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BACKGROUND: Assess the correlation between the position of the third molar (M3) and fractures of the mandibular angle and condyle using panoramic radiographs to offer valuable data references for oral clinical research. MATERIAL AND METHODS: A retrospective cross-sectional study was undertaken, involving the collection of 409 cases of mandibular fracture in the Yanbian University Hospital. The case records and panoramic radiographs of mandibular angle fracture (78 cases) and condylar fracture (106 cases) were evaluated. RESULTS: In the comparative analysis between the mandibular angle fracture group and the condylar fracture group, statistical significance was observed in the variables of M3 existence (P = 0.002), eruption of M3 from the alveolar cavity (P = 0.003), P&G position classification (P = 0.001), deep impactions (Classes IC, IIC, IIIB, and IIIC) (P < 0.001), and the presence of impacted M3 in both groups (P < 0.001).Regarding M3 roots, the mandibular angle fracture group exhibited the highest prevalence of multiple roots at 75.4%, surpassing the 64.6% observed in the condylar fracture group. The prevalence of proximal angles in the mandibular angle group and the condyle group was the highest, accounting for 64.6% and 61.5%, respectively. The percentage of M3 in the two groups was 80% and 43.1%, respectively, with a significant difference (P < 0.001). CONCLUSIONS: Impacted mandibular third molars (M3) elevate the risk of mandibular angle fractures, while their absence or normal eruption reduces this risk and protects against condylar process fractures. The fracture risk is influenced by the M3's position: P&G Class II and Class B impactions, where M3s emerge partially from the alveolar bone, are significantly associated with mandibular angle fractures. In contrast, the absence of M3 or its placement in P&G Class I and Class A positions tends to correlate with a higher incidence of condylar process fractures.
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Purpose Clinically, hypoxia is associated with increased distant metastasis and poor survival in gastric cancer (GC). In this study, we set out from the cellular interaction to further explain the molecular mechanism of invasion in GC cells under hypoxic conditions. Methods Gastric cancer cells were cultured under 1% O2 (hypoxia-cultured gastric cancer cells, HGC) and 20% O2 condition (normoxic-cultured gastric cancer cells, NGC). NGC was co-cultured with HGC-medium. Scrape and Transwell were used to evaluate invasion and migration. Exosomes from GC were extracted by ultracentrifugation. Electron microscopy images, western-blot used to analyze the size distributions and the number of exosomes. Results HGC-medium induced NGC dissociated. Long non-coding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) was specifically expressed in HGC exosomes. HGC-derived PCGEM1-riched exosomes could promote the invasion and migration of NGC. On the mechanism, PCGEM1 maintained stability and reduced the degradation of SNAI1, which could induce the epithelialmesenchymal transition of GC. Conclusion LncRNA PCGEM1 was overexpressed in GC cells. And part of the PCGEM1 can be encapsulated into exosomes. These exosomes promoted invasion and migration of other GC cells. We considered PCGEM1 might act as a "scaffold" combined with SNAI1 and prompt the invasion and migration of GC (AU)
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Humanos , Exossomos/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Hipóxia Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/fisiologia , Exossomos/ultraestrutura , Invasividade Neoplásica , Metástase Neoplásica , RNA Longo não Codificante , Fatores de Transcrição da Família Snail/genética , Microambiente Tumoral , Regulação para BaixoRESUMO
PURPOSE: Clinically, hypoxia is associated with increased distant metastasis and poor survival in gastric cancer (GC). In this study, we set out from the cellular interaction to further explain the molecular mechanism of invasion in GC cells under hypoxic conditions. METHODS: Gastric cancer cells were cultured under 1% O2 (hypoxia-cultured gastric cancer cells, HGC) and 20% O2 condition (normoxic-cultured gastric cancer cells, NGC). NGC was co-cultured with HGC-medium. Scrape and Transwell were used to evaluate invasion and migration. Exosomes from GC were extracted by ultracentrifugation. Electron microscopy images, western-blot used to analyze the size distributions and the number of exosomes. RESULTS: HGC-medium induced NGC dissociated. Long non-coding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) was specifically expressed in HGC exosomes. HGC-derived PCGEM1-riched exosomes could promote the invasion and migration of NGC. On the mechanism, PCGEM1 maintained stability and reduced the degradation of SNAI1, which could induce the epithelial-mesenchymal transition of GC. CONCLUSION: LncRNA PCGEM1 was overexpressed in GC cells. And part of the PCGEM1 can be encapsulated into exosomes. These exosomes promoted invasion and migration of other GC cells. We considered PCGEM1 might act as a "scaffold" combined with SNAI1 and prompt the invasion and migration of GC.
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Exossomos/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Hipóxia Tumoral , Comunicação Celular , Movimento Celular/genética , Técnicas de Cocultura/métodos , Meios de Cultura/farmacologia , Transição Epitelial-Mesenquimal/fisiologia , Exossomos/ultraestrutura , Humanos , Invasividade Neoplásica , Metástase Neoplásica , RNA Mensageiro/metabolismo , Fatores de Transcrição da Família Snail/genética , Microambiente Tumoral , Regulação para CimaRESUMO
OBJECTIVE: To detect the expression pattern of UCHL1 in glioma samples and its influence on the metastasis of glioma, as well as the underlying mechanism. PATIENTS AND METHODS: UCHL1 levels in 42 paired glioma tissues and paracancerous ones were detected. The relationship between UCHL1 level and pathological indexes in glioma patients was analyzed. After establishing UCHL1 knockdown model in U251 and T98-G cells, their migratory ability was assessed by transwell and wound healing assay. At last, Luciferase assay, Western blot and rescue experiments were conducted to explore the role of UCHL1 in aggravating the development of glioma through targeting GAS2. RESULTS: UCHL1 was upregulated in glioma samples than paracancerous ones. High level of UCHL1 indicated high rates of lymphatic metastasis and distant metastasis, as well as low rates of overall survival and progression-free survival in glioma. Knockdown of UCHL1 markedly inhibited migratory ability in glioma cells. GAS2 was the downstream gene of UCHL1. A positive correlation was found between expression levels of UCHL1 and GAS2 in glioma tissues. Overexpression of GAS2 could reverse the inhibitory effects of silenced UCHL1 on migratory ability in glioma cells. CONCLUSIONS: UCHL1 level is linked to lymphatic metastasis, distant metastasis and prognosis in glioma patients. It stimulates migratory ability in glioma by positively regulating GAS2 level.
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Glioma/metabolismo , Proteínas dos Microfilamentos/metabolismo , Ubiquitina Tiolesterase/metabolismo , Linhagem Celular , Feminino , Glioma/patologia , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Ubiquitina Tiolesterase/genéticaRESUMO
OBJECTIVE: Hepatocellular carcinoma (HCC) is a hypervascularized tumor. Aberrant angiogenesis is the main cause, which results in cancer growth and progression. It has been showed that microRNA-302 cluster (miR-302) may be associated with angiogenesis. Here, we aimed to identify the role of miR-302a/b/c in the regulation of cell angiogenesis in HCC. PATIENTS AND METHODS: MRNA expression of miR-302a/b/c and MACC1 was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The protein of MACC1 was measured using Western blot. Cells proliferation, migration, and invasion abilities were investigated via Cell Counting Kit-8 (CCK-8) assay or transwell assay, respectively. Tube formatting assays were used to explore the tube formation capacity. The interaction among miR-302a/b/c was analyzed by luciferase assay. RESULTS: The expression of miR-302a/b/c was greatly reduced while MACC1 expression, whether mRNA or protein was conspicuously elevated in HCC tissues and cells. Then, functional experiment results showed miR-302a/b/c overexpression and MACC1 down-regulation inhibited the proliferation, migration, invasion ability, and tube formation capacity of HUVECs. In addition, we detected that miR-302a/b/c directly targeted MACC1 and suppressed MACC1 expression, and miR-302a/b/c could suppress tumor angiogenesis in HCC by targeting MACC1. CONCLUSIONS: MiR-302a/b/c may function as a potential suppressor of tumor angiogenesis in HCC by targeting MACC1, indicating a promising target for HCC therapy.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Neovascularização Patológica/genética , Carcinoma Hepatocelular/mortalidade , Estudos de Casos e Controles , Linhagem Celular Tumoral/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , China/epidemiologia , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Neovascularização Patológica/patologia , Transativadores/metabolismoRESUMO
The Grand Canal, also known as the Beijing-Hangzhou Grand Canal, is a UNESCO World Heritage Site and the longest canal in the world. It is an important trunk line of the South-to-North Water Diversion Project in China. The contamination status and spatial distributions of perfluoroalky substances (PFASs) in waters of the Grand Canal were investigated. The total concentrations of PFASs (∑PFASs) range from 7.8 ng/L to 218.0 ng/L, with high ∑PFASs occurring in the southern part of the Grand Canal which is located in a highly urbanized and economically developed region. The dominance of PFOA showed a decreasing trend toward north while shorter chain homologue proportions increased in the northern part of the Canal which mainly traverses underdeveloped and rural areas in Eastern China. Positive correlations were observed between ∑PFASs and the population density as well as GDP per capita. Intersection with large rivers may affect the contamination levels and composition of PFASs in the water of the Grand Canal near the intersection sites.
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Monitoramento Ambiental , Fluorocarbonos/análise , Poluentes Químicos da Água/análise , Pequim , Caprilatos , China , Rios/química , Urbanização , Água/químicaRESUMO
Patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) have better responses to radiotherapy and higher overall survival rates than do patients with HPV-negative HNSCC, but the mechanisms underlying this phenomenon are unknown. p16 is used as a surrogate marker for HPV infection. Our goal was to examine the role of p16 in HPV-related favorable treatment outcomes and to investigate the mechanisms by which p16 may regulate radiosensitivity. HNSCC cells and xenografts (HPV/p16-positive and -negative) were used. p16-overexpressing and small hairpin RNA-knockdown cells were generated, and the effect of p16 on radiosensitivity was determined by clonogenic cell survival and tumor growth delay assays. DNA double-strand breaks (DSBs) were assessed by immunofluorescence analysis of 53BP1 foci; DSB levels were determined by neutral comet assay; western blotting was used to evaluate protein changes; changes in protein half-life were tested with a cycloheximide assay; gene expression was examined by real-time polymerase chain reaction; and data from The Cancer Genome Atlas HNSCC project were analyzed. p16 overexpression led to downregulation of TRIP12, which in turn led to increased RNF168 levels, repressed DNA damage repair (DDR), increased 53BP1 foci and enhanced radioresponsiveness. Inhibition of TRIP12 expression further led to radiosensitization, and overexpression of TRIP12 was associated with poor survival in patients with HPV-positive HNSCC. These findings reveal that p16 participates in radiosensitization through influencing DDR and support the rationale of blocking TRIP12 to improve radiotherapy outcomes.
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Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/virologia , Proteínas de Transporte/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/virologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/radioterapia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Camundongos , Papillomaviridae/genética , Infecções por Papillomavirus/metabolismo , Tolerância a Radiação , Distribuição Aleatória , Carcinoma de Células Escamosas de Cabeça e Pescoço , Transfecção , Ubiquitina-Proteína Ligases/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rheb is a Ras family GTPase, which binds to and activates mammalian target of rapamycin complex 1 (mTORC1) when GTP loaded. Recently, cancer genome sequencing efforts have identified recurrent Rheb Tyr35Asn mutations in kidney and endometrial carcinoma. Here we show that Rheb-Y35N causes not only constitutive mTORC1 activation, but sustained activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and mTORC1-independent manner, contributing to intrinsic resistance to rapamycin. Rheb-Y35N transforms NIH3T3 cells, resulting in aggressive tumor formation in xenograft nude mice, which could be suppressed by combined treatment with rapamycin and an extracellular signal-regulated kinase (ERK) inhibitor. Furthermore, Rheb-Y35N inhibits AMPKα activation in response to nutrient depletion or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), leading to attenuated phosphorylation of BRAF-S729 and retained mitogen-activated protein kinase (MAPK) activation. Finally, we demonstrate that Rheb-WT can bind AMPK to facilitate AMPK activation, whereas Rheb-Y35N competitively binds AMPK, impairing AMPK phosphorylation. In summary, our findings indicate that Rheb-Y35N is a dominantly active tumor driver that activates both mTORC1 and MAPK to promote tumor growth, suggesting a combination of mTORC1 and MAPK inhibitors may be of therapeutic value in patients whose cancers sustain this mutation.
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Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Neuropeptídeos/metabolismo , Proteínas Supressoras de Tumor/genética , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células NIH 3T3 , Proteína Enriquecida em Homólogo de Ras do Encéfalo , TransfecçãoRESUMO
Objective: To investigate the methods for qualitative pathological assessment of dynamic changes in liver fibrosis/cirrhosis after antiviral therapy in patients with chronic hepatitis B (CHB), since antiviral therapy can partially reverse liver fibrosis and cirrhosis caused by hepatitis B and semi-quantitative, rather than qualitative, pathological assessment is often used for the research on liver fibrosis regression. Methods: Previously untreated CHB patients with liver fibrosis and cirrhosis were enrolled, and liver biopsy was performed before treatment and at 78 weeks after the antiviral therapy based on entecavir. The follow-up assessment was performed once every half a year. Based on the proportion of different types of fibrous septum, we put forward the new qualitative criteria called P-I-R classification (predominantly progressive, predominantly regressive, and indeterminate) for evaluating dynamic changes in liver fibrosis. This classification or Ishak fibrosis stage was used to evaluate the change in liver fibrosis after treatment and Ishak liver inflammation score was used to evaluate the change in liver inflammation after treatment. Results: A total of 112 CHB patients who underwent liver biopsy before and after treatment were enrolled, and among these patients, 71 with an Ishak stage of ≥3 and qualified results of live biopsy were included in the final analysis. Based on the P-I-R classification, 58% (41/71) were classified as predominantly progressive, 29% (21/71) were classified as indeterminate, and 13% (9/71) were classified as predominantly regressive; there were no significant differences between the three groups in alanine aminotransferase, aspartate aminotransferase, albumin, HBeAg positive rate, HBV DNA, and liver stiffness (P < 0.05). After treatment, the proportion of predominantly progressive, indeterminate, or predominantly regressive patients changed to 11% (8/71), 11% (8/71), and 78% (55/71), respectively. Among the 35 patients who had no change in Ishak stage after treatment, 72% (25/35) were classified as predominantly regressive and had certain reductions in the Laennec score, percentage of collagen area, and liver stiffness. Conclusion: This new P-I-R classification can be used to assess the dynamic changes in liver fibrosis after antiviral therapy in CHB patients.
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Hepatite B Crônica/patologia , Cirrose Hepática/patologia , Fígado/patologia , Alanina Transaminase/sangue , Antivirais/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/tratamento farmacológicoRESUMO
OBJECTIVE: In the early pregnancy, large number of decidual natural killer (dNK) cells are present in decidua, which exhibit distinctive phenotype and functions from peripheral blood NK cells (pNK)1. Unlike the cytotoxic pNK cells, dNK cells display more pronounced characteristics of immune tolerance, which contribute the Th2 bias at the maternal-fetal interface and ensure successful pregnancy2. However, the origin and the differentiation program of dNK still remain unknown. MATERIALS AND METHODS: Our previous study has demonstrated that the CXCL12/CXCR4 signal axis is involved in the shaping of Th2 bias at the maternal-fetal interface3,4. RESULTS: In this study, we demonstrated the first-trimester human trophoblast cells secrete chemokine CXCL12 that can recruit pNK cells to the decidua. We've also found that the pNK cells differentiate locally under the influence of trophablast cells. After co-culture with trophoblast cells, pNK cells could acquire dNK characteristics phenotypically while compared to the dNK cells; however, the blocking of CXCL12/CXCR4 signal of pNK cells has abrogated the modulation of trophoblast cells on the pNK cells. We've also found that JNK1/2/MAPK and ERK/MAPK signal pathways were required for the modulation of trophoblast cells on the pNK cells. MAPK signal pathway is involved in the functional modulation of human first-trimester trophoblast cells and decidual stromal cells on pNK and dNK cells. CONCLUSIONS: Our study has elucidated that CXCL12/CXCR4 can recruit pNK cells to the decidua, then positively modulate pNK cells differentiation into the dNK cells, which thus results in Th2 bias and maternal-fetal immune tolerance.
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Quimiocina CXCL12/biossíntese , Células Matadoras Naturais/fisiologia , Troca Materno-Fetal/fisiologia , Receptores CXCR4/biossíntese , Células Th2/fisiologia , Trofoblastos/fisiologia , Adulto , Movimento Celular/fisiologia , Técnicas de Cocultura , Decídua/citologia , Decídua/fisiologia , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez/fisiologia , Transdução de Sinais/fisiologia , Células Estromais/fisiologiaRESUMO
CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.
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Linfócitos T CD8-Positivos/metabolismo , Decídua/metabolismo , Proteínas de Membrana/metabolismo , Gravidez/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cocultura , Decídua/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Gravidez/sangue , Gravidez/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/imunologia , Trofoblastos/imunologia , Trofoblastos/metabolismo , Regulação para CimaRESUMO
We have investigated three-dimensional (3D) spin configurations of a one-dimensional (1D) array composed of three ferromagnetic nanocubes by means of micromagnetic simulations. In order to modulate the magnetostatic interaction between adjacent nanocuboids, the magnetic field was applied as a controllable external magnetostatic environment. Without any external field, the spin configurations of the asymmetric 3D magnetic vortex structures in each nanocube exhibit identical magnetic chirality. With the increase of the external field, the magnetostatic environment was gradually dominated by the external field, and enhanced the component along field direction of the magnetostatic interaction between nanocuboids, and even accelerated the formation of the cylindrical 3D vortex spin structure at the center of each cuboid lying in the field direction. Interestingly, under a 100 mT field less than the saturation field, the ferromagnetic array exhibited negative magnetic energy, with the three vortex structures occasionally exhibiting opposing chiralities. There was a competitive relationship amongst the shape anisotropy, magnetic energy minimization, and magnetostatic interaction between ferromagnetic nanocuboids, leading to the complex spin configuration and the negative energy phenomenon of the ferromagnetic array.
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High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting.
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Neoplasias da Mama/genética , Cistadenocarcinoma Seroso/genética , Elafina/genética , Neoplasias Ovarianas/genética , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Elafina/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Proteômica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMO
During the course of the past two decades, our group has worked towards the development of increasingly potent inotropic agents by making structural modifications to compounds derived from 3,4-dihydro-2(1H)-quinolinone (DHQO) and related analogues. Herein, we describe the design and synthesis of a new series of DHQO derivatives and the subsequent evaluation of their positive inotropic activity towards left atrium stroke volume in isolated rabbit-heart preparations. Some of these derivatives presented favorable in vitro activities compared with the reference drug, milrinone, and compound 10a, in particular is currently being investigated as a preclinical drug candidate. This review also describes our progress towards the development of DHQO derivatives and related analogues with positive inotropic activities from 1999 to 2013.
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Cardiotônicos/química , Quinolonas/química , Animais , Cardiotônicos/síntese química , Cardiotônicos/farmacologia , Pirazinas , Quinolinas/química , Quinolonas/síntese química , Quinolonas/farmacologia , Coelhos , Volume Sistólico/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: As one of the key molecules in the extracellular matrix in human conceptus, hyaluronan (HA) has been receiving particular attention. Here, we have investigated the expression and regulation of different molecular weight HA on the biological behaviors of primary human trophoblasts during the first trimester of pregnancy. METHODS: The expression of HA and HA synthetase (HAS) by human first trimester trophoblasts was analyzed in placentae from normal pregnancy or miscarriage by immunochemistry and real-time RT-PCR, respectively. ELISA was used to measure the secretion of HA by primary trophoblasts. The effects of HA on the proliferation, apoptosis and invasiveness of trophoblasts were examined. We also investigated the signaling pathways involved in HA activation in human trophoblasts. RESULTS: The higher HAS2 expression and HA secretion were observed in normal villi than that of miscarriage, and the primary trophoblasts secreted HA continuously. High molecular weight HA (HMW-HA) and medium molecular weight HA (MMW-HA) promoted proliferation and invasiveness while inhibited apoptosis of trophoblasts. However, low molecular weight HA (LMW-HA) had no obvious effect on the growth or invasiveness of human trophoblasts. In addition, HMW-HA showed more efficiently than MMW-HA on the growth while MMW-HA displayed a more obvious effect on the invasiveness of trophoblasts than HMW-HA. HMW-HA activated PI3K/AKT and MAPK/ERK1/2 signaling pathways in trophoblasts. Blocking PI3K/AKT or MAPK/ERK1/2 signaling inhibited the HA-upregulated growth and invasiveness of human trophoblasts. CONCLUSION: Our results suggest that higher level and greater molecular mass of HA can promote trophoblast growth and invasion in an autocrine manner, which was beneficial to placentation and maintenance of human early pregnancy.
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Aborto Espontâneo/metabolismo , Regulação para Baixo , Glucuronosiltransferase/metabolismo , Ácido Hialurônico/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais , Trofoblastos/metabolismo , Aborto Espontâneo/enzimologia , Aborto Espontâneo/patologia , Adulto , Apoptose/efeitos dos fármacos , Comunicação Autócrina/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Feminino , Glucuronosiltransferase/genética , Humanos , Hialuronan Sintases , Ácido Hialurônico/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Peso Molecular , Inibidores de Fosfoinositídeo-3 Quinase , Gravidez , Primeiro Trimestre da Gravidez , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Trofoblastos/enzimologia , Trofoblastos/patologia , Adulto JovemRESUMO
INTRODUCTION: As a calcineurin inhibitor in T-cell activation, cyclosporine A (CsA) has provided the pharmacologic foundation for organ transplantation. We have previously demonstrated that CsA promotes trophoblast growth and invasion in vitro. Here, we further investigated the regulation of CsA on trophoblast migration and the intracellular signaling pathways involved. METHODS: We evaluated the migration of human primary trophoblasts by using transwell migration assay. CsA-mediated induction of nuclear factor-kappa B (NF-κB) was evaluated by cotransfection with luciferase reporter constructs and luciferase activity assays. RESULTS: Treatment with CsA-promoted migration of primary trophoblasts and the HTR8 cell line in a dose-dependent manner. CsA also increased NF-κB-transcriptional activity in trophoblasts in time- and dose-dependent manners. Pharmacologically inhibiting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) 1/2 signaling with U0126 attenuated the CsA-induced cell migration and NF-κB activity in trophoblasts. Furthermore, pretreatment with PDTC, a specific NF-κB inhibitor, inhibited the CsA-induced migration of trophoblasts in dose-dependent manners. Although NFAT activation by ionomycin via calcineurin is accompanied by increased transactivation of NF-κB, pretreatment with the NFAT inhibitor did not affect NF-κB-transcriptional activity. Interestingly, ionomycin and CsA synergize to transactivate NF-κB. Ionomycin-inhibited basal migration of trophoblasts, and pretreatment with CsA reversed the ionomycin-inhibited trophoblast migration. However, the NFAT inhibitor increased basal migration, but not CsA-induced migration, of trophoblasts. CONCLUSION: These observations indicate that both the MAPK/ERK/NF-κB pathway and Ca(2+)/calcineurin/NFAT pathways are involved in the CsA-promoted trophoblast migration. Our findings may help expand the clinical applications of this drug in trophoblast disorder.
Assuntos
Movimento Celular/efeitos dos fármacos , Ciclosporina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Trofoblastos/fisiologia , Calcineurina/metabolismo , Sinalização do Cálcio/fisiologia , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , NF-kappa B/antagonistas & inibidores , Fatores de Transcrição NFATC/fisiologia , Gravidez , Primeiro Trimestre da Gravidez , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/citologia , Trofoblastos/efeitos dos fármacosRESUMO
BACKGROUND: Our previous studies have demonstrated that cyclosporin A (CsA) can increase the cell number in and invasion by human first-trimester trophoblasts and induce maternal-fetal tolerance. C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine ligand 12 (CXCL12) are important mediators at the maternal-fetal interface during early pregnancy. In this study, we further investigate the molecular mechanisms underlying modulation by CsA of the crosstalk between human cytotrophoblast and decidual stromal cell (DSC). METHODS: Human first-trimester cytotropoblast and DSC were treated with CsA in the absence or presence of U0126 pretreatment, and then the mRNA and protein levels of CXCL12 and CXCR4 were measured by RT-PCR, qPCR, in-cell western blots and enzyme-linked immunosorbent assay (ELISA), respectively. 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and Matrigel invasion assays were used to determine the invasiveness of cytotrophoblast, respectively. The activity of matrix metalloproteinase (MMP)-9 and MMP-2 was detected by gelatin zymography. A co-culture with direct contact between cytotrophoblast and DSC was established and used to investigate the interaction between these two cells. RESULTS: CsA up-regulated CXCL12 and CXCR4 expression in human first-trimester cytotrophoblast cells, but not in DSCs. Blocking the mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK1/2) signaling by U0126 abrogated the CsA-induced increase in CXCL12 and CXCR4 expression and neutralizing antibodies to CXCL12 or CXCR4 completely inhibited the CsA-induced increase in cell number, invasion and MMP-9 and MMP-2 activity of cytotrophoblast. CsA also significantly promoted the activity of MMP-9 and MMP-2 in DSCs, but this was unaffected by CXCL12 or CXCR4 neutralizing antibody. Furthermore, the CsA-induced MMP-9 and MMP-2 activity and the invasiveness of cytotrophoblast in the cytotrophoblast and DSC co-culture were significantly increased compared with CsA-treated trophoblast cultured alone, and CXCR4 blocking antibody effectively abolished the increased MMP activity and invasion of cytotrophoblasts in the cytotrophoblast-DSC co-culture stimulated by CsA. CONCLUSIONS: CsA can promote the crosstalk between cytotrophoblast and DSC through up-regulating CXCL12/CXCR4 interaction via MAPK signaling, resulting in the increased numbers of and invasion by human cytotrophoblast cells.
Assuntos
Quimiocina CXCL12/biossíntese , Ciclosporina/farmacologia , Regulação da Expressão Gênica , Receptores CXCR4/biossíntese , Células Estromais/citologia , Trofoblastos/citologia , Regulação para Cima , Butadienos/farmacologia , Técnicas de Cocultura , Colágeno/química , Decídua/fisiologia , Combinação de Medicamentos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Laminina/química , Troca Materno-Fetal , Nitrilas/farmacologia , Gravidez , Primeiro Trimestre da Gravidez , Proteoglicanas/química , Trofoblastos/metabolismoRESUMO
Understanding the interaction between the magnetic domain wall and the various artificial defects in ferromagnetic nanowires has been of utmost importance for the future realization of the spintronic devices based on the magnetic domain wall motion in nanowires. In this work, the chirality filter effect of the magnetic domain wall in T-shaped ferromagnetic nanowires with a stray field filter was investigated via micromagnetic simulation. A tapered wire was attached to the flat nanowires to form a potential barrier or well for the domain wall propagating along them. For the domain wall passing through the potential barrier or the potential well, the spin structure of the domain wall and the interaction between the domain wall and the potential barrier/well were investigated in detail. The chirality-dependent translational positioning of the domain wall was intensively examined for the potential barrier and potential well cases. The domain wall chirality transmission on relatively long length scales using a series of potential wells was explored.
RESUMO
The interaction of antiparallel transverse domain walls in ferromagnetic nanowires was investigated via micromagnetic simulation with systematic variations of the external field strength as well as the wire thickness. The interaction of antiparallel transverse walls after domain wall collision exhibited damped multiple collisions due to the rigid structure of the antiparallel transverse walls. The detailed process during the multiple collisions was analyzed via the Fast Fourier Transform technique, along with a careful examination of the inner spin structures of the colliding domain walls. It was found that a frequency peak of multiple collisions shifted to a higher peak position as the external field strength increases. With a stronger field strength of around a few hundred mT, it was found that two antiparallel transverse walls were finally annihilated with formation of complex antivortex structures.
RESUMO
We have systematically investigated three-dimensional spin configurations in ferromagnetic nanocubes using micromagnetic simulation with variation of cube geometry. For thin cuboids, a spin configuration exhibits a four-domain Landau state with a magnetic vortex structure at the center as in the case of a thin film square. For a thick cube, a complex spin configuration with an S-type cylindrically asymmetric vortex having two cores on a pair of surfaces while a leaf-like and a C-type states are observed on the other two pairs of cube surfaces. Competition between the geometrical symmetry and magnetic energy minimization condition in ferromagnetic nanocubes leads to the complex spin structure with a spontaneously broken symmetry.