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Over the past few decades, there have been advancements in the development of high-performance tissue adhesives as alternatives to traditional sutures and staples for rapid and effective wound closure post-surgery. While tissue adhesives offer advantages such as ease of use, short application time, and minimal tissue damage, they also face challenges related to biocompatibility, biodegradability, and adhesive strength. In this study, L-lysine diisocyanate (LDI) and trimethylolpropane (TMP) were utilized as the primary raw materials to produce a prepolymer terminated with NCO, resulting in the development of a new biocompatible polyurethane tissue adhesive (TMP-LDI). Additionally, SiO2 nanoparticles were incorporated into the prepolymer, significantly enhancing the adhesive strength of the TMP-LDI tissue adhesive through the "nanobridging effect," achieving a strength of 170.4 kPa. Furthermore, the SiO2/TMP-LDI tissue adhesive exhibited satisfactory temperature change during curing and degradation performance. In vitro and in vivo studies demonstrated that SiO2/TMP-LDI exhibited good biocompatibility, efficient hemostasis, antimicrobial properties, and the ability to promote wound healing. This research presents a novel approach for the development of tissue adhesives with superior adhesive performance.
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Dental pulp regeneration is a promising strategy for addressing tooth disorders. Incorporating this strategy involves the fundamental challenge of establishing functional vascular networks using dental pulp stem cells (DPSCs) to support tissue regeneration. Current therapeutic approaches lack efficient and stable methods for activating DPSCs. In the study, we used a chemically modified microRNA (miRNA)-loaded tetrahedral-framework nucleic acid nanostructure to promote DPSC-mediated angiogenesis and dental pulp regeneration. Incorporating chemically modified miR-126-3p into tetrahedral DNA nanostructures (miR@TDNs) represents a notable advancement in the stability and efficacy of miRNA delivery into DPSCs. These nanostructures enhanced DPSC proliferation, migration, and upregulated angiogenesis-related genes, enhancing their paracrine signaling effects on endothelial cells. This enhanced effect was substantiated by improvements in endothelial cell tube formation, migration, and gene expression. Moreover, in vivo investigations employing matrigel plug assays and ectopic dental pulp transplantation confirmed the potential of miR@TDNs in promoting angiogenesis and facilitating dental pulp regeneration. Our findings demonstrated the potential of chemically modified miRNA-loaded nucleic acid nanostructures in enhancing DPSC-mediated angiogenesis and supporting dental pulp regeneration. These results highlighted the promising role of chemically modified nucleic acid-based delivery systems as therapeutic agents in regenerative dentistry and tissue engineering.
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MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , Células Endoteliales , Pulpa Dental , Células Madre , Diferenciación Celular , Regeneración , ADN/metabolismo , Proliferación Celular/fisiologíaRESUMEN
The primary challenges posed by oral mucosal diseases are their high incidence and the difficulty in managing symptoms. Inspired by the ability of bioelectricity to activate cells, accelerate metabolism, and enhance immunity, a conductive polyacrylamide/sodium alginate crosslinked hydrogel composite containing reduced graphene oxide (PAA-SA@rGO) is developed. This composite possesses antibacterial, anti-inflammatory, and antioxidant properties, serving as a bridge to turn the "short circuit" of the injured site into a "completed circuit," thereby prompting fibroblasts in proximity to the wound site to secrete growth factors and expedite tissue regeneration. Simultaneously, the PAA-SA@rGO hydrogel effectively seals wounds to form a barrier, exhibits antibacterial and anti-inflammatory properties, and prevents foreign bacterial invasion. As the electric field of the wound is rebuilt and repaired by the PAA-SA@rGO hydrogel, a 5 × 5 mm2 wound in the full-thickness buccal mucosa of rats can be expeditiously mended within mere 7 days. The theoretical calculations indicate that the PAA-SA@rGO hydrogel can aggregate and express SOX2, PITX1, and PITX2 at the wound site, which has a promoting effect on rapid wound healing. Importantly, this PAA-SA@rGO hydrogel has a fast curative effect and only needs to be applied for the first three days, which significantly improves patient satisfaction during treatment.
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Grafito , Hidrogeles , Cicatrización de Heridas , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Grafito/química , Grafito/farmacología , Ratas , Resinas Acrílicas/química , Mucosa Bucal/metabolismo , Mucosa Bucal/efectos de los fármacos , Ratas Sprague-Dawley , Alginatos/química , Alginatos/farmacología , Conductividad Eléctrica , Antibacterianos/farmacología , Antibacterianos/química , Masculino , HumanosRESUMEN
Epitranscriptomic abnormalities, which are highly prevalent in primary central nervous system malignancies, have been identified as crucial contributors to the development and progression of gliomas. RNA epitranscriptomic modifications, particularly the reversible modification methylation, have been observed throughout the RNA cycle. Epitranscriptomic modifications, which regulate RNA transcription and translation, have profound biological implications. These modifications are associated with the development of several cancer types. Notably, three main protein types-writers, erasers, and readers, in conjunction with other related proteins, mediate these epitranscriptomic changes. This review primarily focuses on the role of recently identified RNA methylation modifications in gliomas, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), and N1-methyladenosine (m1A). We delved into their corresponding writers, erasers, readers, and related binding proteins to propose new approaches and prognostic indicators for patients with glioma.
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Glioma , Transcriptoma , Humanos , Metilación , ARN/metabolismo , 5-Metilcitosina/metabolismo , Glioma/genéticaRESUMEN
Postoperative sore throat (POST) is a prevalent complication after general anesthesia and targeting high-risk patients help in its prevention. This study developed and validated a machine learning model to predict POST. A total number of 834 patients who underwent general anesthesia with endotracheal intubation were included in this study. Data from a cohort of 685 patients was used for model development and validation, whilst a cohort of 149 patients served for external validation. The prediction performance of random forest (RF), neural network (NN), and XGBoost models was compared using comprehensive performance metrics. The Local Interpretable Model-Agnostic Explanations (LIME) methods elucidated the best-performing model. POST incidences across training, validation, and testing cohorts were 41.7%, 38.4%, and 36.2%, respectively. Five predictors were age, sex, endotracheal tube cuff pressure, endotracheal tube insertion depth, and the time interval between extubation and the first drinking of water after extubation. After incorporating these variables, the NN model demonstrated superior generalization capabilities in predicting POST when compared to the XGBoost and RF models in external validation, achieving an area under the receiver operating characteristic curve (AUROC) of 0.81 (95% CI 0.74-0.89) and a precision-recall curve (AUPRC) of 0.77 (95% CI 0.66-0.86). The model also showed good calibration and clinical usage values. The NN model outperforms the XGBoost and RF models in predicting POST, with potential applications in the healthcare industry for reducing the incidence of this common postoperative complication.
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Background: Tumor necrosis factor (TNF) is an inflammatory cytokine that can coordinate tissue homeostasis by co-regulating the production of cytokines, cell survival, or death. It widely expresses in various tumor tissues and correlates with the malignant clinical features of patients. As an important inflammatory factor, the role of TNFα is involved in all steps of tumorigenesis and development, including cell transformation, survival, proliferation, invasion and metastasis. Recent research has showed that long non-coding RNAs (lncRNAs), defined as RNA transcripts >200 nucleotides that do not encode a protein, influence numerous cellular processes. However, little is known about the genomic profile of TNF pathway related-lncRNAs in GBM. This study investigated the molecular mechanism of TNF related-lncRNAs and their immune characteristics in glioblastoma multiforme (GBM) patients. Methods: To identify TNF associations in GBM patients, we performed bioinformatics analysis of public databases - The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). The ConsensusClusterPlus, CIBERSORT, Estimate, GSVA and TIDE and first-order bias correlation and so on approaches were conducted to comprehensively characterize and compare differences among TNF-related subtypes. Results: Based on the comprehensive analysis of TNF-related lncRNAs expression profiles, we constructed six TNF-related lncRNAs (C1RL-AS1, LINC00968, MIR155HG, CPB2-AS1, LINC00906, and WDR11-AS1) risk signature to determine the role of TNF-related lncRNAs in GBM. This signature could divide GBM patients into subtypes with distinct clinical and immune characteristics and prognoses. We identified three molecular subtypes (C1, C2, and C3), with C2 showing the best prognosis; otherwise, C3 showing the worst prognosis. Moreover, we assessed the prognostic value, immune infiltration, immune checkpoints, chemokines cytokines and enrichment analysis of this signature in GBM. The TNF-related lncRNA signature was tightly associated with the regulation of tumor immune therapy and could serve as an independent prognostic biomarker in GBM. Conclusion: This analysis provides a comprehensive understanding of the role of TNF-related characters, which may improve the clinical outcome of GBM patients.
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The gut microbiome is critically involved in maintaining normal physiological function in the host. Recent studies have revealed that alterations in the gut microbiome contribute to the development and progression of cerebrovascular disease via the microbiota-gut-brain axis (MGBA). As a broad communication network in the human body, MGBA has been demonstrated to have significant interactions with various factors, such as brain structure and function, nervous system diseases, etc. It is also believed that the species and composition of gut microbiota and its metabolites are intrinsically linked to vascular inflammation and immune responses. In fact, in fecal microbiota transplantation (FMT) research, specific gut microbiota and downstream-related metabolites have been proven to not only participate in various physiological processes of human body, but also affect the occurrence and development of cerebrovascular diseases directly or indirectly through systemic inflammatory immune response. Due to the high mortality and disability rate of cerebrovascular diseases, new treatments to improve intestinal dysbacteriosis have gradually attracted widespread attention to better ameliorate the poor prognosis of cerebrovascular diseases in a non-invasive way. This review summarizes the latest advances in the gut microbiome and cerebrovascular disease research and reveals the profound impact of gut microbiota dysbiosis and its metabolites on cerebrovascular diseases. At the same time, we elucidated molecular mechanisms whereby gut microbial metabolites regulate the expression of specific interleukins in inflammatory immune responses. Moreover, we further discuss the feasibility of novel therapeutic strategies targeting the gut microbiota to improve the outcome of patients with cerebrovascular diseases. Finally, we provide new insights for standardized diagnosis and treatment of cerebrovascular diseases.
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Background: Histone acetylation-related lncRNAs (HARlncRNAs) play significant roles in various cancers, but their impact on lung adenocarcinoma (LUAD) remains unclear. This study aimed to develop a new HARlncRNA-based prognostic model for LUAD and to explore its potential biological mechanisms. Methods: We identified 77 histone acetylation genes based on previous studies. HARlncRNAs related to prognosis were screened by co-expression, univariate and multivariate analyses, and least absolute shrinkage selection operator regression (LASSO). Afterward, a prognostic model was established based on the screened HARlncRNAs. We analysed the relationship between the model and immune cell infiltration characteristics, immune checkpoint molecule expression, drug sensitivity, and tumour mutational burden (TMB). Finally, the entire sample was divided into three clusters to further distinguish between hot and cold tumours. Results: A seven-HARlncRNA-based prognostic model was established for LUAD. The area under the curve (AUC) of the risk score was the highest among all the analysed prognostic factors, indicating the accuracy and robustness of the model. The patients in the high-risk group were predicted to be more sensitive to chemotherapeutic, targeted, and immunotherapeutic drugs. It was worth noting that clusters could effectively identify hot and cold tumours. In our study, clusters 1 and 3 were considered hot tumours that were more sensitive to immunotherapy drugs. Conclusion: We developed a risk-scoring model based on seven prognostic HARlncRNAs that promises to be a new tool for evaluating the prognosis and efficacy of immunotherapy in patients with LUAD.
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Adenocarcinoma , Histonas , Humanos , Acetilación , Biomarcadores , Pronóstico , Inmunidad , PulmónRESUMEN
Electrotherapy is a promising tissue repair technique. However, electrotherapy devices are frequently complex and must be placed adjacent to injured tissue, thereby limiting their clinical application. Here, we propose a general strategy to facilitate tissue repair by modulating endogenous electric fields with nonadjacent (approximately 44 mm) wireless electrotherapy through a 3D-printed entirely soft and bioresorbable triboelectric nanogenerator based stimulator, without any electrical accessories, which has biomimetic mechanical properties similar to those of soft tissue. In addition, the feasibility of using the stimulator to construct an electrical double layer with tissue for nonadjacent wireless electrotherapy was demonstrated by skin and muscle injury models. The treated groups showed significantly improved tissue repair compared with the control group. In conclusion, we developed a promising electrotherapy strategy and may inspire next-generation electrotherapy for tissue repair.
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Implantes Absorbibles , Polímeros , Electricidad , Cicatrización de Heridas , Impresión TridimensionalRESUMEN
Conductive fibers are vital for next-generation wearable and implantable electronics. However, the mismatch of mechanical, electrical, and biological properties between existing conductive fibers and human tissues significantly retards their further development. Here, the concept of neuro-like fibers to meet these aforementioned requirements is proposed. A new wet spinning process is established to continuously produce pure gelatin hydrogel fibers. The key is the controllable and rapid gelation of spinning solutions based on the salting-out effect, which is inspired by the Chinese food tofu. The resultant fibers exhibit neuro-like features of soft-while-strong mechanical properties, high ionic conductivity, and superior biological properties including biodegradability, biocompatibility, and edibility, which are crucial for implanted applications but seldom reported. Furthermore, all-weather suitable neuro-like fibers with excellent anti-freezing and water retention properties are developed by introducing glycerol for wearable applications. The optical fiber, transient electronics, and electronic data glove made of neuro-like fibers profoundly demonstrate their potential in biomedical applications.
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Dispositivos Electrónicos Vestibles , Humanos , Biomimética , Electrónica , Conductividad EléctricaRESUMEN
Hydrogels are emerging as the most promising dressings due to their excellent biocompatibility, extracellular matrix mimicking structure, and drug loading ability. However, existing hydrogel dressings exhibit limited breathability, poor environmental adaptability, potential drug resistance, and limited drug options, which extremely restrict their therapeutic effect and working scenarios. Here, the current research introduces the first paradigm of hydrogel textile dressings based on novel gelatin glycerin hydrogel (glyhydrogel) fibers fabricated by the Hofmeister effect based wet spinning. Benefiting from the unique knitted structure, the textile dressing features excellent breathability (1800 times that of the commercially available 3 M dressing) and stretchability (535.51 ± 38.66%). Furthermore, the glyhydrogel textile dressing can also withstand the extreme temperature of -80 °C, showing the potential for application in subzero environments. Moreover, the introduction of glycerin endows the textile dressing with remarkable antibacterial property and expands the selection of loaded drugs (e.g., clindamycin). The prepared glyhydrogel textile dressing shows an excellent infected wound healing effect with a complete rat skin closure within 14 days. All these functions have not been achievable by traditional hydrogel dressings and provide a new approach for the development of hydrogel dressings.
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The cerebrospinal fluid (CSF)-contacting nucleus is implicated in the descending inhibitory pathway in pain processing, whereas the cellular and molecular mechanisms underpinning CSF-contacting nucleus regulating pain signals remains largely elusive. ATP is evidenced to inhibit pain transmission at supraspinal level by the mediation of the receptor P2X, wherein its subtype P2X3 is identified as the most potent. Our present experiment investigated the functionality of P2X3 receptors in CSF-contacting nucleus in the formalin-evoked inflammatory pain. Immunofluorescence and western blot revealed the expression of P2X3 receptors in the CSF-contacting nucleus and their upregulated expression subsequent to administration of formalin in rat model. ATP (a P2X3 receptor agonist, 100nmol/5µl) by intracerebroventricular (i.c.v.) administration ameliorated pain behaviors and enhanced c-Fos immunoreactivity in the neurons of the periaqueductal gray (PAG), both of which were discounted by pre-administration of A-317491 (a selective P2X3 receptor antagonist, 25nmol/5µl). After the CSF-contacting nucleus was ablated by cholera toxin subunit B-saporin, ATP failed to induce analgesia, with the c-Fos immunoreactivity in the PAG neurons remaining intact. Our results validated that P2X3 receptors in the CSF-contacting nucleus are pivotal in inflammatory pain processing via the activation of PAG neurons.
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Líquido Cefalorraquídeo , Neuronas/metabolismo , Dolor/metabolismo , Sustancia Gris Periacueductal/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Toxina del Cólera , Modelos Animales de Enfermedad , Desinfectantes/toxicidad , Formaldehído/toxicidad , Inyecciones Intraventriculares , Masculino , Neuronas/efectos de los fármacos , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/patología , Fenoles/uso terapéutico , Compuestos Policíclicos/uso terapéutico , Agonistas del Receptor Purinérgico P2X/uso terapéutico , Ratas , Ratas Sprague-Dawley , Proteínas Inactivadoras de Ribosomas Tipo 1 , SaporinasRESUMEN
Endoplasmic reticulum stress (ERS) activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. Recently, TSA has shown protective effects on ERS and its mechanisms related to ER pathway has been previously characterized. However, whether TSA exerts its protective role via metabolic events remain largely undefined. Objectives: To explore the possible involvement of the metabolic changes during ERS and to better understand how TSA influence mitochondrial function to facilitate cellular adaptation. Results: TSA is an inhibitor of histone deacetylase which could significantly inhibit H9c2 cell apoptosis induced by Thapsigargin (TG). It also intervene the decrease of mitochondrial membrane potential. By immunofluorescence staining, we have shown that GRP78 was concentrated in the perinuclear region and co-localized with ER. However, treatments with TG and TSA could let it overlap with the mitochondrial marker MitoTracker. Cellular fractionation also confirmed the location of GRP78 in mitochondrion. CONCLUSIONS: TSA decreases ERS-induced cell apoptosis and mitochondrial injury may related to enhance the location of GRP78 in mitochondrion.
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In this paper, we propose a salient object detection algorithm that considers both background and foreground cues. It integrates both coarse salient region extraction and a top-down background weight map measure via boundary label propagation into a unified optimization framework to acquire a refined salient map. The coarse saliency map is additionally fused by three prior components: a local contrast map with greater alignment to physiological law, a global focus prior map, and a global color prior map. During the formation of the background weight map, we first construct an affinity matrix and select nodes existing on the border as labels to represent the background. Then we perform a propagation to generate the regional background weight map. Our proposed model was verified on four benchmark datasets, and the experimental results demonstrate that our method has excellent performance.
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MicroRNAs are emerging as critical regulators in cerebral ischemia/reperfusion injury; however, their exact roles remain poorly understood. miR-153 is reported to be a neuron-related miRNA involved in neuroprotection. In this study, we aimed to investigate the precise role of miR-153 in regulating neuron survival during cerebral ischemia/reperfusion injury using an oxygen-glucose deprivation and reoxygenation (OGD/R) cellular model. We found that miR-153 was significantly upregulated in neurons subjected to OGD/R treatment. Inhibition of miR-153 significantly attenuated OGD/R-induced injury and oxidative stress in neurons. Nuclear factor erythroid 2-related factor 2 (Nrf2) was identified as a target gene of miR-153. Inhibition of miR-153 significantly promoted the expression of Nrf2 and heme oxygenase-1 (HO-1). However, silencing of Nrf2 significantly blocked the protective effects of miR-153 inhibition. Our study indicates that the inhibition of miR-153 protects neurons against OGD/R-induced injury by regulating Nrf2/HO-1 signaling and suggests a potential therapeutic target for cerebral ischemia/reperfusion injury.
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Hemo-Oxigenasa 1/metabolismo , MicroARNs/antagonistas & inhibidores , Modelos Neurológicos , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/metabolismo , Daño por Reperfusión/prevención & control , Transducción de Señal , Glucosa/metabolismo , Hemo-Oxigenasa 1/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Factor 2 Relacionado con NF-E2/genética , Neuronas/patología , Estrés Oxidativo/genética , Oxígeno/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patologíaRESUMEN
Estimating transformations from degraded point sets is necessary for many computer vision and pattern recognition applications. In this paper, we propose a robust non-rigid point set registration method based on spatially constrained context-aware Gaussian fields. We first construct a context-aware representation (e.g., shape context) for assignment initialization. Then, we use a graph Laplacian regularized Gaussian fields to estimate the underlying transformation from the likely correspondences. On the one hand, the intrinsic manifold is considered and used to preserve the geometrical structure, and a priori knowledge of the point set is extracted. On the other hand, by using the deterministic annealing, the presented method is extended to a projected high-dimensional feature space, i.e., reproducing kernel Hilbert space through a kernel trick to solve the transformation, in which the local structure is propagated by the coarse-to-fine scaling strategy. In this way, the proposed method gradually recovers much more correct correspondences, and then estimates the transformation parameters accurately and robustly when facing degradations. Experimental results on 2D and 3D synthetic and real data (point sets) demonstrate that the proposed method reaches better performance than the state-of-the-art algorithms.
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Evidence has suggested that cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) is correlated with the development and recurrence of pain. A recent research showed that the CSF-contacting nucleus acts as a component of the descending 5-hydroxytryptamine (5-HT) system and plays a role in descending pain inhibition. However, limited studies are conducted to investigate the relationship between the CSF-contacting nucleus and pain. In present study, we explored the effect of CSF-contacting nucleus on nociceptive behaviors in both normal and neuropathic rats via targeted ablation of the CSF-contacting nucleus in the brainstem, using cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to cholera toxin subunit B. The CB-SAP-treated rats showed aggravated thermal hyperalgesia and mechanical allodynia. Also, results from immunohistochemical experiments showed that rostral ventromedial medulla (RVM) received fiber projection from the CSF-contacting nucleus, which disappeared after ablation of the CSF-contacting nucleus, and the CB-SAP treated rats showed downregulation of c-Fos expression in the RVM as compared with the rats receiving i.c.v. injection of phosphate buffer saline (PBS). A significant downregulation of 5-HT-labeled neurons and tryptophan hydroxylase 2 (TPH2) as the marker of 5-HT cells in the RVM, and 5-HT expression in spinal dorsal horn in both normal and chronic constriction injury (CCI) rats after i.c.v. injection of CB-SAP was observed. These results suggested that RVM may be involved in descending pain modulation originating from the CSF-contacting nucleus.
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Bulbo Raquídeo/química , Bulbo Raquídeo/fisiología , Dolor/metabolismo , Dolor/patología , Tractos Piramidales/química , Tractos Piramidales/fisiología , Animales , Hiperalgesia/metabolismo , Hiperalgesia/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The cerebrospinal fluid-contacting nucleus (CSF-CN) has been demonstrated to be involved in neuropathic pain, but the underlying molecular mechanisms remain unclear. Previous work has shown that mTOR and ERK1/2 are important signaling pathways regulating neuropathic pain. However, studies on the interactions between these major pathways in neuropathic pain are very rare. Therefore, the purpose of this study is to determine whether mTOR and ERK1/2 exist in the CSF-CN and elucidate their alterations in neuropathic pain, especially, the crosstalk between them. Our results showed that mTOR and ERK1/2 were distributed in the CSF-CN, and their expression levels were increased in chronic constriction injury (CCI)-induced neuropathic pain. Furthermore, the injection of both the mTOR antagonist rapamycin and the ERK1/2 antagonist U0126 into the lateral ventricle of the brain attenuated CCI-induced neuropathic pain. Inhibition of the ERK1/2 pathway had little impact on mTOR signaling, but inhibition of the mTOR pathway significantly increased ERK/2 signaling. The coadministration of rapamycin and U0126 inhibited the rapamycin-induced upregulation of ERK, and had a greater effect on pain behaviors than did the single-drug administrations. These data extend our understanding of the relationship between mTOR and ERK in the supraspinal site and demonstrate that the CSF-CN participates in neuropathic pain via the regulation of mTOR and ERK1/2.