RESUMEN
Peripheral nerve injury potentially destroys the quality of life by inducing functional movement disorders and sensory capacity loss, which results in severe disability and substantial psychological, social, and financial burdens. Autologous nerve grafting has been commonly used as treatment in the clinic; however, its rare donor availability limits its application. A series of artificial nerve guidance conduits (NGCs) with advanced architectures are also proposed to promote injured peripheral nerve regeneration, which is a complicated process from axon sprouting to targeted muscle reinnervation. Therefore, exploring the interactions between sophisticated NGC complexes and versatile cells during each process including axon sprouting, Schwann cell dedifferentiation, nerve myelination, and muscle reinnervation is necessary. This review highlights the contribution of functional NGCs and the influence of microscale biomaterial architecture on biological processes of nerve repair. Progressive NGCs with chemical molecule induction, heterogenous topographical morphology, electroactive, anisotropic assembly microstructure, and self-powered electroactive and magnetic-sensitive NGCs are also collected, and they are expected to be pioneering features in future multifunctional and effective NGCs.
Asunto(s)
Regeneración Tisular Dirigida , Traumatismos de los Nervios Periféricos , Humanos , Regeneración Tisular Dirigida/métodos , Calidad de Vida , Traumatismos de los Nervios Periféricos/terapia , Materiales Biocompatibles/farmacología , Axones , Regeneración Nerviosa , Nervio Ciático/fisiologíaRESUMEN
AIMS: Osteopontin (OPN) has demonstrated neuroprotective effects in various stroke models. Its role in neuroinflammation after brain injury remains to be elucidated. This study aims to clarify the effect of OPN on neuroinflammation, particularly on the functional states of microglia after subarachnoid hemorrhage (SAH). METHODS: 77 rats were randomly divided into the following groups: Sham, SAH 24 h, SAH + rOPN, SAH + Vehicle (PBS), SAH + OPN siRNA, and SAH + Scr siRNA, SAH + rOPN+Fib-14 and SAH + rOPN+DMSO. Modified Garcia and beam balance tests were used to evaluate neurobehavioral outcomes. Semi-quantitative immunofluorescence staining was performed to measure expression of myeloperoxidase (MPO) and microglia activation state markers CD16, CD206 after SAH and recombinant OPN treatment. The quantification of microglia activation and functional markers CD16, CD206, TNF-α and IL-10 were further evaluated using Western-blotting. RESULTS: Nasal administration of rOPN improved neurological dysfunction, attenuated neutrophil infiltration, and decreased expression of phenotypic and functional markers of pro-inflammatory microglia CD16 and TNF-α. It also promoted an anti-inflammatory microglial state, as evidenced by increased expression of CD206 and IL-10. Furthermore, after blocking the phosphorylation of FAK signaling, the effects of rOPN on microglial activation states were partially reversed. The downstream pathways of STAT3 and NF-κB also exhibited consistent changes, suggesting the involvement of the STAT3 and NF-κB pathways in OPN's modulation of microglial activation via integrin-FAK signaling. CONCLUSION: OPN attenuates inflammatory responses after SAH by promoting an anti-inflammatory microglial state, potentially mediated through the integrin-FAK-STAT3 and NF-κB signaling pathways.
Asunto(s)
Osteopontina , Hemorragia Subaracnoidea , Ratas , Animales , Osteopontina/uso terapéutico , Osteopontina/metabolismo , Osteopontina/farmacología , Ratas Sprague-Dawley , FN-kappa B/metabolismo , Interleucina-10 , Microglía/metabolismo , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedades Neuroinflamatorias , Antiinflamatorios/farmacología , Integrinas/metabolismo , Integrinas/uso terapéutico , ARN Interferente Pequeño/farmacología , Modelos Animales de EnfermedadRESUMEN
Zinc titanate phosphors containing Eu3+/ Mn4+ as active ions were synthesized by using the solid-state method. XRD patterns of the powders confirmed that the samples were a mixture of cubic Zn2TiO4 and hexagonal ZnTiO3 phases. The luminous intensity of ZTO: Eu3+phosphors and ZTO: Mn4+ phosphors both increased with the increase of doping concentration, reaching the maximum at 2 mol% Eu3+ and 0.3 mol% Mn4+, respectively. In the photoluminescence spectra of ZTO: Eu3+(2 mol%) phosphors with different Mn4+ doping amounts excited at 465 nm, the emission spectra revealed the characteristic peaks of Eu3+ with low Mn4+ content, and with the Mn4+ content increasing, the emission spectra contained both Mn4+ and Eu3+ luminescence peaks. In the variable temperature spectra, the relative sensitivity of the samples was improved with the concentration of Mn4+ increasing and achieved the maximum value of 3.2 %/K.
RESUMEN
Background: Evaluate the effect of the miRNA-106a/20b on the efficacy of DCs pulsed with GSCs in activating GSC-specific T cell responses. Methods: We cultured GSCs and prepared GSC antigen lysates by apoptosis. Then, immature DCs were pulsed with GSC antigen lysates in vitro. STAT3 levels in DCs were assessed by Western blotting, and the expression of CD80, CD86, and MHC-II was tested by fluorescence-activated cell sorting. The production and secretion of the cytokines IL-6, IL-12, TNF-α, and IL-10 in DCs induced by GSCs were determined by enzyme-linked immunosorbent assay. Finally, the cytotoxic functions of T cells stimulated by GSC-DC fusion cells transfected with a miR-106a/20b mimic in vitro and the antitumour activity in vivo were detected. Results: We found that the levels of miR-106a/20b were downregulated, but the expression of STAT3 was significantly upregulated. Simultaneously, the inhibition of STAT3 in the fusion cells by STAT3-specific siRNA caused significant upregulation of the expression of CD80, CD86, and MHC-II, and the secretion of the cytokines IL-6 and IL-12 was substantially increased, IL-10 was markedly decreased. These findings revealed that STAT3 is an important regulator of DC maturation. Furthermore, the interactional binding sites between the 3'-untranslated region (3'-UTR) of STAT3 mRNA and miR-106a/20b were predicted by bioinformatics and verified by a dual-luciferase assay. Moreover, the reduction in STAT3 levels in GSC-DCs enhanced the generation of CD8+ T cells and reduced the generation of Foxp3+ regulatory T cells. Meanwhile, the secretion of the T cell cytokine IFN-γ was significantly increased. Further research showed that DCs after miR-106a/20b-mimics transfection could promote the inhibition of GSC proliferation by T cells in vitro and suppress tumour growth in vivo. Conclusions: This study indicted that the miR-106a/20b activation could be one of the important molecular mechanisms leading to enhance antitumour immune responses of GSC-mediated DCs, which downregulated the expression of STAT3 to alleviate its the inhibitory effect.
Asunto(s)
Interleucina-10 , MicroARNs , Regiones no Traducidas 3' , Antígeno B7-1/metabolismo , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas , Factores de Transcripción Forkhead/metabolismo , Inmunidad , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Luciferasas/farmacología , MicroARNs/genética , MicroARNs/metabolismo , Células Madre Neoplásicas/metabolismo , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Peripheral nerve injury (PNI) is a clinical problem with high morbidity that can cause severe damage. Surgical suturing or implants are usually required due to the slow speed and numerous factors affecting repair after PNI. An autologous nerve graft is the gold standard for PNI repair among implants. However, there is a potential problem of the functional loss of the donor site. Therefore, tissue-engineered nerve biomaterials are often used to bridge the gap between nerve defects, but the therapeutic effect is insufficient. In order to enhance the repair effect of nerve biomaterials for PNI, researchers are seeking to combine various stimulation elements, such as the addition of biological factors such as nerve growth factors or physical factors such as internal microstructural modifications of catheters and their combined application with physical stimulation therapy. Physical stimulation therapy is safer, is more convenient, and has more practical features than other additive factors. Its feasibility and convenience, when combined with nerve biomaterials, provide broader application prospects for PNI repair, and has therefore become a research hot spot. This paper will review the combined application of physical stimulation and biomaterials in PNI repair in recent years to provide new therapeutic ideas for the future use of physical stimulation in PNI repair.
RESUMEN
OBJECTIVES: To study the effect of self-management intervention programs based on the health belief model and planned behavior theory on self-management behavior and quality of life in middle-aged stroke patients. Most of the intervention studies on the self-management of middle-aged stroke patients focus on traditional Chinese medicine nursing and continuous nursing, lacking theoretical support. In particular, there is a lack of interventions based on the integration of two or more theories. METHOD: The middle-aged stroke patients were divided into the control group and the intervention group according to the disease area. A total of 70 patients were included, and 35 patients were included in the control group and the intervention group, respectively. The control group received routine neurological treatment and health education during hospitalization and continued to receive routine health education for 3 months after discharge. On this basis, the intervention group received an intervention program based on an integrated model of health beliefs and planned behavior theory, including 3 health education sessions during hospitalization and 3 months of postdischarge health education. A self-administered stroke general information questionnaire was used to collect basic information on patients' age, gender, and comorbidities. The Stroke Self-Management Behavior Rating Scale and Stroke-Specific Quality-of-Life Scale (SS-QOL) were used to evaluate the management behavior and quality of life of the patients in both groups before and after the intervention. RESULTS: Before the intervention, there was no statistically significant difference between the two groups in terms of self-management score, quality of life total score, and scores of each dimension (P > 0.05). At different periods after the intervention, the total score of self-management, total score of quality of life, and scores of each dimension were significantly higher in both groups than before the intervention (P < 0.05). In particular, the self-management and quality of life scores of the intervention group were higher than those of the control group at 1 and 3 months after the intervention (P < 0.05). CONCLUSION: The self-management intervention scheme based on the integrated model of health belief and planned behavior theory is beneficial to improve the self-management ability and quality of life of stroke patients. It provides basis for clinical nurses to further improve the self-management ability and quality of life of stroke patients. Our findings may also serve as a reference for caregivers in other countries to improve the self-management and quality of life of stroke patients.
RESUMEN
Ischemic stroke is a severe cerebrovascular disease with high mortality and morbidity. In recent years, reperfusion treatments based on thrombolytic and thrombectomy are major managements for ischemic stroke patients, and the recanalization time window has been extended to over 24 h. However, with the extension of the time window, the risk of ischemia/reperfusion (I/R) injury following reperfusion therapy becomes a big challenge for patient outcomes. I/R injury leads to neuronal death due to the imbalance in metabolic supply and demand, which is usually related to mitochondrial dysfunction. Mitophagy is a type of selective autophagy referring to the process of specific autophagic elimination of damaged or dysfunctional mitochondria to prevent the generation of excessive reactive oxygen species (ROS) and the subsequent cell death. Recent advances have implicated the protective role of mitophagy in cerebral ischemia is mainly associated with its neuroprotective effects in I/R injury. This review discusses the involvement of mitochondria dynamics and mitophagy in the pathophysiology of ischemic stroke and I/R injury in particular, focusing on the therapeutic potential of mitophagy regulation and the possibility of using mitophagy-related interventions as an adjunctive approach for neuroprotective time window extension after ischemic stroke.
RESUMEN
Osteosarcoma is a malignant tumor that often occurs in adolescents and children. Zoledronic acid, a new-generation bisphosphonate, has been widely used as an antitumor drug to inhibit bone metastasis. However, the rapid renal elimination results in low effective concentrations. Meanwhile, high-dose intravenous zoledronic acid administration leads to severe side effects. The present study fabricated an organic-inorganic hybrid nanoparticle as the carrier of zoledronic acid. The rod-like nanoparticle, which had 150-nm length and 40-nm cross-sectional diameter, consisted of a hyaluronic acid/polyethylene glycol (HA-PEG) polymer shell and a nano-hydroxyapatite (nHA) core, with zoledronic acid molecules loading on the surface of nHA and clearance of HA-PEG shell. The nanoparticle was characterized by microscopic analysis, in vitro release study, cytotoxicity analysis, and in vivo immune response examination. Results showed that the compact and stable structure could achieve high drug loading efficiency, sustained drug release, and great biocompatibility. In vitro and in vivo experiments revealed the low cytotoxicity and acceptable immune response under low-dose nanoparticle treatment, indicating its potential application for future osteosarcoma therapeutic strategies.
RESUMEN
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.
Asunto(s)
Trasplante de Células/métodos , Terapia Genética , Distrofia Muscular de Duchenne/terapia , Animales , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologíaRESUMEN
Subarachnoid hemorrhage (SAH) is the most devastating form of stroke. Reducing neuronal apoptosis is an important countermeasure against early brain injury (EBI) after SAH. Recent evidence indicates that OX40-OX40L coupling is critical for cell survival and proliferation. Current study was performed to detect the role of recombinant OX40 (ReOX40) against neuronal apoptosis after SAH. The endovascular perforation model of SAH was performed on Sprague-Dawley (SD) rats. ReOX40 was injected intracerebroventricularly (i.c.v) 1 h after SAH induction and the following methods were employed: neurological function evaluation, immunofluorescence staining, fluoro-Jade C staining, and western blot. To study the underlying precise molecular mechanism, small interfering ribonucleic acid (siRNA) for OX40L and a specific inhibitor of PI3K, LY294002, were injected i.c.v. into SAH + ReOX40 rats before induction of SAH. When compared with sham rats, the expression of OX40 and OX40L was seen to decrease in the brain at 24 h after SAH induction. Administration of ReOX40 (5 µg/kg) increased expression of the OX40L, reduced the neuronal apoptosis, and improved short and long-term neurological function deficits. Furthermore, ReOx40 heightened activation of OX40L/PI3K/AKT axis, increased the downstream anti-apoptotic protein (Bcl2, Bcl-XL), and depressed the apoptotic protein (cleaved caspase 3, Bax). However, the protective effects of ReOX40 were abolished by the administration of OX40L siRNA and LY294002, respectively. These results demonstrate that ReOX40 attenuates neuronal apoptosis through OX40-OX40L/PI3K/AKT pathway in EBI after SAH.
Asunto(s)
Apoptosis/efectos de los fármacos , Neuronas/efectos de los fármacos , Receptores OX40/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/genética , Animales , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Inyecciones Intraventriculares , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteína Oncogénica v-akt/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Interferente Pequeño/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptores OX40/farmacología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Factores de Necrosis TumoralRESUMEN
Osteopontin (OPN) enhances autophagy, reduces apoptosis, and attenuates early brain injury (EBI) after a subarachnoid hemorrhage (SAH). A total of 87 Sprague-Dawley rats were subjected to sham or SAH operations to further investigate the signaling pathway involved in osteopontin-enhanced autophagy during EBI, and the potential effect of recombinant OPN (rOPN) administration to improve long-term outcomes after SAH. Rats were randomly divided into five groups: Sham, SAH + Vehicle (PBS, phosphate-buffered saline), SAH + rOPN (5 µg/rat recombinant OPN), SAH + rOPN + Fib-14 (30 mg/kg of focal adhesion kinase (FAK) inhibitor-14), and SAH + rOPN + DMSO (dimethyl sulfoxide). Short-term and long-term neurobehavior tests were performed, followed by a collection of brain samples for assessment of autophagy markers in neurons, pathway proteins expression, and delayed hippocampal injury. Western blot, double immunofluorescence staining, Nissl staining, and Fluoro-Jade C staining assay were used. Results showed that rOPN administration increased autophagy in neurons and improved neurobehavior in a rat model of SAH. With the administration of FAK inhibitor-14 (Fib-14), neurobehavioral improvement and autophagy enhancement induced by rOPN were abolished, and there were consistent changes in the phosphorylation level of ERK1/2. In addition, early administration of rOPN in rat SAH models improved long-term neurobehavior results, possibly by alleviating hippocampal injury. These results suggest that FAK-ERK signaling may be involved in OPN-enhanced autophagy in the EBI phase after SAH. Early administration of rOPN may be a preventive and therapeutic strategy against delayed brain injury after SAH.
Asunto(s)
Autofagia , Lesiones Encefálicas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Osteopontina/metabolismo , Hemorragia Subaracnoidea/metabolismo , Animales , Modelos Animales de Enfermedad , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Masculino , Osteopontina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/metabolismoRESUMEN
AIM: To determine the effect of osteopontin (OPN) on autophagy and autophagy-apoptosis interactions after SAH. METHODS: The endovascular perforation model of SAH or sham surgery was performed in a total of 86 Sprague-Dawley male rats. The temporal expressions of endogenous OPN and autophagy-related proteins (Beclin 1, ATG5, LC3 II to I ratio) were measured in sham and SAH rats at different time points (3, 6, 12, 24, and 72 hours). Rats were randomly divided into three groups: Sham, SAH + Vehicle (PBS, phosphate-buffered saline), and SAH + rOPN (5 µg/rat recombinant OPN). Neurobehavioral tests were performed 24 hours after SAH, followed by the collection of brain samples for assessment of autophagy and apoptosis proteins. These tests assessed whether an autophagy-apoptosis relationship existed on the histological level in the brain. RESULTS: Endogenous OPN and autophagy-related proteins all increased after SAH. rOPN administration improved neurological dysfunction, increased the expression of autophagy-related proteins (Beclin 1, ATG5, LC3 II to I ratio) and antiapoptotic protein Bcl-2, while decreasing the expression of proapoptotic proteins (cleaved Caspase-3 and Bax). rOPN also regulated autophagy-apoptosis interactions 24 hours after SAH. CONCLUSION: rOPN attenuates early brain injury and inhibits neuronal apoptosis by activating autophagy and regulating autophagy-apoptosis interactions.
Asunto(s)
Apoptosis/fisiología , Autofagia/fisiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/prevención & control , Osteopontina/administración & dosificación , Hemorragia Subaracnoidea/metabolismo , Administración Intranasal , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Lesiones Encefálicas/patología , Masculino , Osteopontina/biosíntesis , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/patologíaRESUMEN
Background and Purpose- Mitoquinone has been reported as a mitochondria-targeting antioxidant to promote mitophagy in various chronic diseases. Here, our aim was to study the role of mitoquinone in mitophagy activation and oxidative stress-induced neuronal death reduction after subarachnoid hemorrhage (SAH) in rats. Methods- Endovascular perforation was used for SAH model of male Sprague-Dawley rats. Exogenous mitoquinone was injected intraperitoneally 1 hour after SAH. ML385, an inhibitor of Nrf2 (nuclear factor-E2-related factor 2), was given intracerebroventricularly 24 hours before SAH. Small interfering RNA for PHB2 (prohibitin 2) was injected intracerebroventricularly 48 hours before SAH. Nuclear, mitochondrial, and cytoplasmic fractions were gathered using nucleus and mitochondria isolation kits. SAH grade evaluation, short- and long- term neurological function tests, oxidative stress, and apoptosis measurements were performed. Pathway related proteins were investigated with Western blot and immunofluorescence staining. Results- Expression of Keap1 (Kelch-like epichlorohydrin-associated protein 1, 2.84× at 24 hours), Nrf2 (2.78× at 3 hours), and LC3II (light chain 3-II; 1.94× at 24 hours) increased, whereas PHB2 (0.46× at 24 hours) decreased after SAH compared with sham group. Mitoquinone treatment attenuated oxidative stress and neuronal death, both short-term and long-term. Administration of mitoquinone resulted in a decrease in expression of Keap1 (0.33×), Romo1 (reactive oxygen species modulator 1; 0.24×), Bax (B-cell lymphoma-2 associated X protein; 0.31×), Cleaved Caspase-3 (0.29×) and an increase in Nrf2 (2.13×), Bcl-xl (B-cell lymphoma-extra large; 1.67×), PINK1 (phosphatase and tensin-induced kinase 1; 1.67×), Parkin (1.49×), PHB2 (1.60×), and LC3II (1.67×) proteins compared with SAH+vehicle group. ML385 abolished the treatment effects of mitoquinone on behavior and protein levels. PHB2 small interfering RNA reversed the outcomes of mitoquinone administration through reduction in protein expressions downstream of PHB2. Conclusions- Mitoquinone inhibited oxidative stress-related neuronal death by activating mitophagy via Keap1/Nrf2/PHB2 pathway after SAH. Mitoquinone may serve as a potential treatment to relieve brain injury after SAH.
Asunto(s)
Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Mitofagia/fisiología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Proteínas Represoras/metabolismo , Transducción de Señal/fisiología , Hemorragia Subaracnoidea/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Masculino , Compuestos Organofosforados/farmacología , Ratas , Ratas Sprague-Dawley , Ubiquinona/análogos & derivados , Ubiquinona/farmacologíaRESUMEN
Bone marrow-derived mesenchymal stem cells (BMSCs) exhibit potential regenerative effects on the injured brain. However, these effects are constrained by their limited ability to migrate to the injured site. Oncostatin M (OSM) has been shown to affect the proliferation and migration of mesenchymal stem cells. Therefore, in the present study, we explored whether OSM improves BMSC migration and secretion of growth factors and cytokines in a rat middle cerebral artery occlusion (MCAO) stroke model. The effect of OSM on the proliferation and apoptosis of rat BMSCs was first assessed in vitro, and the gene and secretion levels of factors related to cell nutrition and migration, such as SDF-1 and VEGF, were detected. To further explore underlying pathways triggered by OSM, BMSCs were treated with OSM in the presence or absence of inhibitors of the STAT3 and ERK pathways. Effects of OSM on SDF-1 expression in astrocytes and BMSC migration were also evaluated. In the rat MCAO model, OSM secretion levels were detected in the brain for up to 72â¯h after model establishment. Ventricle injection of OSM alone or OSM combined with caudal vein graft of BMSCs was then performed in MCAO stroke rats. After 72â¯h, production of SDF-1 and grafted BMSCs was detected in the lesion areas of the brain, and the nerve function score was evaluated. We found that the production of OSM continually increased in the brains of MCAO rats from 12â¯h to 72â¯h. OSM significantly upregulated SDF-1 in BMSCs via the STAT3 and ERK pathways and significantly promoted the expression of VEGF and MMP-2. OSM also promoted the secretion of SDF-1 in astrocytes through the STAT3 and ERK pathways to in turn enhance BMSC migration. Combination treatment with OSM and BMSCs in MCAO rats increased the migration efficiency of BMSCs in the brain, which significantly improved neurofunctional recovery while reducing the expression of inflammatory mediators and promoting the secretion of nutrition factors. Overall, these results show that OSM is highly expressed in the brains of MCAO stroke rats and can upregulate SDF-1 to promote BMSC migration. Thus, combination treatment with OSM and BMSCs improves the graft efficiency of BMSCs and neurofunctional recovery.
Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Quimiocina CXCL12/biosíntesis , Inhibidores de Crecimiento/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Oncostatina M/farmacología , Animales , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Inhibidores de Crecimiento/metabolismo , Inhibidores de Crecimiento/uso terapéutico , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Trasplante de Células Madre Mesenquimatosas , Oncostatina M/metabolismo , Oncostatina M/uso terapéutico , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Factor de Transcripción STAT3/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Neuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles. METHODS: Two hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed. RESULTS: Expression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1ß. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002. CONCLUSIONS: Taken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway.
Asunto(s)
Proteínas Angiogénicas/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Encefalitis/tratamiento farmacológico , Encefalitis/etiología , Transducción de Señal/efectos de los fármacos , Hemorragia Subaracnoidea/complicaciones , Proteínas Angiogénicas/genética , Animales , Barrera Hematoencefálica/fisiología , Edema Encefálico/etiología , Permeabilidad Capilar/efectos de los fármacos , Cromonas/uso terapéutico , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Morfolinas/uso terapéutico , Proteínas del Tejido Nervioso/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/fisiología , Ratas , Ratas Sprague-Dawley , Hemorragia Subaracnoidea/mortalidad , Hemorragia Subaracnoidea/patologíaRESUMEN
Tumor initiating cells or cancer stem cells (CSCs) play an important role in the initiation, development, metastasis, and recurrence of tumors. However, traditional therapies have limited effects against CSCs and targeting these cells is crucial when developing new therapeutic strategies against cancer. One potentially targetable factor is CD47, a member of the immunoglobulin superfamily. This protein acts as an anti-phagocytic "don't eat me" signal and is often found expressed by cancer cells, particularly CSCs. CD47 functions by activating signal regulatory protein-α (SIRP-α) expressed on macrophages, preventing phagocytosis. However, the role of CD47 in glioma stem cells (GSCs) has been not been thoroughly investigated. Our study therefore examined the expression and function of this protein in glioma cells and GSCs. We found that CD47 was highly expressed on glioma cells, especially GSCs, and that expression associated with worse clinical outcomes. We also found that CD47+ glioma cells possessed stem/progenitor cell-like characteristics and knocking down CD47 expression resulted in a reduction in these characteristics. Treatment with anti-CD47 antibody led to increased phagocytosis of glioma cells and GSCs by macrophages. We next examined the effects of anti-CD47 antibody on glioma cells/GSCs in an immune competent mouse glioma model, revealing significant inhibition of tumor growth and prolonged survival times. Importantly, there were no apparent side effects in the animal model. In summary, we have shown that CD47 is a potentially safe and effective therapeutic target for glioma.
RESUMEN
Neuronal apoptosis is considered to be a crucial therapeutic target against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that Exendin-4 (Ex-4), a glucagon-like peptide 1 receptor (GLP-1R) agonist, plays a neuroprotective role in cerebrovascular disease. This study was conducted in order to verify the neuroprotective role of EX-4 in EBI after SAH in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats (n = 153). Ex-4 was intraperitoneally injected 1 h after SAH induction in the rats (SAH + Ex-4). To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and a specific inhibitor of PI3K, LY294002, were injected intracerebroventricularly into SAH + Ex-4 rats before induction of SAH (n = 6 per group). SAH grading evaluation, immunohistochemistry, Western blots, neurobehavioral assessment, and Fluoro-Jade C (FJC) staining experiments were performed. Expression of GLP-1R was significantly increased and mainly expressed in neurons at 24 h after SAH induction. Administration of Ex-4 significantly improved both short- and long-term neurobehavior in SAH + Ex-4 group compared to SAH + Vehicle group after SAH. Ex-4 treatment significantly increased the expression of GLP-1R, PI3K, p-Akt, Bcl-xl, and Bcl-2, while at the same time was found to decrease expression of Bax in the brain. Effects of Ex-4 were reversed by the intervention of GLP-1R siRNA and LY294002 in SAH + Ex-4+GLP-1R siRNA and SAH + Ex-4+LY294002 groups, respectively. In conclusion, the neuroprotective effect of Ex-4 in EBI after SAH was mediated by attenuation of neuronal apoptosis via GLP-1R/PI3K/Akt signaling pathway, therefore EX-4 should be further investigated as a potential therapeutic agent in stroke patients.
Asunto(s)
Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/etiología , Péptido 1 Similar al Glucagón/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Péptidos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Hemorragia Subaracnoidea/complicaciones , Ponzoñas/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Lesiones Encefálicas/patología , Proteínas de Unión al Calcio/metabolismo , Cromonas/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Exenatida , Péptido 1 Similar al Glucagón/genética , Inyecciones Intraventriculares , Masculino , Proteínas de Microfilamentos/metabolismo , Morfolinas/farmacología , Proteínas del Tejido Nervioso/metabolismo , Proteína Oncogénica v-akt/metabolismo , Péptidos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Ponzoñas/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway. METHODS: SAH was induced by endovascular perforation in male Sprague-Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKIIα (calcium/calmodulin-dependent protein kinase II α) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short- and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed. RESULTS: DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKIIα and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIα, p-TAK1 (phosphorylated transforming growth factor-ß-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIα small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH. CONCLUSIONS: DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteínas de Membrana de los Lisosomas/metabolismo , Lisosomas/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Hemorragia Subaracnoidea/tratamiento farmacológico , Ácido Tióctico/análogos & derivados , Animales , Lisosomas/patología , Masculino , Ratas , Ratas Sprague-Dawley , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/patología , Ácido Tióctico/farmacologíaRESUMEN
Mesenchymal stem cell (MSC) transplantation is a promising therapeutic strategy for myocardial infarction. The survival rate of the grafted MSCs is limited by the conditions of hypoxia and low nutrient levels. In this study, we investigated the role of hypoxia-inducible factor 1 alpha (Hif-1α) in oxygen-glucose deprivation (OGD)-induced injury in MSCs. Hif-1α was overexpressed or suppressed in MSCs by transfection with a Hif-1α expressing vector or Hif-1α-specific siRNA, respectively. Then MSCs were exposed to OGD, and the changes in cell viability, cell cycle distribution and apoptosis were respectively monitored by MTT assay and flow cytometry. Additionally, expression levels of Beclin1, LC3 I and LC3 II, as well phosphorylation of PI3K, AKT and mTOR were detected by RT-PCR and Western blotting. The results indicated that Hif-1α overexpression improved cell viability, reduced G1 phase cells accumulation, and suppressed apoptosis under OGD condition (P<0.05). Beclin1 expression and the LC3 II/LC3 I ratio were increased by Hif-1α overexpression, and were decreased by Hif-1α knock-down (P<0.05). In addition, PI3K, AKT and mTOR were inactivated by Hif-1α overexpression, and phosphorylated by Hif-1α knock-down (P<0.05). In conclusion, these data suggest that Hif-1α overexpression protects MSCs from OGD-induced injury via a mechanism in which autophagy and PI3K/AKT/mTOR pathway are implicated.