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Limited success has been achieved in ferroptosis-induced cancer treatment due to the challenges related to low production of toxic reactive oxygen species (ROS) and inherent ROS resistance in cancer cells. To address this issue, a self-assembled nanodrug have been investigated that enhances ferroptosis therapy by increasing ROS production and reducing ROS inhibition. The nanodrug is constructed by allowing doxorubicin (DOX) to interact with Fe2+ through coordination interactions, forming a stable DOX-Fe2+ chelate, and this chelate further interacts with sorafenib (SRF), resulting in a stable and uniform nanoparticle. In tumor cells, overexpressed glutathione (GSH) triggers the disassembly of nanodrug, thereby activating the drug release. Interestingly, the released DOX not only activates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) to produce abundant H2O2 production for enhanced ROS production, but also acts as a chemotherapeutics agent, synergizing with ferroptosis. To enhance tumor selectivity and improve the blood clearance, the nanodrug is coated with a related cancer cell membrane, which enhances the selective inhibition of tumor growth and metastasis in a B16F10 mice model. Our findings provide valuable insights into the rational design of self-assembled nanodrug for enhanced ferroptosis therapy in cancer treatment. STATEMENT OF SIGNIFICANCE: Ferroptosis is a non-apoptotic form of cell death induced by the iron-regulated lipid peroxides (LPOs), offering a promising potential for effective and safe anti-cancer treatment. However, two significant challenges hinder its clinical application: 1) The easily oxidized nature of Fe2+ and the low concentration of H2O2 leads to a low efficiency of intracellular Fenton reaction, resulting in poor therapeutic efficacy; 2) The instinctive ROS resistance of cancer cells induce drug resistance. Therefore, we developed a simple and high-efficiency nanodrug composed of self-assembling by Fe2+ sources, H2O2 inducer and ROS resistance inhibitors. This nanodrug can effectively deliver the Fe2+ sources into tumor tissue, enhance intracellular concentration of H2O2, and reduce ROS resistance, achieving a high-efficiency, precise and safe ferroptosis therapy.
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Antineoplásicos , Doxorrubicina , Ferroptose , Nanopartículas , Espécies Reativas de Oxigênio , Animais , Ferroptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Doxorrubicina/química , Nanopartículas/química , Humanos , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Sinergismo FarmacológicoRESUMO
The process of wound healing includes the inflammatory stage, which plays an important role. Macrophages can promote inflammatory response and also promote angiogenesis, wound contraction and tissue remodeling required for wound healing. It is crucial to promote macrophages to polarize from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype at a critical time for the quality of wound healing. Because mesenchymal stem cell-derived exosomes have broad therapeutic prospects in the field of tissue repair and regeneration, in this study, we explored whether trichostatin A pretreated bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (T-Exo) could promote wound healing by binding to biomaterial scaffolds through certain anti-inflammatory effects. In the cell experiment, we established macrophage inflammation model and then treated with T-Exo, and finally detected the expression levels of macrophage polarization proteins CD206, CD86 and TNF-α, iNOS, and Arg-1 by Western Blot and immunofluorescence staining; detected the expression levels of inflammation-related genes TNF-α, iNOS, IL-1ß, IL-10 and anti-inflammatory genes CD206 and Arg-1 by qRT-PCR; explored the promoting ability of T-Exo to promote cell migration and tube formation by cell scratch experiment and angiogenesis experiment. The results showed that T-Exo could promote the polarization of M1 macrophages to M2 macrophages, and promote the migration and angiogenesis of HUVECs. Because TSA pretreatment may bring about changes in the content and function of BMSCs-derived exosomes, proteomic analysis was performed on T-Exo and unpretreated BMSCs-derived exosomes (Exo). The results showed that the differentially expressed proteins in T-Exo were related to some pathways that promote angiogenesis, cell migration, proliferation, and re-epithelialization. Then, exosome/collagen sponge (T-Exo/Col) biological scaffolds were prepared, and the physicochemical properties and biocompatibility of the scaffolds were investigated. Animal skin wound models were established, and the therapeutic effect and anti-inflammatory effect of T-Exo/Col in wound repair were evaluated by small animal in vivo imaging, H&E staining, Masson trichrome staining, immunohistochemical staining, Western Blot, and qRT-PCR. The results showed that T-Exo significantly promoted wound healing by inhibiting inflammation, thereby further promoting angiogenesis and collagen formation in vivo. Moreover, the existence of Col scaffold in T-Exo/Col enabled T-Exo to achieve a certain sustained release effect. Finally, we further explored whether TSA exerts beneficial effects by inhibiting HDAC6 gene of BMSCs, but the results showed that knockdown of HDAC6 gene would cause oxidative stress damage to BMSCs, which means that TSA does not produce these beneficial effects by inhibiting HDAC6 gene. What molecular mechanisms TSA exerts beneficial effects through needs to be further elucidated in the future.
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Colágeno , Exossomos , Ácidos Hidroxâmicos , Macrófagos , Células-Tronco Mesenquimais , Pele , Alicerces Teciduais , Cicatrização , Exossomos/metabolismo , Exossomos/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/química , Alicerces Teciduais/química , Colágeno/metabolismo , Camundongos , Pele/efeitos dos fármacos , Pele/lesões , Pele/metabolismo , Movimento Celular/efeitos dos fármacos , Masculino , Ativação de Macrófagos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Humanos , Células RAW 264.7RESUMO
Exosomes are small extracellular vesicles secreted by cells, ranging in size from 30 to 150 nm. They contain proteins, nucleic acids, lipids, and other bioactive molecules, which play a crucial role in intercellular communication and material transfer. In tumor immunity, exosomes present various functions while the following two are of great importance: regulating the immune response and serving as delivery carriers. This review starts with the introduction of the formation, compositions, functions, isolation, characterization, and applications of exosomes, and subsequently discusses the current status of exosomes in tumor immunotherapy, and the recent applications of exosome-based tumor immunity regulation and antitumor drug delivery. Finally, current challenge and future prospects are proposed and hope to demonstrate inspiration for targeted readers in the field.
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Ultraviolet (UV) radiation is a major cause of skin photoaging through generating excessive oxidative stress and inflammation. One of the strategies is to use photo-chemoprotectors, such as natural products with antioxidant and anti-inflammatory properties, to protect the skin from photo damage. The present study investigates the photoprotective potentials of topical administration of unhydrolyzed collagen, epigallocatechin gallate (EGCG), and their combination against ultraviolet B (UVB)-induced photoaging in nude mice. It is found that both the solo and combined pretreatments could recover UVB-induced depletion of antioxidative enzymes, including superoxide dismutase and glutathione peroxidase (GSH-Px), as well as an increase of lipid peroxide malondialdehyde and inflammatory tumor necrosis factor-α. Meanwhile, the UVB-stimulated skin collagen degradation is attenuated significantly with drug treatments, which is evidenced by expression analysis of matrix metalloproteinase-1 and hydroxyproline. Additionally, the mouse skin histology shows that the drug-pretreated groups possess decreased epidermis thickness and normal collagen fiber structure of the dermis layer. These results demonstrate that both EGCG and collagen can protect the skin against UVB-induced skin photoaging. Synergistically, the combination of them shows the maximum prevention to skin damage, showing its potential in the application of anti-photoaging formulation products.
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Envelhecimento da Pele , Animais , Camundongos , Camundongos Nus , Antioxidantes/farmacologia , Colágeno/metabolismo , Pele/metabolismo , Raios Ultravioleta/efeitos adversosRESUMO
The second most common male cancer is prostate cancer (PCa), which has a high tendency for bone metastasis. Long non-coding RNAs, including TMPO-AS1, play a crucial role in PCa progression. However, TMPO-AS1's function in PCa bone metastasis (BM) and its underlying molecular mechanisms are unclear. Herein, we found that the long transcript of TMPO-AS1 (TMPO-AS1L) was upregulated in PCa tissues with bone metastasis, and overexpression of TMPO-AS1L correlated with advanced clinicopathological features and reduced BM-free survival in patients with PCa. Upregulated TMPO-AS1L promoted, whereas downregulated TMPO-AS1L inhibited, the PCa cell bone metastatic capacity in vitro and in vivo. Mechanistically, TMPO-AS1L was demonstrated to act as a scaffold, that strengthened the interaction of casein kinase 2 alpha 1 (CSNK2A1) and DEAD-box helicase 3 X-linked (DDX3X), and activated the Wnt/ß-catenin signaling pathway, thus promoting BM of PCa. Moreover, upregulation of TMPO-AS1L in PCa resulted from transcription elongation modulated by general transcription factor IIF subunit 2 (GTF2F2). Collectively, our study provides critical insights into the role of TMPO-AS1L in PCa BM via Wnt/ß-catenin signaling, identifying TMPO-AS1L as a candidate marker of PCa bone metastasis prognosis and therapeutic target.
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There is growing evidence that mesenchymal stem cell-derived extracellular vesicles and exosomes can significantly improve the curative effect of oxidative stress-related diseases. Mesenchymal stem cell extracellular vesicles and exosomes (MSC-EVs and MSC-Exos) are rich in bioactive molecules and have many biological regulatory functions. In this review, we describe how MSC-EVs and MSC-Exos reduce the related markers of oxidative stress and inflammation in various systemic diseases, and the molecular mechanism of MSC-EVs and MSC-Exos in treating apoptosis and vascular injury induced by oxidative stress. The results of a large number of experimental studies have shown that both local and systemic administration can effectively inhibit the oxidative stress response in diseases and promote the survival and regeneration of damaged parenchymal cells. The mRNA and miRNAs in MSC-EVs and MSC-Exos are the most important bioactive molecules in disease treatment, which can inhibit the apoptosis, necrosis and oxidative stress of lung, heart, kidney, liver, bone, skin and other cells, and promote their survive and regenerate.
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Exossomos , Vesículas Extracelulares , Células-Tronco Mesenquimais , Administração Cutânea , Estresse OxidativoRESUMO
BACKGROUND: The molecular characteristics of prostate cancer (PCa) cells and the immunosuppressive bone tumor microenvironment (TME) contribute to the limitations of immune checkpoint therapy (ICT). Identifying subgroups of patients with PCa for ICT remains a challenge. Herein, we report that basic helix-loop-helix family member e22 (BHLHE22) is upregulated in bone metastatic PCa and drives an immunosuppressive bone TME. METHODS: In this study, the function of BHLHE22 in PCa bone metastases was clarified. We performed immunohistochemical (IHC) staining of primary and bone metastatic PCa samples, and assessed the ability to promote bone metastasis in vivo and in vitro. Then, the role of BHLHE22 in bone TME was determined by immunofluorescence (IF), flow cytometry, and bioinformatic analyses. RNA sequencing, cytokine array, western blotting, IF, IHC, and flow cytometry were used to identify the key mediators. Subsequently, the role of BHLHE22 in gene regulation was confirmed using luciferase reporter, chromatin immunoprecipitation assay, DNA pulldown, co-immunoprecipitation, and animal experiments. Xenograft bone metastasis mouse models were used to assess whether the strategy of immunosuppressive neutrophils and monocytes neutralization by targeting protein arginine methyltransferase 5 (PRMT5)/colony stimulating factor 2 (CSF2) could improve the efficacy of ICT. Animals were randomly assigned to treatment or control groups. Moreover, we performed IHC and correlation analyses to identify whether BHLHE22 could act as a potential biomarker for ICT combination therapies in bone metastatic PCa. RESULTS: Tumorous BHLHE22 mediates the high expression of CSF2, resulting in the infiltration of immunosuppressive neutrophils and monocytes and a prolonged immunocompromised T-cell status. Mechanistically, BHLHE22 binds to the CSF2 promoter and recruits PRMT5, forming a transcriptional complex. PRMT5 epigenetically activates CSF2 expression. In a tumor-bearing mouse model, ICT resistance of Bhlhe22+ tumors could be overcome by inhibition of Csf2 and Prmt5. CONCLUSIONS: These results reveal the immunosuppressive mechanism of tumorous BHLHE22 and provide a potential ICT combination therapy for patients with BHLHE22+ PCa.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias Ósseas , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Modelos Animais de Doenças , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Microambiente Tumoral , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
There is an urgent need for a flexible and simple programmed cell death ligand 1 (PD-L1) dynamic measurement method enabling real-time monitoring of cancer progression and assessment of immunotherapy efficacy. In the current study, we show facile in situ synthesis of vertical alignment two-dimensional molybdenum disulfide (2D MoS2) layers on graphene-oxide-modified ITO (MoS2â´GO-ITO) using a hydrothermal approach and demonstrate the importance of the alignment of 2D in achieving high-probe capturing, enhanced electrochemical properties and target selectivity during sensing. After modification of designed PD-L1 binding peptides on the MoS2â´GO-ITO, a sensitive PD-L1 electrochemical sensor was designed using vertical alignment MoS2 to capture more probes for PD-L1 recognition and excellent in plane electron transport to accelerate electrochemical signals. The fabricated electrochemical sensor could sensitively determine PD-L1 in a wide linear range of 25-500 ng/mL and exhibit desirable accuracy and reliability in clinical samples application. This simple and sensitive method is likely to investigate further research into the exploration of the perpendicular alignment of 2D surfaces for diverse applications.
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Técnicas Biossensoriais , Molibdênio , Antígeno B7-H1 , Técnicas Biossensoriais/métodos , Molibdênio/química , Reprodutibilidade dos TestesRESUMO
Two-dimensional (2D) transition metal dichalcogenide (TMD) nanosheets (e.g., MoS2) with metallic phase (1T or 1T´ phase) have been proven to exhibit superior performances in various applications as compared to their semiconducting 2H-phase counterparts. However, it remains unclear how the crystal phase of 2D TMD nanosheets affects their sonodynamic property. In this work, we report the preparation of MoS2 nanosheets with different phases (metallic 1T/1T´ or semiconducting 2H) and exploration of its crystal-phase effect on photothermal-enhanced sonodynamic antibacterial therapy. Interestingly, the defective 2D MoS2 nanosheets with high-percentage metallic 1T/1T´ phase (denoted as M-MoS2) present much higher activity towards the ultrasound-induced generation of reactive oxygen species (ROS) as compared to the semiconducting 2H-phase MoS2 nanosheets. More interestingly, owing to its metallic phase-enabled strong absorption in the near-infrared-II (NIR-II) regime, the ultrasound-induced ROS generation performance of the M-MoS2 nanosheets can be further enhanced by the photothermal effect under a 1064 nm laser irradiation. Thus, after modifying with polyvinylpyrrolidone, the M-MoS2 nanosheets can be used as an efficient sonosensitizer for photothermal-enhanced sonodynamic bacterial elimination under ultrasound treatment combining with NIR-II laser irradiation. This study demonstrates that metallic MoS2 nanosheets can be used as a promising sonosensitizer for antibacterial therapy, which might be also promising for cancer therapies.
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Antibacterianos , Molibdênio , Antibacterianos/farmacologia , Bactérias , Molibdênio/química , Molibdênio/farmacologia , PovidonaRESUMO
Separation and purification of surfactant-stabilized oil-in-water nanoemulsions is a great environmental challenge. Membrane-based separation strategies are more effective over conventional methods in the treatment of nanoemulsion waste water. In this paper, we construct a superhydrophilic membrane by coating a thin photothermal-responsive iron tetrakis(4-carboxyphenyl)porphyrin (Fe-TCPP) nanofibrous metal organic framework (MOF) selective layer on a macroporous polyethersulfone membrane. The as-prepared membrane exhibits high separation performance of oil-in-water nanoemulsions with permeance of 46.4 L·m-2·h-1·bar-1 and separation efficiency of 99%. It also demonstrates nice anti-oil/ionic-fouling property, good recyclability, and desirable stability. The high separation performance is accredited to the superhydrophilicity, highly charged surface, and nanometer pore sizes of the Fe-TCPP nanofibrous membrane. Due to the unique photothermal property of Fe-TCPP nanofibers, the permeance can be enhanced more than 50% by visible light without deteriorating the rejection. This photo-stimuli MOF-based thin-layer membrane offers great potential for the generation of point-of-use water treatment devices.
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BACKGROUND: Bone metastasis is the leading cause of tumor-related death in prostate cancer (PCa) patients. Long noncoding RNAs (lncRNAs) have been well documented to be involved in the progression of multiple cancers. Nevertheless, the role of lncRNAs in PCa bone metastasis remains largely unclear. METHODS: The expression of prostate cancer-associated transcripts was analyzed in published datasets and further verified in clinical samples and cell lines by RT-qPCR and in situ hybridization assays. Colony formation assay, MTT assay, cell cycle analysis, EdU assay, Transwell migration and invasion assays, wound healing assay, and in vivo experiments were carried out to investigate the function of prostate cancer-associated transcript 6 (PCAT6) in bone metastasis and tumor growth of PCa. Bioinformatic analysis, RNA pull-down, and RIP assays were conducted to identify the proteins binding to PCAT6 and the potential targets of PCAT6. The therapeutic potential of targeting PCAT6 by antisense oligonucleotides (ASO) was further explored in vivo. RESULTS: PCAT6 was upregulated in PCa tissues with bone metastasis and increased PCAT6 expression predicted poor prognosis in PCa patients. Functional experiments found that PCAT6 knockdown significantly inhibited PCa cell invasion, migration, and proliferation in vitro, as well as bone metastasis and tumor growth in vivo. Mechanistically, METTL3-mediated m6 A modification contributed to PCAT6 upregulation in an IGF2BP2-dependent manner. Furthermore, PCAT6 upregulated IGF1R expression by enhancing IGF1R mRNA stability through the PCAT6/IGF2BP2/IGF1R RNA-protein three-dimensional complex. Importantly, PCAT6 inhibition by ASO in vivo showed therapeutic potential against bone metastasis in PCa. Finally, the clinical correlation of METTL3, IGF2BP2, IGF1R, and PCAT6 was further demonstrated in PCa tissues and cells. CONCLUSIONS: Our study uncovers a novel molecular mechanism by which the m6 A-induced PCAT6/IGF2BP2/IGF1R axis promotes PCa bone metastasis and tumor growth, suggesting that PCAT6 may serve as a promising prognostic marker and therapeutic target against bone-metastatic PCa.
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Adenosina/análogos & derivados , Neoplasias Ósseas/secundário , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/patologia , Estabilidade de RNA , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Receptor IGF Tipo 1/metabolismo , Adenosina/química , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Ciclo Celular , Movimento Celular , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante/química , Proteínas de Ligação a RNA/genética , Receptor IGF Tipo 1/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.
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Proteínas de Ciclo Celular/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Antagonistas de Androgênios/farmacologia , Castração/métodos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Via de Sinalização Hippo , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Células PC-3 , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proto-Oncogene Mas , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Pyogenic spondylodiscitis (PSD) is challenging to the orthopedist with regards to diagnosis and treatment. The present study was designed to assess and suggest the most indicative diagnostic method and evaluate the effect of surgery comprising of debridement, instrumentation and fusion in treating PSD. METHODS: Seventy-six patients with PSD who underwent surgical intervention were retrospectively enrolled. Their medical documents, corrections of spinal alignment and improvements in neurological function were assessed. Surgical approaches were compared in lumbar surgeries regarding the improvements in lordotic angle and neurological function. RESULTS: Elevated c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were found in 77.6 and 71.1% patients respectively. Infectious lesions were found at lumbar (85.5%), cervical (10.5%) and thoracic (3.9%), ascertained with contrast-enhanced MRI. For lumbar patients, surgery was performed through the anterior (26.2%), posterior (49.2%) or combined approach (24.6%), and differences in improvement of lordosis and neurological function between each approach were insignificant. The pathogen was identified in 22.4% of the patients. Postoperative antibiotic therapy was managed against the result of susceptibility test, or empirically given to patients with negative cultures. All antibiotic therapy was initiated intravenously for 4-6 weeks and orally for 6 weeks. CONCLUSION: Elevated CRP and/or ESR, with focal hyper-intensity on contrast-enhanced MRI are suggestive of possible PSD. Surgical intervention comprising of debridement, short-segment instrumentation and fusion that early applied to the PSD patients followed by postoperative antibiotic therapy have demonstrated preferable outcomes, but require further study. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This article advocates early surgery to enable prompt diagnosis and treatment of PSD, and thus guarantee favorable outcomes for patients, as is shown in our study. In addition, different surgical approaches to the lesions were compared and discussed in this manuscript, but no differences in outcome between approaches were found. This suggests that thorough debridement should be prioritized over selection of surgical approach. In summary, this article has large translational potential to be applied clinically.
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Discite , Fusão Vertebral , Antibacterianos/uso terapêutico , Desbridamento , Discite/diagnóstico por imagem , Discite/tratamento farmacológico , Discite/cirurgia , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Estudos Retrospectivos , Fusão Vertebral/efeitos adversos , Resultado do TratamentoRESUMO
Background: Management of patients with prostate cancer and bone metastatic disease remains a major clinical challenge. Loss or mutation of p53 has been identified to be involved in the tumor progression and metastasis. Nevertheless, direct evidence of a specific role for wild-type p53 (wt-p53) in bone metastasis and the mechanism by which this function is mediated in prostate cancer remain obscure. Methods: The expression and protein levels of wt-53, AIP4, and CXCR4 in prostate cancer cells and clinical specimens were assessed by real-time PCR, immunohistochemistry and western blot analysis. The role of wt-p53 in suppressing aggressive and metastatic tumor phenotypes was assessed using in vitro transwell chemotaxis, wound healing, and competitive colocalization assays. Furthermore, whether p53 deletion facilitates prostate cancer bone-metastatic capacity was explored using an in vivo bone-metastatic model. The mechanistic model of wt-p53 in regulating gene expression was further explored by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Results: Our findings revealed that wt-p53 suppressed the prostate cancer cell migration rate, chemotaxis and attachment toward the osteoblasts in vitro. The bone-metastatic model showed that deletion of wt-p53 remarkably increased prostate cancer bone-metastatic capacity in vivo. Mechanistically, wt-p53 could induce the ligand-induced degradation of the chemokine receptor CXCR4 by transcriptionally upregulating the expression of ubiquitin ligase AIP4. Treatment with the CXCR4 inhibitor AMD3100 or transduction of the AIP4 plasmid abrogated the pro-bone metastasis effects of TP53 deletion. Conclusion: Wt-p53 suppresses the metastasis of prostate cancer cells to bones by regulating the CXCR4/CXCL12 activity in the tumor cells/bone marrow microenvironment interactions. Our findings suggest that targeting the wt-p53/AIP4/CXCR4 axis might be a promising therapeutic strategy to manage prostate cancer bone metastasis.
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BACKGROUND: Dynamic somatosensory evoked potentials (DSSEP) can be used to disclose abnormalities of ascending sensory pathways at dynamic positions and diagnose cervical spondylotic myelopathy (CSM). However, radiographic tests including magnetic resonance imaging (MRI) and dynamic X-ray are used much more widely in the management of CSM. Our study aims to clarify the correlations between several radiographic parameters and the DSSEP results, and further determine their reliability with clinical data. METHODS: We retrospectively enrolled 38 CSM patients with surgical intervention. DSSEP tests were performed before surgery. Amplitude ratios of DSSEP N13 and N20 waves at extension and flexion were calculated and recorded as N13_E, N20_E, N13_F, N20_F, respectively. Baseline severity was evaluated with the modified Japanese Orthopedic Association (mJOA) score and the Nurick grades. Prognosis was evaluated based on the 2-year recovery rate. Sagittal diameter and transverse areas of the cord and canal were measured and the the compressive ratios at the compressed site (Compression_Ratio), central (Central_Ratio), and 1/4-lateral points (1/4-Lateral_Compression_Ratio), and spinal cord/Canal Area Ratio were calculated. The intramedullary T2 hyperintensity patterns (Ax-CCM types) were also collected from MRI axial images. Dynamic X-rays were used to test for segmental instability of the cervical spine. The correlations between radiologic findings, DSSEP data, and clinical assessments were investigated. RESULTS: We found that DSSEP N13_E and N13_F correlated with the Compression_Ratio, Central_Ratio, 1/4-Lateral_Compression_Ratio (Pearson, p < 0.05) and Ax-CCM types (ANOVA, p < 0.05) in MRI axial images and cervical segmental instability in dynamic X-ray (t-test, p < 0.05). Apart from the 1/4-Lateral_Compression_Ratio, these radiographic parameters above also correlated with the baseline clinical assessments (Spearman or ANOVA or t-test, p < 0.05) and postoperative recovery rate (Pearson or ANOVA or t-test, p < 0.05). CONCLUSIONS: We found that the preoperative Compression_Ratio, Central_Ratio and 1/4-Lateral_Compression_Ratio in MRI and cervical segmental instability in dynamic X-ray could reflect the dynamic neural dysfunction of the spinal cord. Different Ax-CCM types corresponded to different DSSEP results at extension and flexion, suggesting divergent pathophysiology. These radiographic parameters could help evaluate disease severity and predict postoperative prognosis.
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Doenças da Medula Espinal/patologia , Doenças da Medula Espinal/fisiopatologia , Adulto , Idoso , Vértebras Cervicais/patologia , Estudos de Coortes , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Doenças da Medula Espinal/etiologia , Espondilose/complicaçõesRESUMO
miR-532-3p is a widely documented microRNA (miRNA) involved in multifaceted processes of cancer tumorigenesis and metastasis. However, the clinical significance and biological functions of miR-532-3p in bone metastasis of prostate cancer (PCa) remain largely unknown. Herein, we report that miR-532-3p was downregulated in PCa tissues with bone metastasis, and downexpression of miR-532-3p was significantly associated with Gleason grade and serum prostate-specific antigen (PSA) levels and predicted poor bone metastasis-free survival in PCa patients. Upregulating miR-532-3p inhibited invasion and migration abilities of PCa cells in vitro, while silencing miR-532-3p yielded an opposite effect on invasion and migration abilities of PCa cells. Importantly, upregulating miR-532-3p repressed bone metastasis of PCa cells in vivo. Our results further demonstrated that overexpression of miR-532-3p inhibited activation of nuclear facto κB (NF-κB) signaling via simultaneously targeting tumor necrosis factor receptor-associated factor 1 (TRAF1), TRAF2, and TRAF4, which further promoted invasion, migration, and bone metastasis of PCa cells. Therefore, our findings reveal a novel mechanism contributing to the sustained activity of NF-κB signaling underlying the bone metastasis of PCa.
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This study demonstrates the efficacy of collagen/tussah silk fibroin (Col/TSF) hybrid scaffolds loaded with bone mesenchymal stem cells (BMSCs) in skin repair. Collagen (Col) and tussah silk fibroin (TSF) were extracted from bovine tendons and tussah cocoons, respectively. Col/TSF scaffolds were obtained using a freeze-drying method and were characterised using fourier transform infrared spectroscopy, scanning electron microscopy, porosity, water retention, thermal stability, and biocompatibility. The results revealed that addition of TSF to scaffolds could enhance their moisturising ability and cell infiltration. The antibacterial properties of Col/TSF scaffolds loaded with antibiotics were also excellent. BMSCs cultured in contact with developed Col/TSF scaffolds showed increased cell adhesion, viability, and differentiation. An in vivo study on rats showed that the Col/TSF scaffold seeded with BMSCs was more conducive to wound healing compared to the Col/TSF scaffold alone. The present study suggests that Col/TSF scaffold seeded with BMSCs could be a promising candidate for skin tissue engineering, due to its excellent skin affinity, good air and water permeability, and improved wound healing potential.
Assuntos
Células da Medula Óssea/metabolismo , Células Imobilizadas/transplante , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Pele/metabolismo , Alicerces Teciduais/química , Cicatrização , Ferimentos e Lesões/terapia , Animais , Células da Medula Óssea/patologia , Células Imobilizadas/metabolismo , Células Imobilizadas/patologia , Colágeno/química , Colágeno/farmacologia , Fibroínas/química , Fibroínas/farmacologia , Masculino , Células-Tronco Mesenquimais/patologia , Ratos , Ratos Sprague-Dawley , Pele/lesões , Pele/patologia , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologiaRESUMO
Metal-organic frameworks (MOFs) have been identified as promising materials for the delivery of therapeutics to cure cancer owing to their intrinsic porous structure. However, in a majority of cases, MOFs act as only a delivery cargo for anticancer drugs while little attention has been focused on the utilization of their intriguing physical and chemical properties for potential anticancer purposes. Herein for the first time, an ultrathin (16.4 nm thick) ferrocene-based MOF (Zr-Fc MOF) nanosheet has been synthesized for synergistic photothermal therapy (PTT) and Fenton reaction-based chemodynamic (CDT) therapy to cure cancer without additional drugs. The Zr-Fc MOF nanosheet acts not only as an excellent photothermal agent with a prominent photothermal conversion efficiency of 53% at 808 nm but also as an efficient Fenton catalyst to promote the conversion of H2O2 into hydroxyl radical (â¢OH). As a consequence, an excellent therapeutic performance has been achieved in vitro as well as in vivo through this combinational effect. This work aims to construct an "all-in-one" MOF nanoplatform for PTT and CDT treatments without incorporating any additional therapeutics, which may launch a new era in the investigation of MOF-based synergistic therapy platforms for cancer therapy.
Assuntos
Antineoplásicos/uso terapêutico , Estruturas Metalorgânicas/uso terapêutico , Nanoestruturas/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Catálise , Linhagem Celular Tumoral , Terapia Combinada/métodos , Compostos Ferrosos/química , Compostos Ferrosos/efeitos da radiação , Compostos Ferrosos/uso terapêutico , Radical Hidroxila/metabolismo , Hipertermia Induzida/métodos , Raios Infravermelhos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/efeitos da radiação , Metalocenos/química , Metalocenos/efeitos da radiação , Metalocenos/uso terapêutico , Camundongos , Nanoestruturas/química , Nanoestruturas/efeitos da radiação , Fotoquimioterapia/métodos , Zircônio/química , Zircônio/efeitos da radiação , Zircônio/uso terapêuticoRESUMO
Type II porous liquids are demonstrated to be promise porous materials. However, the category of porous hosts is very limited. Here, a porous host metal-organic polyhedra (MOP-18) is reported to construct type II porous liquids. MOP-18 is dissolved into 15-crown-5 as an individual cage (5 nm). Both the molecular dynamics simulations and experimental gravimetric CO2 solubility test indicate that the inner cavity of MOP-18 in porous liquids is unoccupied by 15-crown-5 and is accessible to CO2 . Thus, the prepared porous liquids show enhanced gas solubility. Furthermore, the prepared porous liquid is encapsulated into graphene oxide (GO) nanoslits to form a GO-supported porous liquid membrane (GO-SPLM). Owing to the empty cavity of MOP-18 unit cages in porous liquids that reduces the gas diffusion barrier, GO-SPLM significantly enhances the permeability of gas.