Search

Innovative therapeutic strategies are urgently needed for Alzheimer’s disease (AD) due to the increasing size of the aging population and the lack of effective drug treatment. Here, we report the therapeutic effects of extracellular vesicles (EVs) secreted by microglia, including macrosomes and small EVs, on AD-associated pathology. Macrosomes strongly inhibited β-amyloid (Aβ) aggregation and rescued cells from Aβ misfolding–induced cytotoxicity. Furthermore, macrosome administration reduced Aβ plaques and ameliorated cognitive impairment in mice with AD. In contrast, small EVs slightly promoted Aβ aggregation and did not improve AD pathology. Proteomic analysis of small EVs and macrosomes revealed that macrosomes harbor several important neuroprotective proteins that inhibit Aβ misfolding. In particular, the small integral membrane protein 10–like protein 2B in macrosomes has been shown to inhibit Aβ aggregation. Our observations provide an alternative therapeutic strategy for the treatment of AD over conventional ineffective drug treatments.

Alzheimer's disease (AD) is an incurable and fatal progressive neurodegenerative disorder associated with memory and cognition impairment. AD is one of the top medical care concerns across the world with a projected economic burden of $2 trillion by 2030. To date, however, there remains no effective disease-modifying therapy available. It is more important than ever to reveal novel therapeutic approaches. Peptide-based biotherapeutics has been a great potential strategy attributed to their distinct and superior biochemical characteristics, such as reproducible chemical synthesis and modification, rapid cell and tissue permeability, and fast blood clearance. Phage display, one of today's most powerful platforms, allows selection and identification of suitable peptide drug candidates with high affinities and specificity toward target, demonstrating the potential to overcome challenges and limitations in AD diagnosis/treatment. We aim to provide the first comprehensive review to summarize the status in this research direction. The biological overview of phage display is described, including basic biology of the phage vectors and construction principle of phage library, biopanning procedure, mirror image phage display, and various binding affinity evaluation approaches. Further, the applications of phage display in AD therapy, targeted drug delivery, and early detection are presented. Finally, we discuss the current challenges and offer a future outlook for further advancing the potential application of phage display on AD and other neurodegenerative diseases.

Nanopores, due to their advantages of being modifiable, controllability and sensitivity, have made a splash in recent years in the fields of biomolecular sequencing, small molecule detection, salt differential power generation, and biomimetic ion channels. In these applications, the role of chemical or biological modification is indispensable. Compared with small molecules, the modification of polymers is more difficult and the methods are more diverse. Choosing an appropriate modification method directly determines the success or failure of a research project; therefore, it is necessary to summarize polymer modification methods toward nanopores. In addition, it is also important to provide clear and convincing evidence that the nanopore modification is successful, the corresponding characterization methods are also indispensable. Therefore, this review will summarize the methods of polymer modification of nanopores and efficient characterization methods. We hope that this review will provide some reference value for like-minded researchers.

Misfolding and accumulation of amyloid-β (Aβ) to form senile plaques are the main neuropathological signatures of Alzheimer's disease (AD). Decreasing Aβ production, inhibiting Aβ aggregation, and clearing Aβ plaques are thus considered an important strategy for AD treatment. However, numerous drugs cannot enter the AD clinical trials due to unsatisfactory biocompatibility, poor blood-brain barrier penetration, little biomarker impact, and/or low therapeutic indicators. Here, a pair of chiral aspartic acid-modified 1,2-dipalmitoyl

Protein glycosylation is among the most important post-translational modifications in living organisms and the research in the field of protein glycosylation continues to garner attention. Currently, the efficient separation and enrichment of glycoproteins and glycopeptides is the primary challenge of glycoproteomics research. The number of glycoproteins is small in complex biological samples. Moreover, the presence of highly-abundant, non-glycosylated, and modified peptides makes the detection of low-abundance glycopeptides more difficult. Therefore, efficient glycopeptide enrichment methods are required to improve the detection of these compounds. The development of highly selective glycopeptide enrichment tools is important to efficiently capture glycoproteins or glycopeptides at the molecular level. Compared with traditional glycopeptide-enriched materials, covalent organic framework materials have the advantages of large specific surface area and rich modification sites, thereby exhibiting great application potential in the field of glycopeptide enrichment. In this study, a novel covalent organic framework material (O-T-D-COFs) was prepared and applied for selective glycopeptide enrichment. We applied the solvothermal method, using 2,5-dimethoxy benzene-1,4-2 formaldehyde and 1,3,5-Tris(4-aminophenyl) benzene, to synthesize imino-based COFs. The Schiff base generated via copolymerization condensation reaction constitutes the framework of the material. Next, the synthesized intermediate material was oxidized to improve the enrichment performance of the material. The functional, specific glycopeptide-binding groups were modified on the COF channels and the structure of the material was characterized using scanning and transmission electron microscope, as well as infrared spectrum and solid-state nuclear magnetic resonance. The enrichment conditions comprised the loading and elution steps, including the optimization of the elution conditions. We could observe the clear profile of 32 glycopeptides derived from human serum immunoglobulin G (IgG) tryptic digests with a significantly improved signal-to-noise (S/N) ratio. We applied a complex sample system to verify the enrichment selectivity of the material when the molar ratios of the IgG and bovine serum albumin (BSA) tryptic digest mixtures reached 1∶50. In addition, we investigated the enrichment performance of the detection limit, enrichment capacity, recovery rate of the material, and the application potential in glycopeptides enrichment using real samples. The material showed a good detection limit (2.5 fmol/μL), an ideal enrichment capacity (120 mg/g), and enrichment recovery (103.5%±6.6% and 101.5%±10.4%). We identified a total of 86 glycopeptides derived from 53 glycoproteins with 94 N-glycosylation sites from only 1 μL human serum. The O-T-D-COFs exhibited a good glycopeptide separation and enrichment potential, indicating that the COF material has promising application potential in glycoproteomics.

A chiral nematic mesoporous molybdenum carbide film (CN-Mo2C) was fabricated through the self-assembly of cellulose nanocrystal with peroxomolybdate. CN-Mo2C exhibits a tunable chiral nematic structure by varying the ratio of constituents, enabling a surface area of 210 m2 g−1. Importantly, it shows a typical chiroptical feature through polarized optical microscopy and circular dichroism spectral analysis. As it has an excellent conductivity of 2.4 × 10−2 S cm−1, we try to use CN-Mo2C in the electrocatalytic HER production, presenting an efficient H2 production capacity. It is a versatile synthetic strategy that can conveniently enable other large-area macroscopic chiral metal-based materials.

Organoboron compounds are powerful precursors of value-added organic compounds in synthetic chemistry, and transition metal-catalysed borylation has always been dominant. To avoid toxic reagents and costs associated with metal catalysts, simpler, more economical and effective approaches for delivering organoborons are highly desirable. Here, without the use of any metal catalysts, a CH3CN-involved electrochemical borylation reaction is reported with alkenes and HBpin as substrates. The site-selectivity is realised to achieve mono- or di-functional borylation of an unsaturated bond by regulating the proportion of HBpin. In addition, the success of gram-scale experiments and versatile conversions confirms the potential applications of this strategy in industrial synthesis. The vital auxiliary role of N,N-diisopropylethylamine (DIEA) in the process of acetonitrile electrolysis is disclosed in the mechanism study. The proposed new strategy provides a generic platform for the discovery of additional challenging electrochemical systems for hydrogenation reactions.

A phosphopeptide-modified nanochannel was prepared based on a conical polymeric nanopore. It shows a reversible Ca2+-induced inactivation effect toward the ion flow and molecular transport, resulting from Ca2+ binding-caused surface charge neutralization and hydrophilicity reduction, and Ca2+ removal by the competitive binding.

Sialic acids located at the terminal end of glycans are densely attached to cell surfaces and play crucial and distinctive roles in a variety of physiological and pathological processes, such as neural development, cell-cell interactions, autoimmunity and cancers. However, due to the subtle structural differences of sialic acid species and the complicated composition of glycans, the precise recognition of sialylated glycans is difficult. Here, a fluorescent dynamic response system based on a pyrene-conjugated histidine (PyHis) supramolecular gel is proposed. Driven by π-π stacking and intermolecular hydrogen bonds, PyHis exhibits a strong self-assembly ability and forms stable gels. It is found that introduction of N-acetylneuraminic acid (a typical sialic acid) can prevent this self-assembly process, whereas other monosaccharides or sialic acid analogs have no significant effect on it. Interestingly, a sialylated glycan also has a remarkable inhibitory effect on the gel formation, which highlights the high selectivity of the gel dynamic response system. Analysis of the mechanism reveals that the sialic acid or sialylated glycan can interact closely with two PyHis molecules stacked together in the assemblies via hydrogen bonding interactions, thereby preventing the ordered accumulation of the gelators. It is worth noting that the high-efficiency sialic acid recognition effect is not observed at the single molecule level but at the supramolecular level, indicating the unique superiority of the supramolecular self-assembly system in biomolecular recognition and response. This work shows the promising prospects of using supramolecular gels in assembly engineering, regenerative medicine, tumour cell sorting and cancer diagnosis.

Ion channels play key roles in regulating the ion environment inside and outside the cell. Sialylated glycans (SGs) at the terminus of voltage-gated ion channels (VGICs) are abundant and directly control the switch of VGICs, while SGs on the cell surface are also closely related to virus infection, tumor growth, and metastasis. Here, we report a biomimetic ion nanochannel device that can be precisely regulated by SG. The nanochannel device is composed of a chemically etched polyethylene terephthalate film featuring conical nanochannels and a polyethyleneimine-g-malcopyranoside (abbreviated to Mal-PEI). Maltose, core-binding units in Mal-PEI, forms multiple hydrogen-bonding interactions with SG, which triggers globule-to-coil transition of the polymer chain and blocks transmembrane ion transport, resulting in a remarkable decrease in the ionic current of the nanochannel. Based on the changes in the ionic current, this device can precisely discriminate α2-3- and α2-6-linked sialyllactose, as well as SGs and neutral saccharides. Importantly, the nanochannel device can monitor the sialylation process of lactose catalyzed by α2,6-sialyltransferase in real time, showing its good potential in enzyme activity determination and in vitro enzyme identification. This work constructs an SG-modulated nanochannel with selective and smart ion-gating behavior, exhibiting unique advantages in SG responsiveness and enzymatic activity monitoring.

Tyrosine phosphorylation (pTyr), much of which occurred on localized multiple sites, initiates cellular signaling, governs cellular functions, and its dysregulation is implicated in many diseases, especially cancers. pTyr-specific sensing is of great significance for understanding disease states and developing targeted anticancer drugs, however, it is very challenging due to the slight difference from serine (pSer) or threonine phosphorylation (pThr). Here we present polyethylenimine-g-phenylguanidine (PEI-PG)-modified nanochannels that can address the challenge. Rich guanidinium groups enabled PEI-PG to form multiple interactions with phosphorylated residues, especially pTyr residue, which triggered the conformational change of PEI-PG. By taking advantage of the "OFF-ON" change of the ion flux arising from the conformational shrinkage of the grafted PEI-PG, the nanochannels could distinguish phosphorylated peptide (PP) from nonmodified peptide, recognize PPs with pSer, pThr, or pTyr residue and PPs with different numbers of identical residues, and importantly could sense pTyr peptides in a biosample. Benefiting from the strong interaction between the guanidinium group and the pTyr side-chain, the specific sensing of pTyr peptide was achieved by performing a simple logic operation based on PEI-PG-modified nanochannels when Ca2+ was introduced as an interferent. The excellent pTyr sensing capacity makes the nanochannels available for real-time monitoring of the pTyr process by c-Abl kinase on a peptide substrate, even under complicated conditions, and the proof-of-concept study of monitoring the kinase activity demonstrates its potential in kinase inhibitor screening.

Significant progress on electrocatalytic CO2 reduction reaction (CO2RR) has been achieved in recent years. However, the research and development of electrolyzer device for CO2RR is scarce. Here we use anion exchange membrane to develop zero-gap electrolyzers for CO2RR. The electrochemical properties of the electrolyzers with Pd/C and Cu cathodes are investigated. The Pd/C cathode shows a current density of 200 mA cm−2 with CO Faradaic efficiency of 98% and energy efficiency of 48.8%, while the Cu cathode shows a current density of 350 mA cm−2 with total CO2RR Faradaic efficiency of 81.9% and energy efficiency of 30.5%. This work provides a promising demonstration of CO2 electrolyzer using anion exchange membrane for CO2 electrolysis at industrial current densities.

Molecular configuration strongly impacts on its functions; however, due to complicated and diverse configuration as well as easy and rapid conversion among various configurations, research of molecular configuration is extremely difficult. If the free rotation of a molecule could be "slowed down" or even "frozen" by an external stimulus, such as ultralow temperature, then one configuration of the molecule could be captured and characterized relatively easily. Here, we show that the rotation of a hemicyanine-labeled 2-(2'-hydroxyphenyl)-4-methyloxazole (H-HPMO) molecule could be specifically and reversibly restricted by sequential additions of copper ion (Cu2+) and pyrophosphate (P2O74-), reflecting as remarkable fluorescence quenching and recovery, which could be directly observed by naked eyes. Binding affinity tests and cryogenic 1H NMR indicate that Cu2+ forms intensive coordinate bonds with phenolic hydroxyl, oxazole, and methoxyl groups of HPMO, which strongly restricts the free rotations of these groups and blocks charge transfer. This study provides a precise, rapid, visible, reversible, and low-cost method to monitor the molecular configuration, indicating the broad application prospects of near-infrared fluorescent sensors in configuration analysis, biosensing, and drug-substrate complexation.

The aberrant expression of sialylated glycans (SGs) is closely associated with the occurrence, progression, and metastasis of various cancers, and sialylated glycoproteins have been widely used as clinical biomarkers for cancers. However, the identification and comprehensive analysis of SGs are exceptionally complex, which urgently need an innovative and effective method of capturing SGs from biosamples prior to MS analysis. Here, we report that a novel dynamic covalent chemistry strategy based on Schiff base hydrolysis can be applied to the precise capture of SGs. The prepared glucopyranoside-Schiff base-modified silica gel displays extraordinary enrichment selectivity (even at a ratio of 1:5000 with interference), high adsorption capacity (120 mg·g-1), and satisfying enrichment recovery (95.5%) toward sialylated glycopeptides, contributing to a highly specific, efficient, mild, and reversible SG capturing approach that can remarkably promote the development of glycoproteomics and sialic acid sensing devices and can be considerably promising in cancer biomarker discovery. Meanwhile, the facile hydrolysis characteristic of our Schiff base material completely subverts conventional knowledge of enrichment materials, the chemical stability of which is usually regarded as a prerequisite. Importantly, we find an exciting story hidden behind the Schiff base hydrolysis reaction, which demonstrates the unique advantage of dynamic covalent chemistry in glycoproteomics and biomolecule sensing.

Aberrant protein phosphorylation and glycosylation are closely associated with a number of diseases. In particular, an interplay between phosphorylation and glycosylation regulates the hyperphosphorylation of protein tau, which is regarded as one of the pathologic features of Alzheimer's disease (AD). However, simultaneous characterization of these two types of post-translational modifications (PTMs) in the complex biological samples is challenging. TiO2 and the immobilized ion affinity chromatography (IMAC)-based enrichment method suffers from low selectivity and/or low recovery of phosphopeptides and glycopeptides because of the inherent limitations in intermolecular interactions. Here, we introduce a hydrogen bond-based poly[(N-isopropylacrylamide-co-4-(3-acryloylthioureido)benzoic acid0.2] (referred to as PNI-co-ATBA0.2) as a bifunctional enrichment platform to solve this bottleneck problem. Benefited from multiple hydrogen bonding interactions of ATBA with N-acetylneuraminic acid (Neu5Ac) located at the terminals of sialylated glycans and from favorable conformational transition of the copolymer chains, the smart copolymer has high adsorption capacity (370 mg·g-1) and high recovery (ranging from 74.1% ± 7.0% to 106% ± 5.0% (n = 3)) of sialylated glycopeptides. The smart copolymer also has high selectivity (79%) for simultaneous enrichment of glycopeptides and phosphopeptides from 50 μg HeLa cell lysates, yielding 721 unique phosphorylation sites from 631 phosphopeptides and 125 unique glycosylation sites from 120 glycopeptides. This study will open a new avenue and provide a novel insight for the design of enrichment materials used in PTM-proteomics.

One of the neuropathological features of Alzheimer's disease (AD) is the misfolding of amyloid-β to form amyloid aggregates, a process highly associated with biological membranes. However, how molecular chirality affects the amyloid formation on phospholipid surfaces has seldom been reported. Here, l- and d-aspartic acid-modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (l-/d-Asp–DPPE) is synthesized to construct chiral phospholipid bilayers. We discover that the l-Asp–DPPE liposomes slightly inhibit the Aβ(1–40) nucleation process but cannot affect the oligomer elongation process. By contrast, the d-Asp–DPPE liposomes strongly inhibit both nucleation and elongation of the peptide. Notably, l- and d-Asp–DPPE liposomes not only have good biocompatibility but can also rescue Aβ(1–40)-aggregation induced cytotoxicity with significant chiral discrimination, in which the cell viability is higher in the presence of d-Asp–DPPE liposomes. Mechanism analysis and molecular dynamics simulation clearly demonstrate that differential electrostatic interactions of Lys16 in Aβ(1–40) with l- or d-Asp on the phospholipid contribute to the remarkable chiral discrimination. This study provides a deeper understanding of the crucial amyloidosis process from the perspective of the chiral interface and reveals that the convergence of d-amino acids with the liposomes might be a feasible route for AD prevention., A remarkable inhibition effect and chiral discrimination are observed when the amyloid peptide aggregates on chiral phospholipid surfaces.

Cationic polymers, known for their highly positive charges, have historically dominated the materials used in bioengineering. However, the demand for intelligent systems with high efficiency, bio-mimetic and tunable features is increasing. Artificial composites that mimic biorecognition and periodic structures may propel the development of advanced materials with outstanding properties. Polyethyleneimines (PEIs) constitute a valuable class of polycations because they have repetitive structural units, a wide molecular weight range and flexible polymeric chains, which facilitate customization of functional composites. Specific advantageous features could be introduced by purposeful modification or functionalization, such as specificity and sensitivity, distinct geometry, biocompatibility, and long service life. Thus, PEIs have been rapidly used in a wide range of applications in the fields of biomedicine, biotechnology and biomaterials science. This article provides an overview of recent advancements in the fabrication of PEI-based materials and corresponding applications in gene and drug delivery, bio-inhibitors, bio-separation, bioimaging, cell culture, and production of antibacterial and self-healing materials. The effects of molecular weight, topological structure, positive charges and hydrophilic properties on the performance of PEIs have been illustrated in detail. Finally, current technological limitations, research challenges, and future aspects are also discussed.

Sialylated glycans that are attached to cell surface mediate diverse cellular processes such as immune responses, pathogen binding, and cancer progression. Precise determination of sialylated glycans, particularly their linkage isomers that can trigger distinct biological events and are indicative of different cancer types, remains a challenge, due to their complicated composition and limited structural differences. Here, we present a biomimetic nanochannels system integrated with the responsive polymer polyethyleneimine-g-glucopyranoside (Glc-PEI) to solve this problem. By using a dramatic “OFF–ON” change in ion flux, the nanochannels system achieves specific recognition for N-acetylneuraminic acid (Neu5Ac, the predominant form of sialic acid) from various monosaccharides and sialic acid species. Importantly, different “OFF–ON” ratios of the conical nanochannels system allows the precise and sensitive discrimination of sialylated glycan linkage isomers, α2–3 and α2–6 linkage (the corresponding ion conductance increase ratios are 96.2% and 264%, respectively). Analyses revealed an unusual tug-of-war mechanism between polymer-glycan binding and polymer shrinkage. The low binding affinity of Glc-PEI for the α2–6-linked glycan caused considerable shrinkage of Glc-PEI layer, but the high affinity for the α2–3-linked glycan resulted in only a slight shrinkage. This competition mechanism provides a simple and versatile materials design principle for recognition or sensing systems that involve negatively charged target biomolecules. Furthermore, this work broadens the application of nanochannel systems in bioanalysis and biosensing, and opens a new route to glycan analysis that could help to uncover the mysterious and wonderful glycoworld.