover multiple functions of PG-1 against Aβ, including the following: (i) complete inhibition of Aβ aggregation at a low molar ratio of PG-1/Aβ = 0.25:1, (ii) disassembly of the preformed Aβ fibrils into amorphous aggregates, (iii) reduction of Aβ-induced cytotoxicity in SH-SY5Y cells and transgenic GMC101 nematodes, and (iv) preservation of original antimicrobial activity against P.A., E.coli., S.A., and S.E. strains in the presence of Aβ. Mechanistically, the dual anti-amyloid and anti-bacterial functions of PG-1 primarily arise from its strong binding to distinct Aβ seeds (KD = 1.24–1.90 μM) through conformationally similar β-sheet associations. This work introduces a promising strategy to repurpose antimicrobial peptides as amyloid inhibitors, effectively targeting multiple pathological pathways in AD. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email