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Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor ß. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy.
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Neoplasias Encefálicas/patología , Glioblastoma/patología , Células Madre Neoplásicas/patología , Pericitos/patología , Animales , Encéfalo/patología , Neoplasias Encefálicas/irrigación sanguínea , Diferenciación Celular , Células Endoteliales/patología , Glioblastoma/irrigación sanguínea , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Factor de Crecimiento Transformador beta/metabolismo , Trasplante HeterólogoRESUMEN
Hypoxia regulates tumor angiogenesis, metabolism, and therapeutic response in malignant cancers including glioblastoma, the most lethal primary brain tumor. The regulation of HIF transcriptional factors by the ubiquitin-proteasome system is critical in the hypoxia response, but hypoxia-inducible deubiquitinases that counteract the ubiquitination remain poorly defined. While the activation of ERK1/2 also plays an important role in hypoxia response, the relationship between ERK1/2 activation and HIF regulation remains elusive. Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. USP33 is preferentially induced in glioma stem cells by hypoxia and interacts with HIF-2alpha, leading to its stabilization through deubiquitination. The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33. Silencing of USP33 disrupted glioma stem cells maintenance, reduced tumor vascularization, and inhibited glioblastoma growth. Our findings highlight USP33 as an essential regulator of hypoxia response in cancer stem cells, indicating a novel potential therapeutic target for brain tumor treatment.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Neoplasias Encefálicas , Glioma , Células Madre Neoplásicas , Ubiquitina Tiolesterasa , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias Encefálicas/patología , Hipoxia de la Célula , Glioma/patología , Humanos , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
BACKGROUND: The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. METHODS: Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RTâPCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. RESULTS: Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. CONCLUSION: Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.
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Proteínas Portadoras , Ácidos Grasos , Proteínas de la Membrana , Proteínas de Neoplasias , Neoplasias Ováricas , Proteínas de Unión a Hormona Tiroide , Hormonas Tiroideas , Microambiente Tumoral , Femenino , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Animales , Hormonas Tiroideas/metabolismo , Ratones , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Línea Celular Tumoral , Ácidos Grasos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Efecto Warburg en Oncología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular , ProteoglicanosRESUMEN
BACKGROUND: Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. METHODS: The expression of ANGPTL4 was confirmed by bioinformatics and IHC in OC. The potential molecular mechanism of ANGPTL4 was measured by RNA-sequence. We used a series of molecular biological experiments to measure the ANGPTL4-JAK2-STAT3 and ANGPTL4-ESM1 axis in OC progression, including MTT, EdU, wound healing, transwell, xenograft model, oil red O staining, chick chorioallantoic membrane assay and zebrafish model. Moreover, the molecular mechanisms were confirmed by Western blot, Co-IP and molecular docking. RESULTS: Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving JAK2-STAT3 signaling pathway activation. The interaction between ANGPTL4 and ESM1 promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. CONCLUSION: Our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1.
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Cistadenocarcinoma Seroso , Janus Quinasa 2 , Neoplasias Ováricas , Factor de Transcripción STAT3 , Animales , Femenino , Humanos , Microambiente Tumoral , Simulación del Acoplamiento Molecular , Angiogénesis , Pez Cebra/metabolismo , Carcinogénesis , Proliferación Celular , Carcinoma Epitelial de Ovario , Neoplasias Ováricas/genética , Línea Celular Tumoral , Proteína 4 Similar a la Angiopoyetina/genética , Proteínas de Neoplasias , ProteoglicanosRESUMEN
8-oxo guanine DNA glycosylase (8-oxoG DNA glycosylase), a crucial DNA repair enzyme, is essential for maintaining genome integrity and preventing diseases caused by DNA oxidative damage. Imaging 8-oxoG DNA glycosylase in living cells requires a dependable technique. In this study, we designed a DNAzyme-modified DNA tetrahedral nanomachine (DTDN) powered by 8-oxoG restoration. Incorporating a molecular beacon probe (MB), the constructed platform was used for amplified in situ monitoring of 8-oxoG DNA glycosylase. Under normal conditions, duplexing with a complementary strand modified with two 8-oxoG sites inhibited the activity of DNAzyme. The restoration of DNAzyme activity by the repair of intracellular 8-oxoG DNA glycosylase on 8-oxoG bases can initiate a signal amplification reaction. This detection system can detect 8-oxoG DNA glycosylase activity linearly between 0 and 20 U mL-1, with a detection limit as low as 0.52 U mL-1. Using this method, we were able to screen 14 natural compounds and identify 6 of them as 8-oxoG DNA glycosylase inhibitors. In addition, a novel approach was utilized to assess the activity of 8-oxoG DNA glycosylase in living cells. In conclusion, this method provides a universal tool for monitoring the activity of 8-oxoG DNA glycosylase in vitro and in living cells, which holds great promise for elucidating the enzyme's functionality and facilitating drug screening endeavors.
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ADN Glicosilasas , ADN Catalítico , Reparación del ADN , Guanina , Evaluación Preclínica de Medicamentos , ADN , ADN-Formamidopirimidina GlicosilasaRESUMEN
In the deep-sea environment, the volume available for an in-situ gene sequencer is severely limited. In addition, optical imaging systems are subject to real-time, large-scale defocusing problems caused by ambient temperature fluctuations and vibrational perturbations. To address these challenges, we propose an edge detection algorithm for defocused images based on grayscale gradients and establish a defocus state detection model with nanometer resolution capabilities by relying on the inherent critical illumination light field. The model has been applied to a prototype deep-sea gene sequencing microscope with a 20× objective. It has demonstrated the ability to focus within a dynamic range of ±40 µm with an accuracy of 200 nm by a single iteration within 160 ms. By increasing the number of iterations and exposures, the focusing accuracy can be refined to 78 nm within a dynamic range of ±100 µm within 1.2 s. Notably, unlike conventional photoelectric hill-climbing, this method requires no additional hardware and meets the wide dynamic range, speed, and high-accuracy autofocusing requirements of deep-sea gene sequencing in a compact form factor.
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Algoritmos , Microscopía/métodos , Microscopía/instrumentación , Iluminación/instrumentación , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ADN/instrumentaciónRESUMEN
The gas chromatography-ion mobility spectrometry (GC-IMS) method is a new technology for detecting volatile organic compounds. This study was carried out to evaluate the effects of volatile aroma compounds of Curcuma essential oils (EOs) after 60Co radiation by GC-IMS. Dosages of 0, 5, and 10 kGy of 60Co were used to analyze EOs of Curcuma after 60Co irradiation (named EZ-1, EZ-2, and EZ-3). The odor fingerprints of volatile organic compounds in different EOs of Curcuma samples were constructed by headspace solid-phase microextraction and GC-IMS after irradiation. The differences in odor fingerprints of EOs were compared by principal component analysis (PCA). A total of 92 compounds were detected and 65 compounds were identified, most of which were ketones, aldehydes, esters, and a small portion were furan compounds. It was found that the volatile matter content of 0 kGy and 5 kGy was closer, and the use of 10 kGy 60Co irradiation would have an unstable effect on the EOs. In summary, it is not advisable to use a higher dose when using 60Co irradiation for sterilization of Curcuma. Due to the small gradient of irradiation dose used in the experiment, the irradiation dose can be adjusted appropriately according to the required sterilization requirements during the production and storage process of Curcuma to obtain the best irradiation conditions. GC-IMS has the advantages of GC's high separation capability and IMS's fast response, high resolution, and high sensitivity, and the sample requires almost no pretreatment; it can be widely used in the analysis of traditional Chinese medicines containing volatile components. It is shown that irradiation technology has good application prospects in the sterilization of traditional Chinese medicines, but the changes in irradiation dose and chemical composition must be paid attention to.
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Aceites Volátiles , Compuestos Orgánicos Volátiles , Aceites Volátiles/análisis , Cromatografía de Gases y Espectrometría de Masas/métodos , Curcuma/química , Compuestos Orgánicos Volátiles/análisis , Microextracción en Fase Sólida/métodosRESUMEN
Ampelopsis grossedentata is a valuable medicinal and edible plant, which is often used as a traditional tea by the Tujia people in China. A. grossedentata has numerous biological activities and is now widely used in the pharmaceutical and food industries. In this study, two new flavonoids (1-2) and seventeen known compounds (3-19) were isolated and identified from the dried stems and leaves of A. grossedentata. These isolated compounds were characterized by various spectroscopic data including mass spectrometry and nuclear magnetic resonance spectroscopy. All isolates were assessed for their α-glucosidase inhibitory, antioxidant, and hepatoprotective activities, and their structure-activity relationships were further discussed. The results indicated that compound 1 exhibited effective inhibitory activity against α-glucosidase, with an IC50 value of 0.21 µM. In addition, compounds 1-2 demonstrated not only potent antioxidant activities but also superior hepatoprotective properties. The findings of this study could serve as a reference for the development of A. grossedentata-derived products or drugs aimed at realizing their antidiabetic, antioxidant, and hepatoprotective functions.
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Ampelopsis , Antioxidantes , Inhibidores de Glicósido Hidrolasas , alfa-Glucosidasas , Ampelopsis/química , Antioxidantes/farmacología , Antioxidantes/química , Flavonoides/química , Extractos Vegetales/química , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacologíaRESUMEN
A new methodology was developed to print pizza dough with a gluten free flour blend or commercial gluten whole wheat flour using extrusion-based 3-D printing technology. Their physical properties were compared to commercially available pizza dough and crust. The optimized nozzle size, print speed, ingredient flow speed, and line thickness for the 3-D printing of pizza dough were: 0.04 cm, 800 cm/minutes, 1.8, and 0.34 cm, respectively. The printed gluten-free pizza dough required 120 min of fermentation to obtain a comparable color and textural profile (P < 0.05) to that of the gluten whole wheat flour dough fermented for 60 min. The 3-D printed gluten free, whole-wheat pizza and commercially available wheat flour dough and standard crusts demonstrated identical Δ E ab ∗ values of 0.14 and 0.13, respectively with brownness index (BI) values of 1.47 and 1.62, respectively. Textural profile analysis (TPA) of 3-D printed gluten free and whole wheat pizza dough, crust and the commercial standard wheat flour pizza dough and crust demonstrated significant (P < 0.05) correlations in terms of hardness, fracturability, adhesiveness, springiness, cohesiveness, chewiness, and resilience. An optimized method was developed to prepare gluten-free pizza dough and crust with similar functional properties to that of gluten whole wheat flour dough and crust.
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BACKGROUND: Chemotherapy is a common approach for cancer treatment, but intrinsic genetic mutations in different individuals may cause different responses to chemotherapy, resulting in unique histopathological changes. The genetic mutation along with the distinct histopathological features may indicate new tumor entities. BCOR-CCNB3 sarcomas is a kind of Ewing-like sarcomas (ELS) occurring mostly in bone and soft tissues. No gene fusion other than BCOR-CCNB3 has been found in this type of tumor. CASE PRESENTATION: We herein report a case of 17-year-old male patient, presented with a mass on his left shoulder that was diagnosed as undifferentiated small round cell sarcoma according to core biopsy. The patient received 5 courses of preoperational chemotherapy, and the tumor was resected and analyzed. Primitive small round cells and larger myoid cells in the resected tumor tissue but not in biopsy were observed, and arterioles stenosis and occlusion were also detected, indicating a dramatic change of histopathological features of this tumor. In addition, the immunohistochemical results showed the altered staining patterns of BCOR, bcl2, CyclinD1, TLE1, AR, SMA, CD117, STAB2, CD56, and CD99 in tumor tissues after chemotherapy. Notably, RNA sequencing revealed a RNF213-SLC26A11 fusion in the tumor sample. CONCLUSIONS: The BCOR-CCNB3 sarcoma with RNF213-SLC26A11 fusion may indicate a subset of tumors that undergo histopathological changes in response to chemotherapy. More similar cases in the future may help to clarify the clinical meanings of RNF213-SLC26A11 fusion in BCOR-CCNB3 sarcomas and the underlying mechanisms.
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Neoplasias Óseas , Sarcoma , Neoplasias de los Tejidos Blandos , Adenosina Trifosfatasas/genética , Adolescente , Biomarcadores de Tumor/genética , Neoplasias Óseas/patología , Ciclina B/genética , Fusión Génica , Humanos , Masculino , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
This work proposes and demonstrates a novel interferometric sensor based on a zigzag-shaped tapered optical microfiber (Z-OMF) working at the dispersion turning point (DTP). The Z-OMF can be fabricated in a controllable manner through a modified fiber tapering method. Our study shows that the bending taper can transfer a portion of the fundamental HE11 mode to higher-order modes, and when the bending angle of the Z-OMF reaches 1.61°, high contrast interference fringes can be formed between the HE11 and the HE21 modes. More importantly, we find that by optimizing the diameter of the OMF, the group effective refractive index (RI) difference between HE11 and HE21 mode equals zero, and the refractive index sensing performance can be dramatically improved. To validate our proposed sensing mechanism, we experimentally demonstrate an ultrahigh sensitivity of 1.46×105 ± 0.09×105 nm/RIU. The proposed Z-OMF interferometer has the advantage of high sensitivity and low cost and shows excellent potential in chemical and biological detection.
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Desmoplastic myxoid tumor (DMT), SMARCB1 mutant is a recently proposed new entity that mainly occurs in the pineal region and has epigenetic features similar to those of atypical teratoid/rhabdoid tumors (AT/RT)-MYC and poorly differentiated chordomas. Herein, we present a new case of a 33-year-old man with headaches, dizziness, nausea, vomiting, and blurred vision, who was initially found to have a suspicious germinoma on imaging. After surgical removal of the lesion, the postoperative pathological diagnosis was DMT, SMARCB1 mutant. To the best of our knowledge, this is the first case reported in China. Our findings also extend the range of the immunohistochemical phenotype of this rare tumor.
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Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Mutación/genética , Glándula Pineal/diagnóstico por imagen , Proteína SMARCB1/genética , Adulto , Neoplasias Encefálicas/cirugía , Humanos , Masculino , Glándula Pineal/cirugía , Tumor Rabdoide/diagnóstico por imagen , Tumor Rabdoide/genética , Tumor Rabdoide/cirugía , Teratoma/diagnóstico por imagen , Teratoma/genética , Teratoma/cirugíaRESUMEN
Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98-7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00-7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38-4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI.
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Insuficiencia Ovárica Primaria , Oligoelementos , Estudios de Casos y Controles , China , Femenino , Hormona Folículo Estimulante , HumanosRESUMEN
Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape through multiple mechanisms including suppressing antitumor activities of T lymphocytes. However, therapeutic abrogation of MDSCs often causes severe adverse effects, compensatory recruitment of alternative cell populations, and the multiplicity and complexity of relevant cytokines/receptors. Alternatively, suppressing the expansion and tumor trafficking of MDSCs may be a proficient and safe way for cancer treatment. Here we report that pseudoneutrophil cytokine sponges (pCSs) can disrupt expansion and tumor trafficking of MDSCs and reverse immune tolerance. Coated with plasma membranes of neutrophils phenotypically and morphologically similar to polymorphonuclear MDSCs (PMN-MDSCs), the nanosized pCSs inherited most membrane receptors from the "parental" neutrophils, enabling the neutralization of MDSC-related cytokines. Upon pCSs administration, the expansion of MDSCs and their enrichment in peripheral lymphoid organs and tumors were reduced without the compensatory influx of alternative myeloid subsets. In murine breast cancer and melanoma syngeneic models, pCSs treatment dramatically increased the number of tumor-infiltrating T lymphocytes and restored their antitumor functions. In addition, when pCSs were combined with the programmed cell death protein 1 (PD-1), the immune checkpoint blockade synergistically suppressed tumor progression and prolonged animal survival. Overall, the pseudocell nanoplatform opens up new paths toward effective cancer immunotherapy.
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Citocinas , Inmunoterapia , Neoplasias Mamarias Experimentales , Melanoma Experimental , Neutrófilos/inmunología , Animales , Línea Celular Tumoral , Citocinas/inmunología , Citocinas/farmacología , Implantes de Medicamentos/farmacología , Femenino , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/terapia , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos ICR , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Neutrófilos/patología , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs) has been regarded as a central issue in fracture healing. MicroRNAs (miRNAs, miRs) participate in diverse physiological processes such as osteoblastic differentiation of BMSCs. In this study, we found that miR-664a-5p was upregulated during osteogenic differentiation of human BMSCs, and this upregulation positively correlated with the expression of osteogenic genes Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and osteocalcin (OCN). Overexpression of miR-664a-5p promoted the osteogenic differentiation of BMSCs, whereas a knockdown of miR-664a-5p suppressed it. Additionally, high-mobility group A2 (HMGA2) mRNA was identified as a direct target of miR-664a-5p that mediates the function of this miRNA. Overexpression of HMGA2 obviously attenuated miR-664a-5p-induced osteogenic differentiation of BMSCs. Thus, the newly identified miR-664a-5p-HMGA2 pathway expands our understanding of the mechanisms underlying the osteogenic differentiation of human BMSCs, may provide deeper insights into the regulation of this differentiation, and can point to new effective methods for treating osteoporosis.
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Regulación hacia Abajo , Proteína HMGA2/metabolismo , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Médula Ósea/metabolismo , Diferenciación Celular , Células Cultivadas , Humanos , Células Madre Mesenquimatosas/citología , MicroARNs/genética , OsteogénesisRESUMEN
Transmembrane protein 18 (Tmem18) is an obesity-associated gene essential for adipogenesis; however, its function in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) is still unclear. In this study, we found that Tmem18 was significantly downregulated in rat BMSCs after osteogenic induction. TMEM18 overexpression remarkably downregulated osteo-specific genes including alkaline phosphatase (Alp), Runt-related transcription factor 2 (Runx2), osteocalcin (Ocn), and osteopontin (Opn), and reduced the number of mineral deposits and ALP activity in vitro, whereas knockdown of Tmem18 yielded the opposite results. In vivo assays also indicated that TMEM18 knockdown BMSCs have an increased bone formation potential in a rat model of calvarial defects. Analyses of the mechanism suggested that TMEM18 overexpression decreased ß-catenin expression, whereas the TMEM18 knockdown enhanced ß-catenin expression and promoted its nuclear translocation. The positive effects on osteogenic differentiation of rat BMSCs owing to the TMEM18 knockdown were attenuated by ß-catenin downregulation. Taken together, these results indicate that TMEM18 plays an inhibitory role in osteogenic differentiation of BMSCs via inactivation of ß-catenin.
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Diferenciación Celular/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Células Madre Mesenquimatosas/citología , Osteoblastos/citología , Osteogénesis , beta Catenina/antagonistas & inhibidores , Animales , Células Cultivadas , Regulación hacia Abajo , Proteínas de la Membrana/administración & dosificación , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Objective: To assess the clinical utility of the ratio of CD4+CD25+CD127low regulatory T cells (Tregs) in subjects at high risk of HCC, investigate the relationship between the percentage of Tregs and the expression of transforming growth factor (TGF)-ß1 and interleukin (IL)-10 in patients with hepatocellular carcinoma before and after treatment. Methods: Peripheral venous blood was collected from patients with liver cancer before and after treatment. The proportion of CD4+CD25+CD127low Tregs was detected by flow cytometry. The levels of TGF-ß1 and IL-10 in serum were detected by enzyme-linked immunosorbent assay, and were compared with healthy subjects as a control group. Results: The proportion of CD4+CD25+CD127low to CD4+T lymphocytes in patients with hepatocellular carcinoma was significantly higher than that in healthy controls (P<0.01). The proportion of CD4+CD25+CD127lowTregs, whose AUC of ROC curve was 0.917, could effectively separate the HCC patients from the healthy subjects with a diagnostic sensitivity of 90%, specificity of 80%. The proportion of CD4+CD25+CD127low to CD4+T lymphocytes and the levels of TGF-ß1 and IL-10 in patients with hepatocellular carcinoma after the operation and chemotherapy were significantly lower than those before treatment (P<0.05).The proportion of CD4+CD25+CD127lowTregs was positively correlated with the concentrations of TGF-ß1 and IL-10 before and after treatment of primary liver cancer (P<0.05). Conclusion: CD4+CD25+CD127lowTregs may be a significant predictor of HCC biopsy outcome and play an inhibitory role on effector T cells by regulating cytokines.
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Carcinoma Hepatocelular/sangre , Neoplasias Hepáticas/sangre , Hígado/metabolismo , Linfocitos T Reguladores/inmunología , Adulto , Biopsia , Antígenos CD4/sangre , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Femenino , Citometría de Flujo , Humanos , Interleucina-10/sangre , Subunidad alfa del Receptor de Interleucina-2/sangre , Subunidad alfa del Receptor de Interleucina-7/sangre , Hígado/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta1/sangreRESUMEN
The microvascular profile has been included in the WHO glioma grading criteria. Nevertheless, microvessels in gliomas of the same WHO grade, e.g., WHO IV glioblastoma (GBM), exhibit heterogeneous and polymorphic morphology, whose possible clinical significance remains to be determined. In this study, we employed a fractal geometry-derived parameter, microvascular fractal dimension (mvFD), to quantify microvessel complexity and developed a home-made macro in Image J software to automatically determine mvFD from the microvessel-stained immunohistochemical images of GBM. We found that mvFD effectively quantified the morphological complexity of GBM microvasculature. Furthermore, high mvFD favored the survival of GBM patients as an independent prognostic indicator and predicted a better response to chemotherapy of GBM patients. When investigating the underlying relations between mvFD and tumor growth by deploying Ki67/mvFD as an index for microvasculature-normalized tumor proliferation, we discovered an inverse correlation between mvFD and Ki67/mvFD. Furthermore, mvFD inversely correlated with the expressions of a glycolytic marker, LDHA, which indicated poor prognosis of GBM patients. Conclusively, we developed an automatic approach for mvFD measurement, and demonstrated that mvFD could predict the prognosis and response to chemotherapy of GBM patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas , Glioma , Interpretación de Imagen Asistida por Computador/métodos , Microvasos/patología , Neovascularización Patológica/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Fractales , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Inmunohistoquímica , Microvasos/diagnóstico por imagen , Clasificación del Tumor/métodos , Neovascularización Patológica/diagnóstico por imagen , PronósticoRESUMEN
BACKGROUND: Colorectal cancer (CRC) is a heterogeneous disease with distinct clinical subsets based on underlying genetic and epigenetic changes. DNA hypermethylation yields a unique CRC subset with a distinct phenotype and clinical behaviour, but this oncogenic pathway is not fully characterised. This study identifies and characterises miR-1247 as a novel tumour suppressor microRNA in methylated human colon cancers. METHOD: Tumour samples from patients with hypermethylated and non-methylated colon cancer and cell lines were evaluated for miR-1247 expression and function. A murine subcutaneous xenograft model was used for in vivo functional studies. RESULTS: miR-1247 was methylated and underexpressed in methylator colon cancers. Overexpression of miR-1247 significantly inhibited cell proliferation, decreased tumour cell motility, induced apoptosis, and mitigated tumour formation capacity both in vivo and in vitro. Pharmacologic demethylation increased miR-1247 expression and produced similar anti-tumour activities. Mechanistic investigations revealed that MYCBP2, a member of the c-myc oncogene family, is a direct functional target of miR-1247. Furthermore, in CRC patients, MYCBP2 protein levels are associated with miR-1247 levels and survival. CONCLUSIONS: miR-1247 acts as a tumour suppressor by inhibiting MYCBP2 in methylator colon cancer. The MYCBP2/c-myc axis may underlie the anti-tumour activities of miR-1247 and is a potential therapeutic target via demethylation agents.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias del Colon/genética , Metilación de ADN , Epigénesis Genética , Genes Supresores de Tumor , MicroARNs/genética , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Xenoinjertos , Humanos , Ratones , Ratones DesnudosRESUMEN
A photonic nanojet generated by the transparent dielectric microparticle (microsphere or microcylinder) is a sub-wavelength focused beam. The properties of the photonic nanojet have been modified by changing the refractive index and structure of the micropaticles. In this Letter, a super-narrow photonic nanojet with a full width at half-maximum waist of approximately 116.6 nm (λ/4.3, with 500 nm excitation wavelength) is obtained by a horizontal graded-index microcylinder, which is divided by multilayers parallel to the direction of light propagation. The method for side lobes controlling by the waves' superposition from the modified graded refractive index and that of the center layer is proposed and discussed. Also, a structure with the composition of different height plates approaching the desired circular section is suggested for decreasing the difficulties in fabrication, and generates a similar photonic nanojet.