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Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas.
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Bleomicina , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Hemangioma , Ácido Hialurónico , Agujas , Poliésteres , Bleomicina/farmacología , Animales , Ratones , Conejos , Hemangioma/tratamiento farmacológico , Ácido Hialurónico/química , Preparaciones de Acción Retardada/química , Sistemas de Liberación de Medicamentos/métodos , Poliésteres/química , Humanos , Microesferas , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Liberación de FármacosRESUMEN
Introduction: This study explored the causal connections between gut microbiota (GM), urinary tract infection (UTI), and potential metabolite mediators using Mendelian randomization (MR). Methods: We utilized summary statistics from the most comprehensive and extensive genome-wide association studies (GWAS) available to date, including 196 bacterial traits for GM, 1,091 blood metabolites, 309 metabolite ratios, alongside UTI data from ukb-b-8814 and ebi-a-GCST90013890. Bidirectional MR analyses were conducted to investigate the causal links between GM and UTI. Subsequently, two MR analyses were performed to identify the potential mediating metabolites, followed by a two-step MR analysis to quantify the mediation proportion. Results: Our findings revealed that out of the total 15 bacterial traits, significant associations with UTI risk were observed across both datasets. Particularly, taxon g_Ruminococcaceae UCG010 displayed a causal link with a diminished UTI risk in both datasets (ukb-b-8814: odds ratio [OR] = 0.9964, 95% confidence interval [CI] = 0.9930-0.9997, P = 0.036; GCST90013890: OR = 0.8252, 95% CI = 0.7217-0.9436, P = 0.005). However, no substantial changes in g_Ruminococcaceae UCG010 due to UTI were noted (ukb-b-8814: ß = 0.51, P = 0.87; ebi-a-GCST90013890: ß = -0.02, P = 0.77). Additionally, variations in 56 specific metabolites were induced by g_Ruminococcaceae UCG010, with N-acetylkynurenine (NAK) exhibiting a causal correlation with UTI. A negative association was found between g_Ruminococcaceae UCG010 and NAK (OR: 0.8128, 95% CI: 0.6647-0.9941, P = 0.044), while NAK was positively associated with UTI risk (OR: 1.0009; 95% CI: 1.0002-1.0016; P = 0.0173). Mediation analysis revealed that the association between g_Ruminococcaceae UCG010 and UTI was mediated by NAK with a mediation proportion of 5.07%. Discussion: This MR study provides compelling evidence supporting the existence of causal relationships between specific GM taxa and UTI, along with potential mediating metabolites.
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BACKGROUND: Percutaneous kyphoplasty (PKP) is commonly used to treat severe osteoporotic vertebral compression fractures (OVCFs) by restoring vertebral height. However, its application in mild cases is not frequently discussed. METHODS: The study retrospectively included 100 treated vertebral bodies of the 91 patients mentioned before, and efficacy was evaluated using visual analog scale (VAS) and Oswestry Disability Index (ODI) scores preoperatively, 2 days postoperatively, and at 1 and 6 months after treatment, as well as mean variation in vertebral body height. The study also examined complications such as pain recurrence, delayed vertebral fracture, and loss of vertebral height, and developed a scale to assess the shape and filling effect of cement (SFEC) and its impact on complications. RESULTS: The results showed significant reductions in mean VAS and ODI scores from pre-to post-surgery and an increase in vertebral body height. However, complications occurred in 10 patients who received treatment for 11 vertebral bodies, including pain recurrence, fractures, and loss of vertebral height. Among the 10 patients with complications, 7 (63.6%) vertebral bodies had dissatisfied SFEC scores, compared with 22 (24.7%) vertebral bodies with dissatisfied SFEC scores in 81 patients without complications (89 vertebral bodies). CONCLUSIONS: PKP is a safe and effective method for treating mild OVCFs, but attention should be paid to the shape and filling effects of cement during surgery to prevent later complications. The developed SFEC scale provides a specific and quantitative standards for evaluating the recovery status after PKP, which need further validations.
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Cementos para Huesos , Fracturas por Compresión , Cifoplastia , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Humanos , Cifoplastia/métodos , Fracturas por Compresión/cirugía , Femenino , Estudios Retrospectivos , Anciano , Masculino , Fracturas de la Columna Vertebral/cirugía , Fracturas Osteoporóticas/cirugía , Cementos para Huesos/uso terapéutico , Persona de Mediana Edad , Anciano de 80 o más Años , Resultado del Tratamiento , Evaluación de la Discapacidad , Dimensión del DolorRESUMEN
Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint homeostasis by simultaneously remodeling the anti-inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease-modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral-biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)-based nanoparticles (NPs) are integrated into poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self-assembled ChS and ε-poly-l-lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin-1ß (IL-1ß)-mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS-based hydrogel system offers a potential strategy to regulate the chondrocyte-macrophage crosstalk, thus re-establishing the anti-inflammatory and immunomodulatory microenvironment for OA therapy.
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Condrocitos , Sulfatos de Condroitina , Homeostasis , Nanopartículas , Osteoartritis , Osteoartritis/patología , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Animales , Condrocitos/metabolismo , Condrocitos/efectos de los fármacos , Homeostasis/efectos de los fármacos , Nanopartículas/química , Sulfatos de Condroitina/química , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/farmacología , Ratones , Hidrogeles/química , Biónica , Células RAW 264.7 , Masculino , Sistemas de Liberación de Medicamentos/métodos , Humanos , Ratas , Ratas Sprague-Dawley , Cartílago Articular/patología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismoRESUMEN
This study aimed to elucidate the roles of microRNA (miR)-4738-3p and the collagen type I alpha 2 chain (COL1A2) gene in the pathogenesis of osteoarthritis (OA) through bioinformatics analysis and cellular assays. The GSE55235 dataset was analyzed using the weighted gene co-expression network analysis (WGCNA) method to identify gene modules associated with OA. Key overlapping genes were identified from these modules and the GSE55235-differential expressed genes (DEGs). The expression levels of selected genes were determined in C28/I2 cells using the quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between miR-4738-3p and COL1A2 was examined in the context of interleukin 1 beta (IL-1ß) induction. Exosome characterization was achieved through transmission electron microscopy (TEM), western blotting (WB), and other analyses. The study also investigated the functional relevance of miR-4738-3p in OA pathology through various molecular and cellular assays. Our findings revealed that the green module exhibited a strong correlation with the OA phenotype in the GSE55235 dataset, with COL1A2 emerging as a hub gene and miR-4738-3p as its key downstream target. IL-1ß induction suggested that COL1A2 is involved in inflammation and apoptosis, while miR-4738-3p appeared to play an antagonistic role. The analysis of exosomes underscored the significance of miR-4738-3p in cellular communication, with an enhanced level of exo-miR-4738-3p antagonizing IL-1ß-induced inflammation and promoting cell survival. Conversely, a reduction in exo-miR-4738-3p led to increased cell damage. This study established a clear regulatory relationship between miR-4738-3p and COL1A2, with the nuclear factor kappa B (NF-κB) signaling pathway playing a central role in this regulation. The miR-4738-3p significantly influences the OA-associated inflammation, primarily through modulation of COL1A2 and the NF-κB pathway. Therefore, targeting miR-4738-3p offers a potential therapeutic approach for OA, with exosome miR-4738-3p presenting a promising strategy.
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Invasive fungal diseases are increasing in incidence and mortality. A variety of immune cells are required to fight against fungal infections. The four subpopulations of innate lymphoid cells (ILCs), namely natural killer cell (NK cell), ILC1, ILC2 and ILC3, have different roles in the immune response to fungal infection. NK cells and ILC3 play the main role in killing fungi and protecting the host, while ILC2 itself does not have significant resistance to fungal infection, but because of its cell plasticity, inflammatory ILC2 can be transformed into ILC3 under certain conditions. The main function of ILCs is to produce cytokines which either directly kill fungi or indirectly regulate the immune response, promoting the body to complete the antifungal immune process.
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Linfocitos , Micosis , Humanos , Inmunidad Innata , Antifúngicos/farmacología , Células Asesinas Naturales , CitocinasRESUMEN
AIM: Blood-brain barrier (BBB) dysfunction is one of the hallmarks of ischemic stroke. USP14 has been reported to play a detrimental role in ischemic brain injury. However, the role of USP14 in BBB dysfunction after ischemic stroke is unclear. METHODS: In this study, we tested the role of USP14 in disrupting BBB integrity after ischemic stroke. The USP14-specific inhibitor IU1 was injected into middle cerebral artery occlusion (MCAO) mice once a day. The Evans blue (EB) assay and IgG staining were used to assess BBB leakage 3 days after MCAO. FITC-detran test was slected to examine the BBB leakage in vitro. Behavior tests were conducted to evaluate recovery from ischemic stroke. RESULTS: Middle cerebral artery occlusion increased endothelial cell USP14 expression in the brain. Furthermore, the EB assay and IgG staining showed that USP14 inhibition through IU1 injection protected against BBB leakage after MCAO. Analysis of protein expression revealed a reduction in the inflammatory response and chemokine release after IU1 treatment. In addition, IU1 treatment was found to rescue neuronal loss resulting from ischemic stroke. Behavior tests showed a positive effect of IU1 in attenuating brain injury and improving motor function recovery. In vitro study showed that IU1 treatment could alleviate endothelial cell leakage induced by OGD in cultured bend.3 cells through modulating ZO-1 expression. CONCLUSIONS: Our results demonstrate a role for USP14 in disrupting the integrity of the BBB and promoting neuroinflammation after MCAO.
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Barrera Hematoencefálica , Lesiones Encefálicas , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Animales , Ratones , Barrera Hematoencefálica/metabolismo , Lesiones Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Células Endoteliales/metabolismo , Azul de Evans/metabolismo , Azul de Evans/farmacología , Inmunoglobulina G , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/metabolismoRESUMEN
Circadian rhythm (CR) disruption contributes to tumor initiation and progression, however the pharmacological targeting of circadian regulators reversely inhibits tumor growth. Precisely controlling CR in tumor cells is urgently required to investigate the exact role of CR interruption in tumor therapy. Herein, based on KL001, a small molecule that specifically interacts with the clock gene cryptochrome (CRY) functioning at disruption of CR, we fabricated a hollow MnO2 nanocapsule carrying KL001 and photosensitizer BODIPY with the modification of alendronate (ALD) on the surface (H-MnSiO/K&B-ALD) for osteosarcoma (OS) targeting. The H-MnSiO/K&B-ALD nanoparticles reduced the CR amplitude in OS cells without affecting cell proliferation. Furthermore, nanoparticles-controlled oxygen consumption by inhibiting mitochondrial respiration via CR disruption, thus partially overcoming the hypoxia limitation for photodynamic therapy (PDT) and significantly promoting PDT efficacy. An orthotopic OS model demonstrated that KL001 significantly enhanced the inhibitory effect of H-MnSiO/K&B-ALD nanoparticles on tumor growth after laser irradiation. CR disruption and oxygen level enhancement induced by H-MnSiO/K&B-ALD nanoparticles under laser irradiation were also confirmed in vivo. This discovery first demonstrated the potential of CR controlling for tumor PDT ablation and provided a promising strategy for overcoming tumor hypoxia.
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Fungal infections cause serious health problems, especially in patients with an immune-deficiency. Histone deacetylase 11 (HDAC11) mediates various immune functions, yet little is known about its role in regulating host immune responses to fungal infection. Here we report that HDAC11 negatively controls antifungal immunity in macrophages and dendritic cells. Deleting Hdac11 protects mice from morbidity and markedly improves their survival rate upon systemic infection with Candida albicans (C. albicans). Moreover, HDAC11 deficiency results in increased production of NO and reactive oxygen species, which enhances fungal killing. Mechanistically, loss of HDAC11 increases histone 3 and 4 acetylation at the Nos2 promoter and leads to enhanced Nos2 transcription and corresponding iNOS levels in macrophages. In addition, STAT3, a transcriptional repressor of Nos2, physically interacts with HDAC11, serving as a scaffold protein supporting the HDAC11 association with the Nos2 promoter. Notably, treatment with the HDAC11 inhibitor, FT895, exhibits antifungal therapeutic effects in both mouse and human cells challenged with C. albicans. These data support that HDAC11 may be a therapeutic target for fungal infection.
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Antifúngicos , Histonas , Animales , Antifúngicos/farmacología , Candida albicans/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
Poor immunogenicity and compromised T cell infiltration impede the application of immune-checkpoint blockade (ICB) immunotherapy for osteosarcoma (OS). Although autophagy is involved in enhancing the immune response, the synergistic role of autophagy in ICB immunotherapy and the accurate control of autophagy levels in OS remain elusive and challenging. Here, we designed a pH-sensitive autophagy-controlling nanocarrier, CUR-BMS1166@ZIF-8@PEG-FA (CBZP), loading a natural derivative, curcumin (CUR), to boost the immunotherapeutic response of PD-1/PD-L1 blockade by activating immunogenic cell death (ICD) via autophagic cell death, and BMS1166 to inhibit the PD-1/PD-L1 interaction simultaneously, enhancing the tumor immunogenicity and sensitizing the antitumor T cell immunity. After entering tumor cells, the pH-sensitive nanoparticles induced autophagy and decreased the intracellular pH, which in turn further facilitated the release of CUR to enhance autophagic activity. Transferring CBZP to orthotopic OS tumor-bearing mice showed powerful antitumor effects and established long-term immunity against tumor recurrence, accompanied by enhanced dendritic cell maturation and tumor infiltration of CD8+ T lymphocytes. Collectively, CBZP exhibited synergistic effects in treating OS by combining ICD induction with checkpoint blockade, thereby shedding light on the use of autophagy control as a potential clinical therapy for OS.
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Neoplasias Óseas , Estructuras Metalorgánicas , Osteosarcoma , Animales , Autofagia , Antígeno B7-H1/metabolismo , Neoplasias Óseas/terapia , Línea Celular Tumoral , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Ratones , Recurrencia Local de Neoplasia , Osteosarcoma/terapia , Receptor de Muerte Celular Programada 1 , Microambiente TumoralRESUMEN
Osteoporosis (OP) has the characteristics of a systematically impaired bone mass, strength, and microstructure. Long non-coding RNAs (lncRNAs) are longer than 200 nt, and their functions in osteoporosis is yet not completely understood. We first harvested the bone marrow mesenchymal stem cells (BMSCs) from ovariectomy (OVX) and sham mice. Then, we systematically analyzed the differential expressions of lncRNAs and messenger RNAs (mRNAs) and constructed lncRNA-mRNA coexpression network in order to identify the function of lncRNA in osteoporosis. Totally, we screened 743 lncRNAs (461 upregulated lncRNAs and 282 downregulated lncRNAs) and 240 mRNAs (128 upregulated and 112 downregulated) with significantly differential expressions in OP compared to normal. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses to investigate the functions and pathways of the differential expression of messenger RNAs (mRNAs), a coexpressed network of lncRNA/mRNA. Quantitative PCR (qPCR) validated that the expressions of NONMMUT096150.1, NONMMUT083450.1, and NONMMUT029743.2 were all downregulated, whereas NONMMUT026970.2, NONMMUT051734.2, NONMMUT003617.2, and NONMMUT034049.2 were all upregulated in the OVX group. NONMMUT096150.1, as a key lncRNA in OP, was identified to modulate the adipogenesis of BMSCs. Further analysis suggested that NONMMUT096150.1 might modulate the adipogenesis of BMSCs via the peroxisome proliferator-activated receptor (PPAR) signaling pathway, AMPK signaling pathway, and the lipolysis regulation in adipocyte and adipocytokine signaling pathway. Our study expands the understanding of lncRNA in the pathogenesis of OP.
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BACKGROUND: Osteonecrosis of the femoral head (ONFH) seriously affects the quality of life and labor ability of patients. It is urgent and vital to find the methods for necrosis clinical treatment. OBJECTIVE: This study aims to study the potential protective effects of Alendronate in the early stage of femur head necrosis. METHODS: Ten clinal ONFH tissue samples were employed. H&E staining was employed for the observation of the pathological characteristics of ONFH. The rat model (n=12) was established by the treatment of liquid nitrogen and then treated with Alendronate. The protein expression of BMP2, EIF2AK3, EIF2A and ATF4 were detected via Western blotting and IHC. RESULTS: Fibrin and necrotizing granulation tissue were observed in ONFH tissues with lymphocytes and plasma cells infiltrating in the necrotic area, exhibiting the inflammatory muscle with abnormal shape and color. In the Model group, the BMP2 and ATF4 were mainly distributed in the cell boundaries. The relative protein expression of BMP2, EIF2AK3, EIF2A, ATF4 was decreased in the Model group, compared to the NC group, which was partially recovered by the Alendronate application. CONCLUSION: Alendronate application partially reversed the suppression of expression of BMP2, EIF2AK3, EIF2A, ATF4 caused by liquid nitrogen. Alendronate could be a promising strategy of curing ONFH via targeting BMP2/EIF2AK3/EIF2A/ATF4 pathway.
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Factor de Transcripción Activador 4/metabolismo , Alendronato/farmacología , Proteína Morfogenética Ósea 2/metabolismo , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacos , eIF-2 Quinasa/metabolismo , Factor de Transcripción Activador 4/antagonistas & inhibidores , Factor de Transcripción Activador 4/genética , Animales , Proteína Morfogenética Ósea 2/antagonistas & inhibidores , Proteína Morfogenética Ósea 2/genética , Femenino , Necrosis de la Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/patología , Humanos , Masculino , Persona de Mediana Edad , Nitrógeno/farmacología , Osteonecrosis/tratamiento farmacológico , Osteonecrosis/metabolismo , Osteonecrosis/patología , Ratas , Ratas Sprague-Dawley , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/genéticaRESUMEN
The extracellular matrix (ECM) degradation of nucleus pulposus cells (NPCs) is mainly induced by metalloproteinases (MMPs). Zn2+ is an essential component of MMPs, but the effect of Zn2+ importers in controlling ECM metabolism remains unclear. The purpose of this research was to identify the involvement of Zn2+ importers in ECM degradation induced by inflammatory stimuli and excessive mechanical stressing. In this study, NPCs from Sprague-Dawley (SD) rats were separated and cultured. FluoZin-3 AM staining was applied to detect [Zn2+]i in NPCs treated with Interleukin-1ß (IL-1ß) or cyclic tensile strain (CTS) with a Flexcell Strain Unit. We found that intracellular Zn2+ concentration ([Zn2+]i) elevated dramatically, and ZIP8 is the predominant Zn2+ importer among all importers in senescent NPCs. The [Zn2+]i and MMP expression level both increased in IL-1ß and CTS treated NPCs. Furthermore, the expression of ZIP8 was also markedly increased. However, knockdown of ZIP8 with siRNA alleviated ECM degradation induced by inflammatory stimuli and CTS. Both stimuli activated NF-κB signaling pathway, and knockdown of ZIP8 effectively inhibited NF-κB signaling pathway activation. In conclusion, knockdown of ZIP8 can alleviate NPCs' ECM degradation caused by inflammatory stimuli and excessive mechanical stressing.
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Proteínas de Transporte de Catión/metabolismo , Matriz Extracelular/metabolismo , FN-kappa B/metabolismo , Núcleo Pulposo/metabolismo , Transducción de Señal , Animales , Proteínas de Transporte de Catión/deficiencia , Proteínas de Transporte de Catión/genética , Colágeno Tipo II/metabolismo , Técnicas de Silenciamiento del Gen , Inflamación/metabolismo , Masculino , Núcleo Pulposo/citología , Ratas , Zinc/metabolismoRESUMEN
Activated osteoclasts release large amounts of small extracellular vesicles (sEVs) during bone remodeling. However, little is known about whether osteoclast-derived sEVs affect surrounding cells. In this study, osteoclasts were generated by stimulating bone marrow macrophages (BMMs) with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear actor κB ligand (RANKL). We performed microarray analysis of sEV-microRNAs (miRNAs)s secreted from osteoclast at different stages and identified four miRNAs that were highly expressed in mature osteoclast-derived sEVs. One of these miRNAs, miR-324, significantly induced osteogenic differentiation and mineralization of primary mesenchymal stem cells (MSCs) in vitro by targeting ARHGAP1, a negative regulator of osteogenic differentiation. We next fabricated an sEV-modified scaffold by coating decalcified bone matrix (DBM) with osteoclast-derived sEVs, and the pro-osteogenic regeneration activities of the sEV-modified scaffold were validated in a mouse calvarial defect model. Notably, miR-324-enriched sEV-modified scaffold showed the highest capacity on bone regeneration, whereas inhibition of miR-324 in sEVs abrogated these effects. Taken together, our findings suggest that miR-324-contained sEVs released from mature osteoclast play an essential role in the regulation of osteogenic differentiation and potentially bridge the coupling between osteoclasts and MSCs.
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BACKGROUND: Long noncoding RNAs (lncRNAs) played a crucial role in a number of biological processes. lncRNA HAGLROS was demonstrated to facilitate cell proliferation and migration in various cancers. However, the functions and molecular mechanisms of HAGLROS in osteosarcoma remained to be elucidated. METHODS: qRT-PCR assay was used to detect the relative expression of HAGLROS in osteosarcoma tissue samples and cells. CCK-8 and Transwell assays were performed to assess the effects of HAGLROS on OS cells proliferation and invasion. Luciferase reporter assay verified the interaction between ROCK1 and miR-152. RESULTS: In our study, we found that the expression of HAGLROS increased osteosarcoma samples and cell lines compared with normal tissues and cells. HAGLROS knockdown inhibited certain functions of U2OS and SW1353 cells in vitro. Moreover, HAGLROS depletion inhibited tumor growth and metastasis in vivo. Mechanically, we found that HAGLROS sponged miR-152 to promote ROCK1 expression in U2OS and SW1353 cells. CONCLUSION: In summary, our study indicated that HAGLROS could promote osteosarcoma progression by sponging miR-152 to promote ROCK1 expression. The results showed HAGLROS/miR-152/ROCK1 axis might act as a novel therapeutic strategy for osteosarcoma.
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Neoplasias Óseas/genética , MicroARNs/genética , Osteosarcoma/genética , ARN Largo no Codificante/genética , Quinasas Asociadas a rho/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , MicroARNs/metabolismo , Invasividad Neoplásica/genética , Metástasis de la Neoplasia/genética , Osteosarcoma/metabolismo , Osteosarcoma/secundario , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/metabolismo , Regulación hacia ArribaRESUMEN
Osteosarcoma is a malignant tumor that seriously threatens human health. Numerous studies have pointed out the potential of long noncoding RNAs (lncRNAs) as new therapeutic targets for various human cancers. Therefore, we mainly investigate whether there is a new type of lncRNA pathway involved in regulating the development of osteosarcoma. The present study shows the higher expression levels of LINC00511 correlates to a shorter overall survival and disease-free survival time in patients with sarcoma. It is significantly higher in the clinical samples of osteosarcoma patients than in normal adjacent cancer tissues. We used U373 and SW1353 osteosarcoma cells to determine the effect of lncRNA on osteosarcoma proliferation and invasion by knocking down LINC00511 compared with controls. The results showed that the LINC00511 knockdown significantly suppressed osteosarcoma cell growth and metastasis. To explore the mechanisms of LINC00511 in osteosarcoma, we tested whether LINC00511 could competitively stimulate miR-185-3p and regulate E2F1 as a ceRNA. The results showed that LINC00511 knockdown induced the increased level of miR-185-3p levels; however, miR-185-3p overexpression suppressed LINC00511 levels. In addition, the results also demonstrated that LINC00511 knockdown or miR-185-3p overexpression could reduce E2F1 levels in osteosarcoma cells. The dual-luciferase reporter assay verified the direct interaction between miR-185-3p and LINC00511 or E2F1. These results may offer an explanation of how the lncRNA affects the progression of osteosarcoma, and our study shows that LINC00511 can be a novel biomarker in osteosarcoma.
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Carcinogénesis/genética , Factor de Transcripción E2F1/genética , MicroARNs/genética , Invasividad Neoplásica/genética , Osteosarcoma/genética , Osteosarcoma/patología , ARN Largo no Codificante/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , HumanosRESUMEN
As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. Nevertheless, how circRNAs participate in osteosarcoma (OS) development and progression are not well understood. In the present study, we identified a circRNA circFAT1(e2) with an upregulated expression level in OS tissues. By functional experiments, we found that circFAT1(e2) depletion significantly suppressed the proliferation and reduced migration in OS. In terms of mechanism, we found that circFAT1(e2) inhibited miR-181b, while miR-181b targeted HK2. By releasing the inhibition of miR-181b on HK2 expression, leading to attenuated OS progression. Mechanistic investigations suggested that circFAT1(e2) served as a competing endogenous RNA (ceRNA) of miR-181b to enhance HK2 expression. On the whole, our study indicated that circFAT1(e2) exerted oncogenic roles in OS and suggested the circFAT1(e2)/miR-181b/HK2 axis might be a potential therapeutic target.
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Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Hexoquinasa/metabolismo , MicroARNs/metabolismo , Osteosarcoma/genética , Osteosarcoma/patología , ARN Circular/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , MicroARNs/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , ARN Circular/genéticaRESUMEN
Recent studies have suggested that circular RNAs play an important role in the progression of various cancers. However, few studies have revealed the great value of circRNAs in the diagnosis and prognosis prediction of osteosarcoma (OS). In this study, we performed experiments with the human OS cell lines and the results showed that the expression of circHIPK3 in OS cell lines was significantly upregulated compared to that in the normal cell line. In addition, the results showed that circHIPK3 could promote the migration, invasion, and growth of OS cells. Furthermore, miR-637 was identified as a target of circHIPK3, while STAT3 was targeted by miR-637. circHIPK3 could promote STAT3 expression via interacting with miR-637 in OS cells. In conclusion, our research uncovered an important role of the circHIPK3/miR-637/STAT3 pathway in the migration and invasion of OS cells and suggested that circHIPK3 may be a prognostic marker and a promising therapeutic target for OS.
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Neoplasias Óseas/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Osteosarcoma/metabolismo , ARN Circular/metabolismo , ARN Neoplásico/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Línea Celular Tumoral , Humanos , MicroARNs/genética , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Osteosarcoma/genética , Osteosarcoma/patología , ARN Circular/genética , ARN Neoplásico/genética , Factor de Transcripción STAT3/genéticaRESUMEN
Nitroreductase (NTR) has been recognized as a biomarker for identifying the hypoxic status of cancers. Therefore, it is of high scientific interest to design effective fluorescent probes for tracking NTR activity. However, studies on elucidation of the structure-performance relationship of fluorescent probes and those providing valuable insight into optimized probe design have rarely been reported. Three BODIPY based fluorescent probes were made by conjugation of para-, ortho-, and meta-nitrobenzene to the BODIPY core via a thiolether bond, respectively. Our study revealed that the linkage and nitro substituent position significantly influence the capability of nitroreductase detection.
Asunto(s)
Biomarcadores de Tumor/análisis , Compuestos de Boro/química , Colorantes Fluorescentes/química , Neoplasias/diagnóstico por imagen , Nitrorreductasas/análisis , Biomarcadores de Tumor/metabolismo , Compuestos de Boro/síntesis química , Colorantes Fluorescentes/síntesis química , Humanos , Modelos Moleculares , Estructura Molecular , Nitrobencenos/química , Nitrorreductasas/metabolismoRESUMEN
Osteoporosis (OP) is a systemic skeletal disorder with the characteristics of bone mass reduction and microarchitecture deterioration, resulting in bone fragility and increased fracture risk. A reduction in the osteoblast-differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered as a basic pathogenesis of osteoporosis. miRNAs play a substantial role in the development and differentiation of BMSCs. In the present study, we found that miR-1-3p was significantly downregulated in the bones of Chinese osteoporotic patients (n = 29). Secreted frizzled-related protein 1 (SFRP1) was predicted as a target gene of miR-1-3p via the TargetScan and PicTar softwares and validated by dual-luciferase reporter assays. The findings revealed that the expression of SFRP1 was inversely correlated with miR-1-3p in osteoporotic patients. We induced mouse MSCs (mMSCs) to osteogenesis or adipogenesis and found that miR-1-3p was upregulated during osteogenesis but downregulated during adipogenesis. The overexpression of miR-1-3p stimulated osteogenesis and inhibited adipogenesis of mMSCs. In addition, ovariectomized (OVX) mice were tested and the function of miR-1-3p in vivo was explored. Immunohistochemistry and histomorphometric assays showed that in vivo inhibition of miR-1-3p increased the expression level of SFRP1 and reduced bone formation and bone mass. Furthermore, tartrate-resistant acid phosphatase (TRAP) staining indicated that the in vivo suppression of miR-1-3p promoted osteoclast activity, suggesting that miR-1-3p may influence bone mass by regulating bone resorption. It can be concluded that miR-1-3p plays a pivotal role in the pathogenesis of osteoporosis via targeting SFRP1 and may be a potential therapeutic target for osteoporosis.