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Background Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism. Methods Electron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms. Results Our results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain- and loss-of-function experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p. Conclusion Hypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.

A thermosensitive hydrogel dressing was developed for the healing of diabetic foot ulcers (DFUs) using Epigallocatechin gallate (EGCG) and recombinant human epidermal growth factor (rhEGF). Hyaluronic acid (HA), poloxamer 407 (P407), and pectin (PE) were used to form the sol-gel transition matrix, which exhibited a sol-to-gel transition around 30 °C. The hydrogel was physiologically stable. Structural and morphological characterization using Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) confirmed the efficient incorporation of EGCG and rhEGF in a porous nanoarchitecture. Rheological analysis showed the storage modulus is quite constant over the frequency range (0.01–10 Hz), and compression analysis showed a compressive strength of 40.85 kPa, ensuring mechanical appropriateness for various wound conditions. This hydrogel had a water content of 76.64% and a water vapor transmission rate of 6011.44 g/m 2 /day, favorable to maintain a moist wound surface. Antibacterial tests showed inhibition rates of 73.53% against Escherichia coli and 75.37% against Staphylococcus aureus . In vitro with RAW 264.7 macrophages and L929 fibroblasts showed >90% cell survival, increased migration with 92.53% wound closure by 48 h, strong antioxidant activity, and considerable decrease in TNF-α and IL-6 (pro-inflammatory cytokines). Combining a natural antioxidant and bioactive protein within a responsive hydrogel matrix presented a synergistic solution, holding significant promise for enhancing diabetic wound healing by antimicrobial, anti-inflammatory, and regenerative processes. Graphical Abstract The fabrication of the EGCG-rhEGF@HA-P407-PE hydrogel, an advanced wound dressing designed for diabetic foot ulcers

Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.

Drug delivery systems with high content of drug can minimize excipients administration, reduce side effects, improve therapeutic efficacy and/or promote patient compliance. However, engineering such systems is extremely challenging, as their loading capacity is inherently limited by the compatibility between drug molecules and carrier materials. To mitigate the drug-carrier compatibility limitation towards therapeutics encapsulation, we developed a sequential solidification strategy. In this strategy, the precisely controlled diffusion of solvents from droplets ensures the fast in-droplet precipitation of drug molecules prior to the solidification of polymer materials. After polymer solidification, a mass of drug nanoparticles is embedded in the polymer matrix, forming a nano-in-micro structured microsphere. All the obtained microspheres exhibit long-term storage stability, controlled release of drug molecules, and most importantly, high mass fraction of therapeutics (21.8–63.1 wt%). Benefiting from their high drug loading degree, the nano-in-micro structured acetalated dextran microspheres deliver a high dose of methylprednisolone (400 μg) within the limited administration volume (10 μL) by one single intrathecal injection. The amount of acetalated dextran used was 1/433 of that of low drug-loaded microspheres. Moreover, the controlled release of methylprednisolone from high drug-loaded microspheres contributes to improved therapeutic efficacy and reduced side effects than low drug-loaded microspheres and free drug in spinal cord injury therapy. High drug loading improves therapeutic efficacy and reduces side effects in drug delivery. Here, the authors use controlled diffusion of solvents to precipitate drug nanoparticles in polymer particles while the polymer is solidifying and demonstrate the particles for drug delivery in a spinal cord injury model.

Glutathione S-transferase Pi (GSTP1) is an isozyme encoded by the GST pi gene that plays an important regulatory role in detoxification, anti-oxidative damage, and the occurrence of various diseases. The aim of the present study was to review the association between the expression of GSTP1 and the development and treatment of various cancers, and discuss GSTP1 methylation in several malignant tumors, such as prostate, breast and lung cancer, as well as hepatocellular carcinoma; to review the association between polymorphism of the GSTP1 gene and various diseases; and to review the effects of GSTP1 on electrophilic oxidative stress, cell signal transduction, and the regulation of carcinogenic factors. Collectively, GSTP1 plays a major role in the development of various diseases.

Transplantation of mesenchymal stem cells (MSCs) has been considered an effective therapeutic treatment for a variety of diseases including bone fracture. However, there are associated complications along with MSCs transplantation. There is evidence to show that exosomes (Exos) derived from MSCs exert a similar paracrine function. In addition, repair capabilities of MSCs decline with age. Hence, this study aims to confirm whether the Exos protective function on osteogenic differentiation and fracture healing from aged MSCs was attenuated. This information was used in order to investigate the underlying mechanism. MSCs were successfully isolated and identified from young and aged rats, and Exos were then obtained. Aged-Exos exhibited significantly attenuated effects on MSCs osteogenic differentiation in vitro and facture healing in vivo. Using miRNA array analysis, it was shown that miR-128-3p was markedly upregulated in Aged-Exos. In vitro experiments confirmed that Smad5 is a direct downstream target of miR-128-3p, and was inhibited by overexpressed miR-128-3p. A series gain- and loss- function experiment indicated that miR-128-3P serves a suppressor role in the process of fracture healing. Furthermore, effects caused by miR-128-3P mimic/inhibitor were reversed by the application of Smad5/siSmad5. Taken together, these results suggest that the therapeutic effects of MSCs-derived Exos may vary according to differential expression of miRNAs. Exosomal miR-128-3P antagomir may act as a promising therapeutic strategy for bone fracture healing, especially for the elderly.

Eukaryotic cytochrome P450 enzymes, generally colocalizing with their redox partner cytochrome P450 reductase (CPR) on the cytoplasmic surface of organelle membranes, often perform poorly in prokaryotic cells, whether expressed with CPR as a tandem chimera or free-floating individuals, causing a low titer of heterologous chemicals. To improve their biosynthetic performance in Escherichia coli , here, we architecturally design self-assembled alternatives of eukaryotic P450 system using reconstructed P450 and CPR, and create a set of N-termini-bridged P450-CPR heterodimers as the counterparts of eukaryotic P450 system with N-terminus-guided colocalization. The covalent counterparts show superior and robust biosynthetic performance, and the N-termini-bridged architecture is validated to improve the biosynthetic performance of both plant and human P450 systems. Furthermore, the architectural configuration of protein assemblies has an inherent effect on the biosynthetic performance of N-termini-bridged P450-CPR heterodimers. The results suggest that spatial architecture-guided protein assembly could serve as an efficient strategy for improving the biosynthetic performance of protein complexes, particularly those related to eukaryotic membranes, in prokaryotic and even eukaryotic hosts. Cytochrome P450 enzymes (P450s) and their redox partner cytochrome P450 reductase (CPR) often perform poorly in bioproduction of natural products by engineered prokaryotic microbes. Here, the authors report spatial architecture-guided P450-CPR assembly for improving the biosynthetic performance of both plant and human P450s in E. coli .

Gallium 68 ( 68 Ga)-labeled DOTA-conjugate ibandronic acid (DOTA-IBA) has been successfully synthesized and utilized for bone metastasis imaging. This study compares the diagnostic efficacy between 68 Ga-DOTA-IBA and fluorine 18 ( 18 F)-labeled fluorodeoxyglucose (FDG) in detecting bone metastases. This prospective study, conducted from October 2022 to September 2023, analyzed images from participants who underwent 68 Ga-DOTA-IBA PET/CT and 18 F-FDG PET/CT scans. Lesions were classified into five groups based on anatomical location (limbs, vertebrae, pelvis, ribs, and skull). Morphological bone changes were categorized as osteolytic, osteoblastic, or mixed. The semi-quantified radiotracer uptake, measured by the maximum standardized uptake value (SUV max ), was compared using a paired t-test. Detection rates between the two scans were analyzed using the McNemar test. A total of 46 participants (median age: 64 years [interquartile range: 53–68 years], 28 men) were evaluated. 68 Ga-DOTA-IBA demonstrated higher diagnostic efficacy than 18 F-FDG in detecting bone metastases in the limbs (73.2% vs. 64.1%), vertebras (78.1% vs. 67.4%), ribs (86.6% vs. 62.2%), pelvis (78.6% vs. 68.9%), and skulls (80.0% vs. 38%). For osteoblastic lesions, the detection rate for 68 Ga-DOTA-IBA and 18 F-FDG was 83.3% and 51.5% respectively ( P  < 0.001). The SUV max of 68 Ga-DOTA-IBA was 7.88 (95% CI 7.09–8.66), which was higher than that of 18 F-FDG at 3.96 (95% CI 3.57–4.35) ( P  < 0.001). In participants with prostate cancer, the detection rate of 68 Ga-DOTA-IBA and 18 F-FDG was 84.7% and 55.0% respectively ( P  < 0.001). The SUV max of 68 Ga-DOTA-IBA was 10.44 (95% CI 8.57–12.30), which was higher than that of 18 F-FDG 4.29 (95% CI 3.51–5.07) ( P  < 0.001). 68 Ga-DOTA-IBA PET/CT demonstrates superior diagnostic performance over 18 F-FDG PET/CT in detecting bone metastases, particularly in osteoblastic lesions and prostate cancer cases.

Addressing the challenges of significant speed overshoot, stability issues, and system oscillations associated with the sliding mode control (SMC) strategy in maximum power point tracking (MPPT) for permanent magnet synchronous wind power systems, this paper introduces a fuzzy sliding mode control (FSMC) method employing an innovative exponential convergence law. By incorporating a velocity adjustment function into the traditional exponential convergence law, a novel convergence law was designed to mitigate oscillations during the sliding phase and expedite the convergence rate. Additionally, a fuzzy controller was developed to implement a fuzzy adaptive SMC strategy, optimizing the MPPT for permanent magnet synchronous wind power generation systems. Simulation results indicated that this approach offered a faster response and superior interference rejection capabilities, compared to conventional and modified SMC strategies. The improved FSMC strategy demonstrated a swift, dynamic response and excellent steady-state performance, improving the efficiency of MPPT, thus confirming the effectiveness of the proposed method.

Francis turbines are most widely used in hydropower due to their characteristics which include a fast response and wide time-scale operation. The vortex rope inside Francis turbines is a common flow phenomenon, which always causes strong vibration, pressure pulsations, fatigue load, and even serious failure of the components. Vortex suppression methods can effectively change the velocity and pressure distribution of the flow field in the draft tube, reduce the volume of vortex rope and the amplitude of pressure pulsation, inhibit the development of cavitation erosion, and improve the operation stability of the hydro turbine. However, the vortex suppression method is not suitable for all working conditions, and the vortex suppression effect is also different. There are still many problems with how to analyze the vortex suppression effect and practicability of the turbine from multi-dimensions. It is of great significance to analyze the vortex suppression techniques and their practicability in hydraulic turbines from various aspects. The primary focus of the present study is to analyze the hazards of vortex rope in draft tubes and summarize the methods of suppressing vortex rope and pressure pulsation. This review article provides a basis for controlling the vortex rope in the draft tube, which can help the designers choose the suitable control method to mitigate it. Future research directions are also briefly discussed.