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OBJECTIVE: In our previous study, we found that local release of curcumin from nanomicelles prevents peritendinous adhesion during Achilles tendon healing. The aim of this study is to further investigate the signaling integrated by curcumin to direct the tenogenetic program of tendon stem cells contributing to tendon healing. METHODS: A surgical model of tendon rupture and repair (TRR) was established in rats. Peritendinous adhesion and inflammation, biomechanical function, and expression of ß-catenin and epithelial cellular adhesion molecule (EpCAM) were determined. A dataset was analyzed to investigate differentially expressed genes and enriched genes related to the signaling pathways. Tendon stem cells were treated with curcumin to investigate the cellular and molecular events as well as the signaling pathway. RESULTS: In rat TRR model, curcumin treatment resulted in not only significantly decreased peritendinous inflammatory but also improved tendon functional recovery along with significantly increased expressions of EpCAM and ß-catenin. Analysis of the dataset indicated that the enriched genes were positively related to differentiation pathways but negatively related to proliferation pathways. In rat tendon stem cells, curcumin treatment inhibited proliferation but promoted differentiation. Curcumin's antioxidative activity was associated with tenogenesis. The upregulated expression of tendon lineage-specific markers was dependent on phosphatidylinositol 3'-kinase/Akt (PI3K/Akt) pathway which could be a potential mechanism of tenogenesis of curcumin treatment. CONCLUSION: Curcumin could improve tendon functional recovery via promoting tenogenesis in addition to its antioxidant and anti-inflammatory activities. Curcumin induced differentiation of tendon stem/progenitor cell into tenocytes via PI3K/Akt signaling pathway. This finding provided evidence for the application of curcumin to prevent adhesion during tendon repair.
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Traumatismos dos Tendões , Ratos , Células-Tronco/citologia , Tendões/citologia , Tendões/crescimento & desenvolvimento , Tendões/patologia , Traumatismos dos Tendões/tratamento farmacológico , Ratos Sprague-Dawley , Modelos Animais de Doenças , Transdução de Sinais , Humanos , Proliferação de Células , Diferenciação CelularRESUMO
Fibrotic scar is one of the main impediments to axon regeneration following spinal cord injury (SCI). In this study, we found that CD44 was upregulated during the formation of fibrotic scar, and blocking CD44 by IM7 caused downregulation of fibrosis-related extracellular matrix proteins at both 2 and 12 weeks post-spinal cord injury. More Biotinylated dextran amine (BDA)-traced corticospinal tract axons crossed the scar area and extended into the distal region after IM7 administration. A recovery of motor and sensory function was observed based on Basso Mouse Scale (BMS) scores and tail-flick test. In vitro experiments revealed that inhibiting CD44 and JAK2/STAT3 signaling pathway decreased the proliferation, differentiation, and migration of fibroblasts induced by the inflammatory supernatant. Collectively, these findings highlight the critical role of CD44 and its downstream JAK2/STAT3 signaling pathway in fibrotic scar formation, suggesting a potential therapeutic target for SCI.
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BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes and the main cause of non-traumatic amputation, with no ideal treatment. Multiple cell-derived exosomes have been reported to improve the progression of DPN. Blood therapy is thought to have a powerful repairing effect. However, whether it could also improve DPN remains unclear. RESULTS: In this study, we found that microRNA (miRNA) expression in plasma-derived exosomes of healthy rats (hplasma-exos) was significantly different from that of age-matched DPN rats. By injection of hplasma-exos into DPN rats, the mechanical sensitivity of DPN rats was decreased, the thermal sensitivity and motor ability were increased, and the nerve conduction speed was accelerated. Histological analysis showed myelin regeneration of the sciatic nerve, increased intraepidermal nerve fibers, distal local blood perfusion, and enhanced neuromuscular junction and muscle spindle innervation after hplasma-exos administration. Compared with plasma exosomes in DPN, miR-20b-3p was specifically enriched in exosomes of healthy plasma and was found to be re-upregulated in the sciatic nerve of DPN rats after hplasma-exos treatment. Moreover, miR-20b-3p agomir improved DPN symptoms to a level similar to hplasma-exos, both of which also alleviated autophagy impairment induced by high glucose in Schwann cells. Mechanistic studies found that miR-20b-3p targeted Stat3 and consequently reduced the amount of p-Stat3, which then negatively regulated autophagy processes and contributed to DPN improvement. CONCLUSIONS: This study demonstrated that miRNA of plasma exosomes was different between DPN and age-matched healthy rats. MiR-20b-3p was enriched in hplasma-exos, and both of them could alleviated DPN symptoms. MiR-20b-3p regulated autophagy of Schwann cells in pathological states by targeting Stat3 and thereby inhibited the progression of DPN.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Exossomos , MicroRNAs , Doenças do Sistema Nervoso Periférico , Animais , Ratos , Diabetes Mellitus Experimental/metabolismo , Exossomos/metabolismo , MicroRNAs/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismoRESUMO
BACKGROUND: Maintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms. METHODS: Western blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote peripheral nerve regeneration after chronic denervation. RESULTS: After peripheral nerve injury, c-Jun expression progressively increased until week 5 and then began to decrease in the distal nerve following denervation. NT-3 upregulated the expression of c-Jun in denervated Schwann cells, both in vitro and in vivo. NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The TrkC receptor was consistently presented on denervated Schwann cells and served as NT-3 receptors following chronic denervation. NT-3 mainly upregulated c-Jun through the TrkC/ERK pathway. CONCLUSION: NT-3 promotes peripheral nerve regeneration by maintaining the repair phenotype of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. It provides a potential target for the clinical treatment of peripheral nerve injury after chronic denervation.
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Regeneração Nervosa , Neurotrofina 3 , Traumatismos dos Nervos Periféricos , Células de Schwann , Humanos , Axônios/metabolismo , Denervação , Sistema de Sinalização das MAP Quinases , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/terapia , Receptores Proteína Tirosina Quinases/metabolismo , Células de Schwann/metabolismoRESUMO
Neuropathic pain caused by somatosensory system injuries is notoriously difficult to treat. Previous research has shown that neuroinflammation and cell death have been implicated in the pathophysiology of neuropathic pain. Pyroptosis is a form of programmed cell death associated with inflammatory processes, as it can enhance or sustain the inflammatory response by releasing pro-inflammatory cytokines. This review presents the current knowledge on pyroptosis and its underlying mechanisms, including the canonical and noncanonical pathways. Moreover, we discuss recent findings on the role of pyroptosis in neuropathic pain and its potential as a therapeutic target. In conclusion, this review highlights the potential significance of pyroptosis as a promising target for developing innovative therapies to treat neuropathic pain.
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Neuralgia , Piroptose , Humanos , Apoptose , Morte Celular , Citocinas/metabolismo , Neuralgia/tratamento farmacológico , Inflamassomos/fisiologiaRESUMO
Peripheral nerve defects are a worldwide problem, and autologous nerve transplantation is currently the gold-standard treatment for them. Tissue-engineered nerve (TEN) grafts are widely considered promising methods for the same, and have attracted much attention. To improve repair, the incorporation of bionics into TEN grafts has become a focus of research. In this study, a novel bionic TEN graft with a biomimetic structure and composition is designed. For this purpose, a chitin helical scaffold is fabricated by means of mold casting and acetylation using chitosan as the raw material, following which a fibrous membrane is electrospun on the outer layer of the chitin scaffold. The lumen of the structure is filled with human bone mesenchymal stem cell-derived extracellular matrix and fibers to provide nutrition and topographic guidance, respectively. The prepared TEN graft is then transplanted to bridge 10 mm sciatic nerve defects in rats. Morphological and functional examination shows that the repair effects of the TEN grafts and autografts are similar. The bionic TEN graft described in this study shows great potential for application and offers a new way to repair clinical peripheral nerve defects.
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Quitosana , Engenharia Tecidual , Ratos , Humanos , Animais , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Biônica , Nervo Isquiático/fisiologia , Quitosana/química , Regeneração NervosaRESUMO
A positive response to scalene muscle block (SMB) is an important indication for the diagnosis of thoracic outlet syndrome. Lidocaine injection is commonly used in clinical practice in SMB, although there have been some cases of misdiagnosis. Botulinum toxin A (BTX-A) is one of the therapeutic agents in SMB, but whether it is also indicated for SMB diagnosis is controversial. To evaluate the muscle block efficiency of these two drugs, the contraction strength was repeatedly recorded on tibialis anterior muscle in rats. It was found that at a safe dosage, 2% lidocaine performed best at 40 µL, but it still exhibits an unsatisfactory partial blocking efficiency. Moreover, neither lidocaine injection in combination with epinephrine or dexamethasone nor multiple locations injection could improve the blocking efficiency. On the other hand, injections of 3, 6, and 12 U/kg BTX-A all showed almost complete muscle block. Gait analysis showed that antagonistic gastrocnemius muscle, responsible for heel rising, was paralyzed for nonspecific blockage in the 12 U/kg BTX-A group, but not in the 3 U/kg or 6 U/kg BTX-A group. Cleaved synaptosomal associated protein 25 (c-SNAP 25) was stained to test the transportation of BTX-A, and was additionally observed in the peripheral muscles in 6 and 12 U/kg groups. c-SNAP 25, however, was barely detectable in the spinal cord after BTX-A administration. Therefore, our results suggest that low dosage of BTX-A may be a promising option for the diagnostic SMB of thoracic outlet syndrome. SIGNIFICANCE STATEMENT: Muscle block is important for the diagnosis and treatment of thoracic outlet syndrome and commonly performed with lidocaine. However, misdiagnosis was observed sometimes. Here, we found that intramuscular injection of optimal dosage lidocaine only partially blocked the muscle contraction in rats, whereas low-dosage botulinum toxin, barely used in diagnostic block, showed almost complete block without affecting the central nervous system. This study suggests that botulinum toxin might be more suitable for muscle block than lidocaine in clinical practice.
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Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Síndrome do Desfiladeiro Torácico , Ratos , Animais , Toxinas Botulínicas Tipo A/farmacologia , Lidocaína/farmacologia , Injeções Intramusculares , Músculo EsqueléticoRESUMO
Background: Previous reports on the treatment of neuropathic arthropathy of the wrist were generally conservative, with few case reports of treatment with osteoarticular surgery. Case Presentation: A 25-year-old right-handed male complained of unpainful swelling of the dorsal aspect of his right wrist for 3 years. He was at that time diagnosed with synovitis and radiocarpal arthritis. The patient underwent a partial Four-Corner Arthrodesis and Synoviectomy to preserve motor function. Over the next 2 months, his right wrist also developed painful redness, with progressive swelling and stiffness. Rheumatoid arthritis, tuberculosis arthritis, and infectious diseases were ruled out in this case. Magnetic resonance imaging (MRI) indicated that he had Chiari II syringomyelia so the patient was eventually diagnosed with destructive neuropathic arthropathy (syringomyelia). After 2 months of conservative treatment, the patient's right wrist spontaneously and completely fused and the pain disappeared. Conclusion: Neuropathic arthropathy of the wrist is a rare but clinically significant disease due to its effect on the function of the active limb. Surgeons should rule out a diagnosis of it when treating patients with wrist swelling and osteoarticular abnormalities, otherwise, limited intercarpal arthrodesis should not be taken as a treatment option. Inappropriate partial surgery is likely to lead to rapid total fusion of neuropathic arthropathy of the wrist.
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Neuropathic pain is usually caused by injury or dysfunction of the somatosensory system, and medicine is a common way of treatment. Currently, there are still no satisfactory drugs, like opioids and lidocaine, which carry a high risk of addiction. Protein tyrosine phosphatase receptor type D (PTPRD) is a known therapeutic target in addiction pathways and small molecule inhibitors targeting it, such as 7-butoxy illudalic acid analog (7-BIA), have recently been developed to tackle addition. PTPRD is also upregulated in the dorsal root ganglion (DRG) in a rat model of neuropathic pain, but is not yet clear whether PTPRD contributes to the development of neuropathic pain. Here, we established a chronic constriction injury (CCI) and evaluated PTPRD expression and its association with neuropathic pain. PTPRD expression was found to gradually increase after CCI in DRGs, and its expression was concomitant with the progressive development of hypersensitivity as assessed by both mechanical and thermal stimuli. Both PTPRD knockdown and administration of PTPRD inhibitor 7-BIA alleviated CCI-induced neuropathic pain while upregulating STING and IFN-α in the DRG. Treatment with H-151, a STING inhibitor, abolished the analgesic effects of PTPRD knockdown. Taken together, our study suggests that increased levels of PTPRD in the DRG following CCI are involved in the development of neuropathic pain via the STING-IFN-I pathway. 7-BIA, a small molecule inhibitor of PTPRD with anti-addiction effects, may represent a novel and safe therapeutic strategy for the clinical management of neuropathic pain without the risk of addiction.
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BACKGROUND: Moderate intraoperative hypothermia promotes myocardial injury, surgical site infections, and blood loss. Whether aggressive warming to a truly normothermic temperature near 37°C improves outcomes remains unknown. We aimed to test the hypothesis that aggressive intraoperative warming reduces major perioperative complications. METHODS: In this multicentre, parallel group, superiority trial, patients at 12 sites in China and at the Cleveland Clinic in the USA were randomly assigned (1:1) to receive either aggressive warming to a target core temperature of 37°C (aggressively warmed group) or routine thermal management to a target of 35·5°C (routine thermal management group) during non-cardiac surgery. Randomisation was stratified by site, with computer-generated, randomly sized blocks. Eligible patients (aged ≥45 years) had at least one cardiovascular risk factor, were scheduled for inpatient non-cardiac surgery expected to last 2-6 h with general anaesthesia, and were expected to have at least half of the anterior skin surface available for warming. Patients requiring dialysis and those with a body-mass index exceeding 30 kg/m2 were excluded. The primary outcome was a composite of myocardial injury (troponin elevation, apparently of ischaemic origin), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery, as assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03111875. FINDINGS: Between March 27, 2017, and March 16, 2021, 5056 participants were enrolled, of whom 5013 were included in the intention-to-treat population (2507 in the aggressively warmed group and 2506 in the routine thermal management group). Patients assigned to aggressive warming had a mean final intraoperative core temperature of 37·1°C (SD 0·3) whereas the routine thermal management group averaged 35·6°C (SD 0·3). At least one of the primary outcome components (myocardial injury after non-cardiac surgery, cardiac arrest, or mortality) occurred in 246 (9·9%) of 2497 patients in the aggressively warmed group and in 239 (9·6%) of 2490 patients in the routine thermal management group. The common effect relative risk of aggressive versus routine thermal management was an estimated 1·04 (95% CI 0·87-1·24, p=0·69). There were 39 adverse events in patients assigned to aggressive warming (17 of which were serious) and 54 in those assigned to routine thermal management (30 of which were serious). One serious adverse event, in an aggressively warmed patient, was deemed to be possibly related to thermal management. INTERPRETATION: The incidence of a 30-day composite of major cardiovascular outcomes did not differ significantly in patients randomised to 35·5°C and to 37°C. At least over a 1·5°C range from very mild hypothermia to full normothermia, there was no evidence that any substantive outcome varied. Keeping core temperature at least 35·5°C in surgical patients appears sufficient. FUNDING: 3M and the Health and Medical Research Fund, Food and Health Bureau, Hong Kong. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Hipotermia , Anestesia Geral/efeitos adversos , China/epidemiologia , Hemorragia/etiologia , Humanos , Hipotermia/etiologia , Hipotermia/prevenção & controle , Infecção da Ferida CirúrgicaRESUMO
[This corrects the article on p. 1900 in vol. 11, PMID: 31938296.].
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Objective.Brachial plexus injuries (BPIs) result in serious dysfunction, especially brachial plexus defects which are currently treated using autologous nerve graft (autograft) transplantation. With the development of tissue engineering, tissue engineered nerve grafts (TENGs) have emerged as promising alternatives to autografts but have not yet been widely applied to the treatment of BPIs. Herein, we developed a TENG modified with extracellular matrix generated by skin-derived precursor Schwann cells (SKP-SCs) and expand its application in upper brachial plexus defects in rats.Approach.SKP-SCs were co-cultured with chitosan neural conduits or silk fibres and subjected to decellularization treatment. Ten bundles of silk fibres (five fibres per bundle) were placed into a conduit to obtain the TENG, which was used to bridge an 8 mm gap in the upper brachial plexus. The efficacy of this treatment was examined for TENG-, autograft- and scaffold-treated groups at several times after surgery using immunochemical staining, behavioural tests, electrophysiological measurements, and electron microscopy.Main results.Histological analysis conducted two weeks after surgery showed that compared to scaffold bridging, TENG treatment enhanced the growth of regenerating axons. Behavioural tests conducted four weeks after surgery showed that TENG-treated rats performed similarly to autograft-treated ones, with a significant improvement observed in both cases compared with the scaffold treatment group. Electrophysiological and retrograde tracing characterizations revealed that the target muscles were reinnervated in both TENG and autograft groups, while transmission electron microscopy and immunohistochemical staining showed the occurrence of the superior myelination of regenerated axons in these groups.Significance.Treatment with the developed TENG allows the effective bridging of proximal nerve defects in the upper extremities, and the obtained results provide a theoretical basis for clinical transformation to expand the application scope of TENGs.
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Plexo Braquial , Quitosana , Animais , Plexo Braquial/cirurgia , Quitosana/química , Quitosana/farmacologia , Matriz Extracelular , Regeneração Nervosa , Ratos , Ratos Sprague-Dawley , Células de Schwann/transplante , Nervo Isquiático , Seda/química , Seda/farmacologia , Engenharia Tecidual/métodos , Alicerces Teciduais/químicaRESUMO
Objectives: The treatment for neurogenic thoracic outlet syndrome (NTOS) conventionally involves first-rib resection (FRR) surgery, which is quite challenging to perform, especially for novices, and is often associated with postoperative complications. Herein, we report a new segmental resection approach through piezo surgery that involves using a bone cutter, which can uniquely provide a soft tissue protective effect. Methods: This retrospective study involved the examination of 26 NTOS patients who underwent piezo surgery and another group of 30 patients who underwent FRR using the conventional technique. In the patient group that underwent piezo surgery, the rib was first resected into two pieces using a piezoelectric device and subsequently removed. In the patient group that underwent conventional surgery, the first rib was removed as one piece using a rib cutter and rongeurs. Results: The piezo surgery group had significantly shorter operative time (96.85 ± 14.66 vs. 143.33 ± 25.64 min, P < 0.001) and FRR duration (8.73 ± 2.11 vs. 22.23 ± 6.27 min, P < 0.001) than the conventional group. The posterior stump length of the residual rib was shorter in the piezo surgery group than in the conventional group (0.54 ± 0.19 vs. 0.65 ± 0.15 cm, P < 0.05). There were no significant differences in postoperative complications and scores of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, the Cervical Brachial Symptom Questionnaire (CBSQ), and the visual analog scale (VAS). Even the TOS index (NTOS Index = [DASH + (0.83 × CBSQ) + (10 × VAS)]/3) and patient self-assessments of both the groups showed no significant differences. Univariate analyses indicated that the type of treatment affected operative time. Conclusion: Our results suggest that piezo surgery is safe, effective, and simple for segmental FRR in NTOS patients. Piezo surgery provides a more thorough FRR without damaging adjacent soft tissues in a relatively short duration and achieves similar functional recovery as conventional techniques. Therefore, piezo surgery can be a promising alternative for FRR during the surgical treatment of NTOS.
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AIMS: Inflammation plays a key role in peripheral nerve adhesion and often leads to severe pain and nerve dysfunction. Minocycline was reported to have potent anti-inflammatory effects and might be a promising drug to prevent or attenuate peripheral nerve adhesion. The present study aimed to clarify whether minocycline contributes to nerve adhesion protection and its underlying mechanism. MATERIALS AND METHODS: Rats with sciatic nerve adhesion induced by glutaraldehyde glue (GG) were intraperitoneally injected with minocycline or saline every 12 h for 7 consecutive days. After that, the adhesion score, Ashcroft score, demyelination, macrophage polarization and inflammatory factors in peripheral nerve adhesion tissues or tissues in sham group were determined with histological staining, western blot and real time-PCR. Murine macrophage RAW264.7 cells were stimulated by LPS alone or together with minocycline at different concentrations and time duration to study the mechanism of minocycline in alleviating nerve adhesion. KEY FINDINGS: We found that minocycline treatment reduced the adhesion score, Ashcroft score, the growth of scar tissue, demyelination, and macrophage recruitment. Moreover, minocycline significantly and dose-dependently promoted regulatory macrophage polarization but decreased pro-inflammatory macrophage polarization. Furthermore, mechanism studies showed that TAK1 and its downstream pathway p38/JNK/ERK1/2/p65 were inhibited by minocycline, which led to lower IL-1ß and TNFα expression, but increased IL-10 expression. SIGNIFICANCE: Altogether, these results suggest that minocycline is highly effective against peripheral nerve adhesion through anti-fibrosis, anti-inflammation, and myelination protection, making it a highly promising candidate for treating adhesion-related disorders.
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Regulação da Expressão Gênica/efeitos dos fármacos , MAP Quinase Quinase Quinases/metabolismo , Ativação de Macrófagos/imunologia , Minociclina/farmacologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Neuropatia Ciática/tratamento farmacológico , Aderências Teciduais/prevenção & controle , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Feminino , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , MAP Quinase Quinase Quinases/genética , Ativação de Macrófagos/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/imunologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologiaRESUMO
Correction for 'Determination of sulfonamides in blood using acetonitrile-salt aqueous two-phase extraction coupled with high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry' by Wei Yu et al., Anal. Methods, 2013, 5, 5983-5989, DOI: 10.1039/C3AY40902C.
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[This corrects the article DOI: 10.3389/fncel.2020.00078.].
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After spinal cord injury (SCI), the irreversible loss of neurons and the dense glial scar are two of the leading causes of axon regeneration failure. The adult mammalian spinal cord lacks the ability to spontaneously produce new neurons, making it a key challenge to provide new neurons for spinal cord regeneration. Additionally, the dual role of the glial scar (both inhibitory and protective) makes it difficult to manipulate it for therapeutic purposes. In this study, using a single transcription factor Sry-related HMG-box 2 (Sox2) delivered by adeno-associated virus (AAV), we reprogrammed some of the astrocytes targeted by the viral vectors in the glial scar into neurons in a severe SCI model. We show that this astrocytic reprogramming alone can propel axon regeneration by not only replenishing the lost neurons, but also moderately reducing the density of the glial scar without interrupting its integrity. Beyond that, astrocytic reprogramming can significantly improve functional recovery when combined with running wheel rehabilitation, which provides use-dependent plasticity. These findings may provide us with a new idea for how to manipulate the glial scar and a promising therapeutic strategy that combines biological intervention with a rehabilitation strategy.
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Astrócitos/citologia , Reprogramação Celular , Regeneração Nervosa , Neurônios/citologia , Condicionamento Físico Animal , Fatores de Transcrição SOXB1/administração & dosagem , Traumatismos da Medula Espinal/reabilitação , Animais , Axônios/fisiologia , Cicatriz , Modelos Animais de Doenças , Gliose , Camundongos , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapiaRESUMO
BACKGROUND: Schwann cells (SCs) play a crucial role in Wallerian degeneration after peripheral nerve injury. The expression of genes in SCs undergo a series of changes, which greatly affect the proliferation and apoptosis of SCs as well as the fate of peripheral nerve regeneration. However, how do these genes regulate the proliferation and apoptosis of SCs remains unclear. RESULTS: SPP1 and PKCα were found upregulated after human median peripheral nerve injury, which promoted SCs proliferation and survival. The promoted proliferation and inhibited apoptosis by SPP1 were blocked after the treatment of PKCα antagonist Gö6976. Whereas, the inhibited proliferation and enhanced apoptosis induced by silence of SPP1 could be rescued by the activation of PKCα, which suggested that SPP1 functioned through PKCα. Moreover, both CD44 and αvß3 were found expressed in SCs and increased after peripheral nerve injury. Silence of CD44 or ß3 alleviated the increased proliferation and inhibited apoptosis induced by recombinant osteopontin, suggesting the function of SPP1 on SCs were dependent on CD44 and ß3. CONCLUSION: These results suggested that SPP1 promoted proliferation and inhibited apoptosis of SCs through PKCα signaling pathway by binding with CD44 and αvß3. This study provides a potential therapeutic target for improving peripheral nerve recovery.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.