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1.
Invest New Drugs ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633577

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. According to reports, leukotriene B4 receptor 2 (LTB4R2, also known as BLT2), a chemokine receptor, is upregulated in different tumors. However, the correlation between BLT2 expression and its prognostic value in ccRCC remains to be explored. METHODS: This study used the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to evaluate the association between BLT2 expression and the clinical outcome of ccRCC. Based on TIMER2.0, the correlation between BLT2 expression in ccRCC and tumor immune characteristics was evaluated. RESULTS: The expression of BLT2 in ccRCC was higher than that in normal tissues. Kaplan-Meier survival analysis indicated that high BLT2 expression was significantly correlated with poor overall survival (HR = 1.75, p < 0.001) and disease-specific survival (HR = 1.60, p = 0.014) for patients with ccRCC. In addition, our findings revealed that there was no significant correlation between the M1 marker genes and the expression of BLT2 in ccRCC, while moderate correlations were observed between the BLT2 expression and the M2 marker genes. Tregs and T cell exhaustion marker genes were positively correlated with BLT2 expression in ccRCC (p < 0.001). CONCLUSION: BLT2 may serve as a novel prognostic biomarker and is related to the shaping of tumor immune microenvironment in ccRCC. The expression of BLT2 potentially contributes to the regulation of TAMs, T cell exhaustion, and Tregs activation in ccRCC, providing new approaches to promote the development of new immunotherapeutic strategies for ccRCC.

2.
Bioengineered ; 12(1): 5830-5838, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34488538

RESUMO

MicroRNAs (miRNAs) have been proved to be involved in many biological processes during tumorigenesis and progression, including cell proliferation and cell cycle progression. However, the potential role of miR-26b-5p in tongue squamous cell carcinoma (TSCC) remains unclear. In the present study, we demonstrated that miR-26b-5p was decreased in TSCC tissues in both TCGA-TSCC subset and eight paired samples from TSCC patients, while Proline Rich 11 (PRR11) was obviously increased. Transfection of miR-26b-5p mimics inhibited CALL7 cell proliferation by arresting the cells at the S/G2 transition. Meanwhile, miR-26b-5p inhibitor had the opposite biological functions. The results of luciferase activity and RNA-pulldown assays indicated that miR-26b-5p directly targeted the PRR11 3' -untranslated region in CAL27 cells. Furthermore, the effects of miR-26b-5p on cell cycle regulation were reversed after treatment with siRNA against PRR11. In summary, our findings indicate that miR-26b-5p induce cell cycle arrest in TSCC by targeting PRR11. Hence, targeting miR-26b-5p could be a promising therapeutic strategy for the treatment of TSCC.

3.
EPMA J ; : 1-18, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34306260

RESUMO

Aims: Coronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19. Methods: Clinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. "Gene Score" and "Drug Score" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs. Results: Our results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient. Conclusion: We recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-021-00247-0.

4.
Mol Ther Nucleic Acids ; 24: 294-309, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33850634

RESUMO

Chronic stress has been proven to accelerate the development and progression of ovarian cancer, but the underlying molecular mechanisms have not been fully elucidated. In a combination survey of ovarian cancer with chronic stress (OCCS) mouse models and high-throughput sequencing, a key lncRNA named LOC102724169 on chromosome 6q27 has been identified, which functions as a dominant tumor suppressor in OCCS. Transcriptionally regulated by CCAAT enhancer binding protein (CEBP) beta (CEBPB), LOC102724169 shows low expression and correlates with poor progression-free survival (PFS) in OCCS patients. LOC102724169 is an instructive molecular inhibitor of malignancy of ovarian cancer cells, which is necessary to improve the curative effect of cisplatin therapy on ovarian cancer. This function stems from the inactivation of molecules in phosphatidylinositol 3-kinase (PI3K)/AKT signaling, repressing MYB expression and retaining the responsiveness of cancer cells to cisplatin. These findings provide a mechanistic understanding of the synergistic anti-tumor purpose of LOC102724169 as a bona fide tumor suppressor, enhancing the therapeutic effect of cisplatin. The new regulatory model of "lncRNA-MYB" provides new perspectives for LOC102724169 as a chronic stress-related molecule and also provides mechanistic insight into exploring the cancer-promoting mechanism of MYB in OCCS, which may be a promising therapeutic strategy for ovarian cancer.

5.
Cancer Cell Int ; 20: 174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32467669

RESUMO

Background: Ovarian cancer is the third most common gynecological cancer in the world but the leading cause of death among gynecological malignancies. Epithelial splicing regulatory protein-1 (ESRP1), a key negative splicing regulator in epithelial-mesenchymal transition (EMT), has been proven to be overexpressed and may plays a role in epithelial ovarian cancer (EOC) progression. However, the functional roles of ESRP1 and the underlying mechanisms in this process still remain unclear. Methods: Tumor invasion, migration, colony formation and animal experiments were used to study the malignant biological behavior of ESRP1. A vector-based system expressing circ-0005585 was established to investigate circRNA as a microRNAs sponge. RNA-Seq and cytoskeleton staining explored underlying mechanisms of ESRP1. Results: Our results demonstrated that circ-0005585 regulates ESRP1 overexpression via sponging miR-23a/b and miR-15a/15b/16. Overexpression of ESRP1 suppresses EOC cell migration, but promotes colonization and drives a switch from mesenchymal to epithelial phenotype (MET) in association with actin cytoskeleton reorganization, mainly by alternative splicing EPB41L5 and RAC1. Furthermore, we have shown that high ESRP1 expression may be associated with immune-suppression in tumor immune microenvironment in vivo. Conclusions: ESRP1 overexpression promotes MET status and correlates with actin cytoskeleton reorganization in EOC. ESRP1 plays an important role in EOC colonization. In addition, a miRs panel from two miR families can inhibit ESRP1, may provide an innovative approach for cancer theranostics.

6.
J Cancer ; 9(14): 2472-2479, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026845

RESUMO

For recurrent ovarian cancer (ROC), secondary cytoreductive surgery (SCS) is recommended as one optional treatment. However, little is known about the expression and clinical significance of biomarkers during SCS. Human epididymis protein 4 (HE4) is a clinical biomarker for ovarian cancer. Eukaryotic translation initiation factor 3a (eIF3a) is investigated extensively as a potential biomarker for malignancy. The purpose of this study was to investigate the expressions of HE4 and eIF3a at SCS, as well as their associations with surgical outcome and survival in ROC patients. Immunohistochemistry was performed to determine the expressions of HE4 and eIF3a in ovarian tumors taken from both initial and secondary cytoreductive surgery of 35 ROC patients. eIF3a levels were significantly increased at SCS, compared to those at initial cytoreductive surgery (ICS), while HE4 levels were similar. Both HE4 and eIF3a expressions were associated with surgical outcome, in terms of residual tumor. For ICS, patients with high HE4 expression achieved a higher incidence of optimal cytoreduction than those with low HE4 expression (81.0% vs. 33.3%, P = 0.015). A similar result happened in SCS, indicated by higher incidence of no residual tumor in patients with high HE4 expression (76.4% vs. 44.4%, P = 0.046). And high HE4 expression at SCS was more likely to enhance surgical outcome of SCS (77.8% vs. 29.4%, P = 0.038). Therefore, high HE4 expression at either surgery is a predictor of better overall survival (OS) (P = 0.011 and 0.002). Furthermore, patients with an elevated total score (TS) of HE4 between the two surgeries tended to have prolonged OS, compared to those with a non-elevated TS of HE4 (P = 0.076). For eIF3a, initial eIF3a expression was associated with secondary residual tumor (P = 0.035), and the difference in eIF3a expression between the two surgeries correlated with OS (P = 0.052). The expressions of HE4 and eIF3a in tumor specimens correlated with surgical outcome and predicted OS in ROC patients with SCS, thus meriting further investigation.

7.
Cell Physiol Biochem ; 46(5): 1971-1984, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719287

RESUMO

BACKGROUND/AIMS: Rap1 interacting factor 1 (RIF1) was deemed to be involved in replication timing regulation and DNA damage response. However, little is known about the role of RIF1 in malignancies. Thus, this study aimed to investigate whether the expression of RIF1 is relevant to the response of epithelial ovarian cancer (EOC) patients to cisplatin chemotherapy and its underlying mechanism. METHODS: Immunohistochemistry was used for detecting the expression of RIF1 in 72 human ovarian cancer tissues followed by association analysis of RIF1 expression with patients' responses to platinum-based chemotherapy. The survival analysis of ovarian patients based on platinum chemotherapy was analyzed using online databases. RNA interference of RIF1 was carried out in OVCAR3 and A2780 cell lines, to determine the effect of lacking RIF1 expression on cellular responses to cisplatin by using MTS assay. The nucleotide excision repair (NER) capacity of these cells was assessed by using host-cell reactivation and UV sensitivity assay. Western Blot analysis was carried out to determine the effect of RIF1 on the proteins of NER and apoptosis signaling pathway by using RIF1 knockdown cells. BALB/c nude mice model was used for detection of response to cisplatin in vivo. RESULTS: RIF1 expression was significantly associated with the response of ovarian patients to platinum-based chemotherapy (P< 0.01). In cohorts from online databases, high expression of RIF1 was associated with higher mortality of EOC patients based on platinum chemotherapy (P < 0.01). RIF1 knockdown increased sensitivity to cisplatin in EOC in vitro and in vivo. Deletion of RIF1 impaired the NER activity by inhibiting the NER proteins in ovarian cancer cells. Besides, knockdown of RIF1 enhanced cisplatin-induced apoptosis. CONCLUSIONS: RIF1 plays an important role in regulating the expression of NER proteins, which in turn contributes to cellular response to cisplatin and EOC patients' response to platinum-based chemotherapy. RIF1 knockdown also promotes cisplatin-induced apoptosis. RIF1 may serve as a novel biomarker for predicting platinum-based chemosensitivity and the prognosis of EOC patients.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Reparo do DNA/efeitos dos fármacos , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Proteínas de Ligação a Telômeros/genética , Adulto , Animais , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Prognóstico , Interferência de RNA , Proteínas de Ligação a Telômeros/análise , Regulação para Cima
8.
J Cancer ; 9(6): 1088-1095, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29581788

RESUMO

Human epididymis protein 4 (HE4) is one of the most promising biomarkers for epithelial ovarian cancer (EOC). The majority of previous studies utilized the serum level or tissue protein expression of HE4 based upon immunohistochemistry (IHC) to evaluate the role of HE4 in the diagnosis, prognosis, and surveillance of EOC, but very little is known about HE4 mRNA expression. Eukaryotic translation initiation factor 3a (eIF3a) is implicated in oncogenesis and has been investigated extensively as a potential biomarker for malignancy. We previously reported a positive correlation between IHC expressions of eIF3a and HE4 in EOC. In the present study, we performed RT-PCR to determine mRNA expressions of HE4 and eIF3a in 30 normal ovarian tissues, 45 benign, 20 borderline and 94 malignant ovarian tumors. The association of HE4 and eIF3a mRNA expressions with clinicopathological characteristics and patient survivals was investigated. IHC was also performed in the same participants to investigate the correlation between mRNA and protein levels of HE4. HE4 mRNA level was found to be 48.42 ± 74.55 (mean ± SD, range: 0.01-343.99), significantly higher in primary EOC than in the borderline tumor, benign tumor, and normal ovarian tissue (P<0.001). The cutoff value was 13.99 for HE4 to discriminate malignant from benign tumors at 68.1% sensitivity and 93.0% specificity. By Spearman's correlation test, HE4 mRNA expression was indicated to positively correlate with serum CA125 level (r=0.530, P<0.001). Higher HE4 mRNA expression was associated with decreased frequency of lymph node metastasis (P=0.038) and better overall survival (OS) (P=0.007) in primary EOC. Multivariable analysis showed an independent prognostic value of the relative mRNA level of HE4 greater than one for OS (Hazard Ratio, 0.069, 95%CI, 0.009-0.530, P=0.010). eIF3a mRNA expression in women with primary EOC was 0.95 ± 1.19 (mean ± SD, range: 0.06-7.46), which was in a positive linear correlation with HE4 mRNA expression (r=0.310, P=0.002). In the present study, the HE4 mRNA level was unparalleled with IHC expression of HE4 (P>0.05). Collectively, our study revealed that increased HE4 mRNA expression correlates with high level of eIF3a mRNA and better survival in women with EOC, which calls for further investigations.

9.
Int J Cancer ; 143(3): 699-708, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29473150

RESUMO

Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single-arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC-P) were similar to the MMAC group in the retrospective study (MMAC-R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.


Assuntos
Soro Antilinfocitário/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Plaquetas , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Adulto Jovem
10.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 41(3): 333-6, 2016 Mar 28.
Artigo em Chinês | MEDLINE | ID: mdl-27033800

RESUMO

The transient receptor potential (TRP) family is a superfamily of cation channels located on the cell membrane. Transient receptor potential melastatin (TRPM) 7, a member of the TRPM subgroup of TRP channels, and was the most representative biofunctional membrane protein. It conducts calcium and monovalent cations to depolarize cells and increase intracellular calcium. It is capable of phosphorylating TRPM7 and other substrates. TRPM7 can mediate sensory transmission, regulate cellular Ca2+ and Mg2+ homeostasis and affect embryonic development. Abnormal expression and/or activity of the TRPM7 channel kinase is involved in a variety of diseases, particularly the development and progression of cancer. TRPM7 channel-kinase is essential for cellular processes, such as proliferation, survival, differentiation, growth, and migration.


Assuntos
Neoplasias , Cálcio , Diferenciação Celular , Humanos , Proteínas Serina-Treonina Quinases , Canais de Cátion TRPM
11.
Mol Med Rep ; 11(5): 3505-10, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25573529

RESUMO

A high expression of CD44v6 has been reported in numerous malignant cancers, including stomach, prostate, lung and colon. However, the pathological role and the regulatory mechanisms of CD44v6 have yet to be elucidated. In the present study, the expression levels of CD44v6 were shown to be significantly higher in ovarian cancer tissues, as compared with adjacent normal tissues. Furthermore, the upregulated expression levels of CD44v6 were correlated with disease recurrence and poor survival in patients. The expression of CD44v6 was knocked down in the CAOV3 ovarian cell line, by transfection of a specific small hairpin RNA. The present study showed a correlation between the aggression, viability, invasion and migration of the ovarian cancer cells, with the expression of CD44v6. In addition, the expression of CD44v6 was positively correlated with the expression levels of ß­catenin and tumor growth factor­ß, which indicates that the effects of CD44v6 on ovarian cancer cell aggression may be mediated by these two signaling pathways. In conclusion, the present study provides a novel insight into the association between CD44v6 expression and ovarian cancer. CD44v6 may provide a novel target for the prognosis and treatment of ovarian cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Receptores de Hialuronatos/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fator de Crescimento Transformador beta/genética , beta Catenina/genética , Progressão da Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Wnt
12.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 39(12): 1240-5, 2014 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-25544161

RESUMO

OBJECTIVE: To investigate the correlation between eukaryotic translation initiation factor 3, subunit A (eIF3a) and human epididymis protein 4 (HE4) expression and ovarian cancer. METHODS: RT-PCR or immunohistochemistry was used to examine eIF3a and HE4 mRNA or protein expression in ovarian tissues from patients with ovarian cancer (n=181) or benign ovarian tumors, or from the healthy women. RESULTS: There were significant differences in mRNA and protein expression of eIF3a and HE4 among normal ovarian tissues, benign ovarian tumor tissues, and ovarian cancer tissues (P< 0.05). There were significant differences in mRNA expression of eIF3a and HE4 between the normal tissues and the ovarian cancer tissues, or between the benign ovarian tumor tissues and the normal tissues (P< 0.001). The mRNA expression of eIF3a in the normal ovarian tissues was significantly higher than that in the benign ovarian tumor tissues or that in the ovarian cancer tissues. The mRNA expression of HE4 was gradually increased from the normal ovarian tissues, the benign ovarian tumor tissues to the ovarian cancer tissues. The mRNA expression of HE4 in the ovarian cancer tissues was significantly higher than that in the benign ovarian tumor tissues (P< 0.001). Positive expression rates for eIF3a or HE4 protein in normal, benign tumor, and cancer tissues were 0, 66.7%, and 81.0% or 0, 27.8%, and 56.2%, respectively. There were significant differences in positive expression rates of eIF3a protein and HE4 protein between the ovarian tumor tissues and benign ovarian tumor tissues, between the ovarian cancer tissues and the normal ovarian tissues, or between the benign ovarian tumor tissues and the normal ovarian tissues (P< 0.001). The eIF3a protein expression was positively correlated with HE4 protein expression (r=0.575, P< 0.05). CONCLUSION: The expressions of eIF3a and HE4 are associated with ovarian cancer, and extracellular regulated protein kinases may play a role in the interaction between eIF3a and HE4.


Assuntos
Biomarcadores Tumorais/metabolismo , Fator de Iniciação 3 em Eucariotos/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas/metabolismo , Feminino , Humanos , Imuno-Histoquímica , RNA Mensageiro , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos
13.
Biochem Biophys Res Commun ; 454(4): 547-53, 2014 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-25450691

RESUMO

Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Transdução de Sinais
14.
PLoS One ; 9(8): e105891, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25148255

RESUMO

UNLABELLED: To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians. TRIAL REGISTRATION: ClinicalTrials.gov NCT02065388.


Assuntos
Anticoagulantes/uso terapêutico , Citocromo P-450 CYP2C9/genética , Vitamina K Epóxido Redutases/genética , Varfarina/farmacocinética , Varfarina/uso terapêutico , Idoso , Anticoagulantes/farmacocinética , Grupo com Ancestrais do Continente Asiático , Sistema Enzimático do Citocromo P-450/genética , Família 4 do Citocromo P450 , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Resultado do Tratamento , Varfarina/sangue
15.
Curr Ther Res Clin Exp ; 76: 7-10, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25067982

RESUMO

BACKGROUND: Olmesartan is an angiotensin II receptor antagonist and is effective and well tolerated in the treatment of arterial hypertension. Probenecid is a well-established hypouricemic agent for the treatment of hyperuricemia and gout. OBJECTIVE: The goal of this study was to examine the impact of coadministration of probenecid on the pharmacokinetic parameters and tolerability of olmesartan in healthy volunteers. METHODS: In a randomized, open-label, 2-way crossover study, 12 volunteers received 2 oral treatments (olmesartan alone or olmesartan plus probenecid) separated by 4 days. Blood samples were obtained for a 48-hour pharmacokinetic evaluation after drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests before and after administration of the study drug. RESULTS: Pharmacokinetic parameters were evaluated in 6 male and 6 female healthy volunteers (mean age, 22 [range, 20-25] years]; weight, 56.0 [range, 51.0-60.0] kg). Probenecid coadministration increased olmesartan Css-av, AUC0→∞, and AUC0-48 by 40%, 50%, and 50%, respectively (P = 0.018, 0.000, 0.000, respectively), but there was no statistical significance for Tmax, t1/2, Css-max, and Css-min between olmesartan plus probenecid and olmesartan alone (P = 0.697, 0.053, 0.521, and 0.734, respectively). No serious adverse event (AE) was reported during the study. The proportion of volunteers with AEs in the olmesartan plus probenecid period (5 of 12 [42%]) was higher than that in the olmesartan-alone period (1 of 12 [8%]). All of the AEs during the olmesartan plus probenecid period were abnormal routine urine test results. The AE in olmesartan-alone period was dizziness. All AEs were classified as mild and considered to be at least possibly related to treatment. All volunteers recovered from the AEs by 2 weeks after the end of the study. CONCLUSIONS: Probenecid increases the exposure speed of olmesartan by increasing the AUC0-48, AUC0→∞, and Css-av. The combined treatment of olmesartan medoxomil with probenecid may increase the occurrence of genitourinary side effects. ClinicalTrials.gov identifier: NCT01907373.

16.
Asian Pac J Cancer Prev ; 15(9): 3955-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24935580

RESUMO

BACKGROUND: The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel that has been shown to promote tumor metastasis and progression. In this study, we determined the expression of TRPM7 in ovarian carcinomas and investigated its possible prognostic value. MATERIALS AND METHODS: Samples were collected from 138 patients with ovarian cancer. Expression of TRPM7 was assessed by real-time PCR and immunohistochemistry, expressed with reference to an established scoring system and related to clinical pathological factors. Kaplan-Meier survival analysis was applied to estimate disease-free survival (DFS) and overall survival (OS). Univariate and multivariate cox regression analyses were performed to correlate TRPM7 expression levels with DFS and OS. RESULTS: TRPM7 was highly expressed in ovarian carcinoma and significantly associated with decreased disease-free survival (DFS: median 20 months vs. 42 months, P=0.0002) and overall survival (OS: median 27 months vs. 46 months, P<0.001). CONCLUSION: Overexpression of TRPM7 expression is significantly associated with poor prognosis in patients with ovarian cancer.


Assuntos
Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Proteínas Serina-Treonina Quinases/biossíntese , Canais de Cátion TRPM/biossíntese , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Canais de Cátion TRPM/genética
17.
Molecules ; 19(1): 1189-200, 2014 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-24445345

RESUMO

A sensitive, reliable and specific LC-MS-MS method was developed and validated for the identification and quantitation of all-trans retinoic acid (ATRA) in human plasma. Acitretin was used as the internal standard (IS). After liquid-liquid extraction of 500 µL plasma with methyl tert-butyl ether (MTBE), ATRA and the IS were chromatographed on a HyPURITY C18 column (150 mm×2.1 mm, 5 µm) with the column temperature set at 40 °C. The mobile phase was consisted of 40% phase A (MTBE-methanol-acetic acid, 50:50:0.5, v/v) and 60% phase B (water-methanol-acetic acid, 50:50:0.5, v/v) with a flow rate of 0.3 mL/min. The API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM) mode via the positive electrospray ionization interface using the transition m/z 301.4→123.1 for ATRA and m/z 326.9→177.1 for IS, respectively. The calibration curve was linear over the range of 0.45-217.00 ng/mL (r≥0.999) with a lower limit of quantitation (LLOQ) of 0.45 ng/mL. The intra- and inter-day precisions values were below 8% relative standard deviation and the accuracy was from 98.98% to 106.19% in terms of relative error. The validated method was successfully applied in a bioequivalence study of ATRA in Chinese healthy volunteers.


Assuntos
Antineoplásicos/sangue , Espectrometria de Massas por Ionização por Electrospray , Tretinoína/sangue , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Análise Química do Sangue , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Extração Líquido-Líquido , Masculino , Éteres Metílicos/química , Solventes/química , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Tretinoína/administração & dosagem , Tretinoína/farmacocinética
18.
Clin Ther ; 32(9): 1674-80, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20974325

RESUMO

BACKGROUND: Olmesartan medoxomil is an angiotensin II-receptor antagonist used in the treatment of hypertension. It is a prodrug and is converted to the pharmacologically active compound on de-esterification by arylesterase in the gastrointestinal tract. OBJECTIVE: This study investigated the relative bioavailability and fasting pharmacokinetic properties of olmesartan after single doses of a 20-mg test tablet, a 20-mg test capsule, and a commercially available 20-mg reference tablet in healthy Chinese male volunteers. The study was conducted to satisfy Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of olmesartan medoxomil. METHODS: This study had an open-label, randomized-sequence, single-dose, 3-treatment, 3-period crossover design. Healthy volunteers were randomly assigned in a 1:1:1 ratio to receive a single 20-mg dose of the test tablet, test capsule, or reference tablet, each administered after a 12-hour overnight fast, followed by a 1-week washout period and administration of the alternate formulation. Blood samples were obtained at baseline and at 0.5, 1, 1.5,2,2.5,3,4,6,8,12,24,36, and 48 hours after dosing. Tolerability was assessed based on vital signs and laboratory values obtained before and after administration of study drug. The formulations were assumed to be bioequivalent if the 90% CIs for the log-transformed ratios of C(max), AUC(0-t), and AUC(0-∞) were within the predetermined equivalence range (70%-143% for C(max); 80%-125% for AUC(0-t) and AUC(0-∞)), as established by the Chinese State Food and Drug Administration. RESULTS: Twenty-one healthy male subjects (mean age, 21 years [range, 18-25 years]; weight, 62.1 kg [range, 54.0-80.0 kg]) were enrolled in and completed the study. No period or sequence effect was observed. The mean AUC(0-∞) values for the test tablet, test capsule, and reference tablet were 3993 (1070), 3567 (850), and 3849 (872) ng/mL/h, respectively. The 90% CIs for the log-transformed ratios of test tablet to reference tablet for C(max), AUC(0-48), and AUC(0-∞) were 103.9 to 124.9, 94.0 to 111.5, and 94.4 to 111.7, respectively (all, P = NS). The corresponding 90% CIs for the log-transformed ratios of test capsule to reference tablet were 90.8 to 109.2, 84.9 to 107.9, and 85.1 to 100.7 (all, P = NS). Ten adverse events were reported during the study; 7 subjects complained of pain during blood sampling, and 3 had a blocked venous catheter. No treatment-related adverse events were reported or observed. CONCLUSIONS: In this single-dose crossover study in healthy Chinese male volunteers, the test and reference formulations of olmesartan medoxomil 20-mg capsules and tablets met the regulatory criteria for assuming bioequivalence. The 3 formulations were well tolerated.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Imidazóis/farmacocinética , Tetrazóis/farmacocinética , Adolescente , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Área Sob a Curva , Disponibilidade Biológica , Cápsulas , China , Estudos Cross-Over , Jejum , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Olmesartana Medoxomila , Pró-Fármacos , Comprimidos , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Equivalência Terapêutica , Adulto Jovem
19.
Clin Chim Acta ; 364(1-2): 287-91, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16182270

RESUMO

BACKGROUND: We investigated whether the CYP2C9 genotypes would affect lornoxicam metabolism in healthy volunteers. METHODS: Twelve healthy volunteers who had been genotyped for CYP2C9 gene were selected to participate in our study. After 8 mg lornoxicam was taken, blood samples were drawn from 0 to 36 h. The plasma concentrations of lornoxicam and 5'-hydroxylornoxicam were determined by HPLC method. 5'-hydroxylornoxicam was purified from rabbits'urine by semi-preparative HPLC. RESULTS: Lornoxicam and 5'-hydroxylornoxicam both exhibit CYP2C9 genotype-dependent pharmacokinetic profiles. The area under the plasma concentration-time curve (AUC) of lornoxicam increased by 60 +/- 9.78% (P <0.05) and the AUC of 5'-hydroxylornoxicam decreased by 65 +/- 11.75% (p <0.001) in heterozygous CYP2C9*1/*3 subjects (n=6) compared with CYP2C9*1/*1 group (n=6). t1/2 value of lornoxicam and 5'-hydroxylornoxicam prolonged by 39 +/- 8.35% and curtailed by 59 +/- 6.83% respectively in CYP2C9*1/*3 subjects. But no significant differences in Tmax of lornoxicam and 5'-hydroxylornoxicam were observed between these 2 genotypes. In addition, for the first time we exploit the purification method for 5'-hydroxylornoxicam from rabbits' urine. CONCLUSION: The CYP2C9*3 allele significantly affected the metabolism of lornoxicam. The pharmacokinetic parameters of both lornoxicam and 5'-hydroxylornoxicam were significantly different between these 2 genotypes.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Piroxicam/análogos & derivados , Adulto , Alelos , Animais , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP2C9 , Genótipo , Compostos Heterocíclicos com 2 Anéis/urina , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Piroxicam/metabolismo , Piroxicam/farmacocinética , Piridinas/urina , Coelhos , Espectrometria de Massas por Ionização por Electrospray
20.
Br J Clin Pharmacol ; 60(6): 629-31, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16305587

RESUMO

AIMS: To investigate the association of CYP2C9*3 and *6 with hyperlipidaemia in Chinese. METHODS: Four hundred and seventy-six Chinese participated in the study, including 211 uncomplicated hyperlipidaemic patients and 265 healthy controls. PCR-RFLP was used to identify CYP2C9*3 and *6. RESULTS: CYP2C9*6 was not detected in this study. The allelic frequency of CYP2C9*3 was 0.039 (95% CI 0.022, 0.056). A nonsignificant difference existed in CYP2C9*3 frequencies between males and females (P = 0.605, OR = 1.194, 95% CI 0.610, 2.336), patients and controls (P = 0.063, OR = 0.506, 95% CI 0.244, 1.049) in the total population. However, in the female group, CYP2C9*3 frequency in patients with hyperlipidaemia was significantly lower than that in controls (P < 0.0001, OR = 0.062, 95% CI 0.008, 0.476). CONCLUSIONS: The association of CYP2C9*3 with hyperlipidaemia was specific for females in this Chinese population.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hiperlipidemias/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , China , Citocromo P-450 CYP2C9 , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , Caracteres Sexuais
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