International Journal of Biological Macromolecules 200 (2022) 151–161

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International Journal of Biological Macromolecules

journal homepage: www.elsevier.com/locate/ijbiomac

Lysozyme amyloid fibril: Regulation, application, hazard analysis, and

future perspectives
Yulun Chen a, b, c, d, Qingrun Liu a, c, d, Fangwei Yang a, b, c, d, Hang Yu a, c, d, Yunfei Xie a, b, c, d,
Weirong Yao a, c, d, *
a
State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, Jiangsu Province, China
b
Engineering Research Center of Dairy Quality and Safety Control Technology, Ministry of Education, Inner Mongolia University, No.235 Daxue West Road, Hohhot
010021, Inner Mongolia Autonomous Region, China
c
School of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, Jiangsu Province, China
d
Joint International Research Laboratory of Food Safety, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, Jiangsu Province, China

A R T I C L E I N F O A B S T R A C T

Keywords: Self-assembly of misfolded proteins into ordered fibrillar aggregates known as amyloid results in various human
Amyloid fibril diseases. However, more and more proteins, whether in human body or in food, have been found to be able to
Protein aggregation form amyloid fibrils with in-depth researches. As a model protein for amyloid research, lysozyme has always
Regulation
been the focus of research in various fields. Firstly, the formation mechanisms of amyloid fibrils are discussed
Techno-functional properties
Health implications
concisely. Researches on the regulation of lysozyme amyloid fibrils are helpful to find suitable therapeutic drugs
and unfriendly substances. And this review article summarizes a number of exogenous substances including small
molecules, nanoparticles, macromolecules, and polymers. Small molecules are mainly connected to lysozyme
through hydrophobic interaction, electrostatic interaction, π-π interaction, van der Waals force and hydrogen
bond. Nanoparticles inhibit the formation of amyloid fibers by stabilizing lysozyme and fixing β-sheet. Besides,
the applications of lysozyme amyloid fibrils in food-related fields are considered furtherly due to outstanding
physical and mechanical properties. Nevertheless, the potential health threats are still worthy of our attention.
Finally, we also give suggestions and opinions on the future research direction of lysozyme amyloid fibrils.

1. Introduction in the context of pathology and diseases (such as Alzheimer’s, Hun­

Lysozyme is well known for its highly effective antibacterial prop­
erties and can inhibit gram-positive bacteria by its ability to cleave the
β-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglu­
cosamine [1,2]. It was found in human organs, tissues, secretions (milk,
tear, saliva) and egg-white, etc. To date, the most researched is hen egg-
white lysozyme (HEWL) in relation to its abundant resources and
functional, belonging to the c-type category [2,3]. The monomeric
protein HEWL is a structural homolog of human lysozyme [4]. As HEWL
shares 60% sequence identity with human lysozyme, which causes he­
reditary systemic amyloidosis [5]. It was found that the backbone dy­
namics of free human and hen lysozymes showed very similar behavior
except for some residues, indicating that the difference in amino acid
sequence did not affect the behavior of entire backbone dynamics [6].
Amyloids are associated with misfolded and partially folded proteins
tington, Parkinson, type II diabetes, and rheumatoid arthritis etc.) [7–9].
Owing to the irreversible assembly and extraordinary stability of amy­
loid fibrils, amyloid-related diseases cannot be effectively prevented and
are incurable. Many researchers expected to regulate the formation of
amyloid fibrils and treat diseases through exogenous substances
(Table 1-3).
Although amyloid fibrils are associated with a plenty of diseases,
they have been used in many fields due to their special physical and
mechanical properties [10–14]. However, these impressive de­
velopments proceed along with concerns on the safe use of amyloid
fibrils.
This review article mainly summarizes the research progress of
lysozyme amyloid fibrils. It will be discussed from the perspectives of
formation mechanism, influencing factors, regulation of amyloid fibrils
by exogenous substances, applications in food and potential hazards

* Corresponding author at: State Key Laboratory of Food Science and Technology, Jiangnan University, No.1800 Lihu Avenue, Wuxi 214122, Jiangsu Province,
China.
E-mail address: yaoweirongcn@jiangnan.edu.cn (W. Yao).

https://doi.org/10.1016/j.ijbiomac.2021.12.163
Received 1 November 2021; Received in revised form 15 December 2021; Accepted 25 December 2021
Available online 4 January 2022
0141-8130/© 2022 Elsevier B.V. All rights reserved.
Y. Chen et al. International Journal of Biological Macromolecules 200 (2022) 151–161

Table 1
Regulation of small molecules on amyloid fibrils.
Substance Concentration pH Promote Explanation Reference
(+)/Inhibit (-)

Pigments/Stains
Allura red (AR) 0.03–15.0 μM 7.0 + Electrostatic interactions between positively charged amino acids (arginine, [36]
lysine and histidine) of HEWL and negatively charged sulfate groups of AR
Erythrosine B 0.05, 0.5, 2.5 mg/ 2.0 – Binding nearly with tryptophan residues [34]
mL
Methylene Blue (MB) 0.5, 1.5 mg/mL 2.0 – Binding with lysozyme's aggregation-prone region. [108]
Sunset Yellow (SY)/Ponceau4R 5–200 μM 2.0 – Binding ability: P4R > SY [35]
(P4R)
Fast green FCF 0.5, 0.05, 0.005 2.0 – Disaggregating activity against the preformed/existing lysozyme fibrils [109]
mg/mL
Natural products
Green tea polyphenols 150 μM 12.8 – Aromatic interactions, hydrophobic interactions, the radical scavenging activity [110]
and autoxidation of polyphenols
Rutin 10–30 μg/mL 9.0 – Structural constraints and specific aromatic interactions [111]
Analog of curcumin 0.8 mM 2.5 – Binding into lysozyme; occupying the whole active site groove; inhibiting HEWL [112]
aggregation and the cytotoxic activity
Curcumin (CUR)/ 10/20 μM 2.0 – Two hydrogen bonds; interaction and Inhibition ability: DAC > CUR [113]
Diacetylcurcumin (DAC)
Boc-L-isoleucine- 0.5 mM 2.0 – The phenolic hydroxyl group; binding nearly tryptophan residues; lower [114]
functionalized curcumin cytotoxicity with HeLa cell
derivatives
Eigallocatechin-gallate (EGCG) 0.7 mM 2.0 – Thiol groups; inhibition of amyloid formation; disruption of preformed fibrils [115]
Txifolin/Silibinin 0–400 μM 2.2 – Decreasing ability to inhibit fibrils and toxicity under condition where the rate [116]
of protein assembly was high (higher protein concentration and stirring)
Quercitrin (QUE)/Loliolid 25 μM 2.5 – Blocking the fibril formation at a concentration of 25 μg/mL (QUE) [117]
(LOL)
Tea catechins 100 μg/mL 2.0 – Antioxidative potency and hydrophobicity [118]
Sennoside A(SA)/Sennoside C 200.09 μM/ 2.2 – Hydrogen bonds, van-der-Waals forces and hydrophobic interactions [119]
(SC) 186.20 μM
Myricetin 50 mM 2.0 – Binding to the aggregation-prone region of the β-domain of HEWL; linking to the [120]
relatively stable α-domain
Halopithys Incurva extrats 20 μM 2.0 – Dependent on their metabolic composition; short and less toxic pre-fibrillary [121]
aggregates
Quercus brantii acorn extract 7–28 mg/mL 2.2 – Elimination of Pre-formed fibrils [122]
Resveratrol/Tyrosol/Rutin 1.4 mM 2.0 – Reducing size, length and number of amyloid fibrils [123]
/Nicotine/dopamine
Surfactants
Triton X-100 22 μM 2.7 – Asn-59, Trp-63 and Ala-107 (TX-100 and DDM); Gln-57 and Ala-107 (TX-100) [124]
N-dodecyl-β-d-maltoside 26 μM 2.7 –
(DDM)
SDS 0.103–14.0 mM 2.0 + Increasing thicknesses along the fibril axis because surfactant-induced surface- [125]
Triton X-100 2.52–800 μM 2.0 + catalyzed secondary nucleation owing to the noncovalent interaction between
the surfactants and HEWL.
Sodium dodecyl 0.03/0.5 mM 7.4 -/+ Stimulated fibrillation at low SDBS concentrations; no fibrillation at higher [126]
benzenesulfonate (SDBS) concentrations
Others
N-benzylisatin 0.2–2 mg/mL 7.4 – Increasing the conformational stability of HEWL; affording considerable [127]
resistance to stress-induced aggregation
Ascorbic acid (Vc) 140 μM-2.1 mM 2.5 – binding to the aggregation prone beta domain to stabilize the partially unfolded [128]
conformation and prevent further conformational changes
Hydroxytyrosol (HT)/ 700 μM 1.6 – Reducing the HEWL fibrils number and length [129]
Dopamine
Glutathione 2 mM 2.0 – Depending upon the redox environment [41]
Melatonin 500 μM 2.0 – Inhibition ability: P-benzoquinone > Melatonin [130]
p-benzoquinone 1000 μM 2.0 –
Clioquionl 30–120 μM 2.0 – Inhibiting the hydrophobic exposure of HEWL [131]
Entacapone (Ent) 70–700 μM 2.2 – Binding with Glu35, Asp53, Gln58, Trp64, Ala108 and Trp109 residues via [132]
hydrogen bonds, van-der-Waals forces and hydrophobic interaction; the
important role of Trp64 and Trp109
Sodium louroyl sarcosinate 0.9–3.0 mM 9.0/ – Electrostatic and hydrophobic interaction [133]
(sarkosyl) 13.0
Deltamethin 30, 120 uM 7.4 + Exposing hydrophobic regions [47]
Arsenic trioxide (As2O3) 60–150 μM 7.4 + Driving the self-assembly of lysozyme towards oligomeric form [134]
Trimethylamine N-oxide 400 mM 2.0 – Inhibiting amyloid fibrillation after the first stage, i.e. protein unfolding [135]
Bis (indolyl) phenylmethane 50 μM 2.5 – Inhibiting the formation of amyloid fibrils and their associated toxicity; [136]
derivatives disaggregating pre-formed fibrils of HEWL
Tacrine/acridone-coumarin 19.2–105.4 μM 2.7 – Hydrophobic interactions, hydrogen bonding and van der Waals interactions [137]
heterodimers
Macrocyclic metal complexes 0.11–20 μM 2.0 – Thinning and elongation of fibrils; binding mainly to the grooves of proto [138]
filaments.
Peptide Fragments from 10–60 μM 2.8 – Docking conformation in the hydrophobic region [139]
Human Lysozyme
Glyoxal 100–400 μM 7.4 – Inducing formation of glycated adducts by glyoxal-mediated modification of the [140]
protein
1-methylisatin 0.2–2 mg/mL 7.4 – Complexing in the form of a dimer with protein

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analysis. Finally, we look forward to speeding up the application
research and possible hazard analysis of amyloid fibers.
The formation mechanism of amyloid fibril
At the atomistic length-scale, the structural features of almost all
amyloid fibrils are remarkably similar, with amino acids arranged into
β-strands (separated by ~ 4.8 Å) running orthogonal to the fibril axis
and closely packed into β-sheets running parallel to the fibril axis
(typical inter-sheet distance ~ 6–12 Å) [7,15,16]. Amyloid fibrils can
have a diameter of approximately 3 to 15 nm and a length of 0.1 to 10
μm [7].
The proteins associated with amyloidosis do not appear to demon­
strate any type of sequence or structural homology, but amyloid ag­
gregates employ a similar nucleation-dependent pathway of fibrillation
which involves the formation of nuclei, dimers, oligomers, protofila­
ments and fibrils [8,9,17]. There are three different mechanisms indi­
cated for amyloid fibrillation: (i) nucleated polymerization; (ii)
nucleated conformational conversion, and (iii) downhill polymerization
[18]. Jansens has introduced the mechanisms comprehensively [19].
Amyloid fibrils are formed by nucleated polymerization as usual under
acidic conditions used most. The simple understanding is that oligomers
are formed due to hydrophobic effect after the protein is hydrolyzed and
unfolded. Then, when a certain aggregation degree is reached (the free
energy is the highest), they begin to connect with each other in a spe­
cific. Balchin explained that there is a competitive relationship between
protein aggregation and folding from the perspective of thermody­
namics and molecular interaction (Fig. 1).
In recent years, researchers have devoted themselves to explaining
the mechanism of amyloid fibril formation and other character. Alku­
daisi et al. synthesized lysozyme encapsulated gold nanoclusters for
probing the early stage of lysozyme aggregation under acidic conditions
to understand the mechanism of lysozyme aggregation [20]. Xing et al.
proposed a four-stage step-by-step transformation mechanism to
describe the exact kinetics by Raman spectroscopy. They thought that
the uncoiling of the α-helical structures prefers to form the statistical
coils of disordered structure as the aggregation cores until reaching
almost exhaustion [21]. Perez et al. presented a self-assembly model for
amyloid fibrils formation in the presence and absence of early stage off-
pathway aggregates to determine the sharp boundary in the protein
concentration which oligomers occur [22]. In another aspect, new re­
searches debated that the central role of protein folding states plays an
important role in regulating the lability and reversibility of amyloids
[23]. Reversible and irreversible amyloid fibrils possess the same full-
length protein sequence but different fibril core structures and β-sheet
arrangements. Cao et al. found that flexible fibrils were not only labile
but also reversible beyond a minimum protein concentration [23]. Liu
et al. supposed that a buried glutamate in cross-β core rendered
β-endorphin fibrils reversible under different pH conditions [24]. Rad­
hika P. Nagarkar described that the folding and association state of each
domain could be controlled by temperature to form reversible or irre­
versible protein fibrils [25]. The identification of this unusual relation­
ship between reversible and irreversible amyloid aggregation greatly
expands the research scopes of amyloids. It might provide original
perspectives into the structural control of functional, artificial, and
pathological amyloids [23].

Table 2
Regulation of nanoparticles the amyloid fibrils
Nanoparticle Size/nm Zeta Shape Concentration pH Promote Explanation Reference
(+)/Inhibit (-)

WS2 50 Irregular 1, 20 mg/mL 2.0–11.5 -/+ Depending on pH of the solution and protein [51]
concentration
Fe3O4 23 globular 5–50 μM 2.7 – Interacting with lysozyme amyloids in vitro; [50]
promoting depolymerization
Fe3O4 5/10/20 − 31.5~− 58.9 globular 10–30 μL 2.2 Segmentation of the slender fibrils into debris [141]
AA-Fe3O4 10–50 globular 83.9–283.3 μg/ 2.7 – Affecting lysozyme fibrillization, namely, the [53]
mL lag phase and steady-state phase of the growth
curves
Dextran- 207–309 + globular 1, 10, 100 μM 2.7 – Influencing inhibiting ability by the size of NPs [54]
Fe3O4MNPs
Si 52 – globular 20, 50, 100 μg/ 2.0 + Preferential adsorption of the non- [57]
mL amyloidogenic regions of HEWL
Trisodium 122.7 11.7 globular 7.35–2940 μg/ 2.7 – Reducing nuclei and oligomers formation for [142]
citrate-Fe3O4 mL amyloid fibrillization
Gum arabic- 232.7 9.9 globular
Fe3O4
Citric acid- 82.6 5.6 globular
Fe3O4
Fe3O4-SiO2- 385 globular 0.1, 0.5 mg/mL 7.4 – Disaggregation and cleansing [143]
EGCG
ZnO-NPs 10/30/ − 19.6/-26.9/- irregular 1–20 μM 2.0 – Decreasing cross β-sheet amount, surface [144]
163 15.5 hydrophobicity; increasing of stability of HEWL
ZnO-NPs 30 – irregular 50, 1000 uM 7.4/9.0 – Causing accumulation of nonamyloidogenic and [145]
functionally active intermediates
AuNPs 50 globular 0.07, 0.33, 3.1 2.0 – Delaying the unfolding of α-helixes present; [146]
mg/mL associating with a larger amount of β-sheet
structures by the addition of AuNPs
Glutathione- 3 globular 5.19–8.26 μg/ 2.7 – Depolymerizing the amyloid aggregates; [147]
AuNPs mL inhibiting lysozyme aggregate formation
HSA-NPs 70–280 − 20 globular 500 μg/mL 2.4 – Reducing HEWL concentration; blocking hot [148]
spot regions for self-assembly via moderate
interaction
FFA/PPA- 18 globular 1–16 μM 2.2 – Broadening lag phase and suppressing growth [149]
CeONP phase of lysozyme amyloid growth; inhibition
ability: PPA-CeONP > FFA
Starch/PEG- 6.6–13.7 − 16.5~− 34 globular 0.1–1 μM 2.0 – Modulating amyloid fibrillation, defibrillation [150]
AuNRs/AgNPs and cytotoxicity of lysozyme via altering protein
surface character
Proline-AuNPs 523–529 –22.7~− 29.3 globular 200 μM 2.0 – Adsorbing through hydrophobic patches; [151]
blocking the intermolecular β-sheet formation

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Factors affecting the formation of lysozyme amyloid fibril
Lysozyme is a water-soluble globular protein. Partial unfolding is an
required step because the fibrillization prone segments are normally
buried in protein interior structures [26]. Conditions including heating
mode, time, temperature, pH, moisture and protein concentration,
shear, and the presence of alcohols, chaotropic/reducing agents, en­
zymes, and/or salt influence amyloid fibril formation as they can affect
the accessibility of amino acid sequences prone to aggregate [16,19].
Supplementary description, it is necessary that the effects of metal ions
on the formation of amyloid fibrils. As one of the main factors of food
and environment, metal ions deserve our attention. Bowman concluded
with a survey on the potential role of manganese in the etiologies of
Alzheimer’s disease and prion disease[27]. Copper (II) chelating mole­
cules could be used as potential drug candidates for neurodegenerative
diseases [28]. Ma et al. founded that the amounts of amyloid fibrils of
HEWL gradually reduced as the concentrations of zinc ions increased
[29]. Al3+ has double-edged roles in amyloid fibrillation of lysozymes.
In addition to postponing α-helix degradation, Al3+ accelerated
conformation transformations from α-helices to organized β-sheets [30].
Generally speaking, the nature of metal ions are bound with amyloid
protein via supramolecular metal–ligand interaction [15].
The regulation of exogenous substances on the formation of lyso­
zyme amyloid fibril
This section mainly discusses the exogenous substances that can
regulate the formation of lysozyme amyloid fibers, including small
molecules, nanoparticles (NPs), and polymers, which have been studied
in recent years (Table 1-3). Among them, NPs are mainly used as in­
hibitors as targeted therapeutic drugs or drug carriers. Small molecules
are mostly studied for polyphenols and flavonoids natural products and
some other exogenous pollutants. Then, the focus of polymer research is
glycosides. There are two main methods for regulating lysozyme amy­
loid fibrils: 1. stabilizing the structure of precursor protein; 2. depoly­
merizing amyloid fibers.
1.1. Small molecule
There are many small molecules that can be found to affect the for­
mation of amyloid fibrils, such as pigments/stains, natural products,
complexes, pesticides, surfactants, etc. (Table 1). Pigment is a raw ma­
terial and toxic that can impart color, commonly used in food, medicine
and engineering [31–33]. Synthetic pigments commonly used in food
have different effects on the formation of lysozyme amyloid fibrils. Most
of pigments play a restraining effect [34,35], while allure Red plays a
promoting role [36]. It is worth noting that the effect of other food
pigments on the formation of amyloid fibers is still unknown. Poly­
phenols and flavonoids have always been research hotspots as natural
products and the materials for drug design [37–39]. A blend of two
resveratrol derivatives could abolished hIAPP amyloid growth and
membrane damage [40]. Polyphenolic and flavonoids compounds play a
vital role in inhibiting amyloid formation as results of the weak forces
between the inhibitors and peptide chains including hydrogen bonding,
hydrophobic and aromatic interactions. Strangely, the effect of
providing antioxidant environment on amyloid fibers is rarely reported,
and its specific mechanism needs to be proven [41–43]. Curcumin and
its derivatives have great significance in the treatment of neurological
diseases. Radbakhsh et al. gave a detailed description of the mechanism
of curcumin inhibiting amyloid fibrils [44], so this review will not
discuss it in depth. There are many researches on the effects of pesticides
on the formation of Alzheimer’s β-amyloid protein in human body, but
less researches on lysozyme [45,46]. Varma et al. reported that delta­
methrin could induce HEWL aggregation at physiological pH [47]. In
recent years, it has been discovered that many other substances can also
affect the formation of lysozyme amyloid fibrils. For example, re­
searchers used reverse research methods to find inhibitors from different
complexity mixtures, ranging from oxidized gallic acid to tea extract,
that inhibit and remove amyloid fibers [48]. Whether it plays a positive
or negative role, it is worth exploring to understand the amyloid fibrils
deeply. This article concludes possible mechanism of small molecules
regulation the formation of amyloid fibrils (Fig. 2).
1.2. Nanoparticle
NPs have been extensively studied as a new type of neurological
disease treatment drug [49]. Researchers employed lysozyme protein
system to examine the effects of different NPs on its fibrillation profile as
it causes hereditary systemic amyloidosis, which is useful to understand
the mechanism of lysozyme amyloid fibrils and design therapeutic in­
terventions for amyloid diseases (Fig. 3.). Fe3O4 magnetic nanoparticles,
gold nanoparticles (AuNPs), silver nanoparticles (AgNPs), etc. have been
demonstrated with positive effects of inhibition or dissociation upon the
amyloid aggregation of different protein origins from past to now.
Generally considered, copolymer particles, cerium oxide particles, car­
bon nanotubes and quantum dots enhance the rate of fibril formation by
decreasing the lag time for nucleation. The observed shorter lag phase
depends on the amount and the nature of particle surface [50]. Recent
papers observed NPs had the ability to affect amyloid aggregation of
proteins differently. The 2D WS2 were shown to have different impact on
secondary structure depending on pH of the solution and protein con­
centration [51]. As early as 2010, Bellova et al. have found that mag­
netic Fe3O4 nanoparticles are able to interact with lysozyme amyloids in
vitro leading to a reduction of the amyloid aggregates, thus promoting
depolymerization [50]. Amyloids structures can be changed by

Table 3
Regulation of Macromolecular/Polymer the amyloid fibrils
Macromolecular Relative Concentration pH Promotion Explanation Reference
/Polymer molecular mass (+)/Inhibition (-)

Bovine serum albumin 664,300 5–100 g/L 2.0 – Inhibiting amyloid formation of lysozyme and [152]
(BSA) maintaining activity via mixed macromolecular
Ficoll 70 25–100 g/L crowding
Polyethylene glycols 20000/35000 50–250 g/L 12.8 – The comparable hydrodynamic radius of PEG and [61]
native HEWL
-10
Polymer poly (6-O- 3.125 × 10 − 3.125 × 2.0 – Inhibiting the formation of HEWL amyloid fibrils [62]
MMAGlc) 10-7 mol/mL
Gum arabic 20 mg/mL 1.5–1.6 + Associating into higher order fibrillar aggregates [63]
Pectin 20 mg/mL 1.5–1.6 +
Arabinogalactan 14,500 2 mg/mL 1.5 – Stabilizing of the native α-helices of the proteins; [64]
protein binding of the inhibitors to the β-sheet precursors
Poly (norbornene 0.2–2 mg/mL 1.5 –
glucose ester)
Poly (norbornene 0.2–2 mg/mL 1.5 –
gluconamide)
Modified glycogen 50–500 μg/mL 2.0 + The π-π interaction between aromatic ring groups and [65]
amyloid fibrils

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Fig. 1. A combined model of protein aggregation and folding. Adapt from [84]

Fig. 2. Mechanisms of small molecules and metal ions regulating the formation of lysozyme amyloid fibrils.

155
Y. Chen et al.
Fig. 3. The ways in which NPs regulate HEWL amyloid fibrils.
magnetic nanoparticles (MNPs) that the diameter is increased whereas
as the length of fibrils is decreased [52]. As coating agents, amino acids
(AAS) may improve the biological compatibility of NPs. The AAS func­
tionalized superparamagnetic NPs significantly inhibited lysozyme
amyloid fibrillization and destroyed amyloid fibrils by affecting the lag
phase and steady-state phase of the growth curves. This maybe related to
large surface area and the presence of aromatic rings on the surface [53].
Dextran-coated magnetic NPs can also inhibit the amyloid fibrillization,
and the size of NPs influenced the extent of their inhibitory properties
[54]. It is believed that the potential to induce protein fibrillation is
linked to the interaction of proteins with NPs surfaces. The main acting
forces between AgNPs and lysozyme may be hydrophobic interactions
[55]. This is unanimous from the electrostatic interactions and surface
tension reduction proposed by Wei et al. [15]. Gold nanorods (AuNRs)
and AuNPs, especially AuNRs, present significant inhibitory effects on
HEWL amyloid fibril formation during all the kinetic processes, from
nucleation to elongation and equilibration stages, resulted from stronger
adsorption capacity of HEWL on AuNRs surface [56]. Konar reported
that silica NPs trigger the amyloid formation of HEWL [57]. Bharti et al.
proposed that protein binding to the silica particles is determined by pH
irrespective of the ionic strength [58]. Selenium NPs have a dual func­
tion in different concentrations [59]. The specific mechanism of the
binding of NPs and amyloid remains to be studied. More importantly, in
any case, whether NPs can pass through the blood–brain barrier (BBB)
also needs to be considered. The co-delivery of metal NPs and mannitol
can temporarily open the BBB [60]. Furthermore, it is unknown that the
binding material of NPs and lysozyme amyloid fibers can make a dif­
ference in the food industry.
1.3. Macromolecule/Polymer
Macromolecular crowing imparts a significant effect on protein self-
assembly and the comparative stability of native and unfolded states of
proteins [61]. Sodium alginate (SA) can take part in amyloid-like
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International Journal of Biological Macromolecules 200 (2022) 151–161
aggregation of the lysozyme to enhances the mechanical strength [11].
Wang et al. synthesized linear polymer poly (6-O-MMAGlc) and reported
that it could inhibit the formation of HEWL amyloid fibrils [62]. It is
fantastic that the carbohydrates act as a template to promote inter-fibril
association, resulting in larger, thicker fibrils [63]. Glycosylated hy­
drophobic macromolecules are identified as a promising class of thera­
peutic agents for amyloid related diseases [64]. Holubova et al. showed
that π-π interactions played an important role in the process of amyloid
fibril formation with aromatic ring group [65]. There are a few studies
on the effect of polymers on other amyloids [66–68]. H. Cho discussed
the phenomenon of protein adsorption on the surface of nano-scale
polymers in depth and deemed that the adsorption behavior of nano-
scale proteins on the polymer surface was completely different from
the adsorption behavior observed on the overall and macroscopic sur­
face [69].
The application of lysozyme amyloid fibril
Protein amyloid fibrils have many features that are potentially of
great value due to their unique physical and mechanical properties.
Physical measurements of amyloid fibers revealed that Amyloid fibrils
are comparable to steel in strength and comparable to silk in mechanical
stiffness [70].Otherwise, the amyloid fibrils network synthesized under
suitable conditions has superior elasticity [71]. Amyloid fibrils have
been studied in the fields of materials engineering and environmental
sciences due to its superior and stable performance [10,11,15,72–74].
This review is going to present three aspects of food-related fields,
namely gelation, antibacterial and antioxidation.
1.4. Gelation
HEWL can contribute to the foaming and gelling capacity of egg
white proteins. Dried egg white contains amyloid-like fibrils and that
such fibrils in spray-dried egg white are longer (ca.100–200 nm) than
those in freeze-dried egg white (ca.20–100 nm) [75]. And the main
factors are pH value, time and temperature. At optimal conditions, a
Y. Chen et al.
higher level of cross-β sheet structures and larger worm-like protein fi­
brils were observed for freeze-dried ovalbumin [2.0%, pH 7.0, 23 h,
76℃] than for egg white [0.5%, pH 7.0, 24 h] [75]. Belwal et al. have
compiled the literature on amyloid hydrogels and discussed their po­
tential application as drug carrier, regenerative medicine, vaccine
adjuvant, and wound-dressing materials, etc. [76].
1.5. Antibacterial
HEWL acts against bacterial cell walls by hydrolyzing β-1,4-linked
glycoside bonds of peptidoglycan, but it is usually effective for Gram-
negative bacterial. In recent years, HEWL fibrils showed significantly
enhanced antibacterial activity against both lysozyme-resistant S.aures
and lysozyme-insensitive E.coil to apply to antimicrobial food pack­
aging, animal feed, antibiotic replacement, etc. [77]. Nuno H.C.S
developed a nanocomposite films with pullulan and lysozyme nano­
fibers [78]. This film not only retains the ability to form silk, but also has
good mechanical properties and shows antioxidant properties. What’s
more, the growth of S.aures was also inhibited by the film [78].
1.6. Antioxidation
Ghosh et al. founded that in vitro fibrillation of HEWL caused com­
plete reduction of Cu (II) to Cu (I) at pH 7, and thought the existence of a
partially reducing environment during fibrillation of HEWL [43].
Nanocomposite films with pullulan and lysozyme nanofibers show
outstanding antioxidant effectiveness [78]. High internal phase emul­
sions with amyloid fibrils can encapsulate and stabilize β-carotene
against ultraviolet irradiation, thermal treatment and iron ions in
aqueous phase [79].
The hazards and risks of lysozyme amyloid fibril
It is worth noting that HEWL amyloid fibrils have a plethora of ad­
vantages and functionalities as discussed above, but its risk to food
safety cannot be denied. Amyloid fibrils and oligomers are associated
with a great variety of human diseases including Alzheimer’s disease
and the prion conditions. High cytotoxicity is characteristic of aggre­
gates formed during lag phase of amyloid formation, whereas mature
fibrils represent the depot of protein molecules incapable of damaging
cell membrane. However, new experimental data show that in case of
some proteins the fibrils are the most toxic type of aggregates [80].
Eisenberg et al. thought in vitro assembly of amyloid fibrils can be
initiated or accelerated by the addition of amyloid seed. What’s more, in
susceptible hosts and under experimental conditions, transmission,
propagation, and spreading of amyloid seeds within and between organs
appear to be possible [81]. J.A.Jansens supposed that adding performed
protein fibrils to protein solutions to accelerate fibril formation holds
promise to tailor aggregation and fibril techno-functionality [7]. The
amyloidogenic proteins, including those contained in foods and cos­
metics, contributed to amyloid β aggregation by binding with amyloid β
[82]. Bovine serum albumin was induced to form amyloid aggregation
at physiological temperature by cross-seeding effect of HEWL amyloid
aggregates. at physiological temperature [83]. It is worried that the
current research on the structure and potential toxicity of amyloid fibrils
is still insufficient.
Misfolded molecules may gradually accumulate that expose hydro­
phobic amino acid residues and thus are in danger of creating potentially
toxic aggregates. In vivo, molecular chaperones play an important role
in ensuring efficient folding and prevent aggregation. Besides, constant
surveillance of the proteome by an integrated network of chaperones
and protein degradation machineries, the proteostasis network (PN), is
required to maintain protein homeostasis in a range of external and
endogenous stress conditions [84,85]. As mentioned above, many
studies have found that especially large molecules such as glycogen,
acacia gum, and pectin can promote the formation of amyloid fibers. But
to date, the impact mechanism is also ambiguous. It is also confused and
fuzzy whether amyloid fibrils will affect the pathways of protein folding
157
International Journal of Biological Macromolecules 200 (2022) 151–161
and safety control in the body.
The interaction between NPs and proteins has always been a research
hotspot [86–88]. Until now, NPs have been shown to inhibit the pro­
duction of amyloid fibrils, but the particle size used in the research is
relatively small, more than 300 nm is less reported. More importantly, it
is still unknown that amyloid fibrils and NPs may be attracted to each
other, which will cause amyloid fibrils as a carrier of NPs to exhibit
stronger toxicity. Environmental conditions play a vital role in deter­
mining toxicity of NPs [89]. Toxicity of NPs is affected by their inherent
properties such as size, shape, nature, surface, chemistry, charge, me­
dium of synthesis, storage time, aggregation, stability, mobility and
reactively [89]. Cheerfully, Shen et al. used biodegradable amyloid fi­
brils from β-lactoglobulin with natural reducing effects, as anti-oxidizing
nanocarriers and colloidal stabilizers for iron NPs [90]. This also shows
that amyloid fibrils may be safe under certain special conditions.
A lot of researches have demonstrated that intermediation for the
formation of amyloid fibrils of many different proteins in vitro aggre­
gation is more cytotoxic than mature amyloid fibrils [85,91]. Whereas,
the fibrils differ in morphology, stability, and cytotoxicity depending on
factors utilized during fibrillization. Wild-type HEWL aggregation in
vitro can form self-seeding amyloid conformational variants [92].
Maria-Magdalena et al. synthesized two different forms of HEWL at pH 2
and pH 6 [93]. The results reveal that both types of HEWL are actively
involved in the cytotoxic process on the LLC-PK1 renal cells. Fibrils
formed at acidic pH affect cell growth in a dose-dependent manner, but a
threshold-dependent inhibition of cell growth was observed in the case
of amyloid fibrils prepared at pH 6. HEWL amyloid fibrils cause exten­
sive aggregation of human erythrocytes and lipid vesicles without any
significant lysis [94]. Trypsin can induce degradation of lysozyme am­
yloid fibrils but the cytotoxicity of amyloids treated with trypsin was not
only failing to decline, but even increasing in the case of beta-2-
microglobulin fibrils [95]. There are many studies on the harm caused
by other source proteins especially body proteins except lysozyme,
which is understandable, but the research on lysozyme is also necessary.
Yiping Cao et al. has described the likely biological fate of food protein
amyloid fibrils upon ingestion and absorption, and then proposed the
potential toxicity mechanism for food protein amyloid fibrils and
experimental protocols to judge their health risks [16]. However, these
hypotheses and conjectures still remain at the theoretical level, and
there are few studies conducted exploration to understand the toxicity of
amyloid fibrils furtherly. As a model protein, lysozyme can just play its
role as the main object of research. Concomitantly, the characteristics of
lysozyme amyloid fibrils including size, structure, charge, hydropho­
bicity/hydrophilicity, and modification types are supported to be
investigated [96].
Concluding remarks and future perspectives
In this review, the formation mechanism of amyloid fibril has been
tracked and reported. Besides, we summarized main exogenous sub­
stances in detail such as pigments/stains, natural products, NPs, and
macromolecular/polymer that could regulate the formation of lysozyme
amyloid fibrils. And the possible impact mechanisms are proposed. Then
existing applications in food sector are analyzed. However, the possible
hazards and risks cannot be ignored, and we have expressed our opin­
ions furtherly. From the formation mechanism to the application value,
the research on lysozyme amyloid fibrils is still insufficient. Therefore,
this review proposes the following four points for future research di­
rections. Firstly, it is feasible to use other detection methods to deeply
study the formation mechanism of amyloid fibers, such as near-infrared
[97–100], fluorescence [101–103], Raman[21], immunization [104],
and dynamic 3D proteomes [105], etc. In-depth theoretical calculations
are also useful and helpful to us [106,107]. Secondly, new types of na­
ture products and extracts that can inhibit the formation of amyloid fi­
brils are also worth continuing to explore, providing more options for
drug treatment. Thirdly, the application of amyloid fibrils in the food
field is also the direction of future research, but its economic cost needs
to be considered. Finally, hazards and risks are still worthy of attention,
Y. Chen et al.
especially residues or accumulation in food, which will eventually cause
toxicity in the human body, causing irreversible harm.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The work described in this article was supported by National Natural
Science Foundation of China (32172326), National Key R&D Program of
China (2018YFC1602300, 2020YFC1606800), Modern agriculture in
Jiangsu Province - key and general projects (BE2019362), Science and
technology planning project of Jiangsu market supervision and
Administration Bureau (KJ204132, KJ21125006), the Open Project of
Engineering Research Center of Dairy Quality and Safety Control
Technology of Ministry of Education of China (R202101), Suzhou sci­
ence and technology development plan (SS2019016), the Project funded
by China Postdoctoral Science Foundation (2020 M680064), the Post­
doctoral Research Startup Fee of Jiangnan University
(1025219032200190).
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