Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis

Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downregulation of microglial activation may aid in the treatment of PD. Polydatin (PLD) has been reported to pass through the blood-brain barrier and protect against motor degeneration in the SN. However, the molecular mechanisms underlying the effects of PLD in the treatment of PD remain unclear. The present study aimed to determine whether PLD protects against dopaminergic neurodegeneration by inhibiting the activation of microglia in a rat model of lipopolysaccharide (LPS)-induced PD. Our findings indicated that PLD treatment protected dopaminergic neurons and ameliorated motor dysfunction by inhibiting microglial activation and the release of pro-inflammatory mediators. Furthermore, PLD treatment significantly increased levels of p-AKT, p-GSK-3βSer9, and Nrf2, and suppressed the activation of NF-κB in the SN of rats with LPS-induced PD. To further explore the neuroprotective mechanism of PLD, we investigated the effect of PLD on activated microglial BV-2 cells. Our findings indicated that PLD inhibited the production of pro-inflammatory mediators and the activation of NF-κB pathways in LPS-induced BV-2 cells. Moreover, our results indicated that PLD enhanced levels of p-AKT, p-GSK-3βSer9, and Nrf2 in BV-2 cells. After BV-2 cells were pretreated with MK2206 (an inhibitor of AKT), NP-12 (an inhibitor of GSK-3β), or Brusatol (BT; an inhibitor of Nrf2), treatment with PLD suppressed the activation of NF-κB signaling pathways and the release of pro-inflammatory mediators in activated BV-2 cells via activation of the AKT/GSK3β-Nrf2 signaling axis. Taken together, our results are the first to demonstrate that PLD prevents dopaminergic neurodegeneration due to microglial activation via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis

Studying the Inflammatory Responses to Amyloid Beta Oligomers in Brain-Specific Pericyte and Endothelial Co-Culture From Human Stem Cells

Background: Recently, the in vitro blood–brain barrier (BBB) models derived from human pluripotent stem cells have been given extensive attention in therapeutics due to the implications they have with the health of the central nervous system. It is essential to create an accurate BBB model in vitro in order to better understand the properties of the BBB, and how it can respond to inflammatory stimulation and be passed by targeted or non-targeted cell therapeutics, more specifically extracellular vesicles.Methods: Brain-specific pericytes (iPCs) were differentiated from iPSK3 cells using dual SMAD signaling inhibitors and Wnt activation plus fibroblast growth factor 2 (FGF-2). The derived cells were characterized by immunostaining, flow cytometry, and RT-PCR. In parallel, blood vessels organoids were derived using Wnt activation, BMP4, FGF2, VEGF, and SB431542. The organoids were replated and treated with retinoic acid to enhance the blood–brain barrier (BBB) features in the differentiated brain endothelial cells (iECs). Co-culture was performed for iPCs and iECs in the transwell system and 3D microfluidics channels.Results: The derived iPCs expressed common markers PDGFRb and NG2, and brain-specific genes FOXF2, ABCC9, KCNJ8, and ZIC1. The derived iECs expressed common endothelial cell markers CD31, VE-cadherin, and BBB-associated genes BRCP, GLUT-1, PGP, ABCC1, OCLN, and SLC2A1. The co-culture of the two cell types responded to the stimulation of amyloid β42 oligomers by the upregulation of the expression of TNFa, IL6, NFKB, Casp3, SOD2, and TP53. The co-culture also showed the property of trans-endothelial electrical resistance. The proof of concept vascularization strategy was demonstrated in a 3D microfluidics-based device.Conclusion: The derived iPCs and iECs have brain-specific properties, and the co-culture of iPCs and iECs provides an in vitro BBB model that show inflammatory response. This study has significance in establishing micro-physiological systems for neurological disease modeling and drug screening

Dynamic 3D On-Chip BBB Model Design, Development, and Applications in Neurological Diseases

The blood–brain barrier (BBB) is a vital structure for maintaining homeostasis between the blood and the brain in the central nervous system (CNS). Biomolecule exchange, ion balance, nutrition delivery, and toxic molecule prevention rely on the normal function of the BBB. The dysfunction and the dysregulation of the BBB leads to the progression of neurological disorders and neurodegeneration. Therefore, in vitro BBB models can facilitate the investigation for proper therapies. As the demand increases, it is urgent to develop a more efficient and more physiologically relevant BBB model. In this review, the development of the microfluidics platform for the applications in neuroscience is summarized. This article focuses on the characterizations of in vitro BBB models derived from human stem cells and discusses the development of various types of in vitro models. The microfluidics-based system and BBB-on-chip models should provide a better platform for high-throughput drug-screening and targeted delivery

Cable-Partial-Discharge Recognition Based on a Data-Driven Approach with Optical-Fiber Vibration-Monitoring Signals

The effective pattern recognition of cable partial discharges (PDs) enables prompt corresponding measures to ensure cable safety. Traditional PD monitoring methods have limitations in online monitoring and accurate positioning, and the feature extraction of the monitored electrical signals requires significant prior knowledge. Therefore, this paper reports the performance of the distributed optical-fiber vibration-sensing monitoring of PDs on a cable with different insulation defects, and proposes a data-driven recognition approach based on the monitoring signals. The time series of the backscattered Rayleigh light intensity (BRLI) changes at the PD position were collected as the sample data. The coefficients of the time series’ autoregressive moving average (ARMA) models were extracted as features. Next, a classification model trained by the random forest (RF) algorithm was established. After the model’s validation with the experimental data and a comparative analysis with previously published methods, the PD recognition model was simply optimized based on the RF principle. The results showed that the proposed method achieved a high recognition accuracy, of about 98%, indicating that the data-driven approach—combining the ARMA model and the RF—is effective for cable-PD pattern recognition in distributed optical-fiber vibration-sensing systems

Exosomal MicroRNAs as Novel Cell-Free Therapeutics in Tissue Engineering and Regenerative Medicine

Extracellular vesicles (EVs) are membrane-bound vesicles (50–1000 nm) that can be secreted by all cell types. Microvesicles and exosomes are the major subsets of EVs that exhibit the cell–cell communications and pathological functions of human tissues, and their therapeutic potentials. To further understand and engineer EVs for cell-free therapy, current developments in EV biogenesis and secretion pathways are discussed to illustrate the remaining gaps in EV biology. Specifically, microRNAs (miRs), as a major EV cargo that exert promising therapeutic results, are discussed in the context of biological origins, sorting and packing, and preclinical applications in disease progression and treatments. Moreover, advanced detection and engineering strategies for exosomal miRs are also reviewed. This article provides sufficient information and knowledge for the future design of EVs with specific miRs or protein cargos in tissue repair and regeneration

Engineering Stem Cell-Derived Extracellular Matrices: Decellularization, Characterization, and Biological Function

International audienceStem cells, including mesenchymal stem cells and pluripotent stem cells, have attracted considerable attention in tissue engineering and regenerative medicine primarily because of their unique ability in self-renewal and multilineage differentiation. However, stem cells also have important secretory functions that form a specialized in vivo microenvironment and direct tissue development and regeneration. Extracellular matrices (ECMs) derived from stem cells retain the functional properties of their native environment and exhibit unique signaling that mediates stem cell self-renewal and lineage commitment. Stem cell-derived ECMs (scECMs) also have tunable properties corresponding to their developmental stages, suggesting that their lineage- and developmental specificity can be engineered for a wide range of applications. Hence, there is a growing interest in reconstructing stem cell microenvironment through decellularization and obtaining decellularized matrices that exhibit unique biological properties. This article summarizes recent advances in the use and understanding of scECMs. Moreover, future directions to extend the spectrum of applications of stem-derived ECMs in tissue engineering by comprehensively elucidating and engineering their regulatory function is highlighted. Impact statement Stem cells bear unique potency for multilineage differentiation as well as the capacity to secrete a vast amount of regulatory molecules. At different developmental stages, the extracellular matrices (ECMs) secreted by stem cells regulate their microenvironment and direct tissue development. The decellularization of stem cells effectively preserves ECM functional properties and can provide suitable templates to regulate stem cell fate decision, which can hardly be reproduced using single ECM proteins or synthetic scaffolds. This review highlights the unique regulatory functions of stem cell-derived ECMs, which can serve as novel sources of highly bioactive materials for tissue engineering and cell therapy

Tolerogenic Nano-/Microparticle Vaccines for Immunotherapy

Autoimmune diseases, allergies, transplant rejections, generation of antidrug antibodies, and chronic inflammatory diseases have impacted a large group of people across the globe. Conventional treatments and therapies often use systemic or broad immunosuppression with serious efficacy and safety issues. Tolerogenic vaccines represent a concept that has been extended from their traditional immune-modulating function to induction of antigen-specific tolerance through the generation of regulatory T cells. Without impairing immune homeostasis, tolerogenic vaccines dampen inflammation and induce tolerogenic regulation. However, achieving the desired potency of tolerogenic vaccines as preventive and therapeutic modalities calls for precise manipulation of the immune microenvironment and control over the tolerogenic responses against the autoantigens, allergens, and/or alloantigens. Engineered nano-/microparticles possess desirable design features that can bolster targeted immune regulation and enhance the induction of antigen-specific tolerance. Thus, particle-based tolerogenic vaccines hold great promise in clinical translation for future treatment of aforementioned immune disorders. In this review, we highlight the main strategies to employ particles as exciting tolerogenic vaccines, with a focus on the particles' role in facilitating the induction of antigen-specific tolerance. We describe the particle design features that facilitate their usage and discuss the challenges and opportunities for designing next-generation particle-based tolerogenic vaccines with robust efficacy to promote antigen-specific tolerance for immunotherapy

In Situ Growth of ZIF-8 Nanocrystals on the Pore Walls of 3D Ordered Macroporous TiO2 for a One-Pot Cascade Reaction

It is wise to mimic a bioinspired system to design a nanoreactor as a catalyst containing multiple components for a cascade reaction. Here, we report the uniform growth of well-dispersed nano-scale ZIF-8 crystals on the pore walls of 3DOM TiO2 via the TEA-assisted crystallization process. The UV-vis spectra indicate that the ZIF-8 photosensitizer can extend the visible-light absorption of 3DOM TiO2. The obtained nanoreactor can efficiently catalyze the one-pot aromatic alcohol oxidization and Knoevenagel condensation cascade reaction for larger molecules. This work offers an important strategy for preparing semiconductor–MOF multifunctional composites with a spatially separated compartmentation for the cascade reaction