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.

Corrigendum: Therapy of spinal cord injury by folic acid polyethylene glycol amine-modified zeolitic imidazole framework-8 nanoparticles targeted activated M/Ms.

[This corrects the article DOI: 10.3389/fbioe.2022.959324.].

Therapy of spinal cord injury by folic acid polyethylene glycol amine-modified zeolitic imidazole framework-8 nanoparticles targeted activated M/Ms.

Excessively activated microglia/macrophages (M/Ms) re-establish the proinflammatory microenvironment that exacerbates motor and/or sensory dysfunction after spinal cord injury (SCI). Thus, proinflammatory M/Ms-suppressed treatments may be effective strategies for SCI. However, the utilization of anti-inflammatory drugs for clinical approaches and biomedical research has side effects, such as nephrotoxicity and hepatotoxicity. In this study, we fabricated folic acid-polyethylene glycol (FA-PEG) amine-modified zeolitic imidazole framework-8 (ZIF-8) nanoparticles (FA-PEG/ZIF-8) and found that it effectively restored function in vivo. FA-PEG/ZIF-8 treatment significantly eliminated proinflammatory M/Ms without targeting other nerve cells and downregulated inflammation in the injured lesion. Furthermore, FA-PEG/ZIF-8 caused little toxicity in SCI mice compared to normal mice. These results suggest that FA-PEG/ZIF-8 has the potential to help recover from early-stage SCI by suppressing proinflammatory M/Ms.

Preparation of NIR-Responsive Gold Nanocages as Efficient Carrier for Controlling Release of EGCG in Anticancer Application.

Hepatocellular carcinoma (HCC) is a type of cancer that has a restricted therapy option. Epigallocatechin gallate (EGCG) is one of the main biologically active ingredients in tea. A large number of studies have shown that EGCG has preventive and therapeutic effects on various tumors. In addition, the development of near-infrared (NIR)-responsive nano-platforms has been attracting cancer treatment. In this work, we designed and synthesized a strategy of gold nanocages (AuNCs) as an efficient carrier for controlling release of EGCG for anti-tumor to achieve the synergistic functions of NIR-response and inhibited tumor cell proliferation. The diameter of AuNCs is about 50 nm and has a hollow porous (8 nm) structure. Thermal imaging-graphic studies proved that the AuNCs-EGCG obtained have photothermal response to laser irradiation under near-infrared light and still maintain light stability after multiple cycles of laser irradiation. The resulted AuNCs-EGCG reduced the proliferation rate of HepG2 cells to 50% at 48 h. Western blot analysis showed that NIR-responsive AuNCs-EGCG can promote the expression of HepG2 cell apoptosis-related proteins HSP70, Cytochrome C, Caspase-9, Caspase-3, and Bax, while the expression of Bcl-2 is inhibited. Cell confocal microscopy analysis proved that AuNCs-EGCG irradiated by NIR significantly upregulates Caspase-3 by nearly 2-fold and downregulates Bcl-2 by nearly 0.33-fold, which is beneficial to promote HepG2 cell apoptosis. This study provides useful information for the NIR-responsive AuNCs-EGCG as a new type of nanomedicine for HCC.

Gold nanoclusters conjugated berberine reduce inflammation and alleviate neuronal apoptosis by mediating M2 polarization for spinal cord injury repair.

Spinal cord injury (SCI) leads to nerve cell apoptosis and loss of motor function. Herein, excessive activation of the M1 phenotype macrophages/microglia is found to be the main reason for the poor prognosis of SCI, but the selective activation phenotype (M2) macrophages/microglia facilitates the recovery of SCI. Thereafter, we used gold nanoclusters loaded berberine (BRB-AuNCs) to reduce inflammation by inhibiting the activation of M1 phenotype macrophages/microglia, which simultaneously inhibited neuronal apoptosis after SCI. In vitro and in vivo experiments showed that BRB-AuNCs reduced M1 protein marker CD86, increased M2 protein marker CD206, reduced inflammation and apoptotic cytokines (IL-1ß, IL-6, TNF-α, Cleaved Caspase-3 and Bax). These results indicate that BRB-AuNCs have excellent anti-inflammatory and anti-apoptotic effects by inducing the polarization of macrophages/microglia from M1 phenotype to M2 phenotype. Thereafter, the motor functions of SCI rats were significantly improved after treatment with BRB-AuNCs. This work not only provides a new way for the treatment of SCI but also broadens BRB utilization strategies.

Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway.

Spinal cord injury (SCI) is an extreme neurological impairment with few effective drug treatments. Pyroptosis is a recently found and proven type of programmed cell death that is characterized by a reliance on inflammatory caspases and the release of a large number of proinflammatory chemicals. Pyroptosis differs from other cell death mechanisms such as apoptosis and necrosis in terms of morphological traits, incidence, and regulatory mechanism. Pyroptosis is widely involved in the occurrence and development of SCI. In-depth research on pyroptosis will help researchers better understand its involvement in the onset, progression, and prognosis of SCI, as well as provide new therapeutic prevention and treatment options. Herein, we investigated the role of AMPK-mediated activation of the NLRP3 inflammasome in the neuroprotection of MET-regulated pyroptosis. We found that MET treatment reduced NLRP3 inflammasome activation by activating phosphorylated AMPK and reduced proinflammatory cytokine (IL-1ß, IL-6, and TNF-α) release. At the same time, MET improved motor function recovery in rats after SCI by reducing motor neuron loss in the anterior horn of the spinal cord. Taken together, our study confirmed that MET inhibits neuronal pyroptosis after SCI via the AMPK/NLRP3 signaling pathway, which is mostly dependent on the AMPK pathway increase, hence decreasing NLRP3 inflammasome activation.

Zinc Promotes Microglial Autophagy Through NLRP3 Inflammasome Inactivation via XIST/miR-374a-5p Axis in Spinal Cord Injury.

Zinc has reported to play a neuroprotective role in the development of spinal cord injury (SCI). The protective mechanism of zinc remains to be uncovered. The aim of the current study was to investigate the neuroprotective mechanism of zinc in the progression of SCI. The C57BL/6J mouse SCI model was established to confirm the protective role of zinc in vivo, while the cellular model was induced in mouse microglial BV2 cells by using lipopolysaccharide (LPS). The expression levels of XIST, miR-374a-5p and NLRP3 inflammasome as well as the autophagy-related proteins were detected using real-time PCR and immunoblotting. Cell viability was assessed by CCK-8 assay. Apoptosis was evaluated by TUNEL staining, flow cytometry, the determination of apoptosis-related proteins. The target relationship was confirmed by luciferase reporter assays. Zinc improved locomotor function in SCI mice and alleviated LPS-induced BV2 cell injuries by inhibiting apoptosis and initiating autophagy processes. XIST and NLRP3 inflammasome was upregulated while miR-374a-5p was downregulated in spinal cords of SCI mice and LPS-treated BV2 cells. All these effects were inhibited by Zinc treatment. XIST knockdown triggered microglial autophagy-mediated NLRP3 inactivation in LPS-induced BV2 cells by regulating miR-374a-5p. Zinc treatment protected BV2 cells from LPS-induced cell injury by the downregulation of XIST. This process might be through autophagy­mediated NLRP3 inflammasome inactivation by targeting miR-374a-5p. Zinc downregulates XIST and induces neuroprotective effects against SCI by promoting microglial autophagy-induced NLRP3 inflammasome inactivation through regulating miR-374a-5p. Our finding provides novel opportunities for the understanding of zinc-related therapy of SCI.

Nischarin downregulation attenuates cell injury induced by oxidative stress via Wnt signaling.

Nischarin (NISCH) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. Here, we aimed to investigate whether NISCH downregulation could protect rat pheochromocytoma (PC12) cells against oxidative stress-induced injury using a model of cell injury induced by hydrogen peroxide (H2O2). Cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis rate was evaluated using flow cytometry. The expressions of apoptosis-related proteins Bax, Bcl-2, caspase-3 and NISCH were examined via Western blot analysis and immunofluorescence staining analyses. The expressions of NISCH, glycogen synthase kinase-3ß (GSK-3ß) and T-cell factor-1 (TCF-1) were examined using Western blot analysis. The results showed that incubation of H2O2 for 48 h significantly decreased the cell viability, increased the cell apoptosis rate and the NISCH expression in PC12 cells, whereas NISCH downregulation blocked the effects of H2O2 on cells. In addition, the expression of Bcl-2 was significantly reduced, and the expression of Bax and caspase-3 were significantly increased by H2O2 treatment. However, these effects were partially inhibited by the downregulation of NISCH. Furthermore, H2O2 significantly weakened the transduction of Wnt signaling, including the increases of GSK-3ß and TCF-1 expressions and the decrease of ß-catenin expression, while NISCH downregulation attenuated the effect of H2O2 on Wnt signaling. Moreover, inhibition of the Wnt pathway further decreased the cell viability and promoted the cell apoptosis induced by H2O2 in PC12 cells. Our results suggest that NISCH downregulation may protect cells against oxidative stress-induced injury through regulating the transduction of Wnt signaling.

Zinc promotes autophagy and inhibits apoptosis through AMPK/mTOR signaling pathway after spinal cord injury.

Autophagy is a intracellular biological process that controls the homeostasis of nutrition deprivation and starvation and has been associated with the development of traumatic diseases. Zinc, an important chemical element involved in life activities, has improved nerve recovery effects through intraperitoneal injection. The purpose of this study was to probe the possible modulation of autophagy and apoptosis from the injured spinal cord and neurons by zinc administration. It was shown that zinc significantly induced the level of Beclin1 and LC3B by activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. In addition, zinc suppressed apoptosis in the injured spinal cord. Taken together, these findings suggested that zinc through promoting neurons autophagy and inhibiting apoptosis.

Outcome of Humeral Shaft Fracture Treated with Intramedullary Nail and Plate Fixation.

OBJECTIVE: To compare the results of the intramedullary nail (IMN) and compression plate fixation performed for humeral shaft fracture as to determine a better option out of the two. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: First Affiliated Hospital of Jinzhou Medical University, Liaoning, PR China, from October 2016 to January 2019. METHODOLOGY: Patients treated with IMN (n=26) or plate fixation (n=30) for humeral shaft fracture were included in this study. Assessment was done in terms of perioperative parameters, complications, union time, and functional outcomes. Functional outcome were compared between the two groups at each follow-up (6 weeks, 3, 6, and 12 months) and between the subsequent follow-ups in both groups using the repeated measures ANOVA. RESULTS: Intraoperative blood loss, operative time, hospital stay, and union time were significantly lower in the IMN group. There was no significant difference in the functional outcomes when it was compared between the two groups at each follow-up. However, when it was compared between subsequent follow-ups, a significant improvement was observed in both groups. Increase incidence of individual complication and reoperation were established in the plating group, but without a significant difference. Yet, the overall complications rate was significantly higher in the plating group. CONCLUSION: IMN fixation led to a significant decrease in intraoperative blood loss, shorter operating time, hospital stay, union time, and a lower rate of overall complications. Thus, IMN may be a better choice of internal fixation as it also accelerates the patients' recovery, and increases their satisfaction.

Nischarin attenuates apoptosis induced by oxidative stress in PC12 cells.

Nischarin (NISCH) is a cytoplasmic protein known to serve an inhibitory role in breast cancer cell apoptosis, migration and invasion. Recently, NISCH has been reported to be involved in the regulation of spinal cord injury (SCI). However, the molecular mechanism is still unclear. Oxidative stress contributes to tissue injury and cell apoptosis during the development of various diseases, including SCI. The aim of the present study was to investigate the role of NISCH in the regulation of apoptosis induced by oxidative stress in PC12 cells. H2O2 was used to establish an oxidative stress model in PC12 cells. Apoptosis levels were examined using flow cytometry analysis, and the expression of NISCH, Bcl-2, Bcl-2-associated X (Bax) and caspase-3 were examined using western blot and immunofluorescence staining analyses. The results demonstrated that treatment with 100 µM H2O2 significantly increased the apoptotic rate and expression of NISCH in PC12 cells. At 48 h following incubation with 100 µM H2O2, NISCH downregulation partially inhibited apoptosis of PC12 cells. In addition, the expression of Bcl-2 was significantly reduced and the expression of Bax and caspase-3 were significantly increased by H2O2 treatment. These effects were also partially inhibited by the downregulation of NISCH. The authors of the present study therefore hypothesize that NISCH may function as a pro-apoptotic protein that participates in the regulation of oxidative stress, and NISCH downregulation may protect cells from oxidative stress-induced apoptosis.

Blockade of receptor for advanced glycation end products promotes oligodendrocyte autophagy in spinal cord injury.

Receptor for advanced glycation end product (RAGE) is involved in neuronal inflammation, cell cycle and differentiation. However, the role of RAGE in autophagy in the process of spinal cord injury (SCI) is yet unknown. The present study investigated the effect of RAGE blockade on autophagy in SCI. A rat Allen SCI model was established and the animals were micro-injected with rabbit RAGE neutralizing antibody or rabbit polyclonal Ig G immediately after the injury. The oligodendrocytes(OLs) marker, 2', 3'-cyclic nucleotide 3'-phosphodiesterase(CNPase) and autophagy-related marker microtubule associated protein light chain 3B(LC3B) were evaluated by Western blot. Furthermore, myelin basic protein (MBP) and LC3B double staining were observed in the SCI via immunofluorescence. The results showed that RAGE blockade reduced the expression of CNPase, promoted LC3B-II/I and p62 expression after SCI. In addition, the MBP/LC3B double positive oligodendrocytes-expressing LC3B was up-regulated by RAGE blockade. Moreover, RAGE blockade attenuated the neuronal survival at ventral horn after SCI. The present study revealed the role of RAGE in maintaining oligodendrocyte autophagy to promote neuronal regeneration post-SCI.

MiR-429 improved the hypoxia tolerance of human amniotic cells by targeting HIF-1α.

MicroRNA-429(miR-429) plays an important role in mesenchymal stem cells. Hypoxia-inducible factor 1α (HIF-1α) is a nuclear transcription factor that regulates the proliferation, apoptosis and tolerance to hypoxia of mesenchymal stem cells. HIF-1α is also a target gene of miR-429. We investigated whether miR-429 plays a role in hypoxia tolerance with HIF-1α in human amniotic mesenchymal stem cells (hAMSCs). The expression of miR-429 was increased by hypoxia in hAMSCs. miR-429 expression resulted in decreased HIF-1α protein level, but little effect on HIF-1α mRNA. While overexpression of HIF-1α increased the survival rate and exhibited anti-apoptosis effects in hAMSCs under hypoxia, co-expression of miR-429 reduced survival and increased apoptosis. However, miR-429 silencing with HIF-1α overexpression stimulated cell survival and reduced apoptosis. Co-expression of HIF-1α and miR-429 reduced VEGF and Bcl-2 proteins and increased Bax and C-Caspase-3 levels in hAMSCs under hypoxia compared with cells expressing only HIF-1α; cells with HIF-1α overexpression and miR-429 silencing showed the opposite effects. These results indicate that HIF-1α and angomiR-429 reciprocally antagonized each other, while HIF-1α and antagomiR-429 interacted with each other to regulate survival and apoptosis in hAMSCs under hypoxia. miR-429 increased VEGF and Bcl-2 protein levels and decreased Bax and cleaved Caspase-3 protein levels by promoting the synthesis of HIF-1α. These results indicate that miR-429 negatively regulates the survival and anti-apoptosis ability of hAMSCs by mediating HIF-1α expression and improves the ability of hAMSCs to tolerate hypoxia.

Receptor for Advanced Glycation End-Products (RAGE) Blockade Do Damage to Neuronal Survival via Disrupting Wnt/ß-Catenin Signaling in Spinal Cord Injury.

Wnt signaling are recognized key factors in neuronal development, cell proliferation and axonal guidance. However, RAGE effect on wnt signaling after spinal cord injury (SCI) are poorly understood. Our study aims to explore RAGE blockade effect on wnt signaling after SCI. We constructed Allen SCI model and micro-injected with RAGE neutralizing antibody or IgG after injury. We determined ß-catenin, wnt3a and its receptor frizzled-5 via Western blot. We determined ß-catenin/NeuN expression at 2 weeks after SCI via immunofluorescence (IF). We found that ß-catenin, wnt3a and wnt receptor frizzled5 expression were activated after SCI at 3 days after injury. However, RAGE blockade inhibit ß-catenin, wnt3a and frizzled5 expression. We found that ß-catenin accumulation in NeuN cells were activated after SCI via IF, however, RAGE blockade reduced ß-catenin and NeuN positive cells. RAGE blockade attenuated number of survived neurons and decreased area of spared white matter around the epicenter. RAGE signaling may involved in disrupting wnt signaling to aids neuronal recovery after SCI.

The Role of Netrin-1 in Improving Functional Recovery through Autophagy Stimulation Following Spinal Cord Injury in Rats.

Our previous findings indicated that treatment with Netrin-1 could improve functional recovery through the stimulation of autophagy, by activating the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway in rats following spinal cord injury (SCI). However, the underlying mechanisms were not elucidated. The purpose of this study was to investigate the underlying mechanisms by which Netrin-1 promotes autophagy and improves functional recovery after SCI. Following controlled SCI in Sprague-Dawley rats, we observed that the autophagic flux in neurons was impaired, as reflected by the accumulation of light chain 3-II (LC3-II)-positive and LC3-positive autophagosomes (APs), accompanied by the accumulation of the autophagic substrate, Sequestosome 1 (SQSTM1; also known as p62). Our results showed that treatment with Netrin-1 increases the levels of the lysosomal protease cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1), through the regulation of the nuclear localization of Transcription factor EB (TFEB) via the AMPK/mTOR signaling pathway. In addition, this enhancement of lysosomal biogenesis correlated strongly with the restoration of autophagic flux, inhibition of neural apoptosis and improved functional recovery. Suppression of lysosomal biogenesis via the inhibition of the nuclear translocation of TFEB by Compound C abolished this restoration of autophagic flux and the functional recovery effects of Netrin-1 following SCI. Taken together, these results indicate that Netrin-1 enhances lysosomal biogenesis by regulating the nuclear translocation of TFEB via the AMPK/mTOR signaling pathway. Furthermore, the enhancement of lysosomal biogenesis by Netrin-1 following SCI promotes autophagic flux and improves functional recovery in rats. Thus, the regulation of lysosomal biogenesis by modulating the nuclear localization of TFEB might be a novel approach for the treatment of SCI.

Berberine attenuated pro-inflammatory factors and protect against neuronal damage via triggering oligodendrocyte autophagy in spinal cord injury.

Berberine exerts neuroprotective effect in neuroinflammation and neurodegeneration disease. However, berberine effect in acute spinal cord injury is yet to be elucidated. Herein, we investigated the neuroprotective effect of berberine in spinal cord injury (SCI). Sprague-Dawley rats were subjected to SCI by an intraperitoneal injection of berberine post-injury. The neurobehavioral recovery, cytokines of pro-inflammatory factors (TNF-α and IL-1ß), autophagy-related proteins (LC3B, ATG16L, ATG7), and apoptosis-related protein cleaved caspase-3 were determined. The expressions of 2', 3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), marker of oligodendrocyte, autophagy-related proteins ATG5 and neurons at the ventral horn were assessed. In vitro, the contents of the pro-inflammatory factors, TNF-α and IL-1ß, were detected in the lipopolysaccharide (LPS)-treated primary spinal neuron. Berberine significantly improved the neurobehavior BBB score and attenuated the cytokines of pro-inflammatory factors in cerebrospinal fluid post-SCI. In addition, berberine upregulated CNPase positive oligodendrocyte expressing ATG5, promoted neuronal survival and reduced the cleaved caspase-3 expression after SCI. In primary spinal neuron, the LPS-induced inflammatory factors could be reduced by berberine, whereas the autophagy inhibitor, 3-Methyladenine reverses the effect. Berberine attenuated inflammation of the injured spinal cord and reduced the neuronal apoptosis via triggering oligodendrocyte autophagy in order to promote neuronal recovery.

Novel Biocompatible Au Nanostars@PEG Nanoparticles for In Vivo CT Imaging and Renal Clearance Properties.

Nanoprobes are rapidly becoming potentially transformative tools on disease diagnostics for a wide range of in vivo computed tomography (CT) imaging. Compared with conventional molecular-scale contrast agents, nanoparticles (NPs) promise improved abilities for in vivo detection. In this study, novel polyethylene glycol (PEG)-functionalized Au nanoparticles with star shape (AuNS@PEG) with strong X-ray mass absorption coefficient were synthesized as CT imaging contrast agents. Experimental results revealed that AuNS@PEG nanoparticles are well constructed with ultrasmall sizes, effective metabolisability, high computed tomography value, and outstanding biocompatibility. In vivo imaging also showed that the obtained AuNS@PEG nanoparticles can be efficiently used in CT-enhanced imaging. Therefore, the synthesized contrast agent AuNS@PEG nanoparticles as a great potential candidate can be widely used for CT imaging.

HMGB1/Advanced Glycation End Products (RAGE) does not aggravate inflammation but promote endogenous neural stem cells differentiation in spinal cord injury.

Receptor for advanced glycation end products (RAGE) signaling is involved in a series of cell functions after spinal cord injury (SCI). Our study aimed to elucidate the effects of RAGE signaling on the neuronal recovery after SCI. In vivo, rats were subjected to SCI with or without anti-RAGE antibodies micro-injected into the lesion epicenter. We detected Nestin/RAGE, SOX-2/RAGE and Nestin/MAP-2 after SCI by Western blot or immunofluorescence (IF). We found that neural stem cells (NSCs) co-expressed with RAGE were significantly activated after SCI, while stem cell markers Nestin and SOX-2 were reduced by RAGE blockade. We found that RAGE inhibition reduced nestin-positive NSCs expressing MAP-2, a mature neuron marker. RAGE blockade does not improve neurobehavior Basso, Beattie and Bresnahan (BBB) scores; however, it damaged survival of ventral neurons via Nissl staining. Through in vitro study, we found that recombinant HMGB1 administration does not lead to increased cytokines of TNF-α and IL-1ß, while anti-RAGE treatment reduced cytokines of TNF-α and IL-1ß induced by LPS via ELISA. Meanwhile, HMGB1 increased MAP-2 expression, which was blocked after anti-RAGE treatment. Hence, HMGB1/RAGE does not exacerbate neuronal inflammation but plays a role in promoting NSCs differentiating into mature neurons in the pathological process of SCI.

Activation of the Nrf2/ARE signaling pathway by probucol contributes to inhibiting inflammation and neuronal apoptosis after spinal cord injury.

The nuclear erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway plays an essential role in the cellular antioxidant and anti-inflammatory responses. Spinal cord injury (SCI) results in a massive release of inflammatory factors and free radicals, which seriously compromise nerve recovery and axon regeneration. In this study, we examined the efficacy of probucol on anti-inflammatory responses and functional recovery after SCI by activating the Nrf2/ARE signaling pathway. We also investigated the mechanism by which inflammation is inhibited in this process. We found that treatment of injured rats with probucol significantly increased levels of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), while levels of inflammatory cytokines, interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were decreased. This was associated with a reduction in neural cell apoptosis and promotion of nerve function recovery. These results demonstrate that the neuroprotective effects of probucol after SCI are mediated by activation of the Nrf2/ARE signaling pathway. These findings indicate that the anti-inflammatory effects of probucol represent a viable treatment for improving functional recovery following SCI.

The Neuroprotective Effects of Muscle-Derived Stem Cells via Brain-Derived Neurotrophic Factor in Spinal Cord Injury Model.

Muscle-derived stem cells (MDSCs) possess multipotent differentiation and self-renewal capacities; however, the effects and mechanism in neuron injury remain unclear. The aim of this study was to investigate the effects of MDSCs on neuron secondary injury, oxidative stress-induced apoptosis. An in vivo study showed the Basso, Beattie, and Bresnahan (BBB) score and number of neurons significantly increased after MDSCs' transplantation in spinal cord injury (SCI) rats. An in vitro study demonstrated that MDSCs attenuated neuron apoptosis, and the expression of antioxidants was upregulated as well as the ratio of Bcl-2 and Bax in the MNT (MDSCs cocultured with injured neurons) group compared with the NT (injured neurons) group. Both LC3II/LC3I and ß-catenin were enhanced in the MNT group, while XAV939 (a ß-catenin inhibitor) decreased the expression of nuclear erythroid-related factor 2 (Nrf2) and LC3II/LC3I. Moreover, MDSCs became NSE- (neuron-specific enolase-) positive neuron-like cells with brain-derived neurotrophic factor (BDNF) treatment. The correlation analysis indicated that there was a significant relation between the level of BDNF and neuron injury. These findings suggest that MDSCs may protect the spinal cord from injury by inhibiting apoptosis and replacing injured neurons, and the increased BDNF and ß-catenin could contribute to MDSCs' effects.