RESUMEN

OBJECTIVE: The aim of this study was to investigate and evaluate the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus (T2DM) induced by glucagon-like peptide 1 receptor agonist (GLP-1 RA) hypoglycemic drugs. MATERIALS AND METHODS: We searched papers in PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, Wanfang, Embase, and VIP databases, and the retrieval time limit was set from the establishment of the database to May 2023. Randomized Controlled Trials (RCTs) were collected in which the subjects were T2DM patients, the intervention was GLP-1RA compared with placebo or traditional hypoglycemic drugs, and the outcome indicators included dyspepsia and anorexia. A meta-analysis and a network meta-analysis were performed. RESULTS: The results of the traditional meta-analysis showed that the risk of dyspepsia and anorexia of total GLP-1 RA was 3.01 and 2.56 times that of placebo, respectively. All types of GLP-1RA were compared with placebo and the results also showed a trend towards increased risk of digestive system adverse events (DSAEs). Among all interventions included, liraglutide was the one with the highest risk of dyspepsia in patients with T2DM, and dulaglutide was the one with the highest risk of anorexia. CONCLUSIONS: The results of the two meta-analyses are consistent, and both clearly show that GLP-1RA can increase the risk of dyspepsia and anorexia in T2DM patients.

Asunto(s)

Anorexia , Diabetes Mellitus Tipo 2 , Dispepsia , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Receptor del Péptido 1 Similar al Glucagón/agonistas , Dispepsia/tratamiento farmacológico , Dispepsia/inducido químicamente , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Anorexia/inducido químicamente , Anorexia/tratamiento farmacológico , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

OBJECTIVE: The purpose of this study was to retrospectively assess the efficacy and safety of percutaneous nephrolithotomy (PCNL) for upper urinary stones using upper pole access (UPA) and other (low or middle) pole access (OPA). MATERIALS AND METHODS: A comprehensive literature review of articles investigating the clinical efficacy and safety of UPA and OPA was performed. The relevant literature was obtained from PubMed, EMBASE, Science Direct, Google Scholar and the Cochrane Library. The primary outcomes, including the stone-free rate, were evaluated using Review Manager 5.4 software. The secondary outcomes (peri- and postoperative complications and operative date) were also compared and analyzed. RESULTS: Ten comparative studies involving 5,290 patients were included in the analysis. The pooled data showed that the UPA group had a stone-free rate (SFR) similar to that of the OPA group [odds ratio (OR) 1.38, 95% confidence interval (CI): 0.94 to 2.03; p=0.22] but a higher incidence of blood transfusion [OR: 1.50; 95% CI: (1.03, 2.19), p=0.04]. There was no statistically significant difference in operative time [mean difference (MD): -7.27; 95% CI: (-25.18, 10.65), p=0.43] or hospital stay [MD: -0.13; 95% CI: (-0.64, 0.37), p=0.60] between the two groups. In addition, the results support that UPA causes fewer complications than OPA. CONCLUSIONS: Our findings suggest that UPA and OPA are both effective treatments for the management of upper urinary stones. Compared to OPA, UPA is associated with less need for blood transfusion and fewer complications. Nevertheless, the findings should be further confirmed by well-designed prospective randomized controlled trials (RCTs) with large samples and strict standards.

Asunto(s)

Cálculos Renales , Nefrolitotomía Percutánea , Cálculos Urinarios , Humanos , Nefrolitotomía Percutánea/efectos adversos , Nefrolitotomía Percutánea/métodos , Cálculos Renales/cirugía , Riñón , Cálculos Urinarios/cirugía , Punciones , Resultado del Tratamiento

RESUMEN

MicroRNAs (miRNA) play an essential role in mammary gland development and lactation. Previous studies in cattle have shown that miR-221 is highly expressed in peak compared with early lactation. However, the functions of miR-221 in bovine mammary gland epithelial cells and the mechanisms by which this miRNA affects cell proliferation and milk synthesis remain unclear. We hypothesized that miR-221 targets and modulates the expression of specific genes in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and phosphatidylinositol 3-kinase-proteinkinase B/mammalian target of rapamycin (PI3K-Akt/mTOR) signaling pathways, which have crucial roles in lactation in cattle. Following transfection of miR-221 into cultured bovine mammary gland epithelial cells, inhibition of cell proliferation and reduced viability of these cells were observed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis. To elucidate the molecular mechanisms of the effects of miR-221 on cell proliferation, we selected potential candidate genes that can be targeted by miR-221 using bioinformatics prediction tools. The dual luciferase assay revealed that STAT5a, STAT3, and IRS1 interact with miR-221 by its direct binding to the 3'-untranslated regions (UTR) of these genes. Subsequent analysis showed that transfection of a miR-221 mimic resulted in significantly decreased expression of STAT5a and IRS1 at both the RNA and protein levels using quantitative real-time PCR and Western blot analyses. Furthermore, expression levels of the downstream genes SOCS3, AKT3, and mTOR that are regulated by STAT5a and IRS1 in the JAK-STAT and PI3K-Akt/mTOR signaling pathways, were also altered after miR-221 transfection. This is the first study to reveal the mechanisms by which miR-221 inhibits mammary gland epithelial cell proliferation by targeting STAT5a and IRS1, key genes in the PI3K-Akt/mTOR and JAK-STAT signaling pathways.

Asunto(s)

Bovinos/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , MicroARNs/genética , Leche/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal , Regiones no Traducidas 3'/genética , Animales , Bovinos/fisiología , Proliferación Celular , Células Epiteliales/metabolismo , Femenino , Proteínas Sustrato del Receptor de Insulina/genética , Lactancia , Glándulas Mamarias Animales/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/genética

RESUMEN

OBJECTIVE: It's of great significance to investigate the novel targets of drugs for the treatment of stroke. In this study, we explored the neuroprotective role of miR-424 in oxygen glucose deprivation (OGD)-induced injuries in PC-12 cells. MATERIALS AND METHODS: PC-12 cells were subjected to OGD stimulation to mimic ischemic injury. The expressions of miR-424 and mitogen-activated protein kinase phosphatase-1 (MKP-1) were altered by transient transfection with miR-424 mimic, miR-424 inhibitor, pEX-MKP-1, or sh-MKP-1. Cell counting kit-8 (CCK-8) assay, flow cytometry, and quantitative reverse transcription polymerase chain reaction (qRT-PCR), were conducted to respectively detect cell viability, apoptotic cells, and the expression of miR-424 and MKP-1. The protein expressions of several factors were determined by Western blot. Meanwhile, relative luciferase activity assay was done to verify the predicted targets association. RESULTS: OGD induced injury in PC-12 cells by suppressing cell viability and inducing apoptosis. OGD also induced the expression of miR-424 in PC-12 cells. Overexpression of miR-424 protected PC-12 cells from OGD-induced injury by increasing cell viability and decreasing apoptosis. MKP-1 was a direct target of miR-424, and its expression was negatively regulated by miR-424. Up-regulation of expression of MKP-1 aggravated OGD-induced cell injury by inhibiting the expression of hypoxia-inducible factor 1α (HIF-1α), thus inhibiting the PI3K/AKT/mTOR pathways. CONCLUSIONS: miR-424 protected PC-12 cells from OGD-induced injury through direct suppression of MKP-1 expression, as MKP-1 promoted OGD-induced cell injury by inhibiting the expression of HIF-1α and PI3K/AKT/mTOR pathways.

Asunto(s)

Fosfatasa 1 de Especificidad Dual/fisiología , Hipoxia-Isquemia Encefálica/prevención & control , MicroARNs/fisiología , Neuroprotección , Animales , Supervivencia Celular , Fosfatasa 1 de Especificidad Dual/genética , Glucosa/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Células PC12 , Fosfatidilinositol 3-Quinasas/fisiología , Ratas

RESUMEN

Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we demonstrate that inactivation of Cdkn2b (p15ink4b) is necessary for induction of pancreatic cancer by oncogenic KRASG12D expression and inactivation of Tp53 and Cdkn2a in adult mouse pancreatic ductal cells (P60 or older). KRASG12D overexpression in these cells activated transforming growth factor-ß signaling and expression of CDKN2B, which, along with CDKN2A, led to cellular senescence and protected cells from KRAS-mediated transformation via inhibition of retinoblastoma phosphorylation. These results show a critical role of CDKN2B inactivation in pancreatic carcinogenesis, and provide a useful adult animal model by genetic engineering via lentiviral delivery.

Asunto(s)

Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/genética , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Senescencia Celular/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p18 de las Quinasas Dependientes de la Ciclina/metabolismo , Ingeniería Genética/métodos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , ARN Interferente Pequeño/administración & dosificación , Proteína de Retinoblastoma/metabolismo , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/genética

RESUMEN

Vincristine is an antitumor vinca alkaloid isolated from vinca rosea, and is a medication used to treat a number of types of cancer. In this study, we investigated the impact of vincristine on oncogenic phenotypes of human colorectal cancer HCT116 cells. MTT assay demonstrated that vincristine showed a obviously inhibitory effect on cell growth compared to non-treated cells. However, Transwell assay showed that vincristine promoted migration and invasion of HCT116 cells in vitro in a concentration-dependent manner between 0.5 and 15 µM vincristine treatment, whereas cell growth showed no remarkable difference within the same concentration range. Additionally, Western blot analysis showed that vincristine significantly elevated RhoA activity and Myosin light chain (MLC) phosphorylation, suggesting the involvement of RhoA/ROCK pathway in the vincristine-induced enhancement of cellular motility. Furthermore, we found that both the siRNA for RhoA and ROCK inhibitor Y27632 attenuated the phosphorylation of MLC, as well as vincristine-induced migration and invasion. These data indicate that vincristine enhanced migration and invasion of HCT116 cells possibly through stimulating RhoA/ROCK/MLC signaling pathway.

Asunto(s)

Cadenas Ligeras de Miosina/metabolismo , Transducción de Señal/efectos de los fármacos , Vincristina/farmacología , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Amidas/farmacología , Western Blotting , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Células HCT116 , Humanos , Fosforilación/efectos de los fármacos , Piridinas/farmacología , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Quinasas Asociadas a rho/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/genética

RESUMEN

OBJECTIVE: Long non-coding RNAs (lncRNAs) CRNDE has been identified as a tumor oncogene in glioma. However, its clinical significance and prognostic value in glioma have not been investigated until now. The aim of this study was to explore CRNDE expression levels and evaluated its clinical significance in glioma patients. PATIENTS AND METHODS: Expression levels of lncRNA CRNDE in 164 glioma specimens were determined by quantitative real-time PCR (qRT-PCR). The chi-square test was used to explore CRNDE expression with respect to clinicopathological parameters. The overall survival was analyzed by log-rank test, and survival curves were plotted according to Kaplan-Meier. Univariate and multivariate analyses were performed to analyze the prognostic significance of CRNDE expression. RESULTS: Compared with nonneoplastic brain tissues, the expression level of CRNDE was significantly increased in glioma tissues (p < 0.01). CRNDE upregulation was correlated with larger tumor size (p = 0.011), higher WHO grade (p = 0.001), and recurrence (p = 0.008). Also, survival analysis proved that up-regulated CRNDE expression was associated with poor overall survival of glioma patients (p < 0.001). The multivariate Cox regression analysis indicated that CRNDE expression was an independent prognostic factor for overall survival. CONCLUSIONS: These results indicated that lncRNA CRNDE was associated with tumor progression and could be an independent prognostic factor for glioma patients.

Asunto(s)

Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión Génica , Glioma/genética , ARN Largo no Codificante/genética , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Pronóstico

Asunto(s)

Aciltransferasas/antagonistas & inhibidores , Genes ras , Leucemia/genética , Aciltransferasas/genética , Animales , Humanos , Ratones , Ratones Noqueados

RESUMEN

Saxitoxin (STX), a member of the family of paralytic shellfish poisoning toxins, poses toxicological and ecotoxicological risks. To develop an analytical recognition element for STX, a DNA aptamer (APT(STX1)) was previously discovered via an iterative process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX) by Handy et al. Our study focused on generating an improved aptamer based on APT(STX1) through rational site-directed mutation and truncation. In this study, we generated the aptamer, M-30f, with a 30-fold higher affinity for STX compared with APT(STX1). The Kd value for M-30f was 133 nM, which was calculated by Bio-Layer Interferometry. After optimization, we detected and compared the interaction of STX with aptamers (APT(STX1) or M-30f) through several techniques (ELISA, cell bioassay, and mouse bioassay). Both aptamers' STX-binding ability was demonstrated in all three methods. Moreover, M-30f performs better than its parent sequence with higher suppressive activity against STX. As a molecular recognition element, M-30f has good prospects for practical application.

Asunto(s)

Aptámeros de Nucleótidos/metabolismo , Mutagénesis Sitio-Dirigida , Saxitoxina/antagonistas & inhibidores , Animales , Bioensayo/métodos , Técnicas Biosensibles , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Estudios de Factibilidad , Femenino , Ratones , Ratones Endogámicos ICR , Conformación de Ácido Nucleico , Saxitoxina/química , Saxitoxina/toxicidad

RESUMEN

BACKGROUND: Generalised recalcitrant facial verruca plana responds poorly to current therapeutic options, including cryotherapy, topical drugs and carbon dioxide (CO2 ) laser. Case reports and uncontrolled studies suggested that topical photodynamic therapy (PDT) is effective choice of treatment free from potential complications associated with invasive therapies. AIMS: To investigate the efficacy and safety of PDT with different concentrations of photosensitiser in the treatment of verruca plana. MATERIALS & METHODS: The two sides of a subject's face were separately randomized to receive aminolevulinic acid (ALA) of 5%, 10% or 20% concentration. All patients were irradiated with 633-nm red light for 339 J/cm(2) total dose. Complete response (CR) rate was assessed on Week 4, 8, and 16 respectively. RESULTS: The mean overall clearance rate was 74.1%, 68.8%, and 64.6% on Week 4, 8, and 12, respectively, in the 110 treated sides. The CR rate was lower in the 5%-ALA group than in the 10%-ALA group (14.3% vs. 33.3%, p < 0.05) and 20%-ALA group (14.3% vs. 26.3%, p < 0.05) after 12 weeks. The mean severity of pain measured by visual analogue scale (VAS) scoring was 3.8 (range: 2 to 10, depending on the lesion location). The overall recurrence rate was 16.7% (4/24) on Week 12. Hyperpigmentation was observed in 61% (67/110) of all treated sides. On Week 4, 8, and 16, hyperpigmentation was more developed in the 20%-ALA group than in the other two groups (p < 0.05). DISCUSSION: In terms of complete clearance rate, the 5% ALA-PDT group was significantly inferior to the 10% and 20% ALA-PDT groups at each follow-up. In contrast, the 20% ALA group showed a higher incidence rate of transient hyperpigmentation than the other two groups. CONCLUSIONS: This randomised clinical trial suggests that PDT with ALA of 10% concentration offers better efficacy and safety than 5% or 20% concentration for generalised recalcitrant facial verruca plana.

Asunto(s)

Ácido Aminolevulínico/uso terapéutico , Cara , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Verrugas/tratamiento farmacológico , Ácido Aminolevulínico/administración & dosificación , Relación Dosis-Respuesta a Droga , Humanos , Fármacos Fotosensibilizantes/administración & dosificación

RESUMEN

Chemotherapy remains the common therapeutic for patients with lung cancer. Novel, selective antitumor agents are pressingly needed. This study is the first to investigate a different, however, effective antitumor drug candidate Wentilactone A (WA) for its development as a novel agent. In NCI-H460 and NCI-H446 cell lines, WA triggered G2/M phase arrest and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). It also induced activation of mitogen-activated protein kinase and p53 and increased expression of p21. When we pre-treated cells with ERK, JNK, p38, p53 inhibitor or NAC followed by WA treatment, only ERK and p53 inhibitors blocked WA-induced apoptosis and G2/M arrest. We further observed Ras (HRas, KRas and NRas) and Raf activation, and found that WA treatment increased HRas-Raf activation. Knockdown of HRas by using small interfering RNA (siRNA) abolished WA-induced apoptosis and G2/M arrest. HRas siRNA also halted Raf, ERK, p53 activation and p21 accumulation. Molecular docking analysis suggested that WA could bind to HRas-GTP, causing accumulation of Ras-GTP and excessive activation of Raf/ERK/p53-p21. The direct binding affinity was confirmed by surface plasmon resonance (SPR). In vivo, WA suppressed tumor growth without adverse toxicity and presented the same mechanism as that in vitro. Taken together, these findings suggest WA as a promising novel, potent and selective antitumor drug candidate for lung cancer.

Asunto(s)

Antineoplásicos/farmacología , Guanosina Trifosfato/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fase G2/fisiología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Quinasas raf/metabolismo , Proteínas ras/metabolismo

RESUMEN

OBJECTIVE: MicroRNA-224 (miR-224) has been consistently reported to be dysregulated in various human malignancies and can potentially affect many cancer-related cellular processes, including transcription, cell differentiation, cell death, growth, and cell proliferation. However, its roles in human glioma have not been reported. The aim of this study was to explore the expression pattern, clinical significance, and prognostic value of miR-224 in glioma patients using large cohorts. METHODS: Quantitative real-time polymerase chain reaction analysis was used to characterize the expression patterns of miR-224 in 108 glioma and 20 normal brain tissues. The associations of miR-224 expression with clinicopathological factors and prognosis of glioma patients were also statistically analyzed. RESULTS: miR-224 expression is significantly upregulated in glioma tissues compared with normal brain tissues (P < 0.001). In addition, high expression of miR-224 was significantly associated with advanced pathological grade (P = 0.006) and low Karnofsky performance score (KPS, P = 0.01). Moreover, Kaplan-Meier survival analysis showed that high miR-224 expression group had significantly shorter disease-free survival (DFS) and overall survival (OS) rates than low miR-224 expression group (both P < 0.001). Multivariate analysis with the Cox's proportional hazards model revealed that high expression of miR-224 (P = 0.006 and P = 0.01, respectively) and advanced pathological grade (both P = 0.02) were independent factors for shorter DFS and OS. Furthermore, subgroup analyses showed that miR-224 expression was significantly associated with poor DFS and OS in glioma patients with high pathological grades (for grade III-IV: P < 0.001 and P = 0.005, respectively). CONCLUSIONS: MiR-224 is upregulated and confers a poor prognosis in glioma patients (AU)

Asunto(s)

Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Encefálicas/genética , Glioma/genética , MicroARNs/genética , Regulación hacia Arriba , Estudios de Cohortes , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Glioma/diagnóstico , Glioma/patología , Estimación de Kaplan-Meier , MicroARNs/metabolismo , Análisis Multivariante

RESUMEN

Hepatocellular carcinoma (HCC) is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Wentilactone B (WB), a tetranorditerpenoid derivative extracted from the marine algae-derived endophytic fungus Aspergillus wentii EN-48, has been shown to trigger apoptosis and inhibit metastasis in HCC cell lines. However, the mechanisms of its antitumor activity remain to be elucidated. We report here that WB could significantly induce cell cycle arrest at G2 phase and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). Additionally, treatment with WB induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38 MAP kinase. Among the pathway inhibitors examined, only SP600125 (JNK inhibitor) markedly reversedWB-induced apoptosis, and only U0126 (ERK inhibitor) significantly blocked WB-triggered G2 phase arrest. We also found that WB treatment increased both Ras and Raf activation, and transfection of cells with dominant-negative Ras (RasN17) abolishedWB-induced apoptosis and G2 phase arrest in SMMC-7721 cells. Furthermore, the results of inverse docking (INVDOCK) analysis suggested that WB could bind to Ras-GTP, and the direct binding affinity was also confirmed by surface plasmon resonance (SPR). Finally, in vivo, WB suppressed tumor growth in mouse xenograft models. Taken together, these results indicate that WB induced G2/M phase arrest and apoptosis in human hepatoma SMMC-7721 cells via the Ras/Raf/ERK and Ras/Raf/JNK signaling pathways, and this agent may be a potentially useful compound for developing anticancer agents for HCC.

Asunto(s)

Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Activación Enzimática , Fluorouracilo/farmacología , Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Desnudos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/metabolismo , Proteínas ras/metabolismo

RESUMEN

OBJECTIVE: MicroRNA-224 (miR-224) has been consistently reported to be dysregulated in various human malignancies and can potentially affect many cancer-related cellular processes, including transcription, cell differentiation, cell death, growth, and cell proliferation. However, its roles in human glioma have not been reported. The aim of this study was to explore the expression pattern, clinical significance, and prognostic value of miR-224 in glioma patients using large cohorts. METHODS: Quantitative real-time polymerase chain reaction analysis was used to characterize the expression patterns of miR-224 in 108 glioma and 20 normal brain tissues. The associations of miR-224 expression with clinicopathological factors and prognosis of glioma patients were also statistically analyzed. RESULTS: miR-224 expression is significantly upregulated in glioma tissues compared with normal brain tissues (P < 0.001). In addition, high expression of miR-224 was significantly associated with advanced pathological grade (P = 0.006) and low Karnofsky performance score (KPS, P = 0.01). Moreover, Kaplan-Meier survival analysis showed that high miR-224 expression group had significantly shorter disease-free survival (DFS) and overall survival (OS) rates than low miR-224 expression group (both P < 0.001). Multivariate analysis with the Cox's proportional hazards model revealed that high expression of miR-224 (P = 0.006 and P = 0.01, respectively) and advanced pathological grade (both P = 0.02) were independent factors for shorter DFS and OS. Furthermore, subgroup analyses showed that miR-224 expression was significantly associated with poor DFS and OS in glioma patients with high pathological grades (for grade III-IV: P < 0.001 and P = 0.005, respectively). CONCLUSIONS: MiR-224 is upregulated and confers a poor prognosis in glioma patients.

Asunto(s)

Neoplasias Encefálicas/genética , Glioma/genética , MicroARNs/genética , Regulación hacia Arriba , Adulto , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Estudios de Cohortes , Femenino , Glioma/diagnóstico , Glioma/patología , Humanos , Estimación de Kaplan-Meier , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Análisis Multivariante , Pronóstico

RESUMEN

A great number of studies regarding the association between MTHFR C677T polymorphism and risk of colorectal cancer (CRC) in East Asians were published, but the results were inconsistent. Thus, a meta-analysis was performed to investigate the association. PubMed, Embase, and CBM databases were searched for eligible publications. Pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were calculated using random or fixed effect models. Finally, 24 case-control studies with a total of 7,230 CRC cases and 9,285 controls were included. Meta-analyses of a total of 24 studies showed there was a statistically significant association between MTHFR C677T polymorphism and decreased CRC risk in East Asians under four genetic models (T versus C, OR = 0.92, 95 % CI 0.85-0.99; TT versus CC, OR = 0.80, 95 % CI 0.69-0.94; TT versus CT/CC, OR = 0.82, 95 % CI 0.71-0.95; TT/CT versus CC, OR = 0.92, 95 % CI 0.86-0.98). The cumulative meta-analyses for the allele contrast (T versus C), homozygote (TT versus CC), dominant (TT/CT versus CC), and recessive (TT versus CT/CC) models all showed a trend of more obvious association as information accumulated by year. Subgroup analyses by country further identified this association in Korea and Japan. This meta-analysis suggests that MTHFR C677T polymorphism is associated with decreased risk of colorectal cancer in East Asians, and MTHFR 677T variant has a protective effect on colorectal cancer.

Asunto(s)

Pueblo Asiatico/genética , Neoplasias Colorrectales/etiología , Predisposición Genética a la Enfermedad , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple/genética , Neoplasias Colorrectales/epidemiología , Asia Oriental/epidemiología , Humanos , Pronóstico , Factores de Riesgo

RESUMEN

The molecular characterization of cytogenetic abnormalities has not only provided insights into the mechanisms of leukemogenesis but also led to the establishment of new treatment strategies targeting these abnormalities and thereby further improve the prognosis of patients. We analyzed the prognosis of 1091 Chinese patients with newly diagnosed acute lymphoblastic leukemia (ALL) and explored the prognostic impacts of a large number of cytogenetic/molecular abnormalities. It was demonstrated that, in both B- and T-ALL settings, the prognosis was negatively correlated to the age as reported to date. For childhood T-ALL patients, it was also documented that the HOX11 expression represented a favorable prognostic factor as it was in adult ones. We identified CRLF2 overexpression as an intermediate-risk marker and Ik6 variant of IKZF1 gene as a high-risk one when stratifying pediatric B-ALL cases according to cytogenetic/molecular risks. We also found that Ik6 variant and CRLF2 overexpression had an important role in dictating the prognosis of Ph-negative patients, which may be useful markers in guiding the treatment of ALL in the future, with tyrosine kinase inhibitors on the other hand reversing the fate of Ph-positive ALL patients.

Asunto(s)

Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Aberraciones Cromosómicas , Trastornos de los Cromosomas , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , China , Femenino , Humanos , Inmunofenotipificación , Lactante , Recién Nacido , Cariotipificación , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Pronóstico , Tasa de Supervivencia , Adulto Joven

RESUMEN

Our previous studies revealed that valsartan, an angiotensin II type I receptor blocker, exhibited renoprotective effects through decreasing urine protein excretion levels due to improving glomerular permeability in rats with diabetic nephropathy (DN). In this study, we sought to investigate the underlying mechanisms in perspectives of oxidative stress, transforming growth factor beta-1 (TGF-ß1) and monocyte chemoattractant protein-1 (MCP-1) expressions in glomerular mesangial cells (GMCs) and glomerular epithelial cells (GECs) since their roles are well-established in the development and progression of DN. High-glucose levels significantly increased oxidative stress in GMCs and GECs, as evidenced by enhanced generation of reactive reactive oxygen species (ROS), reduced levels of glutathione (GSH) and antioxidant enzyme superoxide dismutase (SOD), and increased production of malondialdehyde (MDA). Treatment with valsartan significantly restored the levels of those oxidative stress relevant molecules. Furthermore, valsartan obviously diminished the expression of proinflammatory cytokine MCP-1 in GMCs and GECs induced by high-glucose levels both at mRNA and protein levels, as determined by real-time PCR, immunocytochemistry, western blotting, and ELISA. In addition, the increased expressions of TGF-ß1 mRNA and protein induced by high-glucose level were also abrogated by valsartan treatment in GMCs, as evaluated by real-time PCR and ELISA. These results suggest that the renoprotective effects of valsartan may be related to its potential in decreasing oxidative stress and the expressions of MCP-1 and TGF-ß1 in GMCs and GECs.

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Quimiocina CCL2/antagonistas & inhibidores , Células Epiteliales/efectos de los fármacos , Glucosa/farmacología , Células Mesangiales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Tetrazoles/farmacología , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Valina/análogos & derivados , Animales , Técnicas de Cultivo de Célula , Células Cultivadas , Quimiocina CCL2/biosíntesis , Medios de Cultivo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/inmunología , Nefropatías Diabéticas/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Glucosa/metabolismo , Glutatión/metabolismo , Malondialdehído/metabolismo , Células Mesangiales/inmunología , Células Mesangiales/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Factor de Crecimiento Transformador beta1/biosíntesis , Valina/farmacología , Valsartán

RESUMEN

Diabetic nephropathy is the most common and severe renal complication of diabetes mellitus. The present study sought to investigate the renoprotective effects of a combination therapy of valsartan and low molecular weight heparin (LMWH) in rats with diabetic nephropathy induced by uninephrectomy and streptozotocin. The animals were divided into five groups as follows: sham-operated rats, diabetic control rats, diabetic rats treated with 20 mg/kg/day valsartan, diabetic rats treated with 600 IU/kg/day LMWH, diabetic rats treated with a combination of valsartan and LMWH (valsartan 10 mg/kg/day and LMWH 300 IU/kg/day). The treatment regimen was maintained for 8 weeks. Treatment with valsartan, LMWH, or a combination of the two had no significant effect on blood glucose levels. However, the urine protein excretion levels significantly decreased for the three drug treatment groups; the most dramatic decreases were observed in the combination treatment group. Kidney histology was examined using periodic acid-Schiff staining and immunohistochemical staining of extracellular matrix proteins. Results indicated that histopathology improved markedly in the three drug treatment groups; combination therapy had an equal or better effect than monotherapy in terms of decreasing the abnormal thickness of the glomerular basal membrane, the ratio of the area of the mesangial region with respect to the total area of renal glomeruli, and the accumulation of collagen IV and laminin in kidney tissue. In addition, serum levels of transforming growth factor-ß1 (TGF-ß1) also markedly decreased in the drug treatment groups according to ELISA. However, there were no significant differences between the combination therapy group and monotherapy group. These results suggest that a combination of valsartan and LMWH at half the dose used in monotherapy is better at improving glomerular permeability in rats with diabetic nephropathy.

RESUMEN

This review covers natural products isolated from marine microorganisms including bacteria, fungi and actinomycetes published in the recent years. The emphasis is mainly about new compounds, together with their anti-bacterial activities, source organisms and country of origin, biosynthetic studies as well as the mechanisms involved in their anti-bacterial activities.

Asunto(s)

Antibacterianos/química , Organismos Acuáticos/química , Bacterias/química , Hongos/química , Actinobacteria/química , Animales , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Ensayos Clínicos como Asunto , Humanos , Modelos Químicos