RESUMO
The pharmacokinetics (PK) of Rhodiola crenulata in rats were studied, and pharmacokinetic-pharmacodynamic (PK-PD) correlation analysis was performed to elucidate their time-concentration-effect relationship. The myocardial ischemia model was made with pituitrin. Rats were divided into sham operation, sham operation administration, model, and model administration groups (SG, SDG, MG, and MDG, respectively; n = 6). Blood was collected from the fundus venous plexus at different time points after oral administration. The HPLC-QQQ-MS/MS method was established for the quantification of five components of Rhodiola crenulata. CK, HBDH, SOD, LDH, and AST at different time points were detected via an automatic biochemical analyzer. DAS software was used to analyze PK parameters and PK-PD correlation. The myocardial ischemia model was established successfully. There were significant differences in the PK parameters (AUC0-t, AUC0-∞, Cmax) in MDG when compared with SDG. Two PD indicators, CK and HBDH, conforming to the sigmoid-Emax model, had high correlation with the five components, which indicated a delay in the pharmacological effect relative to the drug concentration in plasma. The difference in the PK parameters between modeled and normal rats was studied, and the time-concentration-effect of composition and effect indicators were investigated. This study can provide reference for the rational clinical application of Rhodiola crenulata and for related studies of other anti-myocardial ischemia drugs.
RESUMO
Breast cancer (BC) is the most commonly occurring malignancy in women. This study aimed to investigate the functions of the long noncoding RNA ZBED3-AS1 (ZBED3-AS1) in BC and its molecular mechanisms. qRT-PCR was conducted to access the expression of ZBED3-AS1, microRNA-513a-5p (miR-513a-5p), and Kruppel like factor 6 (KLF6) in BC. Additionally, BC cell viability and proliferative capacity were measured by MTT and 5-Ethynyl-20-deoxyuridine (EdU) assays. A transwell assay was used for evaluating BC cell migration and invasion. The interactions among ZBED3-AS1, miR-513a-5p, and KLF6 in BC were confirmed by dual-luciferase reporter assay. Furthermore, feedback approaches were performed to determine whether ZBED3-AS1 influences BC cell behaviors by regulating the miR-513a-5p/KLF6 axis. The murine xenograft model was established to assess the effect of ZBED3-AS1 on tumor growth. The expression of ZBED3-AS1 and KLF6 was reduced, while miR-513a-5p expression was elevated in BC. ZBED3-AS1 elevation attenuated the malignant behaviors of BC cells, including viability, proliferative capacity, migration, and invasion. Mechanical experiments revealed that ZBED3-AS1 targeted miR-513a-5p, and miR-513a-5p targeted KLF6 in BC. Feedback approaches validated that miR-513a-5p overexpression or KLF6 depletion reversed the inhibitory effects of ZBED3-AS1 upregulation on viability, proliferative capacity, migration, and invasion of BC cells. Furthermore, ZBED3-AS1 elevation attenuated the tumor growth in the murine xenograft model. ZBED3-AS1 hindered the malignant development of BC cells by regulating the miR-513a-5p/KLF6 axis, providing a novel therapeutic target in BC.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fator 6 Semelhante a Kruppel/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The aim of this study was to discuss the antitumor effect of Tegafur combined with Barbadian on S-180 tumor-bearing mice. A murine tumor model was prepared by subcutaneous injection of S-180 sarcoma cells to the armpit of the right limb of healthy female SPF KM mice. The 24 tumor-bearing mice were randomly divided into 4 groups: Combination therapy group of Tegafur and Barbadian, Barbadian group, Tegafur group and normal saline control group. Corresponding test substances were given to each group by intragastric administration, respectively, 0.2 ml/mouse, once/day, continuous 5 days, interval for 2 days, recorded as 1 period, 3 periods were continuously performed. Antitumor rate, immune cells, blood biochemistry and inflammatory mediators and other indexes were then respectively measured. Result showed that the antitumor rate for the Combination group was 78%; Barbadian group, 72%; and Tegafur group, -89%. White blood cells (WBC) in Barbadian group was significantly higher than that in the control group (P<0.01); lymphocytes (LYMPH), Barbadian group was significantly higher than that in the control group (P<0.01), Tegafur group was significantly lower than the control group (P<0.01); monocytes (MONO), all drug groups were significantly higher than the control group (P<0.01); neutrophils (NEUT), combination group (P<0.01) and Barbadian group (P<0.05) were significantly higher than the control group; blood sugar for the combination (P<0.05) and Barbadian (P<0.01) groups were significantly higher than the control group, while the Tegafur group was significantly lower than the control group (P<0.01). Cholesterol and BUN in the Tegafur group were significantly higher than that in control group (P<0.05). For IL-1, the combination and Barbadian groups were significantly higher than the control group (P<0.05), while for IL-6, all the drug groups were significantly higher than the control group (P<0.05). TNF-α in the Tegafur group was significantly lower than that in the control group (P<0.05). In conclusion, the combination of Tegafur and Barbadian has the significant effect of inhibiting mice S-180 sarcoma. The single use of chemotherapeutic drug Tegafur has no significant inhibitory effect on mice S-180 sarcoma. The single use of Barbadian has good antitumor effect and can resist the significant decrease of lymphocytes caused by the chemotherapeutic drug Tegafur. Thus, Barbadian has a good antitumor effect and can protect the immune system of the body, making it a viable treatment option.
RESUMO
Evidence indicated that inflammatory response and some pattern-recognition receptors play important roles in the occurrence and progression of osteoarthritis. This study is conducted to evaluate the role of RIG-I and its adaptor protein MAVS in the pathogenesis of osteoarthritis. Four SNPs in RIG-I gene and four in MAVS gene were genotyped in 1056 Chinese Han population. We also overexpressed MAVS in murine chondrogenic ATDC5 cells and analyzed the cell viability and apoptosis. Rs11795343 (P-allele: 0.063394) in RIG-I, rs17857295 (P-allele: 0.073518) and rs7262903 (P-allele: 0.054052, P-genotype: 0.067930) in MAVS were marginally associated with OA. Rs7269320 (P-allele: 0.014783, P-genotype: 0.03272) in MAVS was significant associated with OA. Further analyses in different genders indicated that rs7262903 (P-allele: 0.017256, P-genotype: 0.045683) and rs7269320 (P-allele: 0.013073, P-genotype: 0.038881) are significantly associated with OA in female group. Haplotype analyses indicated G-C-G (χ2: 4.328, P-value: 0.037503) in rs10813821-rs11795343-rs659527 block of RIG-I, G-C-A-T (χ2: 4.056, P-value: 0.044028) and G-C-C-C (χ2: 14.295, P-value: 0.000158) in rs17857295-rs2326369-rs7262903-rs7269320 block of MAVS were significantly associated with OA. Furthermore, forced expression of MAVS could suppress the viability and promote the apoptosis of ATDC5 chondrogenic cells. In conclusion, this study indicated that RIG-I and MAVS are probably associated with OA in the females of Chinese Han population. And MAVS might be a novel risk factor for OA which may involve in growth of chondrocytes and cartilage homeostasis.
RESUMO
Chemotherapeutic insensitivity is a significant barrier for effective treatment of gastric cancer (GC). Recently, emerging evidence has demonstrated that microRNAs (miRNAs) are critically involved in drug resistance. Here, by a large-scale screen, we noticed low expression of miR-126 in the drug-resistant GC cell lines SGC7901/VCR and SGC7901/ADR compared with their parental cell line SGC7901. Ectopic expression of miR-126 increased sensitivity of SGC7901/VCR and SGC7901/ADR cells to vincristine (VCR) and adriamycin (ADR). Mechanistically, Enhancer of Zeste Homolog 2 (EZH2) was identified as a direct target of miR-126. Genetic silencing of EZH2 mirrored the effects of miR-126 in drug resistance, and restoration of EZH2 blocked the inhibitory effect of miR-126 on GC. Taken together, our results suggest that miR-126 is a tumor suppressor by sensitizing GC cells to chemotherapy and provide a potential therapeutic approach in cancer treatment.
Assuntos
Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Antineoplásicos/farmacologia , Sítios de Ligação/genética , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Vincristina/farmacologiaRESUMO
In this study, gambogic acid (GA) and retinoic acid chlorochalcone (RACC) co-loaded glycol chitosan nanoparticle was successfully developed and studied for its therapeutic efficacy against osteosarcoma cancer cells. The GA/RACC loaded glycol chitosan nanoparticles (RGNP) was nanosized and exhibited a controlled release of drug in either pH 7.4 and pH 5.0. Owing to the strong positive charge on the RGNP surface, efficiency cellular uptake was observed in cancer cells. Moreover, a synergistic combination of GA and RACC were effectively suppressed the tumor growth progression. The half maximal inhibitory concentration (IC50) values in MG63 cells were 0.89µg/ml and 0.35µg/ml for GA and RGNP after 24h. The results clearly suggest the synergist effect of GA and RACC in effectively inhibiting the cancer cell proliferation. The RGNP as expected induced a remarkably higher apoptosis of cancer cells with â¼28%. Overall, combination of GA and RACC encapsulated in a nanocarrier could be an effective strategy to treat osteosarcoma. Future studies will focus on the in vivo evaluation of GA/RACC-loaded polymeric nanoparticles.
Assuntos
Antineoplásicos/uso terapêutico , Cicloexanonas/uso terapêutico , Nanomedicina/métodos , Osteossarcoma/tratamento farmacológico , Tretinoína/análogos & derivados , Xantonas/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cicloexanonas/química , Cicloexanonas/farmacologia , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Humanos , Cinética , Nanopartículas/química , Nanopartículas/ultraestrutura , Osteossarcoma/patologia , Resultado do Tratamento , Tretinoína/química , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Xantonas/química , Xantonas/farmacologiaRESUMO
BACKGROUND: miR-153 has been found to be significantly decreased in non-small cell lung cancer (NSCLC) tissues; however, its clinical significance has not been investigated. METHODS: The expression patterns of miR-153 in 137 pairs of human lung cancer tissues and adjacent normal lung tissues were analyzed using qRT-PCR. The relationships between miR-153 expression and clinicopathological parameters were examined by chi-square test. Kaplan-Meier method and the log-rank test were used to determine the difference in overall survival (OS) rates between two groups. RESULTS: The expression of miR-153 was reduced significantly, compared with adjacent normal lung tissues (P<0.05). We observed that the expression level of miR-153 was positively correlated with the clinical stage (P=0.005), lymph node status (P=0.014), distant metastasis (P=0.004), and differentiated degree (P<0.001) in NSCLC patients. According to the Kaplan-Meier survival analysis, the patients with low miR-153 expression exhibited evidently poorer overall survival rates than those with high miR-153 expression (P=0.003). Multivariate analysis showed that the expression of miR-153 was an independent and significant factor associated with poor OS rates (P=0.002). CONCLUSION: Decreased expression of miR-153 might be a potential unfavorable prognostic factor for patients with NSCLC, and further studies would be needed to prove our findings.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Diferenciação Celular , Distribuição de Qui-Quadrado , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
Taxol is a frontline chemotherapeutic agent for the treatment of patients with multiple types of tumor. However, resistance to Taxol remains one of the principal causes of cancerassociated mortality. Glutamine, which is metabolized via a glutaminase (GLS)dependent process, termed glutaminolysis, is important in cell growth and metabolism. The present study reported a novel mechanism underlying Taxol resistance in breast cancer cells. By investigating the glutamine metabolism of breast cancer cells in response to treatment with Taxol in vitro, it was observed that Taxol induced the uptake of glutamine and the expression of GLS1. Notably, Taxolresistant cancer cells exhibited upregulation in the metabolism of glutamine and expression of GLS1. In addition, overexpression of GLS1 rendered cancer cells resistant to Taxol, indicating that GLS1 may be the therapeutic target for overcoming Taxol resistance in clinical therapeutics. The results also demonstrated that knockdown of GLS1 using small interfering RNA, resensitized the Taxolresistant breast cancer cells to Taxol.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Glutaminase/metabolismo , Paclitaxel/farmacologia , Interferência de RNA , Regulação para Cima/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Glutaminase/antagonistas & inibidores , Glutaminase/genética , Glutamina/metabolismo , Humanos , RNA Interferente Pequeno/metabolismoRESUMO
OBJECTIVE: To evaluate the efficacy and toxicity of a biweekly DOF regimen consisting of docetaxel, oxaliplatin, 5-fluorouracil and leucovorin for advanced gastric cancer. METHODS: The biweekly DOF regimen was administered in 37 advanced gastric cancer patients. Docetaxel, oxaliplatin and leucovorin were given intravenously at a dose of 35 mg/m2, 85 mg/m2 and 200 mg/m2 for 1 h, 2 h and 2 h on D1, respectively, and 5-Fu was administered as continuous intravenous infusion for 48 h at a dose of 1500 mg/m2 on D1 and D2. This regimen was repeated every 2 weeks. The efficacy and toxicity were evaluated after completion of 3 cycles at least. RESULTS: The overall response rate (RR) of this series was 67.6%, complete response rate and partial response rate were 27.0% and 40.5%, respectively. The time to progression (TTP) was 9.2 months, and median survival time (MST) was 13.7 months. The RRs of 11 chemotherpy-naïve patients and 26 patients pre-treated with chemotherapy were 81.8% and 61.5%, respectively. CONCLUSION: Our preliminary results showed that this biweekly combination regimen of docetaxel, oxaliplatin, 5-fluorouracil and leucovorin is effective and tolerable for advanced gastric cancer. However, further investigation of this regimen is mandatory.