Multifunctional nanoparticle-mediated combining therapy for human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 1, 2024

Abstract Combining existing drug therapy is essential in developing new therapeutic agents disease prevention and treatment. In preclinical investigations, combined effect of certain known drugs has been well established treating extensive human diseases. Attributed to synergistic effects by targeting various pathways advantages, such as reduced administration dose, decreased toxicity, alleviated resistance, combinatorial treatment now being pursued delivering combat major clinical illnesses, cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders neurodegenerative Combinatorial involves combining or co-delivering two more for a specific disease. Nanoparticle (NP)-mediated delivery systems, i.e., liposomal NPs, polymeric NPs nanocrystals, are great interest wide range due targeted delivery, extended release, higher stability avoid rapid clearance at infected areas. This review summarizes targets diseases, clinically approved combinations the development multifunctional emphasizes strategies based on severe Ultimately, we discuss challenging NP-codelivery translation provide potential approaches address limitations. offers comprehensive overview recent cutting-edge NP-mediated combination

Language: Английский

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Evidence of Flavonoids on Disease Prevention

Antioxidants, Journal Year: 2023, Volume and Issue: 12(2), P. 527 - 527

Published: Feb. 20, 2023

A growing body of evidence highlights the properties flavonoids in natural foods for disease prevention. Due to their antioxidative, anti-inflammatory, and anti-carcinogenic activities, have been revealed benefit skeletal muscle, liver, pancreas, adipocytes, neural cells. In this review, we introduced basic classification, sources, biochemical flavonoids, then summarize experimental results underlying molecular mechanisms concerning effects flavonoid consumption on obesity, cancers, neurogenerative diseases that greatly threaten public health. Especially, dosage duration intervening these are discussed, which might guide healthy dietary habits people different physical status.

Language: Английский

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Structural mechanism for specific binding of chemical compounds to amyloid fibrils

Nature Chemical Biology, Journal Year: 2023, Volume and Issue: 19(10), P. 1235 - 1245

Published: July 3, 2023

Language: Английский

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Protein amyloid aggregate: Structure and function

Aggregate, Journal Year: 2023, Volume and Issue: 4(4)

Published: March 10, 2023

Abstract Protein amyloid aggregation has been widely observed to occur and plays important roles in both physiological processes pathological diseases. Remarkably, aggregates assembled by native proteins gain a variety of different biological activities, which cannot be adopted the unassembled protein alone. Thus, it is investigate molecular basis self‐assembly how aggregated structure determines its function. In review, we firstly introduce our structural knowledge on undergo conformational transition assemble into aggregate, with main focus fibril, major species aggregate. Then, elaborate structures fibrils enable them fulfill highly diverse functions either or condition. Furthermore, discuss polymorph very unique feature implication understanding structure‐function relationship fibrils. Finally, point out importance applying integrating new approaches for deepening study highlight potential designing fibril‐based functional bio‐nanomaterials application.

Language: Английский

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Conformational Dynamics of an α-Synuclein Fibril upon Receptor Binding Revealed by Insensitive Nuclei Enhanced by Polarization Transfer-Based Solid-State Nuclear Magnetic Resonance and Cryo-Electron Microscopy

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(8), P. 4473 - 4484

Published: Feb. 16, 2023

Many amyloid fibrils associated with neurodegenerative diseases consist of an ordered fibril core (FC) and disordered terminal regions (TRs). The former represents a stable scaffold, while the latter is rather active in binding various partners. Current structural studies mainly focus on FC since high flexibility TRs hinders characterization. Here, by combining insensitive nuclei enhanced polarization transfer-based 1H-detected solid-state NMR cryo-EM, we explored intact structure α-syn including both further studied conformational dynamics upon to lymphocyte activation gene 3 (LAG3)─a cell surface receptor that involved transmission brains. We found N- C-TRs are free featuring similar conformation ensembles as those soluble monomers. While presence D1 domain LAG3 (L3D1), C-TR directly binds L3D1, meanwhile N-TR folds into β-strand integrates FC, which leads alteration overall property. Our work reveals synergistic transition intrinsically α-syn, sheds light mechanistic understanding essential role regulating pathology fibrils.

Language: Английский

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Advanced Techniques for Detecting Protein Misfolding and Aggregation in Cellular Environments

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(21), P. 12254 - 12311

Published: Oct. 24, 2023

Protein misfolding and aggregation, a key contributor to the progression of numerous neurodegenerative diseases, results in functional deficiencies creation harmful intermediates. Detailed visualization this process is paramount importance for improving our understanding disease mechanisms development potential therapeutic strategies. While vitro studies using purified proteins have been instrumental delivering significant insights into protein misfolding, behavior these complex milieu living cells often diverges significantly from such simplified environments. Biomedical imaging performed cell provides cellular-level information with high physiological pathological relevance, surpassing depth attainable through methods. This review highlights variety methodologies used scrutinize within biological systems. includes optical-based methods, strategies leaning on mass spectrometry, in-cell nuclear magnetic resonance, cryo-electron microscopy. Recent advancements techniques notably deepened processes features resulting misfolded species cells. The fields promises catalyze further breakthroughs comprehension interventions.

Language: Английский

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Graphene Quantum Dots Modulate Stress Granule Assembly and Prevent Abnormal Phase Transition of Fused in Sarcoma Protein

ACS Nano, Journal Year: 2023, Volume and Issue: 17(11), P. 10129 - 10141

Published: May 19, 2023

Protein liquid–liquid phase separation (LLPS) plays a crucial role in mediating dynamic assembly of different membraneless organelles such as stress granules (SGs). Dysregulation protein LLPS leads to aberrant transition and amyloid aggregation which is closely associated with neurodegenerative diseases. In this study, we found that three types graphene quantum dots (GQDs) exhibit potent activity preventing SG formation promoting disassembly. We next demonstrate GQDs can directly interact the SGs-containing fused sarcoma (FUS), inhibit reverse FUS LLPS, prevent its abnormal transition. Moreover, display superior disaggregating preformed fibrils. Mechanistic study further demonstrates edge-site distinct binding affinity monomers fibrils, accounts for their activities modulating fibrillation. Our work reveals capability assembly, fibrillation sheds light on rational design effective modulators therapeutics application.

Language: Английский

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Glymphatic inhibition exacerbates tau propagation in an Alzheimer’s disease model

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: April 5, 2024

Abstract Background The aggregation and spread of misfolded amyloid structured proteins, such as tau α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer’s Parkinson’s disease. These proteins possess a prion-like property, enabling their transmission from cell to leading propagation throughout the central peripheral nervous systems. While mechanisms underlying intracellular still being elucidated, targeting extracellular space has emerged potential therapeutic approach. glymphatic system, brain-wide pathway responsible for clearing metabolic waste gained attention promising target removing these toxic proteins. Methods In this study, we investigated impact long-term modulation function on by chronically treating mouse model pharmacological inhibitor AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated into hippocampus overlying cortex, subsequently treated TGN-020 (3 doses/week, 50 mg/kg TGN-020, i.p.) 10-weeks. During time, animal memory was studied using cognitive behavioural tasks, structural MR images acquired brain in vivo prior extraction immunohistochemical characterisation. Results Our findings demonstrate increased transhemispheric following inhibition clearance. Moreover, disruption system aggravated recognition exacerbated regional changes volume detected model. When initiation drug treatment delayed several weeks post-inoculation, alterations attenuated. Conclusions results indicate that modulating AQP4 and, consequently, clearance, it is possible modify brain, particularly during initial stages highlight critical role preserving healthy homeostasis offer valuable insights implications managing diseases characterized protein spread.

Language: Английский

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Cryo-EM structures reveal variant Tau amyloid fibrils between the rTg4510 mouse model and sporadic human tauopathies

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 7, 2024

Language: Английский

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β-Lactoglobulin Forms a Conserved Fibril Core That Assembles into Diverse Fibril Polymorphs

Nano Letters, Journal Year: 2025, Volume and Issue: 25(9), P. 3653 - 3661

Published: Feb. 24, 2025

The β-lactoglobulin (β-LG) protein, sourced from dietary products, is notable for forming amyloid fibrils, which are increasingly recognized as valuable protein-based nanomaterials due to their superior cytocompatibility, chemical resilience, and mechanical characteristics. However, the precise atomic details of β-LG's fibril assembly not understood. In this study, we utilized cryo-electron microscopy elucidate composition architecture β-LG fibrils. We discovered that was rapidly assembled after a short time incubation. Remarkably, these cores were composed first 32 residues, four β-strands adopted serpentine arrangement into single protofilament. This protofilament core's stability reinforced by hydrophobic interactions. Two identical protofilaments then align form distinct structural polymorphs through unique interfacial configurations, stabilized hydrophilic interactions, hydrogen bonding, electrostatic forces. Our findings provide framework understanding formation pave way designing innovative β-LG-based nanomaterials.

Language: Английский

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