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1.
Type 2 diabetes mellitus is characterized by the pathological deposition of fibrillized protein, known as amyloids. It is thought that oligomers and/or amyloid fibrils formed from human islet amyloid polypeptide (hIAPP or amylin) cause cell death by membrane damage. The molecular structure of hIAPP amyloid fibrils is dominated by β‐sheet structure, as probed with conventional infrared and Raman vibrational spectroscopy. However, with these techniques it is not possible to distinguish between the core and the surface structure of the fibrils. Since the fibril surface crucially affects amyloid toxicity, it is essential to know its structure. Here the surface molecular structure and amino acid residue composition of hIAPP fibrils are specifically probed with nanoscale resolution using tip‐enhanced Raman spectroscopy (TERS). The fibril surface mainly contains unordered or α‐helical structures, in contrast to the β‐sheet‐rich core. This experimentally validates recent models of hIAPP amyloids based on NMR measurements. Spatial mapping of the surface structure reveals a highly heterogeneous surface structure. Finally, TERS can probe fibrils formed on a lipid interface, which is more representative of amyloids in vivo.  相似文献   

2.
The self‐assembly of amyloidogenic peptides into β‐sheet‐rich aggregates is a general feature of many neurodegenerative diseases, including Alzheimer's disease, which signifies the need for the effective attenuation of amyloid aggregation toward alleviating amyloid‐associated neurotoxicity. This study reports that photoluminescent carbon nanodots (CDs) can effectively suppress Alzheimer's β‐amyloid (Aβ) self‐assembly and function as a β‐sheet breaker disintegrating preformed Aβ aggregates. This study synthesizes CDs using ammonium citrate through one‐pot hydrothermal treatment and passivates their surface with branched polyethylenimine (bPEI). The bPEI‐coated CDs (bPEI@CDs) exhibit hydrophilic and cationic surface characteristics, which interact with the negatively charged residues of Aβ peptides, suppressing the aggregation of Aβ peptides. Under light illumination, bPEI@CDs display a more pronounced effect on Aβ aggregation and on the dissociation of β‐sheet‐rich assemblies through the generation of reactive oxygen species from photoactivated bPEI@CDs. The light‐triggered attenuation effect of Aβ aggregation using a series of experiments, including photochemical and microscopic analysis, is verified. Furthermore, the cell viability test confirms the ability of photoactivated bPEI@CDs for the suppression of Aβ‐mediated cytotoxicity, indicating bPEI@CDs' potency as an effective anti‐Aβ neurotoxin agent.  相似文献   

3.
Understanding and manipulating amyloid‐β (Aβ) aggregation provide key knowledge and means for the diagnosis and cure of Alzheimer's disease (AD) and the applications of Aβ‐based aggregation systems. Here, we studied the formation of various Aβ aggregate structures with gold nanoparticles (AuNPs) and brain total lipid extract‐based supported lipid bilayer (brain SLB). The roles of AuNPs and brain SLB in forming Aβ aggregates were studied in real time, and the structural details of Aβ aggregates were monitored and analyzed with the dark‐field imaging of plasmonic AuNPs that allows for long‐term in situ imaging of Aβ aggregates with great structural details without further labeling. It was shown that the fluid brain SLB platform provides the binding sites for Aβ and drives the fast and efficient formation of Aβ aggregate structures and, importantly, large Aβ plaque structures (>15 μm in diameter), a hallmark for AD, were formed without going through fibril structures when Aβ peptides were co‐incubated with AuNPs on the brain SLB. The dark‐field scattering and circular dichroism‐correlation data suggest that AuNPs were heavily involved with Aβ aggregation on the brain SLB and less α‐helix, less β‐sheet and more random coil structures were found in large plaque‐like Aβ aggregates.  相似文献   

4.
Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type‐2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation‐3 OH‐terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT‐1 cells as well as in mouse islets. This finding is supported by high‐throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c‐terminal portion of the peptide, where the amyloidogenic sequence (residues 22–29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self‐association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type‐2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation.  相似文献   

5.
Amyloidogenic peptides can self‐assemble into highly ordered nanostructures consisting of cross β‐sheet‐rich networks that exhibit unique physicochemical properties and high stability. Light‐harvesting amyloid nanofibrils are constructed by employing insulin as a building block and thioflavin T (ThT) as a amyloid‐specific photosensitizer. The ability of the self‐assembled amyloid scaffold to accommodate and align ThT in high density on its surface allows for efficient energy transfer from the chromophores to the catalytic units in a similar way to natural photosystems. Insulin nanofibrils significantly enhance the photoactivity of ThT by inhibiting nonradiative conformational relaxation around the central C? C bonds and narrowing the distance between ThT molecules that are bound to the β‐sheet‐rich amyloid structure. It is demonstrated that the ThT‐amyloid hybrid nanostructure is suitable for biocatalytic solar‐to‐chemical conversion by integrating the light‐harvesting amyloid module (for nicotinamide cofactor regeneration) with a redox biocatalytic module (for enzymatic reduction).  相似文献   

6.
The synthesis of 1,18‐nucleotide‐appended bolaamphiphiles (1 , 2 , 4 , and 6) is reported, in which a 3′‐phosphorylated guanidine, adenosine, thymidine, or cytidine is connected to each end of an octadecamethylene chain. Single‐component self‐assemblies and binary self‐assemblies with the complementary oligonucleotides dC 20 , dT 20 , dA 20 , and dG 20 are studied by atomic force microscopy, powder X‐ray diffraction analysis, temperature‐dependent UV absorption, circular dichroism, and attenuated total‐reflection Fourier‐transform infrared spectroscopy. The single‐component self‐assembly of 1 forms a two‐dimensional sheet, whereas the binary self‐assembly 1 / dC 20 gives helical nanofibers. Non‐helical nanofibers are observed for the single‐component self‐assemblies of 2 and 4 , and helical nanofibers form from the binary self‐assembly 2 / dT 20 . Interestingly, helical nanorod structures are obtained from the binary self‐assembly 4 / dA 20 , and the aligned nanorods form a nematic phase. The single‐component and binary self‐assemblies from 6 give unilamellar vesicles owing to a lack of stacking interaction between the cytosine moieties.  相似文献   

7.
Nanomedicine is a rapidly growing field that has the potential to deliver treatments for many illnesses. However, relatively little is known about the biological risks of nanoparticles. Some studies have shown that nanoparticles can have an impact on the aggregation properties of proteins, including fibril formation. Moreover, these studies also show that the capacity of nanoscale objects to induce or prevent misfolding of the proteins strongly depends on the primary structure of the protein. Herein, light is shed on the role of the peptide primary structure in directing nanoparticle‐induced misfolding by means of two model peptides. The design of these peptides is based on the α‐helical coiled‐coil folding motif, but also includes features that enable them to respond to pH changes, thus allowing pH‐dependent β‐sheet formation. Previous studies showed that the two peptides differ in the pH range required for β‐sheet folding. Time‐dependent circular dichroism spectroscopy and transmission electron microscopy are used to characterize peptide folding and aggregate morphology in the presence of negatively charged gold nanoparticles (AuNPs). Both peptides are found to undergo nanoparticle‐induced fibril formation. The determination of binding parameters by isothermal titration calorimetry further reveals that the different propensities of both peptides to form amyloid‐like structures in the presence of AuNPs is primarily due to the binding stoichiometry to the AuNPs. Modification of one of the peptide sequences shows that AuNP‐induced β‐sheet formation is related to the structural propensity of the primary structure and is not a generic feature of peptide sequences with a sufficiently high binding stoichiometry to the nanoparticles.  相似文献   

8.
The unfolding, misfolding, and aggregation of proteins lead to a variety of structural species. One form is the amyloid fibril, a highly aligned, stable, nanofibrillar structure composed of β‐sheets running perpendicular to the fibril axis. β‐Lactoglobulin (β‐Lg) and κ‐casein (κ‐CN) are two milk proteins that not only individually form amyloid fibrillar aggregates, but can also coaggregate under environmental stress conditions such as elevated temperature. The aggregation between β‐Lg and κ‐CN is proposed to proceed via disulfide bond formation leading to amorphous aggregates, although the exact mechanism is not known. Herein, using a range of biophysical techniques, it is shown that β‐Lg and κ‐CN coaggregate to form morphologically distinct co‐amyloid fibrillar structures, a phenomenon previously limited to protein isoforms from different species or different peptide sequences from an individual protein. A new mechanism of aggregation is proposed whereby β‐Lg and κ‐CN not only form disulfide‐linked aggregates, but also amyloid fibrillar coaggregates. The coaggregation of two structurally unrelated proteins into cofibrils suggests that the mechanism can be a generic feature of protein aggregation as long as the prerequisites for sequence similarity are met.  相似文献   

9.
The formation of helical scrolls formed by self‐assembly of tethered nanorod amphiphiles and their molecular analogs are investigated. A model bilayer sheet assembled by laterally tethered nanorods is simulated and shown that it can fold into distinct helical morphologies under different solvent conditions. The helices can reversibly transform from one morphology to another by dynamically changing the solvent condition. This model serves both to inspire the fabrication of laterally tethered nanorods for assembling helices at nanometer scales and as a proof‐of‐concept for engineering switchable nanomaterials via hierarchical self‐assembly.  相似文献   

10.
The oligomerization and aggregation of amyloid β (Aβ) play central role in the pathogenesis of Alzheimer's disease (AD). Molecular binding agents for modulating the formation of Aβ oligomers and fibrils have promising application potential in AD therapies. By screening a peptoid library using surface plasmon resonance imaging, amyloid inhibitory peptoid 1 (AIP1) that has high affinity to Aβ42 is identified. AIP1 is demonstrated to inhibit Aβ42 oligomerization and fibrillation and to rescue Aβ42‐induced cytotoxicity through decreasing the content of Aβ42 oligomers that is related to cell membrane permeability. Molecular docking suggests that the binding sites of AIP1 may be at the N‐terminus of Aβ42. The blood‐brain barrier (BBB) permeability of AIP1 using an in vitro BBB model is also revealed. This work provides a strategy for the design and development of peptoid‐based antiamyloidogenic agents. The obtained amyloid inhibitory peptoid shows prospects in the therapeutic application in AD.  相似文献   

11.
Variable‐temperature scanning tunneling microscopy (STM) and spectroscopy (STS) measurements are performed on heptathioether β‐cyclodextrin (β‐CD) self‐assembled monolayers (SAMs) on Au. The β‐CD molecules exhibit very rich dynamical behavior, which is not apparent in ensemble‐averaged studies. The dynamics are reflected in the tunneling current–time traces, which are recorded with the STM feedback loop disabled. The dynamics are temperature independent, but increase with increasing tunneling current and sample bias, thus indicating that the conformational changes of the β‐CD molecules are induced by electrons that tunnel inelastically. Even for sample biases as low as 10 mV, well‐defined levels are observed in the tunneling current–time traces. These jumps are attributed to the excitations of the molecular vibration of the macrocyclic β‐CD molecule. The results are of great importance for a proper understanding of transport measurements in SAMs.  相似文献   

12.
Self‐assembly of chiral nanostructures is of considerable interest, since the ability to control the chirality of these structures has direct ramifications in biology and materials science. A new approach to design chiral nanostructures from self‐assembly of N‐(9‐fluorenylmethoxycarbonyl)‐protected phenylalanine‐tryptophan‐lysine tripeptides is reported. The terminal charges can induce helical twisting of the assembled β‐sheets, enabling the formation of well‐defined chiral nanostructures. The degree and direction of twisting in the β‐sheets can be precisely tailored through in situ pH and temperature modulations. This enables the assembly of reconfigurable chiral nanomaterials with easily adjustable size and handedness. These results offer new insight into the mechanism of helical twist formation, which may enable the precise assembly of highly dynamical materials with potential applications in biomedicine, chiroptics, and chiral sensing.  相似文献   

13.
MXenes are emerging 2D materials with intriguing properties such as excellent stability and high conductivity. Here, a systematic study on the Raman spectra of 2D α‐Mo2C (molybdenum carbide), a promising member in MXene family, is conducted. Six experimentally observed Raman modes from ultrathin α‐Mo2C crystal are first assigned with the assistance of phonon dispersion calculated from density functional theory. Angle‐resolved polarized Raman spectroscopy indicates the anisotropy of α‐Mo2C in the bc plane. Raman spectroscopy is further used to study the unique domain structures of 2D α‐Mo2C crystals grown by chemical vapor deposition. A Raman mapping investigation suggests that most of the α‐Mo2C flakes contain multiple domains and the c‐axes of neighboring domains tend to form a 60° or 120° angle, due to the weak Mo? C bonds in this interstitial carbide and the low formation energy of the carbon chains along three equivalent directions. This study demonstrates that polarized Raman spectroscopy is a powerful and effective way to characterize the domain structures in α‐Mo2C, which will facilitate the further exploration of the domain‐structure‐related properties and potential applications of α‐Mo2C.  相似文献   

14.
3D‐Rapid Prototyping (3D‐RP) is a novel technique for the construction of highly accurate three‐dimensional polyamide models of biomolecules. This method has been shown to be a valuable tool in the modeling of protein‐protein‐interactions as well as in the analysis of surface topography. Using this technique we were recently able to identify a so far unknown structure on the concave side of bone morphogenetic protein 2 (BMP‐2). Since this structure is the imprint of a left‐handed helix we have called this negative an unthelix. Obviously this novel structural feature of BMP‐2 may act as a binding side for endogenous ligands. BMP‐2 belongs to the highly conserved Transforming Growth Factor‐β (TGF‐β) superfamily, a large group of multifunctional peptides controlling differentiation, proliferation and repair in multicellular organism. The protomer structures of all members share a cystine‐knot motif as a characteristic feature. The question therefore arose whether a) the novel anthelical motif found in BMP‐2 is a common structural feature of this family and b) if there are any differences in terms of pitch and radius of the anthelix. As anthelical structures are difficult to visualize and nearly impossible to quantify using 3D molecular visualization software we constructed models of BMP‐2, BMP‐7 and TGF‐β2 from X‐ray crystallographic data by 3D‐Rapid Prototyping (3D‐RP). The anthelix motif was found in BMP‐2, BMP‐7 and TGF‐β2 with similar values for pitch (ca. 8‐10 nm) and radius (ca. 0.5‐0.7 nm). In contrast the anthelical motif was not found in a 3D‐RP model of human chorionic gonadotropin (HCG) which is also a member of the cystine‐knot family but doesn’t belong to the TGF‐β superfamily. These results were corroborated by measurements of the intersubunit angle of these dimeric proteins (141‐149°) and the distances between the center of mass (1.68‐1.96 nm) of the subunits both of which appear to be determinants of the anthelical pitch. We conclude that the anthelical groove on the concave side is a common structural motif of BMP‐2, BMP‐7 and TGF‐β2 and maybe of the whole group of the TGF‐β superfamily.  相似文献   

15.
Peptide self‐assembly is an attractive route for the synthesis of intricate organic nanostructures that possess remarkable structural variety and biocompatibility. Recent studies on peptide‐based, self‐assembled materials have expanded beyond the construction of high‐order architectures; they are now reporting new functional materials that have application in the emerging fields such as artificial photosynthesis and rechargeable batteries. Nevertheless, there have been few reviews particularly concentrating on such versatile, emerging applications. Herein, recent advances in the synthesis of self‐assembled peptide nanomaterials (e.g., cross β‐sheet‐based amyloid nanostructures, peptide amphiphiles) are selectively reviewed and their new applications in diverse, interdisciplinary fields are described, ranging from optics and energy storage/conversion to healthcare. The applications of peptide‐based self‐assembled materials in unconventional fields are also highlighted, such as photoluminescent peptide nanostructures, artificial photosynthetic peptide nanomaterials, and lithium‐ion battery components. The relation of such functional materials to the rapidly progressing biomedical applications of peptide self‐assembly, which include biosensors/chips and regenerative medicine, are discussed. The combination of strategies shown in these applications would further promote the discovery of novel, functional, small materials.  相似文献   

16.
In the specific context of condensed media, the significant and increasing recent interest in the α‐cyanostilbene (CS) motif [? Ar? CH?C(CN)? Ar? ] is relevant. These compounds have shown remarkable optical features in addition to interesting electrical properties, and hence they are recognized as very suitable and versatile options for the development of functional materials. This progress report is focused on current and future use of CS structures and molecular assemblies with the aim of exploring and developing for the next generations of functional materials. A critical selection of illustrative materials that contain the CS motif, including relevant subfamilies such as the dicyanodistyrylbenzene and 2,3,3‐triphenylacrylonitrile shows how, driven by the self‐assembly of CS blocks, a variety of properties, effects, and possibilities for practical applications can be offered to the scientific community, through different rational routes for the elaboration of advanced materials. A survey is provided on the research efforts directed toward promoting the self‐assembly of the solid state (polycrystalline solids, thin films, and single crystals), liquid crystals, nanostructures, and gels with multistimuli responsiveness, and applications for sensors, organic light‐emitting diodes, organic field effect transistors, organic lasers, solar cells, or bioimaging purposes.  相似文献   

17.
Aggregation of amyloid‐β protein (Aβ) is a pathological hallmark of Alzheimer's disease (AD), so the inhibition of Aβ aggregation is an important strategy for the prevention and treatment of AD. Herein, we proposed to design molecular hybrids of peptide inhibitors by combining two peptide inhibitors, VVIA and LPFFD, into single sequences and examined their effects on Aβ42 aggregation and cytotoxicity. The hybrid peptides exhibit increased but moderate inhibitory activity as compared to their two precursors. By conjugating the peptides onto gold nanoparticles (AuNPs), however, the inhibition activity of the corresponding peptide@AuNPs against Aβ42 aggregation and cytotoxicity is greatly improved. Among them, VVIACLPFFD (VCD10)@AuNP is the most effective, which increases cell viability from 48% to 82% at a dosage as low as 0.1 nmol L?1 (NPs) or 40 nmol L?1 (peptide). The superior capacity of VCD10@AuNPs is considered due to its branched dual‐inhibitor sequence, and its special surface orientation and conformation. These structural features promote its synergetic interactions with Aβ on AuNP surface, leading to strong inhibitions of Aβ oligomerization and fibrillation and the cytotoxicity caused by the aggregation species. The findings suggest that potent inhibitors can be derived by hybridization of multiple peptide inhibitors with the hybrid products coupled onto nanoparticles.  相似文献   

18.
The inhibition of amyloid‐β (Aβ) aggregation by photo‐oxygenation has become an effective way of treating Alzheimer's disease (AD). New near‐infrared (NIR) activated treatment agents, which not only possess high photo‐oxygenation efficiency, but also show low biotoxicity, are urgently needed. Herein, for the first time, it is demonstrated that NIR activated black phosphorus (BP) could serve as an effective nontoxic photo‐oxidant for amyloid?β peptide in vitro and in vivo. The nanoplatform BP@BTA (BTA: one of thioflavin‐T derivatives) possesses high affinity to the Aβ peptide due to specific amyloid selectivity of BTA. Importantly, under NIR light, BP@BTA can significantly generate a high quantum yield of singlet oxygen (1O2) to oxygenate Aβ, thereby resulting in inhibiting the aggregation and attenuating Aβ‐induced cytotoxicity. In addition, BP could finally degrade into nontoxic phosphate, which guarantees the biosafety. Using transgenic Caenorhabditis elegans CL2006 as AD model, the results demonstrate that the 1O2‐generation system could dramatically promote life‐span extension of CL2006 strain by decreasing the neurotoxicity of Aβ.  相似文献   

19.
Rechargeable Zn/MnO2 batteries using mild aqueous electrolytes are attracting extensive attention due to their low cost, high safety, and environmental friendliness. However, the charge‐storage mechanism involved remains a topic of controversy so far. Also, the practical energy density and cycling stability are still major issues for their applications. Herein, a free‐standing α‐MnO2 cathode for aqueous zinc‐ion batteries (ZIBs) is directly constructed with ultralong nanowires, leading to a rather high energy density of 384 mWh g?1 for the entire electrode. Greatly, the H+/Zn2+ coinsertion mechanism of α‐MnO2 cathode for aqueous ZIBs is confirmed by a combined analysis of in situ X‐ray diffractometry, ex situ transmission electron microscopy, and electrochemical methods. More interestingly, the Zn2+‐insertion is found to be less reversible than H+‐insertion in view of the dramatic capacity fading occurring in the Zn2+‐insertion step, which is further evidenced by the discovery of an irreversible ZnMn2O4 layer at the surface of α‐MnO2. Hence, the H+‐insertion process actually plays a crucial role in maintaining the cycling performance of the aqueous Zn/α‐MnO2 battery. This work is believed to provide an insight into the charge‐storage mechanism of α‐MnO2 in aqueous systems and paves the way for designing aqueous ZIBs with high energy density and long‐term cycling ability.  相似文献   

20.
A facile two‐step solution‐phase method has been developed for the preparation of hierarchical α‐MnO2 nanowires@Ni1‐xMnxOy nanoflakes core–shell nanostructures. Ultralong α‐MnO2 nanowires were synthesized by a hydrothermal method in the first step. Subsequently, Ni1‐xMnxOy nanoflakes were grown on α‐MnO2 nanowires to form core–shell nanostructures using chemical bath deposition followed by thermal annealing. Both solution‐phase methods can be easily scaled up for mass production. We have evaluated their application in supercapacitors. The ultralong one‐dimensional (1D) α‐MnO2 nanowires in hierarchical core–shell nanostructures offer a stable and efficient backbone for charge transport; while the two‐dimensional (2D) Ni1‐xMnxOy nanoflakes on α‐MnO2 nanowires provide high accessible surface to ions in the electrolyte. These beneficial features enable the electrode with high capacitance and reliable stability. The capacitance of the core–shell α‐MnO2@Ni1‐xMnxOy nanostructures (x = 0.75) is as high as 657 F g?1 at a current density of 250 mA g?1, and stable charging‐discharging cycling over 1000 times at a current density of 2000 mA g?1 has been realized.  相似文献   

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