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Platinum drugs are widely used in the treatment of various solid tumors, but their resistance to platinum is the most significant obstacle to successful treatment. Copper transporter 1 (CTR1) is the specific transporter for copper, and it mainly locates at the plasma membrane and plays a role in pumping copper into the cell. CTR1 is also the major platinum influx transporter and plays a key role in platinum resistance. The expression, polymorphism, and degradation of CTR1 affect platinum resistance in tumors. Therefore, CTR1 may be a potential predictive biomarker of platinum resistance and a therapeutic target for overcoming platinum resistance.
Subject(s)
Antineoplastic Agents , Therapeutic Uses , Cation Transport Proteins , Genetics , Metabolism , Cisplatin , Therapeutic Uses , Copper , Copper Transporter 1 , Drug Resistance, Neoplasm , Genetics , Platinum , Therapeutic Uses , ResearchABSTRACT
Objective:To evaluate effect of simvastatin on neurons autophagy in the hippocampus following intracerebral hemorrhage( ICH) in rats.Methods:All rats were divided randomly into sham group;ICH group and SIM group.The rat model of ICH was made by injection of Ⅶ type collagenase.The behavioral changes were evaluated with Garcia′s neurologic deficit score.Wet-dry weight method was used to evaluate brain edema.Additionally,localization of LC3 protein was determined by immunohistochemistry, and the expression of Beclin-1 in hippocampus was tested by Western blot methods.Results: Compared with ICH group,simvastatin treatment after ICH significantly improved neurologic deficit score ( P<0.05 ) , reduced the water content of brain tissue ( P<0.05 ) , inhibited the expression of LC3 and Beclin-1 protein(P<0.05).Conclusion:Our findings indicated that administration of simvastatin had neuroprotective effects in ICH rat model,which could be involved in inhibiting activation of autophagy in the hippocampus,finally reducing brain edema and neurobehavioral deficit.
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Aim To investigate the anti-proliferation effect of resveratrol (Res)on human colon cancer cells and dissect the possible mechanism underlaying this effect.Methods We introduced crystal violet staining and Western blot to analyse the anti-proliferation effect of Res on HCT1 1 6 cells.Then,we used flow cytome-try and Western blot assay to detect the Res induced apoptosis in HCT1 1 6 cells.Next,we employed the well established TCF4 /LEF luciferase reporter to meas-ure the effect of Res on Wnt/β-catenin signaling trans-duction.Finally,we took Western blot and PCR assay to analyse the effect of Res on the expression of β-cate-nin in HCT1 1 6 cells.Results Crystal violet staining and Western blot analysis showed that Res could inhib-it the proliferation of HCT1 1 6 cells in a concentration-and time dependent fashion.What’s more,Res could promote apoptosis in HCT1 1 6 cells.The transcriptional activities of TCF4 /LEF reporter were reduced by Res in a concentration-dependent fashion (P <0.05 when the concentration of Res was 20 μmol·L -1 ,and P <0.01 when the concentration of Res was 40 μmol·L -1 or 80 μmol·L -1 ).Res could decrease not only the protein level of β-catenin in HCT1 1 6 cells,but also the mRNA expression of β-catenin.Conclusion Res can inhibit the proliferation of HCT1 1 6 cells,which may be mediated at least by down-regulating the ex-pression of β-catenin to inhibit the Wnt/β-catenin sig-naling transduction.
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An electrochemical sensor has been developed for the selective determination of chlortetracycline ( CTC) using the molecularly imprinted technique. A molecular imprinted polymer ( MIP) on the surface of a glassy carbon electrode ( GCE ) was prepared by electropolymerization of o-aminophenol ( OAP ) in the presence of CTC in the sodium perchlorate ( NaClO4 ) solution using cyclic voltammetry ( CV ) . The electrochemical performance of the sensor was studied by using differential pulse voltammetry ( DPV ) . A linear relationship between the peak current difference and the CTC concentration was found in the range of 2. 0×10-8-6. 1×10-7 mol/L with the detection limit of 1. 5×10-8 mol/L (3σ). After regeneration by washing with the mixture of methanol and sulfuric acid, the sensor showed excellent reproducibility and good stability. The MIP electrode exhibited almost no response to chloramphenicol and penicillin, and very weak responses to tetracycline and oxytetracycline, proving a good selectivity. Recoveries of standard addition measured in the actual samples of milk and chicken meat were between 86 . 4% -96 . 9%. Compared with the reported methods, this sensor showed a low detection limit, simple operation without derivatization, rapid response and low cost.
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OBJECTIVE@#To investigate the relationship between the eukaryotic initiation factor 3a (eIF3a)polymorphisms and chemo-sensitivity to platinum-based drug in ovarian cancer. @*METHODS@#Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis was performed to detect 57 cases of eIF3a polymorphic genotypes (rs3824830, rs77382849, rs10787899 and rs3740556) after platinum-based chemotherapy drugs up to 6 cycles in primary ovarian cancer. The association between these gene sites was analyzed. @*RESULTS@#There were 3 genotypes for eIF3a rs3824830, named AA, GA and GG. The frequency distribution for them was 43.86%, 36.84% and 15.79% (2 cases did not detect the genotype, 3.51%), respectively. There were 2 genotypes for eIF3a rs77382849, named CC and TC. The frequency distribution for them was 85.96% and 12.28%(1 case did not detect the genotype, 1.76%), respectively. There were 3 genotypes for eIF3a rs10787899, named GG, GA and AA, respectively. The frequency distribution for them was 26.32%, 47.36% and 26.32%, respectively. There were significant difference in different genotypes between age group and FIGO stage (P0.05) among these genotype groups. In all blood samples, there was only one genotype for eIF3a rs3740556, named GG. @*CONCLUSION@#There is no mutation genotype in eIF3a rs3740556 loci. Polymorphism in the eIF3a rs3824830, rs77382849 and rs10787899 doesn't affect the response of ovarian cancer to platinum-based chemotherapy.
Subject(s)
Female , Humans , Antineoplastic Agents , Therapeutic Uses , Eukaryotic Initiation Factor-3 , Genetics , Genotype , Mutation , Ovarian Neoplasms , Drug Therapy , Genetics , Platinum , Therapeutic Uses , Polymorphism, Genetic , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
Objective:To explore the influence of IL-18 on the expression of MHCⅠ,MHCⅡ,CD80,CD86 on the surface of 9L cells,to identify the effect of IL-18 on the immunogenicity and the efficiency of tumor antigen presentation of 9L.Methods:Retroviruses were used to transduce the mIL-18 gene into rat glioma cells and the cell clones (9L/IL-18) which steadily expressing mIL-18 gene were obtained ,and got the control cells of 9L/LXSN by the same method.The expression of MHCⅠ,MHCⅡ,CD80,CD86 on the cell surface were assessed by flow cytometry.The cell suspension of 9L/IL-18,9L/LXSN and 9L cells were inoculated into the brain of F344 rat to establish the animal models by the stereotactic technique ,got the tumor tissues to analyze the expression of MHCⅠ, MHCⅡ,CD80 and CD86 on the surface of tumor cells after 14 days.Results:The expression of MHCⅠ,MHCⅡ,CD80 and CD86 on the surface of 9L/IL-18 were (10.9±1.44)%,(0.61±0.14)%,(1.01±0.14)%,(0.57±0.11)% ; had no significant differences with the others in vitro (P>0.05);while the expression of MHCⅠ,CD80 and CD86 on the surface of 9L/IL-18 were(67.51± 1.40)%,(12.51±1.57)%,(6.95±0.56)%which were higher than 9L/LXSN and 9L cells (P0.05) in vivo.Conclusion: IL-18 did not affect the immunogenicity of 9L in vitro,but improve the immunogenicity and tumor antigen presentation in vivo.
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Aim To investigate the role of COX-2 in BMP9 induced osteogenic differentiation,and the pos-sible mechanism underlying this function of COX-2. Methods We introduced real-time PCR, Western blot, and immunocytochemical staing to detect the effect of BMP9 on COX-2 expression.We employed chemiluminescence technique to assay ALP activities, RT-PCR to detect the expression of Smad6 and Smad7 , and Western blot to measure the expression of Runx2, Dlx-5,total Smad1/5/8,and phosphorylated Smad1/5/8.Finally,BMPR-Smad luciferase reporter assay was applied to measure the activation of BMPs/Smads signaling.Results BMP9 could induce the expression of COX-2 in C3H10T1/2 cells.Either inhibiting enzy-matic activity of COX-2 or knockdown of the expression of COX-2 reduced the BMP9 induced ALP activities in C3H10T1/2 cells,and COX-2 knockdown also inhibited the ectopic bone formation induced by BMP9 in C3H10T1/2 cells.Moreover,COX-2 knockdown inhibi-ted BMPR-Smad reporter activities and the phosphoryl-ation of Smad1/5/8,so did the expression of Smad6 and Smad7 .Conclusion COX-2 may play an impor-tant role in BMP9 induced osteogenic differentiation in MSCs by regulating the BMPs/Smads signaling trans-duction.
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Objective:To explore the effects of total saponins of Cornus offlcinalis Sieb.(TSCO) on the contractility and relaxation of mesenteric artery in streptozotocin (STZ)-induced diabetic rats.Methods:Sprague Dawley rats were administrated STZ intra-peritoneally at a dosage of 60 mg/kg to induce diabetes.TSCO was administrated at a dosage of 60 mg/kg or 120 mg/kg (per os) to the diabetic rats for 28 days.Glucose and insulin in the serum as well as the responsiveness ofmesenteric artery rings were determined.Results:TSCO decreased the contractile responsiveness to phenylephrine of mesenteric artery rings from diabetic rats,but increased the reactivity to acethylcholine.TSCO (120 mg/kg) ameliorated the baseline release of nitric oxide of mesenteric artery,but had little effect on the induced release of nitric oxide.Rosiglitazone had less effect on the mesenteric artery function than that of TSCO,though it was more effective on lowering blood glucose.Conclusion:The effects of TSCO on mesenteric artery of diabetic rats are dose dependent,and are possibly exerted by lowering blood glucose and ameliorating the release of nitric oxide in the endothelium.
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BACKGROUND: Metoprolol is a selective β1-Blocker commonly used in essential hypertension. It is metabolized by CYP2D6. CYP2D6*10, which was identified to decrease activity of CYP2D6, is the main variance in Chinese population. β1-adrenergic receptor, with Ser49Gly and Gly389Arg polymorphisms, is the target of metoprolol. It was still unknown that whether the CYP2D6 and β1-adrenergic receptor had a synergic effect on metoprolol antihypertension therapy. AIM: To clarify the genetic polymorphism associated with metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy. METHODS: 125 mild-to-med essential hypertension patients were enrolled in this study. Patients were mono-therapied with metoprolol for 12 weeks. Blood pressure was monitored every 4 weeks. PCR-RFLP method was use to identify CYP2D6*10 and β1-adrenergic receptor Ser49Gly and Gly389Arg polymorphisms. Plasma metoprolol concentration was measured by HPLC- fluorescence detection. RESULTS: Trough blood level (C0) of metoprolol was associated with CYP2D6*10 variance in a gene-dose-effect manner, whereas the extent of blood pressure decrease was not significant different in CYP2D6*1*1, *1*10 and CYP2D6*10*10 patients. After 12 weeks metoprolol therapy, Gly49 carriers had stronger decrease in systolic and diastolic blood pressure than that of Ser49 homozygotes. Similarly, subjects homozygous for Arg389 had stronger decrease in blood pressure than that of Gly389 carriers. CONCLUSION: CYP2D6*10 variance significantly change the pharmacokinetics of metoprolol, and the genetic polymorphisms of β1-adrenergic receptor were associated with the pharmacodynamics of metopolol in antihypertension therapy.
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BACKGROUND: There is a growing recognition that the adipose tissue is an endocrine organ that secretes signaling molecules such as adiponectin and resistin. The peroxisome proliferator activated receptor γ (PPARγ) is expressed in high levels in the adipose tissue. Thiazolidinediones are selective PPARγ agonists with insulin-sensitizing properties. It has been postulated that thiazolidinediones such as rosiglitazone exert their pharmacodynamic effects in part through modulation of resistin (implicated in insulin resistance) and adiponectin (an insulin-sensitizing molecule) expression subsequent to activation of PPARγ. There are conflicting data, however, on the biological direction in which resistin expression is modulated by PPARγ agonists and whether an increase in adiponectin expression can occur in the face of an upregulation of resistin. METHODS: Using the murine 3T3-L1 adipocytes as a model, we evaluated the changes in resistin and adiponectin gene expression after vehicle, rosiglitazone (10 μmol/L, a PPARγ agonist), GW9662 (5 μmol/L, a selective PPARγ antagonist) or GW662 and rosiglitazone co-treatment.RESULTS: In comparison to vehicle treatment, rosiglitazone increased the average adiponectin and resistin mRNA expression by 1.66- and 1.55-fold, respectively (P＜0.05). Importantly, GW9662 also upregulated adiponectin expression (by 1.57-fold, P＜0.05) but did not influence resistin expression (P＞0.05). Co-treatment with rosiglitazone and GW9662 maintained the adiponectin upregulation (1.87-fold increase from vehicle, P＜0.05) while attenuating resistin upregulation (1.31-fold increase from vehicle, P＜0.05) induced by rosiglitazone alone (1.55-fold increase from vehicle, P＜0.05). CONCLUSION: This study presents new evidence that adiponectin transcript is upregulated with both a PPARγ agonist (rosiglitazone) and antagonist (GW9662), while GW9662 co-treatment does not block rosiglitazone-induced adiponectin upregulation. These data collectively suggest that biological mechanisms independent from PPARγ may underlie thiazolidinedione pharmacodynamics on adiponectin expression. Moreover, increased adiponectin expression by GW9662, in the absence of an upregulation of resistin expression, lends further support on the emerging clinical potential of PPARγ antagonists in treatment of insulin resistance. Decreased resistin expression may not be crucial for the insulin-sensitizing effect of rosiglitazone. These findings may serve as a foundation for future dose-ranging and time-course studies of thiazolidinedione pharmacodynamics on adipocytokine expression in human adipocytes.
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Parkinson's disease(PD)is a neurodegenerative disease that predominantly affects the elderly.Dopamine mimicking drug is the mainstay in the treatment of Parkinson's disease.However,there is a large of interindividual variability in response to anti-Parkinson's disease drugs.It is thought that genetic variability in dopamine system genes is one of the important factors in determining interindividual variability in drug response.There are a lot of studies focused on the relationship between the risk of Parkinson's disease and genetic variations in domestic,while it is a lack of the pharmacogenetics study on Parkinson's disease.This review summarizes the relationship between the polymorphism of genes encoding dopamine transporter,dopamine-metabolizing enzymes and dopamine receptors and Parkinson's disease treatment.
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Ten factors of the sexual dimorphism on the cranial breadth were analyzed by using the dis- criminant analysis in order to estimate the sex.Results showed that seven out of ten human skulls have sex difference(P