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1.
Adv Mater ; 32(24): e2000416, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32374446

RESUMO

Small interfering RNA (siRNA) has been considered as a highly promising therapeutic agent for human cancer treatment including glioblastoma (GBM), which is a fatal disease without effective therapy methods. However, siRNA-based GBM therapy is seriously hampered by a number of challenges in siRNA brain delivery including poor stability, short blood circulation, low blood-brain barrier (BBB) penetration, and tumor accumulation, as well as inefficient siRNA intracellular release. Herein, an Angiopep-2 (Ang) functionalized intracellular-environment-responsive siRNA nanocapsule (Ang-NCss (siRNA)) is successfully developed as a safe and efficient RNAi agent to boost siRNA-based GBM therapy. The experimental results demonstrate that the developed Ang-NCss (siRNA) displays long circulation in plasma, efficient BBB penetration capability, and GBM accumulation and retention, as well as responsive intracellular siRNA release due to the unique design of small size (25 nm) with polymeric shell for siRNA protection, Ang functionalization for BBB crossing and GBM targeting, and disulfide bond as a linker for intracellular-environment-responsive siRNA release. Such superior properties of Ang-NCss (siRNA) result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effects, achieving remarkably improved survival benefits. The developed siRNA nanocapsules provide a new strategy for RNAi therapy of GBM and beyond.

2.
Medicine (Baltimore) ; 99(5): e18646, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000369

RESUMO

INTRODUCTION: Clear cell adenocarcinoma of the cervix (CCAC), a rare and more severe type of gynecological cancer, is especially rare in pediatric patients. Traditionally, surgery following chemotherapy (CT) and radiation therapy is the preferred treatment for CCAC; however, patients have poor 5-year survival rates than other types of cervical cancers. PATIENT CONCERNS: A 6-year-old girl with a history of vaginal discharge for 18 months was diagnosed with CCAC by histological examination. Her parents refused the traditional treatment of radical hysterectomy and lymph node dissection because of her young age. DIAGNOSIS: The patient's tests revealed negative human papilloma virus and negative methylated paired box 1 gene results. The tumor mass histopathology revealed stage IIA1 CCAC that originated from the cervix. INTERVENTIONS: Tumor mass excision with preservation of the cervix by electrosurgical biopsy under hysteroscopy was performed. Four cycles of docetaxel and oxaliplatin CT were administered every 3 weeks. OUTCOMES: No signs of recurrence were observed in the 28 months after final treatment and diagnosis on magnetic resonance imaging, color ultrasonic imaging, and gynecological examination. Serologic tumor biomarkers were also within normal ranges. CONCLUSIONS: This is the first reported CCAC case in which the primary treatment included electrosurgical biopsy of the polypoid mass under hysteroscopy, followed by CT without traditional treatment: radical surgery with pelvic and/or lymphadenectomy for fertility preservation. This is a new treatment approach for young CCAC patients without the use of surgery.


Assuntos
Adenocarcinoma/cirurgia , Histeroscopia , Tratamentos com Preservação do Órgão , Neoplasias do Colo do Útero/cirurgia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Antineoplásicos/uso terapêutico , Colo do Útero/patologia , Criança , Docetaxel/uso terapêutico , Feminino , Humanos , Oxaliplatina/uso terapêutico , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
4.
Biomaterials ; 229: 119576, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31704467

RESUMO

Dual-modal imaging guided photodynamic therapy (PDT) of multifunctional nanocomposites holds great promise for precision tumor theranostics. However, poor heterogeneous interfacial compatibility between functional components, low hydrophilicity and complicated preparation of nanocomposites remain major obstacles for further bioapplication. Herein, a facile central metal-derived co-assembly strategy is developed to effectively integrate gadolinium porphyrin (GdTPP) contrast agent and Zinc porphyrin (ZnTPP) photosensitizer into a homogeneous GdTPP/ZnTPP nanocomposites (GZNs). GZNs possesses the following advantages: (1) Greatly improved interfacial compatibility facilitated by incorporating two metalporphyrins with same group (phenyl-) and different central metal atoms (Zn and Gd) leading to higher yield (4.7-5 fold) than either monocomponent nanoparticles. (2) Poor dispersity of GdTPP nanoparticles is greatly improved after integrating with ZnTPP blocks. (3) The GZNs inherit excellent fluorescence imaging, high relaxation rate (8.18 mM-1 s-1) and singlet oxygen production from two raw metalporphyrins. After camouflaging with homotypic cancer cell membrane for immunologic escape, the HeLa membrane coated GZNs (mGZNs) show enhanced in vivo MR/FL imaging guided anti-tumor targeting efficiency of 80.6% for HeLa cells. Our new strategy using central metal-derived co-assembly of homogeneous building blocks greatly improves interfacial compatibility to achieve combined functions for visualized cancer theranostics.

5.
Adv Mater ; 31(37): e1903277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348581

RESUMO

Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at-site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I-NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I-NM@siRNA nanomedicine demonstrates effective at-site siRNA release resulting from tumoral reactive oxygen species (ROS)-triggered sequential destabilization. Furthermore, the utility of 3I-NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I-NM@siRNA nanomedicine with angiopep-2 peptide is enhanced. The targeted Ang-3I-NM@siRNA exhibits superb blood-brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo-like kinase 1 and vascular endothelial growth factor receptor-2, Ang-3I-NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple-interaction stabilization together with inbuilt self-destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.


Assuntos
Terapia Genética , Glioblastoma/terapia , Nanomedicina , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Terapia Combinada , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos
6.
Life Sci ; 232: 116648, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301414

RESUMO

AIMS: Laminin γ2 (LAMC2) is over-expressed in ovarian cancer, and its high expression facilitates cell invasion. Nevertheless, the effects of LAMC2 on other ovarian cancer cell functions and its underlying mechanism remain largely unclear. Bioinformatics analysis shows that LAMC2 is a predicted target of miR-125a-5p and miR-193a-3p. Therefore, the present study aimed to investigate the effects of LAMC2 in ovarian cancer progression and determine whether LAMC2 expression is under the regulation of miR-125a-5p or miR-193a-3p in ovarian cancer. MATERIALS AND METHODS: Immunohistochemistry staining, western blot and qPCR were used to detect LAMC2 expression profiles. CCK-8, flow cytometry and tumour formation assays were used to assess cell proliferation, apoptosis and tumorigenesis. The interaction between miR-125a-5p/miR-193a-3p and LAMC2 were determined by the luciferase gene reporter assay. KEY FINDINGS: The results showed that LAMC2 was over-expressed in ovarian cancer tissues and cell lines. Over-expression of LAMC2 significantly promoted cell proliferation and repressed cell apoptosis, as well as increased the expression levels of p38, p-p38, c-myc and CREB, and translocated p38 protein to the nucleus. In addition, the promotion of cell proliferation and repression of cell apoptosis mediated by LAMC2 over-expression were all weakened when p38 was downregulated. Moreover, LAMC2 expression was negatively regulated by miR-125a-5p, which inhibited the nuclear accumulation of p38 protein. Upregulation of LAMC2 significantly abolished the effects of miR-125a-5p on cell proliferation inhibition and cell apoptosis promotion, as well as tumourigenesis repression. SIGNIFICANCE: The present study clarified that LAMC2 functioned as an oncogene in ovarian cancer through upregulating p38 under the regulation of miR-125a-5p.


Assuntos
Laminina/fisiologia , MicroRNAs/fisiologia , Neoplasias Ovarianas/patologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética
7.
J Cell Biochem ; 120(10): 17303-17311, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31106485

RESUMO

SR splicing-factors (SRSFs) play a vital role in carcinogenesis. SRSF5 was demonstrated to be upregulated in lung cancer and identified as a novel prognostic indicator for small-cell lung cancer. However, the role of SRSF5 in the pathogenesis of non-small cell lung cancer (NSCLC) and the molecular mechanism involved are still undefined. The expression of SRSF5 in NSCLC cells was detected by quantitative real-time polymerase chain reaction and Western blot analysis. The proliferation of cells was evaluated by cell counting kit-8 and BrdU assays. Apoptosis was assessed by flow cytometry and Western blot analysis of apoptosis-associated proteins including B-cell lymphoma 2 (Bcl-2), Bax, and cytochrome C (Cyt C). Glycolysis was detected by determining glucose consumption, lactate production, and pyruvate kinase M2 (PKM2) expression. We found that SRSF5 messenger RNA and protein levels were elevated in NSCLC cells. SRSF5 knockdown inhibited the proliferation and Ki67 expression in NSCLC cells. SRSF5 silencing increased the apoptotic rate, upregulated Bax and Cyt C, and decreased Bcl-2 level in NSCLC cells. Moreover, Knockdown of SRSF5 repressed glycolysis in NSCLC cells via reducing PKM2 expression. Enhanced glycolysis by PKM2 overexpression attenuated the effects of SRSF5 silencing on NSCLC cell proliferation and apoptosis. Overall, knockdown of SRSF5 inhibited proliferative ability and induced apoptosis by suppressing PKM2 expression in NSCLC cells.

8.
Arthritis Res Ther ; 21(1): 105, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023362

RESUMO

INTRODUCTION: Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristane-induced LN in mice. METHODS: The renoprotective effect of baicalein was detected in a pristane-induced lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed. RESULTS: Baicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome. CONCLUSION: The data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.


Assuntos
Flavanonas/uso terapêutico , Heme Oxigenase-1/metabolismo , Nefrite Lúpica/metabolismo , Proteínas de Membrana/metabolismo , Células Supressoras Mieloides/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Terpenos/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Imunossupressores/toxicidade , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/efeitos dos fármacos , Antagonistas de Prostaglandina/farmacologia , Antagonistas de Prostaglandina/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
10.
Adv Mater ; 30(51): e1803717, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30328157

RESUMO

Glioblastoma multiforme (GBM) is a fatal central nervous system tumor without effective treatment. Chemotherapeutic agents are mainstays in the treatment of glioblastoma. However, the effectiveness of these is seriously hindered by poor blood-brain-barrier (BBB) penetrance and tumor targeting, together with short biological half-life. Improved chemotherapy is thus urgently needed for GBM. Multifunctional nanoparticle delivery systems offer much promise in overcoming current limitations. Accordingly, a multifunctional biomimetic nanomedicine is developed by functionalizing the surface of red blood cell membranes (RBCms) with angiopep-2 and loading pH-sensitive nanoparticles (polymer, doxorubicin (Dox), and lexiscan (Lex)) using the functionalized cell membrane to generate the novel nanomedicine, Ang-RBCm@NM-(Dox/Lex). The studies toward orthotopic U87MG human glioblastoma tumor-bearing nude mice show that the Ang-RBCm@NM-(Dox/Lex) nanomedicine has much improved blood circulation time, superb BBB penetration, superior tumor accumulation and retention. Moreover, effective suppression of tumor growth and significantly improved medium survival time are also observed after Ang-RBCm@NM-(Dox/Lex) treatment. The results show that this biomimetic nanoplatform can serve as a flexible and powerful system for GBM treatment which can be readily adapted for the treatment of other central nervous system (CNS) disorders.


Assuntos
Materiais Biomiméticos/química , Transformação Celular Neoplásica , Glioblastoma/patologia , Nanomedicina/métodos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Eritrócitos/citologia , Humanos , Camundongos , Peptídeos/metabolismo
11.
Cell Physiol Biochem ; 49(4): 1289-1303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30205383

RESUMO

BACKGROUND/AIMS: The long noncoding RNA homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) has been demonstrated to be a vital modulator in the proliferation and metastasis of ovarian cancer cells, but its potential molecular mechanism remains to be elucidated. In the current study, we aimed to uncover the biological role of lncRNA HOTAIR and its underlying regulatory mechanism in the progression and metastasis of ovarian cancer. METHODS: HOTAIR expression was detected by quantitative RT-PCR (qRT-PCR) and northern blotting. The SKOV3 ovarian cancer cell line was chosen for the subsequent assays. In addition, the molecular mRNA and protein expression levels were examined by qRT-PCR and western blotting. The competitive endogenous RNA (ceRNA) mechanism was validated by bioinformatics analysis and a dual luciferase reporter gene assay. RESULTS: HOTAIR expression was significantly higher in ovarian carcinoma tissues and cell lines than in the control counterparts. Both CCND1 and CCND2 were downstream targets of miR-206. The inhibition of HOTAIR elevated the expression of miR-206 and inhibited the expression of CCND1 and CCND2. Moreover, CCND1 and CCND2 were highly expressed in ovarian cancer tissues, and their expression was positively correlated with HOTAIR expression. Finally, the functional assays indicated that the anticancer effects of miR-206 could be rescued by the simultaneous overexpression of either CCND1 or CCND2 in ovarian cancer. CONCLUSION: HOTAIR enhanced CCND1 and CCND2 expression by negatively modulating miR-206 expression and stimulating the proliferation, cell cycle progression, migration and invasion of ovarian cancer cells.


Assuntos
Ciclina D1/metabolismo , Ciclina D2/metabolismo , MicroRNAs/metabolismo , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular , Ciclina D1/antagonistas & inibidores , Ciclina D1/genética , Ciclina D2/antagonistas & inibidores , Ciclina D2/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Alinhamento de Sequência
12.
Theranostics ; 8(14): 3932-3948, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30083271

RESUMO

Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors, including colorectal cancer (CRC). The crosstalk between carcinoma- associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment promotes tumor development and confers chemoresistance. In this study, we further investigated the underlying tumor-promoting roles of CAFs and the molecular mediators involved in these processes. Methods: The AOM/DSS-induced colitis-associated cancer (CAC) mouse model was established, and RNA sequencing was performed. Small interfering RNA (siRNA) sequences were used to knock down H19. Cell apoptosis was measured by flow cytometry. SW480 cells with H19 stably knocked down were used to establish a xenograft model. The indicated protein levels in xenograft tumor tissues were confirmed by immunohistochemistry assay, and cell apoptosis was analyzed by TUNEL apoptosis assay. RNA-FISH and immunofluorescence assays were performed to assess the expression of H19 in tumor stroma and cancer nests. The AldeRed ALDH detection assay was performed to detect intracellular aldehyde dehydrogenase (ALDH) enzyme activity. Isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking and Western blotting. Results: H19 was highly expressed in the tumor tissues of CAC mice compared with the expression in normal colon tissues. The up-regulation of H19 was also confirmed in CRC patient samples at different tumor node metastasis (TNM) stages. Moreover, H19 was associated with the stemness of colorectal cancer stem cells (CSCs) in CRC specimens. H19 promoted the stemness of CSCs and increased the frequency of tumor-initiating cells. RNA-FISH showed higher expression of H19 in tumor stroma than in cancer nests. Of note, H19 was enriched in CAF-derived conditioned medium and exosomes, which in turn promoted the stemness of CSCs and the chemoresistance of CRC cells in vitro and in vivo. Furthermore, H19 activated the ß-catenin pathway via acting as a competing endogenous RNA sponge for miR-141 in CRC, while miR-141 significantly inhibited the stemness of CRC cells. Conclusion: CAFs promote the stemness and chemoresistance of CRC by transferring exosomal H19. H19 activated the ß-catenin pathway via acting as a competing endogenous RNA sponge for miR-141, while miR-141 inhibited the stemness of CRC cells. Our findings indicate that H19 expressed by CAFs of the colorectal tumor stroma contributes to tumor development and chemoresistance.


Assuntos
Carcinoma/patologia , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Fibroblastos/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose , Modelos Animais de Doenças , Exossomos/metabolismo , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , MicroRNAs/metabolismo , Transplante de Neoplasias
13.
Biochem Biophys Res Commun ; 503(3): 2095-2100, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30107913

RESUMO

Emerging evidence shows that long noncoding RNA (lncRNA) is implicated in numerous kinds of malignant cancers, including ovarian cancer. In this study, we focused on the expression and function of long noncoding RNA lung cancer associated transcript 1 (LUCAT1) in ovarian cancer progression. We indicated that LUCAT1 expression was significantly upregulated in ovarian cancer tissues. Moreover, LUCAT1 expression was positively associated with tumor metastasis and clinical stage. Elevated expression of LUCAT1 decreased the survival rate of patients with ovarian cancer. In addition, we revealed that repression of LUCAT1 significantly suppressed the proliferation, migration and invasion, whereas promoted apoptotic rate. Through online predictive tools and functional experiments, we demonstrated that LUCAT1 and HOXA13 were targets of miR-612. We showed that LUCAT1 and miR-612 suppressed each other in a reciprocal way. Moreover, LUCAT1 promoted HOXA13 expression through inhibition of miR-612, eventually leading to ovarian cancer development. In conclusion, our findings revealed a novel molecular mechanism that LUCAT1/miR-612/HOXA13 pathway modulates ovarian cancer progression.


Assuntos
Proteínas de Homeodomínio/metabolismo , MicroRNAs/metabolismo , Neoplasias Ovarianas/metabolismo , RNA Longo não Codificante/metabolismo , Apoptose , Movimento Celular , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico , RNA Longo não Codificante/genética
14.
Front Immunol ; 9: 1443, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29988544

RESUMO

The expansion of myeloid-derived suppressor cells (MDSCs) has been documented in murine models and patients with lupus nephritis (LN), but the exact role of MDSCs in this process remains largely unknown. In this study, we investigated whether MDSCs are involved in the process of podocyte injury in the development of LN. In toll-like receptor-7 (TLR-7) agonist imiquimod-induced lupus mice, we found the severe podocyte injury in glomeruli of lupus mice and significant expansion of MDSCs in spleens and kidneys of lupus mice. The function of TLR-7 activated MDSCs was enhanced including the increased generation of reactive oxygen species (ROS) in vivo and in vitro. Moreover, the ROS production of MDSCs induced podocyte injury through activating the p-38MAPK and NF-kB signaling. Furthermore, we verified that podocyte injury was indeed correlated with expansion of MDSCs and their ROS secretion in LN of pristane-induced lupus mice. These findings first indicate that the podocyte injury in LN was associated with the increased MDSCs in kidney and MDSCs may be a promising therapeutic target of LN in the future.

15.
J Mol Neurosci ; 65(1): 43-53, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29696468

RESUMO

The mechanism contributing to blood-brain barrier (BBB) disruption, involved in poststroke edema and hemorrhagic transformation, is important but elusive. We investigated microRNA-21 (miR-21)-mediated mechanism in the disruption of BBB following cerebral ischemia-reperfusion (I/R) injury. Rats with cerebral I/R injury were prepared after middle cerebral artery occlusion and subsequent reperfusion. The underlying regulatory mechanisms of miR-382 were investigated with treatment of miR-382 mimics, miR-382 inhibitors, or SB203580 (an inhibitor of the MAPK signaling pathway) prior to I/R modeling. Compared with sham-operated rats, rats following I/R showed increased Longa's scores, ischemic hemisphere volume, cerebral infarct volume, EB content in brain tissues, enhanced levels of p38, iNOS, and MMP-9. The ectopic expression of miR-21 by mimics and MAPK signaling inhibition by SB203580 reduced Longa's scores, ischemic hemisphere volume, cerebral infarct volume, EB content in brain tissues, decreased levels of p38, MAP2K3, iNOS, and MMP-9. The luciferase activity determination showed miR-21 bound to MAP2K3 in its 3'UTR. miR-21 downregulation mediated by inhibitors appeared to yield an opposed trend. We also found that MAPK signaling inhibition by SB203580 could rescue rats with treatment of miR-382 inhibitors. The study highlights the neuroprotective role of MiR-21 during cerebral I/R injury and its preventive effect against BBB disruption by blocking the MAPK signaling pathway via targeted inhibition of MAP2K3, potentially opening a novel therapeutic avenue for the treatment of cerebral ischemia.


Assuntos
Barreira Hematoencefálica/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Animais , Células HEK293 , Humanos , MAP Quinase Quinase 3/antagonistas & inibidores , MAP Quinase Quinase 3/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Materials (Basel) ; 11(4)2018 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-29690566

RESUMO

In this paper, three kinds of polymer, of epoxy resin (EP), phenolic resin (PF), and unsaturated polyester (UP), were used as fillers to prepare the laminated composite surface, and the tribological properties of a composite surface were studied under dry sliding condition. The results showed that: (i) the composites surface without MoS2 exhibited high friction coefficient and high wear rate at 25 °C, while the friction coefficients were reduced when the temperature increases to 100 °C; (ii) with the addition of MoS2, the friction coefficient of the epoxy resin composite containing MoS2 (E1) was below 0.22 under a temperature of 25⁻150 °C, and the friction coefficient was increased to 0.32 as temperature increased to 150 °C, while the average friction coefficient of the unsaturated polyester composite containing MoS2 (U1) was very low and below 0.20 under a temperature of 25⁻150 °C. Analysis of the wear scars indicated that, for the MoS2-containing composite, the transfer films of the E1 and U1 were smooth and continuous under low temperature, while the transfer film of U1 was comparatively complete than that of E1 under 150 °C. The composites with solid lubrication had excellent high-temperature self-lubricating properties, which was attributed to the synergistic effect of the laminated structure, and the thermal expansion of the polymer, and finally a transfer film was formed on the sliding path.

17.
Carcinogenesis ; 39(3): 397-406, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29346528

RESUMO

Stromal carcinoma-related fibroblasts (CAFs) are the main type of non-immune cells in the tumor microenvironment (TME). CAFs interact with cancer cells to promote tumor proliferation. Long non-coding RNAs (lncRNAs) are known to regulate cell growth, apoptosis and metastasis of cancer cells, but their role in stromal cells is unclear. Using RNA sequencing, we identified a stromal lncRNA signature during the transformation of CAFs from normal fibroblasts (NFs) in oral squamous cell carcinoma (OSCC). We uncovered an uncharacterized lncRNA, FLJ22447, which was remarkably up-regulated in CAFs, referred to LncRNA-CAF (Lnc-CAF) hereafter. Interleukin-33 (IL-33) was mainly located in the stroma and positively co-expressed with Lnc-CAF to elevate the expression of CAF markers (α-SMA, vimentin and N-cadherin) in fibroblasts. In a co-culture system, IL-33 knockdown impaired Lnc-CAF-mediated stromal fibroblast activation, leading to decreased proliferation of tumor cells. Mechanistically, Lnc-CAF up-regulated IL-33 levels and prevented p62-dependent autophagy-lysosome degradation of IL-33, which was independent of LncRNA-protein scaffold effects. Treatment with the autophagy inducer, rapamycin, impaired the proliferative effect of Lnc-CAF/IL-33 by promoting IL-33 degradation. In turn, tumor cells further increased Lnc-CAF levels in stromal fibroblasts via exosomal Lnc-CAF. In patients with OSCC, high Lnc-CAF/IL-33 expression correlated with high TNM stage (n = 140). Moreover, high Lnc-CAF expression predicted poor prognosis. In vivo, Lnc-CAF knockdown restricted tumor growth and was associated with decreased Ki-67 expression and α-SMA+ CAF in the stroma. In conclusion, we identified a stromal lncRNA signature, which reprograms NFs to CAFs via Lnc-CAF/IL-33 and promotes OSCC development.


Assuntos
Carcinoma de Células Escamosas/patologia , Reprogramação Celular/genética , Fibroblastos/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Bucais/patologia , RNA Longo não Codificante/genética , Idoso , Carcinoma de Células Escamosas/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias de Cabeça e Pescoço/genética , Humanos , Interleucina-33/biossíntese , Interleucina-33/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral/genética
18.
J Mater Chem B ; 6(47): 7862-7870, 2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-32255031

RESUMO

Nanohybrids fabricated with upconversion nanoparticles (UCNPs) and gold nanoparticles (NPs) hold great promise for near-infrared photothermal therapy (NIR-PTT) and upconversion fluorescence imaging. However, the obstacles of poor solubility in water and finite hydrophilic modification method for UCNPs limit their application in biological fields. Herein, we report a novel UCNP@Al(OH)3/Au nanohybrid mediated by a highly hydrophilic and biocompatible Al(OH)3 layer to realize a synergistic targeted PTT and fluorescence imaging capability to U87MG tumor-bearing mice under NIR light irradiation. The modification with Al(OH)3 layers can improve the water solubility of UCNPs. And cytotoxicity assays and hemolysis assay showed that the modification with Al(OH)3 layers makes UCNPs have low cytotoxicity and good biocompatibility. In addition, the Al(OH)3 layers are thin enough to allow fluorescence resonance energy transfer (FRET) between UCNPs and gold NPs to occur, giving the NPs a good PTT effect for tumor-bearing mice. Meanwhile, as the pH-sensitive Al(OH)3 layers decompose in acidic tumor microenvironments with Au NPs detached from their surface, the FRET effect no longer occurred, subsequently leading to the fluorescence intensity of naked UCNPs being recovered for good imaging effects. The study suggests that Al(OH)3 mediation layer as a promising hydrophilic nanoplatform can potentially be used for the preparation of superior hydrophilic NPs and pH-stimulated drug release carriers for theranostic application in vivo.

19.
Sci Rep ; 7(1): 16231, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29176691

RESUMO

Midkine (MK) is a heparin-binding growth factor that promotes carcinogenesis and chemoresistance. The tumour microenvironment (TME) can affect chemotherapy sensitivity. However, the role of stromal-derived MK, especially in cancer-associated fibroblasts (CAFs), is unclear. Here, we confirmed that MK decreased cisplatin-induced cell death in oral squamous cell carcinoma (OSCC) cells, ovarian cancer cells and lung cancer cells. We also isolated primary CAFs (n = 3) from OSCC patients and found that CAFs secreted increased levels of MK, which abrogated cisplatin-induced cell death. Moreover, MK increased the expression of lncRNA ANRIL in the tumour cells. Normal tissues, matched tumour-adjacent tissues and OSCC tissues were analysed (n = 60) and showed that lncRNA ANRIL was indeed overexpressed during carcinogenesis and correlated with both high TNM stage and lymph node metastasis (LNM). Furthermore, lncRNA ANRIL knockdown in tumour cells inhibited proliferation, induced apoptosis and increased cisplatin cytotoxicity of the tumour cells via impairment of the drug transporters MRP1 and ABCC2, which could be restored by treatment with human MK in a caspase-3/BCL-2-dependent manner. In conclusion, we firstly describe that CAFs in the TME contribute to the high level of MK in tumours and that CAF-derived MK can promote cisplatin resistance via the elevated expression of lncRNA ANRIL.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Resistencia a Medicamentos Antineoplásicos , Midkina/farmacologia , RNA Longo não Codificante/genética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/toxicidade , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para Cima
20.
Nat Commun ; 8(1): 1785, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29176714

RESUMO

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.


Assuntos
Acarbose/uso terapêutico , Ácidos e Sais Biliares/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Bacteroides/fisiologia , Bifidobacterium/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Fezes/química , Feminino , Glipizida/uso terapêutico , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Lactobacillus/fisiologia , Masculino , Pessoa de Meia-Idade , Dinâmica Populacional
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