Inhibition of UHRF1 Improves Motor Function in Mice with Spinal Cord Injury.

Spinal-cord injury (SCI) is a severe condition that can lead to limb paralysis and motor dysfunction, and its pathogenesis is not fully understood. The objective of this study was to characterize the differential gene expression and molecular mechanisms in the spinal cord of mice three days after spinal cord injury. By analyzing RNA sequencing data, we identified differentially expressed genes and discovered that the immune system and various metabolic processes play crucial roles in SCI. Additionally, we identified UHRF1 as a key gene that plays a significant role in SCI and found that SCI can be improved by suppressing UHRF1. These findings provide important insights into the molecular mechanisms of SCI and identify potential therapeutic targets that could greatly contribute to the development of new treatment strategies for SCI.

Homoharringtonine enhances cytarabine-induced apoptosis in acute myeloid leukaemia by regulating the p38 MAPK/H2AX/Mcl-1 axis.

Acute myeloid leukaemia (AML) is a fatal haematopoietic malignancy and is treated with the conventional combination of cytarabine (Ara-C) and daunorubicin (Dau). The survival rate of AML patients is lower due to the cardiotoxicity of daunorubicin. Clinically, homoharringtonine (HHT) plus Ara-C has been reported to be equally effective as Dau plus Ara-C in some types of AML patients with less toxic effects. We utilized the clinical use of homoharringtonine in combination with Ara-C to test its combination mechanism. We found that the insensitivity of AML cells to cytarabine-induced apoptosis is associated with increased Mcl-1 stability and p38 inactivation. HHT downregulates Mcl-1, phosphorylates H2AX and induces apoptosis by activating p38 MAPK. Inactivation of p38 through inhibitors and siRNA blocks apoptosis, H2AX phosphorylation and Mcl-1 reduction. HHT enhances Ara-C activation of the p38 MAPK signalling pathway, overcoming Ara-C tolerance to cell apoptosis by regulating the p38/H2AX/Mcl-1 axis. The optimal ratio of HHT to Ara-C for synergistic lethality in AML cells is 1:4 (M/M). HHT synergistically induces apoptosis in combination with Ara-C in vitro and prolongs the survival of xenografts. We provide a new mechanism for AML treatment by regulating the p38 MAPK/H2AX/Mcl-1 axis to improve cytarabine therapy.

Alloy nanozyme-reinforced hyaluronic acid-based hydrogel with wound environment-responsive properties for synergistically accelerating infectious wound healing.

The recovery of infectious wound tissues presents a significant global health challenge due to the impediments posed by the harsh healing microenvironment, which includes ongoing bacterial invasion, high oxidative stress, inflammatory response, and impaired angiogenesis. To overcome the above issues, we propose a composite hydrogel based on the multiple-crosslinked mechanism involving the covalent network of CC bonds within catechol and maleic-modified HA (CMHA), the self-assembly network of glycyrrhizic acid (GA), and the metal-polyphenol coordination induced by ZHMCe for accelerating infectious wound healing. The resulting CMHA/GA/ZHMCe hydrogels demonstrate enhanced mechanical, adhesive, antioxidative, and antibacterial properties. Importantly, the hydrogel system possesses wound environment-responsive properties that allow it to adapt to the specific therapeutic requirements of different stages by regulating various enzyme activities in the healing of infected wounds. Furthermore, the biocompatible CMHA/GA/ZHMCe shows the ability to promote cell migration and angiogenesis in vitro while reprogramming macrophages toward an anti-inflammatory phenotype due to the effective release of active ingredients. In vivo experiments confirm that the CMHA/GA/ZHMCe hydrogel significantly enhances infectious wound healing by accelerating re-epithelialization, promoting collagen deposition, regulating inflammation, and contributing to vascularization. These findings underscore the therapeutic potential of our hydrogel dressings for the treatment of bacterially infected cutaneous wound healing.

Modified ZIF-8 Nanoparticles for Targeted Metabolic Treatment of Acute Spinal Cord Injury.

The activation of proinflammatory M1-type macrophages in the injured lesion accelerates the progression of a spinal cord injury (SCI). However, adverse side effects during systemic treatments targeting M1 macrophages have limited their applications. Nanoplatforms are novel carriers of traditional Chinese medicine because of their great efficiency to deliver and accumulation in the lesion. Herein, we synthesized a modified zeolitic imidazolate framework-8 (ZIF-8) nanoplatform for internalization and accumulation in the injured spinal cord and effective administration for SCI. In vitro and in vivo experiments suggested that Prussian blue and Schisandrin B modified ZIF-8 effectively accumulated in M1 macrophages, inhibited reactive oxygen species (ROS), and polarized the macrophage from proinflammatory M1 to anti-inflammatory M2 for rapid tissue infiltration by reprogramming the metabolic macrophages phenotype. This nanoplatform achieves a synergistic therapeutic effect of immunomodulation and neuroprotection, thereby shedding new light on the application of ZIF-8, and provides great potential for SCI.

Prussian blue analogues improves the microenvironment after spinal cord injury by regulating Zn.

Mitochondrial injury, neuronal apoptosis and phenotypic transformation of macrophages are the main mechanisms of spinal cord injury. Based on the Prussian blue nanomase's strong ability to clear free radicals, the treatment of spinal cord injury with nano-zirconium (Pb-Zr) was carried out. The disease treatment strategy based on nanomaterials has excellent therapeutic effect, and Prussian blue analogs have good therapeutic properties, so the application prospects of Prussian blue analogs is broad. From the point of view of Prussian blue content, improving the presence of zirconium in the microenvironment significantly increased the activity of Prussian blue. Prussian Blue zirconium significantly improved lipopolysaccharide (LPS) and interferon (IFN-γ) induced neuronal cell (pc12 cells) and macrophage dysfunction by improving oxidative stress, inflammation, and apoptosis in the microenvironment. It can promote the recovery of motor function after spinal cord injury. In vivo experiments, it shows that Prussian blue zirconium can improve inflammation, apoptosis and oxidative stress of spinal cord tissue, promote regenerative therapy after spinal cord injury, and improve motor function. Moreover, it has been reported that high-priced Zr4+ cations can regulate the deposition and nucleation behavior of Zn2+ in high-performance zinc metal anodes. Therefore, we propose the hypothesis that Pb-Zr modulates Zn2+ be used to promote recovery from spinal cord injury. The results show that nanomaterial is beneficial in the treatment of spinal cord injury. This study provides a good prospect for the application of spinal cord injury treatment. It also provides an important feasibility for subsequent clinical conversions.

Zinc remodels mitochondrial network through SIRT3/Mfn2-dependent mitochondrial transfer in ameliorating spinal cord injury.

Spinal cord injury (SCI) is a traumatic neuropathic condition that results in motor, sensory and autonomic dysfunction. Mitochondrial dysfunction caused by primary trauma is one of the critical pathogenic mechanisms. Moderate levels of zinc have antioxidant effects, promote neurogenesis and immune responses. Zinc normalises mitochondrial morphology in neurons after SCI. However, how zinc protects mitochondria within neurons is unknown. In the study, we used transwell culture, Western blot, Quantitative Real-time Polymerase Chain Reaction (QRT-PCR), ATP content detection, reactive oxygen species (ROS) activity assay, flow cytometry and immunostaining to investigate the relationship between zinc-treated microglia and injured neurons through animal and cell experiments. We found that zinc promotes mitochondrial transfer from microglia to neurons after SCI through Sirtuin 3 (SIRT3) regulation of Mitofusin 2 protein (Mfn2). It can rescue mitochondria in damaged neurons and inhibit oxidative stress, increase ATP levels and promote neuronal survival. Therefore, it can improve the recovery of motor function in SCI mice. In conclusion, our work reveals a potential mechanism to describe the communication between microglia and neurons after SCI, which may provide a new idea for future therapeutic approaches to SCI.

Folic acid-functionalized chitosan nanoparticles with bioenzyme activity for the treatment of spinal cord injury.

Spinal cord injury (SCI) is a central system disease with a high rate of disability. Pathological changes such as ischemia and hypoxia of local tissues, oxidative stress and apoptosis could lead to limb pain, paralysis and even life-threatening. It was reported that catalase (CAT) was the main antioxidant in organisms, which could remove reactive oxygen species (ROS) and release oxygen (O2). However, the efficacy of the drug is largely limited due to its poor stability, low bioavailability and inability to cross the blood spinal cord barrier (BSCB). Therefore, in this study, we prepared folic acid-functionalized chitosan nanoparticles to deliver CAT (FA-CSNCAT) for solving this problem. In vivo small animal imaging results showed that FA-CSN could carry CAT across the BSCB and target to the inflammatory site. In addition, Immunofluorescence, ROS assay and JC-1 probe were used to detect the therapeutic effect of FA-CSNCAT in vitro and in vivo. The results showed that FA-CSNCAT could alleviate the hypoxic environment at the injured site and remove ROS, thereby inhibiting oxidative stress and protecting neurons, which may provide a new idea for clinical medication of SCI.

Biomimetic nanoplatform with anti-inflammation and neuroprotective effects for repairing spinal cord injury in mice.

Regeneration in the therapeutics of spinal cord injury (SCI) remains a challenge caused by the hyperinflammation microenvironment. Nanomaterials-based treatment strategies for diseases with excellent therapeutic efficacy are actively pursued. Here, we develop biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA) obtained by loading celastrol (pCel) for SCI thrapy. Cel, as an antioxidant drug, facilitated reactive oxygen species (ROS) scavenging, and decreased the generation of pro-inflammatory cytokines. To facilitate its administration, pCel is formulated into microspheres by oil-in-water (O/W) emulsion/solvent evaporation technique. The constructed pCel can induced polarization of macrophages and obviously improved lipopolysaccharide (LPS) and interferon-γ (IFN-γ)-induced mitochondrial dysfunction, and increased neurite length in PC12 cells and primary neurons. In vivo experiments revealed that pCel regulated the phenotypic polarization of macrophages, prevented the release of pro-inflammatory cytokines, promoted myelin regeneration and inhibited scar tissue formation, and further improve motor function. These findings indicated that the neuroprotective effect of this artificial biodegradable nanoplatform is benefit for the therapy of SCI. This research opens an exciting perspective for the application of SCI treatment and supports the clinical significance of pCel.

Zinc regulates a specific subpopulation of VEGFA + microglia to improve the hypoxic microenvironment for functional recovery after spinal cord injury.

INTRODUCTION: Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as autonomic dysfunction below the level of injury. Our previous studies have found that zinc ions have important effects on the nervous system and nerve repair, promoting autophagy and reducing inflammatory responses. However, the role of zinc ions in vascular regeneration is unclear. AIMS: We investigated the effect of zinc ions after spinal cord injury from the perspective of a hypoxic microenvironment, and elucidated the role of VEGF-A secreted by microglia for vascular regeneration after spinal cord injury, providing new ideas for the treatment of spinal cord injury. RESULTS: Zinc promotes functional recovery after spinal cord injury by regulating VEGF-A secretion from microglia. On the one hand, VEGF-A secreted by microglia promotes angiogenesis through the PI3K/AKT/Bcl-2 pathway and improves the hypoxic microenvironment after spinal cord injury. On the other hand, VEGF-A secreted by microglia was positively correlated with platelet endothelial cell adhesion molecule-1 (CD31), and zinc could increase the association between microglia and blood vessels. CONCLUSION: Zinc promoted microglia secretion of VEGF-A, increased vascular endothelial cell proliferation and migration through the PI3K/AKT/Bcl-2 pathway, and inhibited microglia apoptosis.

A comprehensive exploration of the latest innovations for advancements in enhancing selectivity of nanozymes for theranostic nanoplatforms.

Nanozymes have captured significant attention as a versatile and promising alternative to natural enzymes in catalytic applications, with wide-ranging implications for both diagnosis and therapy. However, the limited selectivity exhibited by many nanozymes presents challenges to their efficacy in diagnosis and raises concerns regarding their impact on the progression of disease treatments. In this article, we explore the latest innovations aimed at enhancing the selectivity of nanozymes, thereby expanding their applications in theranostic nanoplatforms. We place paramount importance on the critical development of highly selective nanozymes and present innovative strategies that have yielded remarkable outcomes in augmenting selectivities. The strategies encompass enhancements in analyte selectivity by incorporating recognition units, refining activity selectivity through the meticulous control of structural and elemental composition, integrating synergistic materials, fabricating selective nanomaterials, and comprehensively fine-tuning selectivity via approaches such as surface modification, cascade nanozyme systems, and manipulation of external stimuli. Additionally, we propose optimized approaches to propel the further advancement of these tailored nanozymes while considering the limitations associated with existing techniques. Our ultimate objective is to present a comprehensive solution that effectively addresses the limitations attributed to non-selective nanozymes, thus unlocking the full potential of these catalytic systems in the realm of theranostics.

Encapsulation of Selenium Nanoparticles and Metformin in Macrophage-Derived Cell Membranes for the Treatment of Spinal Cord Injury.

Spinal cord injury is an impact-induced disabling condition. A series of pathological changes after spinal cord injury (SCI) are usually associated with oxidative stress, inflammation, and apoptosis. These pathological changes eventually lead to paralysis. The short half-life and low bioavailability of many drugs also limit the use of many drugs in SCI. In this study, we designed nanovesicles derived from macrophages encapsulating selenium nanoparticles (SeNPs) and metformin (SeNPs-Met-MVs) to be used in the treatment of SCI. These nanovesicles can cross the blood-spinal cord barrier (BSCB) and deliver SeNPs and Met to the site of injury to exert anti-inflammatory and reactive oxygen species scavenging effects. Transmission electron microscopy (TEM) images showed that the SeNPs-Met-MVs particle size was approximately 125 ± 5 nm. Drug release assays showed that Met exhibited sustained release after encapsulation by the macrophage cell membrane. The cumulative release was approximately 80% over 36 h. In vitro cellular experiments and in vivo animal experiments demonstrated that SeNPs-Met-MVs decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and reduced the expression of inflammatory (TNF-α, IL-1ß, and IL-6) and apoptotic (cleaved caspase-3) cytokines in spinal cord tissue after SCI. In addition, motor function in mice was significantly improved after SeNPs-Met-MVs treatment. Therefore, SeNPs-Met-MVs have a promising future in the treatment of SCI.

A Targeted Exosome Therapeutic Confers Both CfDNA Scavenging and Macrophage Polarization for Ameliorating Rheumatoid Arthritis.

Only a minority of rheumatoid arthritis (RA) patients achieve disease remission, so the exploration of additional pathogenic factors and the development of new therapeutics are needed. Here, strong correlations among the cell-free DNA (cfDNA) level and the inflammatory response in clinical synovial fluid samples and RA disease activity are discovered. The important role of cfDNA in disease development in a collagen-induced arthritis (CIA) murine model is also demonstrated. Building on these findings, a novel therapeutic based on anti-inflammatory (M2) macrophage-derived exosomes as chassis, that are modified with both oligolysine and matrix metalloproteinase (MMP)-cleavable polyethylene glycol (PEG) on the membrane, is developed. After intravenous injection, PEG-enabled prolonged circulation and C─C motif chemokine ligand-directed accumulation together result in enrichment at inflamed joints. Following subsequent MMP cleavage, the positively charged oligolysine is exposed for cfDNA scavenging, while exosomes induce M2 polarization. By using a classical CIA murine model and a newly established CIA canine model, it is demonstrated that the rationally designed exosome therapeutic substantially suppresses inflammation in joints and provides strong chondroprotection and osteoprotection, revealing its potential for effective CIA amelioration.

Transcriptional and epigenetic decoding of the microglial aging process.

As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, the longitudinal characteristics of microglia remain poorly understood. In this study, we mapped the transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We first discovered unexpected sex differences and identified age-dependent microglia (ADEM) genes during the aging process. We then compared the features of aging and reactivity in female microglia at single-cell resolution and epigenetic level. To dissect functions of aged microglia excluding the influence from other aged brain cells, we established an accelerated microglial turnover model without directly affecting other brain cells. By this model, we achieved aged-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cognitive decline. Collectively, our work provides a comprehensive resource for decoding the aging process of microglia, shedding light on how microglia maintain brain functions.

Manganese-doped albumin-gelatin composite nanogel loaded with berberine applied to the treatment of gouty arthritis in rats via a SPARC-dependent mechanism.

In this study, manganese-doped albumin-gelatin composite nanogels (MAGN) were prepared and used to load berberine (Ber) for the treatment of gouty arthritis (GA). The nanodrug delivery system (Ber-MAGN) can target inflammatory joints due to the intrinsic high affinity of albumin for SPARC, which is overexpressed at the inflammatory site of GA. Characterization of the pharmaceutical properties in vitro showed that Ber-MAGN had good dispersion, and the particle size was 121 ± 10.7 nm. The sustained release effect significantly improved the bioavailability of berberine. In vitro and in vivo experimental results showed that Ber-MAGN has better therapeutic effects in relieving oxidative stress and suppressing inflammation. Therefore, Ber-MAGN, as a potential pharmaceutical preparation for GA, provides a new reference for the clinical treatment plan of GA.

Naringin may promote functional recovery following spinal cord injury by modulating microglial polarization through the PPAR-γ/NF-κB signaling pathway.

OBJECTIVE: The flavonoid Naringin (Nar) has been extensively investigated and found to have multiple pharmacological properties, including neuroprotection. Although recent reports have shown that Nar can effectively treat spinal cord injury (SCI), its potential mechanism remains unknown. This study aimed to investigate the effects of Nar on motor recovery and inflammatory responses after SCI and to elucidate its mechanism. METHODS: SCI rat models were established using Allen's weight-drop method. The rats were intragastrically given Nar (40 mg/kg) for 21 d, and their motor function before surgery and on the 1st, 3rd, 7th, 14th, 21st days after surgery was assessed by the Basso-Beattie-Bresnahan (BBB) scale and examined by the grid walking test (GWT). The enzyme linked immunosorbent assay (ELISA) was used to detect the interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1 levels in rat spinal cord tissues, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to measure the mRNA expression levels of microglial activation markers CD68 and ionized calcium binding adaptor molecule 1 (Iba-1), M1 markers inducible nitric oxide synthase (iNOS) and IL-6, and M2 markers CD206 and Arginase 1 (Arg1). The expression levels of peroxisome proliferator-activated receptor gamma/nuclear factor kappa B (PPAR-γ/NF-κB) pathway-related proteins in rat spinal cord tissues were determined using western blotting. RESULTS: Nar significantly increased the BBB score and decreased the mean error rate of GWT in SCI rats. Additionally, Nar effectively inhibited microglial activation and expression of M1 markers in spinal cord tissues. It also elevated M2 polarization-related gene expression and significantly lowered the levels of inflammatory factors. Further investigation showed that Nar enhanced the expression of PPAR-γ protein and inhibited NF-κB pathway activity. CONCLUSION: Nar promotes functional recovery by regulating microglial polarization and inhibiting the inflammatory response in SCI, and its mechanism may be related to the PPAR-γ/NF-κB signaling pathway activity.

Curcumin-Loaded Macrophage-Derived Exosomes Effectively Improve Wound Healing.

This study aims to investigate the potential therapeutic effect of exosomes derived from macrophages loaded with curcumin (Exos-cur) on the healing of diabetic wounds. As a new type of biomaterial, Exos-cur has better stability, anti-inflammation, and antioxidation biological activity. In in vitro experiments, Exos-cur can promote the proliferation, migration, and angiogenesis of HUVECs (human umbilical vein endothelial cells) while reducing the ROS (reactive oxygen species) produced by HUVECs induced by high glucose, regulating the mitochondrial membrane potential, reducing cell oxidative damage, and inhibiting oxidative stress and inflammation. In the in vivo experiment, the Exos-cur treatment group had an increased percentage of wound closure and contraction compared with the diabetic wound control group. Hematoxylin-eosin staining (HE) and Masson staining showed that the Exos-cur treatment group had more advanced re-epithelialization, and the generated mature granulation tissue was rich in a large number of capillaries and newly deposited collagen fibers. Western blot and immunofluorescence analyses showed that Exos-cur can inhibit inflammation by activating the Nrf2/ARE pathway, upregulate the expression of wound healing-related molecules, promote angiogenesis, and accelerate wound healing in diabetic rats. These results show that Exos-cur has a good therapeutic effect on diabetic skin defects and provide experimental evidence for the potential clinical benefits of Exos-cur.

Preparation of photothermal responsive, antibacterial hydrogel by using PVA-Alg and silver nanofibers as building blocks.

Introduction: Photothermal responsive, antimicrobial hydrogels are very attractive and have great potential in the field of tissue engineering. The defective wound environment and metabolic abnormalities in diabetic skin would lead to bacterial infections. Therefore, multifunctional composites with antimicrobial properties are urgently needed to improve the current therapeutic outcomes of diabetic wounds. We prepared an injectable hydrogel loaded with silver nanofibers for efficient and sustained bactericidal activity. Methods: To construct this hydrogel with good antimicrobial activity, homogeneous silver nanofibers were first prepared by solvothermal method and then dispersed in PVA-lg solution. After homogeneous mixing and gelation, injectable hydrogels (Ag@H) wrapped with silver nanofibers were obtained. Results: By virtue of Ag nanofibers, Ag@H exhibited good photothermal conversion efficiency and good antibacterial activity against drug-resistant bacteria, while the in vivo antibacterial also showed excellent performance. The results of antibacterial experiments showed that Ag@H had significant bactericidal effects on MRSA and E. coli with 88.4% and 90.3% inhibition rates, respectively. Discussion: The above results indicate that Ag@H with photothermal reactivity and antibacterial activity is very promising for biomedical applications, such as wound healing and tissue engineering.

Development of practical techniques for simultaneous detection and distinction of current and emerging SARS-CoV-2 variants.

Countless individuals have fallen victim to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have generated antibodies, reducing the risk of secondary infection in the short term. However, with the emergence of mutated strains, the probability of subsequent infections remains high. Consequently, the demand for simple and accessible methods for distinguishing between different variants is soaring. Although monitoring viral gene sequencing is an effective approach for differentiating between various types of SARS-CoV-2 variants, it may not be easily accessible to the general public. In this article, we provide an overview of the reported techniques that use combined approaches and adaptable testing methods that use editable recognition receptors for simultaneous detection and distinction of current and emerging SARS-CoV-2 variants. These techniques employ straightforward detection strategies, including tests capable of simultaneously identifying and differentiating between different variants. Furthermore, we recommend advancing the development of uncomplicated protocols for distinguishing between current and emerging variants. Additionally, we propose further development of facile protocols for the differentiation of existing and emerging variants.

Development of nanozymes for promising alleviation of COVID-19-associated arthritis.

The COVID-19 pandemic caused by SARS-CoV-2 has been identified as a culprit in the development of a variety of disorders, including arthritis. Although the emergence of arthritis following SARS-CoV-2 infection may not be immediately discernible, its underlying pathogenesis is likely to involve a complex interplay of infections, oxidative stress, immune responses, abnormal production of inflammatory factors, cellular destruction, etc. Fortunately, recent advancements in nanozymes with enzyme-like activities have shown potent antiviral effects and the ability to inhibit oxidative stress and cytokines and provide immunotherapeutic effects while also safeguarding diverse cell populations. These adaptable nanozymes have already exhibited efficacy in treating common types of arthritis, and their distinctive synergistic therapeutic effects offer great potential in the fight against arthritis associated with COVID-19. In this comprehensive review, we explore the potential of nanozymes in alleviating arthritis following SARS-CoV-2 infection by neutralizing the underlying factors associated with the disease. We also provide a detailed analysis of the common therapeutic pathways employed by these nanozymes and offer insights into how they can be further optimized to effectively address COVID-19-associated arthritis.