The impact of hUC MSC-derived exosome-nanoliposome hybrids on α-synuclein fibrillation and neurotoxicity.

Amyloid aggregation of α-synuclein (αSN) protein amplifies the pathogenesis of neurodegenerative diseases (NDs) such as Parkinson's disease (PD). Consequently, blocking aggregation or redirecting self-assembly to less toxic aggregates could be therapeutic. Here, we improve brain-specific nanocarriers using a hybrid of exosomes (Ex) from human umbilical cord mesenchymal stem cells (hUC MSCs) and nanoliposomes containing baicalein (Ex-NLP-Ba) and oleuropein (Ex-NLP-Ole). The hybrids contained both lipid membranes, Ex proteins, and baicalein or oleuropein. Fluorescence resonance energy transfer analysis confirmed their proper integration. The hybrids reduced the extent of αSN fibrillation and interfered with secondary nucleation and disaggregation. They not only reduced αSN pathogenicity but also enhanced drug internalization into cells, surpassing the efficacy of NLP alone, and also crossed the blood-brain barrier in a cellular model. We conclude that Ex can be successfully extracted and efficiently merged with NLPs while retaining its original properties, demonstrating great potential as a theranostic drug delivery vehicle against NDs like PD.

PeptiHub: a curated repository of precisely annotated cancer-related peptides with advanced utilities for peptide exploration and discovery.

Peptihub (https://bioinformaticscollege.ir/peptihub/) is a meticulously curated repository of cancer-related peptides (CRPs) that have been documented in scientific literature. A diverse collection of CRPs is included in the PeptiHub, showcasing a spectrum of effects and activities. While some peptides demonstrated significant anticancer efficacy, others exhibited no discernible impact, and some even possessed alternative non-drug functionalities, including drug carrier or carcinogenic attributes. Presently, Peptihub houses 874 CRPs, subjected to evaluation across 10 distinct organism categories, 26 organs, and 438 cell lines. Each entry in the database is accompanied by easily accessible 3D conformations, obtained either experimentally or through predictive methodology. Users are provided with three search frameworks offering basic, advanced, and BLAST sequence search options. Furthermore, precise annotations of peptides enable users to explore CRPs based on their specific activities (anticancer, no effect, insignificant effect, carcinogen, and others) and their effectiveness (rate and IC50) under cancer conditions, specifically within individual organs. This unique property facilitates the construction of robust training and testing datasets. Additionally, PeptiHub offers 1141 features with the convenience of selecting the most pertinent features to address their specific research questions. Features include aaindex1 (in six main subcategories: alpha propensities, beta propensity, composition indices, hydrophobicity, physicochemical properties, and other properties), amino acid composition (Amino acid Composition and Dipeptide Composition), and Grouped Amino Acid Composition (Grouped amino acid composition, Grouped dipeptide composition, and Conjoint triad) categories. These utilities not only speed up machine learning-based peptide design but also facilitate peptide classification. Database URL: https://bioinformaticscollege.ir/peptihub/.

The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells.

The role of the blood-brain barrier (BBB) is to control trafficking of biomolecules and protect the brain. This function can be compromised by pathological conditions. Parkinson's disease (PD) is characterized by the accumulation of α-synuclein aggregates (αSN-AGs) such as oligomers and fibrils, which contribute to disease progression and severity. Here we study how αSN-AGs affect the BBB in in vitro co-culturing models consisting of human brain endothelial hCMEC/D3 cells (to overcome inter-species differences) alone and co-cultured with astrocytes and neurons/glial cells. When cultivated on their own, hCMEC/D3 cells were compromised by αSN-AGs, which decreased cellular viability, mitochondrial membrane potential, wound healing activity, TEER value, and enhanced permeability, as well as increased the levels of ROS and NO. Co-culturing of these cells with activated microglia also increased BBB impairment according to TEER and systemic immune cell transmigration assays. In contrast, hCMEC/D3 cells co-cultured with astrocytes or dopaminergic neurons or simultaneously treated with their conditioned media showed increased resistance against αSN-AGs. Our work demonstrates the complex relationship between members of the neurovascular unit (NVU) (perivascular astrocytes, neurons, microglia, and endothelial cells), αSN-AGs and BBB.

A fabricated hydrogel of hyaluronic acid/curcumin shows super-activity to heal the bacterial infected wound.

High risk of acute morbidities and even mortality from expanding the antibiotics resistant infectious wounds force indefinite efforts for development of high performance wound-healing materials. Herein, we design a procedure to fabricate a hyaluronic acid (HA)-based hydrogel to conjugate curcumin (Gel-H.P.Cur). The highlight of this work is to provide a favorite condition for capturing curcumin while protecting its structure and intensifying its activities because of the synchronization with HA. Accordingly, HA as a major component of dermis with a critical role in establishing skin health, could fortify the wound healing property as well as antibacterial activity of the hydrogel. Gel-H.P.Cur showed antibacterial properties against Pseudomonas aeruginosa (P. aeruginosa), which were examined by bactericidal efficiency, disk diffusion, anti-biofilm, and pyocyanin production assays. The effects of Gel-H.P.Cur on the inhibition of quorum sensing (QS) regulatory genes that contribute to expanding bacteria in the injured place was also significant. In addition, Gel-H.P.Cur showed high potential to heal the cutaneous wounds on the mouse excisional wound model with repairing histopathological damages rapidly and without scar. Taken together, the results strongly support Gel-H.P.Cur as a multipotent biomaterial for medical applications regarding the treatment of chronic, infected, and dehiscent wounds.

Insights into the inhibitory mechanism of skullcapflavone II against α-synuclein aggregation and its mediated cytotoxicity.

The dangerous self-assembled and infectious seeds of α-synuclein (αSN) play primary roles in Parkinson's disease. Accordingly, the inhibition of αSN fibrillation and elimination of toxic aggregates are the main therapeutic strategies. Skullcapflavone II (S.FII), a compound isolated from S. pinnatifida, has shown multiple neuroprotective features. Herein, we demonstrated that S.FII inhibited αSN aggregation with IC50 of 7.2 µM. It increased nucleation time and decreased fibril elongation rate and the species formed in the presence of S.FII were unable to act as seeds. Additionally, S.FII inhibited both secondary nucleation and seeding of αSN and disaggregated the mature preformed fibrils as well. The species formed in the presence of S.FII showed less toxicity. It also preserved neurite length and dopamine content of SH-SY5Y cells and attenuated the inflammatory responses in mixed glial cells. The Localized Surface Plasmon Resonance (LSPR) analysis indicated that S.FII interacts with αSN. Docking simulation studies on αSN fibrils revealed that S.FII could interact with the key residues of the salt bridges and glutamine ladder, which might lead to the destruction of fibril's structures. We also showed that S.FII passes through the blood-brain barrier in vitro and in vivo. Overall, these findings elucidate the neuroprotective roles of S.FII in reducing αSN pathogenicity.