RESUMO
BACKGROUND: GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown. METHODS: Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65-/-) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65-/- and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting. RESULTS: BTB09089 significantly promoted motor outcomes in WT but not in GPR65-/- mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65-/- mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65-/- mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65-/- mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice. CONCLUSIONS: Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.
Assuntos
AVC Isquêmico , Camundongos Knockout , Neurônios , Receptores Acoplados a Proteínas G , Animais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/agonistas , Camundongos , AVC Isquêmico/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Reabilitação do Acidente Vascular Cerebral , Fármacos Neuroprotetores/farmacologia , Camundongos Endogâmicos C57BLRESUMO
Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.
Assuntos
Peptídeos Penetradores de Células , Doxorrubicina , Sistemas de Liberação de Medicamentos , Lipossomos , Humanos , Animais , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Peptídeos Penetradores de Células/química , Linhagem Celular Tumoral , Lipossomos/química , Camundongos , Portadores de Fármacos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Camundongos Nus , Peptídeos Cíclicos/química , Peptídeos Cíclicos/administração & dosagemRESUMO
Background: T helper 17 (Th17) cells and regulatory T cells (Treg) are known to play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Improving the balance between Treg and Th17 cells can be a promising new therapeutic target in SLE patients. Vitamin D has a significant impact on the immune inflammatory process and the immune cells involved in this process. The purpose of this study is to investigate the relationship between Th17, Treg, cytokines, and serum 25 hydroxyvitamin D [25(OH)D] in patients with initial-onset childhood SLE. Methods: A total of 82 children aged <18 years with initial-onset SLE were included, as well as 60 healthy subjects during the same period at the Pediatrics Department of the Second Hospital of Hebei Medical University. The chemiluminescence method was performed to detect serum 25(OH)D levels. Flow cytometry was used to evaluate Treg and Th17 cells. An enzyme-linked immunosorbent assay kit was used to evaluate plasma interleukin (IL)-23, IL-17, IL-10, IL-6, and tumor necrosis factor alpha (TNF-α) concentrations. Result: The serum 25(OH)D levels in patients with initial-onset childhood SLE were significantly lower than those in the healthy controls. The proportion of lupus nephritis (LN) was higher in the vitamin D insufficiency group (71.4%) compared with the vitamin D sufficiency group (30.3%) (p < 0.05). The SLE disease activity index (SLEDAI) was higher in the vitamin D insufficiency group (median = 14) than that in the vitamin D sufficiency group (median = 9) (p < 0.05).The 25(OH)D level was positively correlated with the Treg ratio (r = 0.337, p = 0.002), and it was negatively correlated with the Th17 cell ratio (r = -0.370, p = 0.001). The serum 25(OH)D level had a negative correlation with IL-23 (r = -0.589, p < 0.001), IL-17(r = -0.351, p = 0.001), TNF-α (r = -0.283, p = 0.01), IL-6 (r = -0.392, p < 0.001), and IL-10 (r = -0.313, p = 0.004) levels. Conclusion: The serum 25(OH)D levels decreased in patients with initial-onset childhood SLE. There was a negative correlation between the serum 25(OH)D levels and SLEDAI. The serum 25(OH)D levels in patients with initial-onset childhood SLE were negatively correlated with the Th17 ratio and related cytokines, while positively correlated with the Treg ratio.
RESUMO
AIMS: Few treatments are available in the subacute phase of traumatic brain injury (TBI) except rehabilitation training. We previously reported that transient CO2 inhalation applied within minutes after reperfusion has neuroprotective effects against cerebral ischemia/reperfusion injury. In this study, it was hypothesized that delayed CO2 postconditioning (DCPC) starting at the subacute phase may promote neurological recovery of TBI. METHODS: Using a cryogenic TBI (cTBI) model, mice received DCPC daily by inhaling 5%/10%/20% CO2 for various time-courses (one/two/three cycles of 10-min inhalation/10-min break) at Days 3-7, 3-14 or 7-18 after cTBI. Beam walking and gait tests were used to assess the effect of DCPC. Lesion size, expression of GAP-43 and synaptophysin, amoeboid microglia number and glia scar area were detected. Transcriptome and recombinant interferon regulatory factor 7 (Irf7) adeno-associated virus were applied to investigate the molecular mechanisms. RESULTS: DCPC significantly promoted recovery of motor function in a concentration and time-course dependent manner with a wide therapeutic time window of at least 7 days after cTBI. The beneficial effects of DCPC were blocked by intracerebroventricular injection of NaHCO3 . DCPC also increased puncta density of GAP-43 and synaptophysin, and reduced amoeboid microglia number and glial scar formation in the cortex surrounding the lesion. Transcriptome analysis showed many inflammation-related genes and pathways were altered by DCPC, and Irf7 was a hub gene, while overexpression of IRF7 blocked the motor function improvement of DCPC. CONCLUSIONS: We first showed that DCPC promoted functional recovery and brain tissue repair, which opens a new therapeutic time window of postconditioning for TBI. Inhibition of IRF7 is a key molecular mechanism for the beneficial effects of DCPC, and IRF7 may be a potential therapeutic target for rehabilitation after TBI.
Assuntos
Lesões Encefálicas Traumáticas , Dióxido de Carbono , Fator Regulador 7 de Interferon , Animais , Camundongos , Lesões Encefálicas Traumáticas/metabolismo , Dióxido de Carbono/metabolismo , Dióxido de Carbono/uso terapêutico , Modelos Animais de Doenças , Proteína GAP-43/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Fator Regulador 7 de Interferon/uso terapêutico , Sinaptofisina/metabolismo , Sinaptofisina/uso terapêuticoRESUMO
Estrogen-induced premature closing of the growth plate in the long bones is a major cause of short stature after premature puberty. Recent studies have found that chondrocytes can directly trans-differentiate into osteoblasts in the process of endochondral bone formation, which indicates that cartilage formation and osteogenesis may be a continuous biological process. However, whether estrogen promotes the direct trans-differentiation of chondrocytes into osteoblasts remains largely unknown. Chondrocytes were treated with different concentrations of 17ß-estradiol, and Alizarin Red staining and alkaline phosphatase activity assay were used to detected osteogenesis. Specific short hairpin RNA and tamoxifen were used to block the estrogen receptor (ER) pathway and osteogenic marker genes and downstream gene expression were detected using real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry staining. The findings showed that 17ß-estradiol promoted the chondrocyte osteogenesis in vitro, even at high concentrations. In addition, blocking of the ERα/ß pathway inhibited the trans-differentiation of chondrocytes into osteogenic cells. Furthermore, we found that dentin matrix protein 1 (DMP1), which is a direct downstream molecular of ER, was involved in 17ß-estradiol/ER pathway-regulated osteogenesis. As well, glycogen synthase kinase-3 beta (GSK-3ß)/ß-catenin signal pathway also participates in ERα/ß/DMP1-regulated chondrocyte osteogenesis. The GSK-3ß/ß-catenin signal pathway was involved in ERα/ß/DMP1-regulated chondrocyte osteogenesis. These findings suggest that ER/DMP1/GSK-3ß/ß-catenin plays a vital role in estrogen regulation of chondrocyte osteogenesis and provide a therapeutic target for short stature caused by epiphyseal fusion.
Assuntos
Condrócitos , beta Catenina , Diferenciação Celular/fisiologia , Transdiferenciação Celular , Células Cultivadas , Condrócitos/metabolismo , Estradiol , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Osteogênese/fisiologia , beta Catenina/metabolismoRESUMO
OBJECTIVE: The present study aimed to investigate the clinical significance and prognostic value of LINC01793 in OSCC patients, and to explore its role in the modulation of OSCC development. METHODS: LINC01793 expression was analyzed in 80 cases of OSCC patients and SCC9, SCC25, Cal27, and HN6 cell lines by qRT-PCR. The association of LINC01793 expression with clinicopathological features and prognosis in OSCC patients was analyzed. The effects of LINC01793 on cell proliferation, cell cycle, migration, and invasion of SCC9 and Cal27 cells were detected by MTT, flow cytometry, and Transwell assays in vitro, respectively. RESULTS: LINC01793 level was upregulated in cancer tissues and cell lines of OSCC, and its expression was increased in cancer tissues from patients with lymph node metastasis. ROC curve for LINC01793 expression and lymph node metastasis revealed a significant AUC of 0.84 (95 % CI: 0.75-0.93), with 76.51 % sensitivity and 83.69 % specificity. Moreover, high LINC01793 level was positively correlated with T category, TNM stage, lymph node metastasis, and local recurrence. OSCC patients with high level of LINC01793 was followed by low overall survival rate, and LINC01793 expression was an independent prognostic indicator for overall survival in patients with OSCC. Functionally, cell proliferation, invasion and migration of SCC9 and Cal27 cells were decreased after knockdown of LINC01793. Consistently, silence of LINC01793 induced G0/G1 cell cycle arrest in OSCC cells. CONCLUSION: High LINC01793 level is correlated with adverse clinicopathological features and poor prognosis of patients with OSCC. LINC01793 act as an oncogenic role in the development of OSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , RNA Longo não Codificante , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Bucais/genética , Recidiva Local de Neoplasia , Prognóstico , RNA Longo não Codificante/genética , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Neoplasias da Mama/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Molécula de Adesão da Célula Epitelial/biossíntese , Transição Epitelial-Mesenquimal/fisiologia , Proteínas de Neoplasias/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Molécula de Adesão da Célula Epitelial/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Mitoxantrona/farmacologia , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/administração & dosagemRESUMO
OBJECTIVE: To establish a diagnostic model of idiopathic central precocious puberty on the basis of transrectal pelvic ultrasound and basal gonadotropin. METHODS: A total of 669 girls with Tanner breast development stage II were enrolled in this study from January 2015 to December 2018. The participants were divided into the ICPP group and the premature thelarche group. We analyzed various variables, including age at initial diagnosis, basal luteinizing hormone levels, the long diameter of the uterus, the transverse diameter of the uterus, the anterior-posterior diameter of the uterus, the volume of the uterus, maximum ovarian diameter, average ovarian volume, maximum ovarian volume, number of follicles (≥4 mm), maximum follicular diameter, endometrial thickness, and vaginal wall thickness. RESULTS: The following diagnostic model was established: Y=-14.123 + 0.630 × age at initial diagnosis + 1.119 × transverse diameter of the uterus + 1.278 × anterior-posterior diameter of the uterus + 0.637 × average ovarian volume + 1.316 × maximum ovarian diameter + 0.146 ×number of follicles ≥4 mm + 2.925 × endometrial thickness + 0.559 × basal luteinizing hormone value. The area under curve was 0.922, sensitivity was 84.9%, and specificity was 86.2%. CONCLUSION: Basal LH levels and transrectal pelvic ultrasound should be applied together to improve the accuracy of diagnosis in ICPP.
Assuntos
Puberdade Precoce , Feminino , Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Gonadotropinas , Humanos , Hormônio Luteinizante , Ovário/diagnóstico por imagem , Puberdade Precoce/diagnóstico por imagem , Útero/diagnóstico por imagemRESUMO
This study aims to improve our understanding of methylmalonic acidemia (MMA) complicated by homocystinuria disease by analyzing the clinical characteristics, treatment response and prognosis of three patients. Hyperhomocysteinemia and developmental retardation were present in all patients, epilepsy was present in one patient, and hemolytic uremic syndrome was present in one patient. The conditions of two patients were complicated by pulmonary arterial hypertension, one patient by left pulmonary vein ectopic drainage to the coronary sinus and the other by noncompaction of the ventricular myocardium. The two MMA patients with the complication of severe pulmonary arterial hypertension died because of late diagnosis and irregular treatment of MMA. Echocardiography is necessary for patients with combined MMA and homocystinuria, and these patients are susceptible to cardiovascular disease. When a patient with combined MMA and homocystinuria has the complication of severe pulmonary arterial hypertension, the prognosis is poor.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/etiologia , Homocistinúria/complicações , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Falência Renal Crônica/etiologia , Masculino , PrognósticoRESUMO
The clinical significance of the expression level of serum adrenergic receptor α1 (ADRA1A) in hysterocarcinoma patients was determined. Peripheral serum samples were collected at the Hubei Cancer Hospital from 455 patients affected by hysterocarcinoma and 380 healthy adults, who served as the normal control group. We determined the expression levels of ADRA1A by ELISA and analyzed its correlation to clinical features and prognosis of the patients. Compared with the normal control group, the expression of ADRA1A in the average peripheral serum level of hysterocarcinoma patients was clearly increased (P<0.05). In addition, the expression level of ADRA1A was positively correlated with the FIGO staging for hysterocarcinoma (r=0.312, P=0.014). Furthermore, the expression levels of serum ADRA1A in patients with metastasis were significantly increased compared to the levels of hysterocarcinoma patients without metastasis (P<0.05). Our analyses also showed that the expression levels of serum ADRA1A in hysterocarcinoma patients did not correlate with patient factors such as age, tumor invasive depth, tumor size or tumor differentiation degree (P>0.05). The Kaplan-Meier survival analysis indicated that the median survival time (37.1 months) of patients with a high expression of serum ADRA1A was lower than that of patients with a low expression of serum ADRA1A (68 months) (P<0.05). The three- and five-year survival rates of patients expressing low serum ADRA1A were, respectively, 74.00 and 62.00%; and the three- and five-year survival rates of patients expressing high levels of serum ADRA1A were 52.00 and 32.00%, respectively, with all the differences being statistically significant (P<0.05). ADRA1A was highly expressed in the peripheral serum in patients with hysterocarcinoma and the expression of ADRA1A was associated with FIGO staging and lymph node metastasis status. The expression of serum ADRA1A can be used to assess the survival rate and may be involved in the pathogenesis and metastasis progression of hysterocarcinoma.
RESUMO
The Bovine jugular vein (BJV) graft for right ventricular outflow tract reconstruction (RVOT) is limited applied due to possible graft failure. In this study, we reported the clinical application of simplified hand-sewn trileaflet valved conduit as an alternative for BJV graft. We retrospectively included 68 patients underwent 76 conduits implantation including 22 new simplified hand-sewn trileaflet valved conduits (Group A) and 54 BJV grafts (Group B). For patients in Group A, a hand-sewn trileaflet valved conduit with valves made of autologous pericardium or expanded polytetrafluoroethylene was applied. Baseline, perioperative, and outcomes were analyzed. No early mortality or perioperative complication occurred in Group A, while 2 patients died and 16 patients suffered from conduits failure due to conduits stenosis (n = 11), stenosis plus regurgitation (n = 3), and regurgitation alone (n = 2) in Group B. Freedom from BJV grafts failure within 1, 3, 5, and 7 years was 98.0%, 88.2%, 83.6% and 83.6% in Group A, and 98.0%, 85.8%, 76.8% and 62.1% in Group B. Endocarditis occurred in 9 patients in Group B, but not in Group A. Subsequent analysis showed that endocarditis is the only significant predictor of BJV grafts failure (odds ratio: 6.202, 95% confidence intervals 1.237â¼31.108). The novel simplified hand-sewn trileaflet valved conduits seems to be associated with lower incidences of perioperative complication, graft failure, and early-phase mortality, as compared with conventional BJV grafts.
Assuntos
Cardiopatias Congênitas/cirurgia , Próteses Valvulares Cardíacas/efeitos adversos , Ventrículos do Coração/cirurgia , Valva Pulmonar/cirurgia , Técnicas de Sutura , Animais , Bioprótese/efeitos adversos , Bovinos , Criança , Pré-Escolar , Feminino , Cardiopatias Congênitas/fisiopatologia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/métodos , Ventrículos do Coração/anormalidades , Ventrículos do Coração/fisiopatologia , Humanos , Lactente , Recém-Nascido , Veias Jugulares/transplante , Masculino , Politetrafluoretileno , Falha de Prótese/etiologia , Valva Pulmonar/anormalidades , Procedimentos de Cirurgia Plástica/efeitos adversos , Procedimentos de Cirurgia Plástica/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Maternal vitamin D deficiency in pregnancy has been associated with an increased risk of preeclampsia. Vascular endothelial dysfunction is a major phenotype of pregnancies with preeclampsia, contributing to increased maternal hypertension and proteinuria. We sought to determine whether vitamin D supplementation would alleviate preeclampsia associated endothelial dysfunction and explore the underlying mechanism using the reduced uterine perfusion pressure (RUPP) rat model. RUPP operated rats were supplemented with 1,25(OH)2D (RUPP+VD) on day 1, 7, and 14 of pregnancy by subcutaneous injection. On day 19 of pregnancy, after the measurement of blood pressure and urine collection, maternal blood serum and placenta samples were collected. 1,25(OH)2D treatment significantly improved endothelial dysfunction by reducing apoptosis and increasing nitric oxide (NO) production in blood vessels of RUPP operated rats compared to untreated RUPP rats. 1,25(OH)2D significantly down-regulated the expression of placental soluble FMS-like tyrosine kinase-1 (sFlt-1) in RUPP rats. Furthermore, the circulating sFlt-1 levels in maternal serum were positively correlated with the expression of placental sFlt-1 and were restored to a normal pregnant level by 1,25(OH)2D treatment in RUPP rats. Incubation of endothelial cell line with rat serum from RUPP+VD group significantly increased NO production and decreased caspase-3 activity compared with serum from untreated RUPP rats. Moreover, neutralization of sFlt-1 using the specific antibody mimicked the effect of 1,25(OH)2D, which abolished the deleterious effect of RUPP rat's serum on NO production and apoptosis. These results suggest that vitamin D supplementation is protective against RUPP induced endothelial dysfunction by downregulating placental sFlt-1, which can possibly alleviate preeclampsia associated symptoms.
Assuntos
Isquemia/prevenção & controle , Placenta/irrigação sanguínea , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Vitamina D/análogos & derivados , Animais , Pressão Sanguínea/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Óxido Nítrico/biossíntese , Placenta/fisiopatologia , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/prevenção & controle , Gravidez , Proteinúria/tratamento farmacológico , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Ratos , Ratos Sprague-Dawley , Solubilidade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Vitamina D/administração & dosagemRESUMO
This study examined the association of CD44V6 expression in ovarian cancer. We recruited 38 patients with ovarian cancer, 23 with benign ovarian tumor, and 20 with normal ovaries using RT-PCR and western block analysis. Compared with normal ovaries, the expression of CD44V6 mRNA was significantly elevated in benign ovarian tumor and ovarian cancer. At the protein level, we found no significant differences in CD44V6 expression between normal ovarian tissue and benign ovarian tumor. However, the expression of CD44V6 in ovarian cancer was significantly elevated compared to normal ovaries and benign ovarian tumor. These results were supported by ELISA and western blot analysis. Immunohistochemistry showed that CD44V6 protein in ovarian cancer cells accumulated at high levels on the membrane of ovarian cancer cells. CD44V6 expression is closely associated with the tumorous transformation of ovarian tissue, suggesting that CD44V6 can promote the occurrence and progression of ovarian cancer.
RESUMO
BACKGROUND Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancers. Promoter hypermethylation of human mutL homolog 1 (hMLH1) has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI), while the connection of the epigenetic inactivation of hMLH1 in colorectal cancers remains unknown. The aim of this study was to evaluate the relationship between the promoter hypermethylation of hMLH1 and colorectal cancers by performing a meta-analysis. MATERIAL AND METHODS Eligible studies were identified through searching PubMed, Cochrane Library, Web of Science, and Google Scholar databases. R Software including meta packages was used to calculate the pooled and odds ratios (ORs) with corresponding confidence intervals (CIs). Funnel plots were also performed to evaluate publication bias. RESULTS This meta-analysis obtained 45 articles, including 4096 colorectal cancer patients, and identified a significant association between hMLH1 hypermethylation and colorectal cancer risk using the fixed-effects model (OR=8.3820; 95% CI, 6.9202~10.1527; z=21.7431; P<0.0001) and random effects model pooled (OR=10.0963; 95% CI, 6.1919~16.4626; z=9.2688; P<0.0001). The significant relationship was found in subgroup analyses. CONCLUSIONS The results of this meta-analysis show a significant association between hMLH1 hypermethylation and colorectal cancer risk.
Assuntos
Neoplasias Colorretais/genética , Metilação de DNA/genética , Proteína 1 Homóloga a MutL/genética , Humanos , Instabilidade de Microssatélites , Regiões Promotoras Genéticas , Viés de Publicação , Fatores de RiscoRESUMO
Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X), SETD2 (I1608V), SMAD4 (G382T), and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies.
Assuntos
Neoplasias Colorretais/genética , Heterogeneidade Genética , Análise de Sequência de DNA/métodos , Idoso , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL/genética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Filogenia , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Selective peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist affects the functions of endothelial progenitor cells (EPCs). This study explores the effect of selective PPAR-γ agonist, pioglitazone, on EPC apoptosis. The cells were cultured and identified via the double staining method in a medium containing different concentrations of pioglitazone. EPC apoptosis was detected by flow cytometry. On Day 7, EPCs engulfed DiL-ac-LDL and FITC-UEA-1, and showed yellow fluorescence in a laser-scanning confocal microscope. EPC apoptosis inhibition was maximal at 50 µmol/L. The ability of pioglitazone to prevent EPC apoptosis may be mediated by the PI3K/Akt signal pathway. The use of thiazolidine two ketone (TZD) to reduce EPC apoptosis may have some potential in treating vascular diseases.
Assuntos
Apoptose/efeitos dos fármacos , Células da Medula Óssea/citologia , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Células-Tronco/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Células Cultivadas , Corantes Fluorescentes/química , Hipoglicemiantes/química , Masculino , PPAR gama/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Pioglitazona , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo , Tiazolidinedionas/químicaRESUMO
In the title compound, [Zn(2)(C(10)H(2)O(8))(C(16)H(20)N(4))(H(2)O)(2)](n), the Zn(II) atom is in a distorted tetra-hedral environment, being coordinated by one N atom from a 1,4-bis-(3-pyridyl-meth-yl)piperazine (3-bpmp) ligand, two O atoms from two carboxyl-ate groups of the pyromellitate anion and one water mol-ecule. The distortion of the tetrahedral coordination may be ascribed to the hydrogen bonds between the carboxyl-ate groups and the adjacent water mol-ecules. Each Zn(II) atom links to three organic ligands and each pyromellitate ligand coordinates to four Zn(II) atoms, forming a (3,4)-connected infinite three-dimensional framework. O-Hâ¯N inter-actions also occur.
RESUMO
Matrine is the major active component of the traditional Chinese medicine Sophora flavescens, but the molecular mechanisms of matrine on tumor invasion inhibition remain unclear. The aim of this study is to elucidate the effects of matrine on invasion ability of human hepatocellular carcinoma (HCC) cells, matrix metalloproteinase-9 (MMP-9), and nuclear factor (NF)-kappa B expression. The expression activity of MMP-9 was measured by reverse transcription polymerase chain reaction, Western blot, and gelatin zymography analysis. The expression of NF-kappa B was measured by the Western blot analysis. Matrine significantly inhibited MMP-9 expression of SMMC-7721 cells. NF-kappa B inhibitor PTDC induced a marked reduction in MMP-9 expression, and it suggested that NF-kappa B could play an important role in MMP-9 expression. Furthermore, matrine significantly suppressed NF-kappa B expression and the invasion of SMMC-7721 cells. Our results showed that matrine inhibited MMP-9 expression and the invasion of human HCC cells. The inhibitory effects are partly associated with the downregulation of the NF-kappa B signaling pathway.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz , Quinolizinas/farmacologia , Alcaloides/química , Alcaloides/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Medicamentos de Ervas Chinesas/química , Humanos , Metaloproteinase 9 da Matriz/genética , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Quinolizinas/química , Quinolizinas/uso terapêutico , Sophora/química , MatrinasRESUMO
BACKGROUND/AIMS: Resveratrol, a polyphenolic phytochemical present in berries, grapes, and wine, has emerged as a promising chemopreventive candidate. The aim of the present study was to determine the inhibitory effect of resveratrol on vascular endothelial growth factor (VEGF) expression and angiogenesis in hepatocellular carcinoma (HCC) and to explore its mechanism. METHODOLOGY: VEGF protein was detected by western blot, whereas VEGF mRNA expression was investigated by RT-PCR. Nuclear factor-kappa B (NF-kappa B) was measured by electrophoretic mobility shift assay (EMSA). Xenograft sections were stained for CD34 to study microvessels in vivo. RESULTS: We found that VEGF protein and mRNA expressions in the cells treated with resveratrol were significantly decreased. The activation of NF-kappa B was also intensely inhibited by resveratrol. Growth of tumours in nude mice was inhibited by resveratrol. Microvessel density was decreased with resveratrol treatment. CONCLUSIONS: The inhibitory effect of resveratrol on VEGF activity may occur partly through suppression of the activation of NF-kappa B in HepG2 cells. Resveratrol also significantly inhibited tumour growth and angiogenesis.
Assuntos
Inibidores da Angiogênese/farmacologia , Anticarcinógenos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Estilbenos/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/fisiologia , RNA Mensageiro/análise , Resveratrol , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
OBJECTIVE: To observe the effects of resveratrol on proliferation of human hepatocellular carcinoma cell line SMMC-7721 cells and expression of matrix metalloproteinase-9 (MMP-9) in vitro. METHODS: SMMC-7721 cells were treated with different concentrations of resveratrol for 24, 48 and 72 h, respectively. The effect of resveratrol on proliferation of SMMC-7721 cells was assessed with methyl thiazolyl tetrazolium (MTT). The expression of MMP-9 mRNA was determined by reverse transcription polymerase chain reaction (RT-PCR). MMP-9 protein was identified by Western blot analysis. RESULTS: Resveratrol could inhibit the proliferation of SMMC-7721 cells with dose- and time-dependent effects. Moreover, both MMP-9 mRNA expression and MMP-9 protein production were markedly reduced after resveratrol treatment. CONCLUSION: Resveratrol can inhibit the proliferation of SMMC-7721 cells and down-regulate MMP-9 expression. It is presumed that resveratrol may suppress the invasion and metastasis of hepatocellular carcinoma.