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Intervertebral disc (IVD) degeneration (IVDD) is usually accompanied by nucleus pulposus (NP) fibrosis and pathologic angiogenesis, which are possibly associated with macrophage infiltration. Previous research indicates a destructive role of macrophages and the protective effect of inhibiting heat shock protein 90 (HSP90) in IVDD. Herein, the effects of inhibiting HSP90 on NP fibrosis and pathologic angiogenesis induced by macrophages were investigated further. Single-cell RNA-sequencing analysis was used to classify fibrotic NP cell (NPC) clusters and healthy NPC clusters in human NP tissues. The fibrotic NPC clusters were possibly associated with angiogenesis-related biological processes. Immunostaining showed the spatial association between blood vessel ingrowth and macrophage infiltration, as well as elevated levels of cell migration-inducing protein (CEMIP) and vascular endothelial growth factor A in severely degenerated human IVD tissues. Particularly, HSP90 inhibitor tanespimycin (17-AAG) ameliorated macrophage-induced fibrotic phenotype of NPCs via inhibiting CEMIP. M2, but not M1, macrophages promoted the pro-angiogenic ability of endothelial cells, which was attenuated by 17-AAG or HSP90 siRNA. Reversing the fibrotic phenotype of NPCs by Cemip siRNA also mitigated the pro-angiogenic effects of M2-conditioned medium-treated NPCs. Moreover, the murine IVDD model supported the 17-AAG-induced amelioration of NP fibrosis and endothelial cell invasion in IVD tissues. In conclusion, inhibiting HSP90 attenuated two interrelated pathologic processes, NP fibrosis and pathologic angiogenesis, induced by macrophages via down-regulating CEMIP.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Ratones , Animales , Núcleo Pulposo/metabolismo , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales/metabolismo , Movimiento Celular , Proteínas de Choque Térmico , Neovascularización Patológica/patología , Macrófagos/metabolismo , Fibrosis , ARN Interferente Pequeño/metabolismoRESUMEN
Lower back pain (LBP) is a common condition closely associated with intervertebral disc degeneration (IDD), causing a significant socioeconomic burden. Inflammatory activation in degenerated discs involves pro-inflammatory cytokines, dysregulated regulatory cytokines, and increased levels of nerve growth factor (NGF), leading to further intervertebral disc destruction and pain sensitization. Macrophage polarization is closely related to autophagy. Based on these pathological features, a structured biomimetic nanoparticle coated with TrkA-overexpressing macrophage membranes (TMNP@SR) with a rapamycin-loaded mesoporous silica core is developed. TMNP@SR acted like sponges to adsorbe inflammatory cytokines and NGF and delivers the autophagy regulator rapamycin (RAPA) into macrophages through homologous targeting effects of the outer engineered cell membrane. By regulating autophagy activation, TMNP@SR promoted the M1-to-M2 switch of macrophages to avoid continuous activation of inflammation within the degenerated disc, which prevented the apoptosis of nucleus pulposus cells. In addition, TMNP@SR relieved mechanical and thermal hyperalgesia, reduced calcitonin gene-related peptide (CGRP) and substance P (SP) expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat IDD model. In summary, TMNP@SR spontaneously inhibits the aggravation of disc inflammation to alleviate disc degeneration and reduce the ingress of sensory nerves, presenting a promising treatment strategy for LBP induced by disc degeneration.
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Autofagia , Degeneración del Disco Intervertebral , Nanopartículas , Ratas Sprague-Dawley , Degeneración del Disco Intervertebral/tratamiento farmacológico , Degeneración del Disco Intervertebral/metabolismo , Animales , Autofagia/efectos de los fármacos , Nanopartículas/química , Ratas , Masculino , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Dolor de la Región Lumbar/tratamiento farmacológico , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Sirolimus/farmacología , Dióxido de Silicio/química , Dióxido de Silicio/farmacología , Núcleo Pulposo/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo , Biomimética/métodos , Modelos Animales de Enfermedad , Factor de Crecimiento Nervioso/metabolismo , Células RAW 264.7RESUMEN
The combination of neoadjuvant chemotherapy and surgery has been promoted for the treatment of osteosarcoma; however, the local recurrence and lung metastasis rates remain high. Therefore, it is crucial to explore new therapeutic targets and strategies that are more effective. The NOTCH pathway is not only involved in normal embryonic development but also plays an important role in the development of cancers. The expression level and signaling functional status of the NOTCH pathway vary in different histological types of cancer as well as in the same type of cancer from different patients, reflecting the distinct roles of the Notch pathway in tumorigenesis. Studies have reported abnormal activation of the NOTCH signaling pathway in most clinical specimens of osteosarcoma, which is closely related to a poor prognosis. Similarly, studies have reported that NOTCH signaling affected the biological behavior of osteosarcoma through various molecular mechanisms. NOTCH-targeted therapy has shown potential for the treatment of osteosarcoma in clinical research. After the introduction of the composition and biological functions of the NOTCH signaling pathway, the review paper discussed the clinical significance of dysfunction in osteosarcoma. Then the paper reviewed the recent relevant research progress made both in the cell lines and in the animal models of osteosarcoma. Finally, the paper explored the potential of the clinical application of NOTCH-targeted therapy for the treatment of osteosarcoma.
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BACKGROUND: Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15-19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported. METHODS: After HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51. RESULTS: HMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway. CONCLUSION: HMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma.
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Neoplasias Óseas , Osteosarcoma , Humanos , Adolescente , Reparación del ADN por Recombinación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Recombinasa Rad51/farmacología , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Proliferación CelularRESUMEN
Nucleus pulposus stem cells (NPSCs) senescence plays a critical role in the progression of intervertebral disc degeneration (IDD). Stem cell-derived extracellular vesicles (EV) alleviate cellular senescence. Whereas, the underlying mechanism remains unclear. Low stability largely limited the administration of EV in vivo. RGD, an arginine-glycine-aspartic acid tripeptide, strongly binds integrins expressed on the EV membranes, allowing RGD to anchor EV and prolong their bioavailability. An RGD-complexed nucleus pulposus matrix hydrogel (RGD-DNP) is developed to enhance the therapeutic effects of small EV (sEV). RGD-DNP prolonged sEV retention in vitro and ex vivo. sEV-RGD-DNP promoted NPSCs migration, decreased the number of SA-ß-gal-positive cells, alleviated cell cycle arrest, and reduced p16, p21, and p53 activation. Small RNA-seq showed that miR-3594-5p is enriched in sEV, and targets the homeodomain-interacting protein kinase 2 (HIPK2)/p53 pathway. The HIPK2 knockdown rescues the impaired therapeutic effects of sEV with downregulated miR-3594-5p. RGD-DNP conjugate with lower amounts of sEV achieved similar disc regeneration with free sEV of higher concentrations in DNP. In conclusion, sEV-RGD-DNP increases sEV bioavailability and relieves NPSCs senescence by targeting the HIPK2/p53 pathway, thereby alleviating IDD. This work achieves better regenerative effects with fewer sEV and consolidates the theoretical basis for sEV application for IDD treatment.
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Degeneración del Disco Intervertebral , MicroARNs , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Degeneración del Disco Intervertebral/terapia , Degeneración del Disco Intervertebral/metabolismo , Matriz Extracelular/metabolismo , MicroARNs/genética , Oligopéptidos , Regeneración , Proteínas Portadoras , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
The epithelial-to-mesenchymal transition (EMT) is a reversible process that may interact with tumour immunity through multiple approaches. There is increasing evidence demonstrating the interconnections among EMT-related processes, the tumour microenvironment, and immune activity, as well as its potential influence on the immunotherapy response. Long non-coding RNAs (lncRNAs) are emerging as critical modulators of gene expression. They play fundamental roles in tumour immunity and act as promising biomarkers of immunotherapy response. However, the potential roles of lncRNA in the crosstalk of EMT and tumour immunity are still unclear in sarcoma. We obtained multi-omics profiling of 1440 pan-sarcoma patients from 19 datasets. Through an unsupervised consensus clustering approach, we categorised EMT molecular subtypes. We subsequently identified 26 EMT molecular subtype and tumour immune-related lncRNAs (EILncRNA) across pan-sarcoma types and developed an EILncRNA signature-based weighted scoring model (EILncSig). The EILncSig exhibited favourable performance in predicting the prognosis of sarcoma, and a high-EILncSig was associated with exclusive tumour microenvironment (TME) characteristics with desert-like infiltration of immune cells. Multiple altered pathways, somatically-mutated genes and recurrent CNV regions associated with EILncSig were identified. Notably, the EILncSig was associated with the efficacy of immune checkpoint inhibition (ICI) therapy. Using a computational drug-genomic approach, we identified compounds, such as Irinotecan that may have the potential to convert the EILncSig phenotype. By integrative analysis on multi-omics profiling, our findings provide a comprehensive resource for understanding the functional role of lncRNA-mediated immune regulation in sarcomas, which may advance the understanding of tumour immune response and the development of lncRNA-based immunotherapeutic strategies for sarcoma.
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ARN Largo no Codificante , Sarcoma , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , ARN Largo no Codificante/genética , Sarcoma/genética , Sarcoma/terapia , Microambiente Tumoral/genéticaRESUMEN
Intervertebral disc (IVD) degeneration (IVDD) is the most common spinal disorder, which can lead to the symptoms of neck pain or low back pain. In healthy mature IVD tissues, extracellular matrix (ECM) complex possesses favorable biochemical and biomechanical properties, withstanding compression and torsion forces. IVD cells and ECM associate with each other to form a coordinated functional system. IVD cells are the main producers of ECM components, while ECM could modulate the viability and phenotype of IVD cells via direct interactions or indirect regulations. However, with the process of IVDD and ageing, ECM of IVD undergoes content loss and structure degeneration. Moreover, the accumulation of catabolic products may further deteriorate the IVD microenvironment. A better understanding of the physiology and the pathology of ECM within the IVD provides new insight into potential IVD regeneration strategies. Natural ECM components, functional motifs, or mimetic peptides are widely used in IVD repair by not only restoring structural support but also regulating cell fate and tissue microenvironment. Herein, we reviewed recent advances in the involvement of ECM in IVD health and disease, with an emphasis on ECM composition and organization, cell-matrix interactions, pathological ECM degradation, and promising matrix-based biomaterials for IVD regeneration.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , Materiales Biocompatibles , Matriz Extracelular/metabolismo , Humanos , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/patología , Dolor de la Región Lumbar/patologíaRESUMEN
Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX-/- mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1ß, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX-/- mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.
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Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Dolor de la Región Lumbar/tratamiento farmacológico , Osteogénesis/efectos de los fármacos , Resveratrol/farmacología , Sirtuina 1/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Ansiedad/metabolismo , Conducta Animal/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Dolor de la Región Lumbar/metabolismo , Masculino , Ratones Endogámicos C57BL , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismoRESUMEN
Osteosarcoma (OS) is a malignant solid tumor prone to lung metastasis that occurs in adolescents aged 15-19 years. Neoadjuvant chemotherapy and surgical treatment aimed at curing OS have gained limited progress over the last 30 years. Exploring new effective second-line therapies for OS patients is a serious challenge for researchers. Quercetin, a multiple biologically active polyphenolic flavonoid, has been used in tumor therapy. However, the exact mechanism of quercetin is still unknown, which limits the application of quercetin. In the current study, we found that quercetin could inhibit JAK2 through the JH2 domain in a non-covalent manner, resulting in the inhibition of OS proliferation and immune escape via the JAK2-STAT3-PD-L1 signaling axis. More importantly, to overcome the shortcomings of quercetin, including low water solubility and low oral availability, we encapsulated it with folic acid-modified liposomes. The transportation of quercetin by folic acid-modified liposomes may provide a feasible strategy to cure OS.
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Neoplasias Óseas , Osteosarcoma , Adolescente , Antígeno B7-H1/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Línea Celular Tumoral , Proliferación Celular , Ácido Fólico , Humanos , Janus Quinasa 2/metabolismo , Liposomas/farmacología , Liposomas/uso terapéutico , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Quercetina/farmacología , Quercetina/uso terapéutico , Factor de Transcripción STAT3/metabolismoRESUMEN
BACKGROUND: Diabetic foot ulcer (DFU), persistent hyperglycemia and inflammation, together with impaired nutrient and oxygen deficiency, can present abnormal angiogenesis following tissue injury such that these tissues fail to heal properly. It is critical to design a new treatment method for DFU patients with a distinct biomechanism that is more effective than current treatment regimens. METHOD: Graphene oxide (GO) was combined with a biocompatible polymer as a kind of modified GO-based hydrogel. The characterization of our biomaterial was measured in vitro. The repair efficiency of the biomaterial was evaluated in the mouse full-skin defect models. The key axis related to diabetic wound (DW) was identified and investigated using bioinformatics analyses and practical experiments. RESULT: In the study, we found that our modified GO-based wound dressing material is a promising option for diabetic wound. Secondly, our biomaterial could enhance the secretion of small EVs (sEVs) with more miR-21 by adipose-derived mesenchymal stem cells (AD-MSCs). Thirdly, the PVT1/PTEN/IL-17 axis was found to be decreased to promote DFU wound healing by modifying miR-21 with the discovery of PVT1 as a critical LncRNA by bioinformatics analysis and tests. CONCLUSION: These findings could aid in the development of clinical care strategies for DFU wounds.
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Diabetes Mellitus , Pie Diabético , MicroARNs/genética , Animales , Materiales Biocompatibles/farmacología , Modelos Animales de Enfermedad , Grafito , Interleucina-17 , Ratones , Fosfohidrolasa PTEN/metabolismo , ARN Largo no Codificante/metabolismo , Cicatrización de HeridasRESUMEN
BACKGROUND Open distal humeral fractures (DHFs) often lead to loss of elbow function, thereby seriously affecting patient quality of life. The aim of this study was to evaluate the treatment outcomes of 2 surgical techniques to determine the better method for repairing open DHFs. Both groups were treated with immediate debridement first, and then group I had only internal fixation (IF), while group II underwent initial external fixation (EF) followed by IF surgery. MATERIAL AND METHODS This retrospective study included 32 patients who had open DHFs between 2013 and 2018. Twelve patients underwent thorough debridement and temporary EF treatment and converted to IF as the ultimate treatment. Twenty patients were treated with immediate open reduction and internal fixation (ORIF). Data of final treatment outcomes were analyzed at the latest follow-up. A comparative analysis of radiological results, function observations, and complications was performed for the 2 surgical groups. RESULTS All DHFs and osteotomized olecranon united after a mean of 5.2±1.21 months. No significant differences were observed in other preoperative demographic data between the 2 groups. Moreover, there was no significant difference in postoperative complications, elbow range of motion, or fracture healing time between the 2 groups. CONCLUSIONS The evidence provided by our study highlights the efficacy of definitive IF in treating open DHFs, which is recommended whenever possible. Furthermore, the combination of EF and ORIF, according to the type of soft tissue damage, may be a promising treatment option with a low revision rate for patients with open DHFs.
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Articulación del Codo/fisiopatología , Fijación Interna de Fracturas/métodos , Curación de Fractura , Fracturas del Húmero/cirugía , Reducción Abierta/métodos , Calidad de Vida , Rango del Movimiento Articular/fisiología , Adulto , Articulación del Codo/diagnóstico por imagen , Articulación del Codo/cirugía , Femenino , Humanos , Fracturas del Húmero/diagnóstico , Masculino , Radiografía , Estudios RetrospectivosRESUMEN
c-Jun activation domain-binding protein-1 (Jab1) is aberrantly overexpressed in multiple cancers and plays an oncogenic role in cancer progression. We examined the association between Jab1 expression and prognosis in patients with cancer by conducting a meta-analysis. A comprehensive search strategy was performed using the PubMed, Web of Science, Ovid and EMBASE in July 2020. Eligible studies were enrolled according to definite criteria. Twenty-seven studies involving 2609 patients were enrolled in this meta-analysis. A significant association between high Jab1 expression and poor overall survival (pooled hazard ratio [HR] 2.344, 95% confidence interval [CI]: 2.037-2.696) was observed. Subgroup analyses of the type of cancer, sample size, follow-up period, Jab1 detection method and preoperative treatment did not alter the significance. On pooling data from Cox multivariate analyses, high Jab1 expression was found to be an independent prognostic indicator for overall survival. In addition, high Jab1 expression was found to be associated with advanced clinicopathological features such as clinical stage, lymphatic metastasis, histological grade and distant metastasis in cancers. Our meta-analysis is the first to demonstrate that high Jab1 expression may be a promising indicator of poor prognosis and has an independent prognostic value for overall survival in patients with cancer.
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Complejo del Señalosoma COP9/genética , Complejo del Señalosoma COP9/metabolismo , Susceptibilidad a Enfermedades , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Humanos , Estadificación de Neoplasias , Neoplasias/mortalidad , Neoplasias/patología , Pronóstico , Modelos de Riesgos Proporcionales , Sesgo de PublicaciónRESUMEN
Cadmium (Cd), a type of heavy metal that accumulates in the body because of smoking, mediates the toxic effect of smoking in many diseases, such as cardiovascular disease, osteoarthritis, and osteoporosis. However, the toxic effect of Cd on intervertebral disc tissues have not been reported. In the current study, we demonstrated that Cd induced the apoptosis of annulus fibrosus (AF) cells, which contributed to intervertebral disc degeneration (IVDD). Specifically, Cd induced the nuclear translocation of FoxO1a, which drives AF cells apoptosis through mitochondrial-related pathway. Phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signal pathway is also involved in this process. The combined use of LY29002, an inhibitor of PI3K, and small interfering RNA-targeting FoxO1a confirmed the relationship between the PI3K/AKT signal pathway and FoxO1a. In summary, present research explores the mechanism behind the contribution of smoking to IVDD and finds a new feasible target for preventing IVDD in smoking.
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Anillo Fibroso/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fumar/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Cadmio/farmacología , Disco Intervertebral/metabolismo , Mitocondrias/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
MicroRNAs and sirtuins are important epigenetic regulators of gene expression and both contribute significantly to postnatal vascular development. However, the crosstalk between miRNAs and sirtuins in the modulation of angiogenesis has rarely been discussed. Here, we investigated the interactions between miR-138 and sirtuins in the process of angiogenesis. We found that overexpression of miR-138 markedly suppressed the proliferation, migration, and tube-forming capacities of the endothelial cells. And, miR-138 inhibitor-treated endothelial cells showed a reversed phenotype. Furthermore, miR-138 plays a negative role in vascular development in vivo. Western blot and qPCR assays demonstrated that SIRT1 was silenced by miR-138, and a luciferase reporter assay showed that miR-138 bound to the 3'-UTR of SIRT1. The re-expression of SIRT1 alleviated miR-138-mediated suppression of angiogenesis. Furthermore, silencing SIRT1 could boost the level of miR-138. And, upon miR-138 inhibitor treatment, SIRT1 silencing no longer reduced the angiogenic ability of endothelial cells significantly. These results demonstrated that the circuitry involving miR-138 and SIRT1 may participate in vascular homeostasis and also offered the possibility of identifying a new approach in the treatment of angiogenic diseases.
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The endogenous repair failure of degenerated intervertebral disk (IVD) is highly related to the exhaustion of nucleus pulposus stem cells (NPSCs). Excessive oxidative stress could induce apoptosis and senescence of NPSCs, thus, declining the quantity and quality of NPSCs. Heat shock protein 70 (HSP70) is a family of cytoprotective and antioxidative proteins. However, there is no report on the protective effects of HSP70 on oxidative stress-induced NPSC impairments and underlying mechanisms. In the present study, we treated NPSCs with tert-butyl hydroperoxide (t-BHP) in vitro to simulate an oxidative stress condition. HSP70 inducer TRC051384 was used to evaluate the cytoprotective effects of HSP70. The results suggested that HSP70 impeded t-BHP-mediated cell viability loss and protected the ultrastructure of NPSCs. Moreover, t-BHP could induce mitochondrial apoptosis and p53/p21-mediated senescence of NPSCs, both of which were significantly inhibited in HSP70 activation groups. Excessive oxidative stress and mitochondrial dysfunction reinforced each other and contributed to the cellular damage processes. HSP70 decreased reactive oxygen species (ROS) production, rescued mitochondrial membrane potential (MMP) collapse, and blocked ATP depletion. Finally, our data showed that HSP70 downregulated the JNK/c-Jun pathway. Taken together, activation of HSP70 could protect against t-BHP-induced NPSC apoptosis and senescence, thus, improving the quantity and quality of NPSCs. Therefore, HSP70 may be a promising therapeutic target for IVD degeneration.
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Apoptosis/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Núcleo Pulposo/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/metabolismo , terc-Butilhidroperóxido/farmacología , Células Cultivadas , HumanosRESUMEN
Purpose: Reactive oxygen species (ROS) are related to compression stress-induced nucleus pulposus (NP) cell autophagy, but the specific mechanism is unknown in compression stress-induced intervertebral disc degeneration (IVDD). Here, we discuss the specific molecular mechanism and explore whether ROS scavengers could be employed as specific drugs to inhibit compression stress-induced IVDD.Methods: Rat NP cells were exposed to 1.0 MPa compression and pretreatment with the ROS scavenger N-acetylcysteine (NAC) or the JNK-selective inhibitor SP600125 not. Intracellular ROS production was monitored by confocal microscopy. Autophagy was detected by observing the NP cell ultrastructural features using TEM and examining autophagic vacuoles by flow cytometry. The levels of autophagy-associated molecules, the JNK pathway and the PI3K/AKT/mTOR pathway were analyzed by western blotting.Results: Compression-mediated autophagy in rat NP cells was implicated in ROS generation. The ROS scavenger NAC could protect compression-induced NP cell injures by inhibiting ROS production. And SP600125, a JNK inhibitor, attenuated compression-induced NP cell autophagy. Additionally, this is the first report showing that compression induces autophagy in rat NP cells by impeding the compression-induced ROS dependent PI3K/AKT/mTOR pathway and the ROS independent activation of JNK pathway. And the involvement of JNK pathway was in different mechanism of action that when inhibited leaded to increased cell death, increased generation of ROS but decreased autophagy.Conclusions: These results show a new regulatory mechanism involving ROS-mediated autophagy in rat NP cells, which may provide ideas for drug development to improve compression stress-induced IVDD and help avoid eventual surgical treatment of IVD herniation.
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Degeneración del Disco Intervertebral , Núcleo Pulposo , Animales , Apoptosis , Autofagia , Degeneración del Disco Intervertebral/tratamiento farmacológico , Degeneración del Disco Intervertebral/metabolismo , Sistema de Señalización de MAP Quinasas , Núcleo Pulposo/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Although lower temperature (< 45 °C) photothermal therapy (LPTT) have attracted enormous attention in cancer therapy, the therapeutic effect is still unsatisfying when applying LPTT alone. Therefore, combining with other therapies is urgently needed to improve the therapeutic effect of LPTT. Recently reported oxygen-irrelevant free radicals based thermodynamic therapy (TDT) exhibit promising potential for hypoxic tumor treatment. However, overexpression of glutathione (GSH) in cancer cells would potently scavenge the free radicals before their arrival to the specific site and dramatically diminish the therapeutic efficacy. METHODS AND RESULTS: In this work, a core-shell nanoplatform with an appropriate size composed of arginine-glycine-aspartate (RGD) functioned polydopamine (PDA) as a shell and a triphenylphosphonium (TPP) modified hollow mesoporous manganese dioxide (H-mMnO2) as a core was designed and fabricated for the first time. This nanostructure endows a size-controllable hollow cavity mMnO2 and thickness-tunable PDA layers, which effectively prevented the pre-matured release of encapsulated azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIBI) and revealed pH/NIR dual-responsive release performance. With the mitochondria-targeting ability of TPP, the smart nanocomposites (AIBI@H-mMnO2-TPP@PDA-RGD, AHTPR) could efficiently induce mitochondrial associated apoptosis in cancer cells at relatively low temperatures (< 45 °C) via selectively releasing oxygen-irrelevant free radicals in mitochondria and facilitating the depletion of intracellular GSH, exhibiting the advantages of mitochondria-targeted LPTT/TDT. More importantly, remarkable inhibition of tumor growth was observed in a subcutaneous xenograft model of osteosarcoma (OS) with negligible side effects. CONCLUSIONS: The synergistic therapy efficacy was confirmed by effectively inducing cancer cell death in vitro and completely eradicating the tumors in vivo. Additionally, the excellent biosafety and biocompatibility of the nanoplatforms were confirmed both in vitro and in vivo. Taken together, the current study provides a novel paradigm toward oxygen-independent free-radical-based cancer therapy, especially for the treatment of hypoxic solid tumors.
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Radicales Libres , Nanopartículas del Metal/química , Mitocondrias , Sistema de Administración de Fármacos con Nanopartículas , Terapia Fototérmica , Animales , Compuestos Azo/química , Línea Celular Tumoral , Frío , Femenino , Radicales Libres/análisis , Radicales Libres/metabolismo , Humanos , Imidazoles/química , Compuestos de Manganeso/química , Ratones , Ratones Desnudos , Mitocondrias/química , Mitocondrias/metabolismo , Óxidos/químicaRESUMEN
BACKGROUND: Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy. METHODS AND RESULTS: A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica-coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice. CONCLUSION: All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.
Asunto(s)
Alcaloides de Amaryllidaceae/farmacología , Oro/química , Nanocompuestos/química , Neoplasias/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Fenantridinas/farmacología , Animales , Materiales Biocompatibles , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico , Ácido Fólico , Humanos , Ratones , Microscopía Fluorescente , Mitocondrias , Nanocompuestos/uso terapéutico , Neoplasias/patología , Osteosarcoma , Especies Reactivas de Oxígeno , Dióxido de SilicioRESUMEN
OBJECTIVE: We focus on providing the first comprehensive national dataset on the incidence, injury aetiology and mortality of TSCI in China. METHODS: A multi-stage stratified cluster sampling method was used. We included TSCI cases from all hospitals in three regions, nine provinces and 27 cities in China via search of electronic medical records and retrospectively analysed the characteristics of TSCI in China from 2009 to 2018. We estimated the incidence of TSCI in the total population and subgroups. RESULTS: There were 5954 actual cases in 2009, corresponding to a total estimated TSCI incidence of 45.1 cases per million population (95% CI, 44.0-46.3). There were 10,074 actual cases in 2018, corresponding to a total estimated TSCI incidence of 66.5 cases per million population (95% CI, 65.2-67.8) (P < 0.001; annual average percentage change (AAPC), 4.4%). From 2009 to 2018, the incidence of almost all sex/age groups showed an increasing trend over time (P < 0.001; AAPC, 0.7-8.8%). The elderly population (aged 65-74) displayed the highest incidence of TSCI (with an average annual incidence of 127.1 cases per million [95% CI, 119.8-134.3]). CONCLUSIONS: The TSCI incidence increased significantly from 2009 to 2018. The incidence in the elderly populations was consistently high and continues to increase over time. The mortality of TSCI patients in hospitals is relatively low and continues to decrease each year, but elderly individuals remain at a high risk of hospital death.
Asunto(s)
Traumatismos de la Médula Espinal , Anciano , China/epidemiología , Humanos , Incidencia , Proyectos de Investigación , Estudios Retrospectivos , Traumatismos de la Médula Espinal/epidemiologíaRESUMEN
PURPOSE: To investigate the indications, approaches, resection methods, and complications of total sacrectomy with a combined antero-posterior approach for malignant sacral tumours. METHODS: Fourteen cases of primary malignant sacral tumours treated with total sacrectomy between January 2012 and 2018 were retrospectively analysed. All patients presented with pre-operative lumbosacral pain or constipation. A combined antero-posterior approach was used for tumour resection, and the spinal pedicle screw rod system was used to achieve ilio-lumbar stability. The visual analogue scale (VAS) and Musculoskeletal Tumor Society (MSTS) scores were used to assess pain and lower limb function, respectively. The mean operative time and intra-operative blood loss were 6.54 hours and 2935 mL, respectively. The mean follow-up period was 62 months. RESULTS: None of the patients died peri-operatively. At the last follow-up, ten patients were continuously disease-free, three were alive with disease, and one died of disease from lung metastasis. Tumour recurrence occurred in three patients. The MSTS scores ranged from 6 to 28 (20.00-93.33%, 6/30-28/30) with an average of 20 (66.67%, 20/30). Seven patients could walk independently in public, five could only walk at home using a walking aid, and two could only lie down and stand for a short time. Thirteen patients developed post-operative complications such as skin necrosis, screw loosening, connecting rod fracture, neuropathic pain, sciatic nerve injury, dysuria, and urinary incontinence. CONCLUSION: Total sacrectomy can effectively treat malignant sacral tumours with good resection boundaries and prognosis. However, the high incidence of post-operative complications may impact post-operative neurological function.