Notes

Estrogen-related receptor alpha (ERRα) is needed for PGC-1α-dependent gene phrase from the computer mouse button mind.
ssemination in a CXCR4+ DLBCL model without associated toxicity. Thereby, T22-PE24-H6 promises to become an effective alternative to treat CXCR4+ disseminated refractory or relapsed DLBCL patients. © The author(s).The purpose of the present study was to investigate the impact of genetic polymorphism on fluvastatin pharmacokinetics. In addition, we compared the fluvastatin pharmacokinetics differences between extended-release (ER) 80 mg tablet and immediate-release (IR) 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. In this open-label, randomized, two-period, two-treatment, crossover study (n = 24), effects of ABCG2, SLCO1B1, ABCB1, CYP2C9 and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed. The administration dosage for IR 40 mg and ER 80 mg were twice and once daily, respectively, for total 7 d. Blood samples for pharmacokinetic evaluation were taken on the 1st and 7th d. selleck The lower exposure following ER was observed. For ER tablets, SLCO1B1 T521C genotype correlated with AUC0-24 of repeat doses (P = 0.010). SLCO1B1 T521C genotype had no statistically significant effect on AUC0-24 of IR capsule of fluvastatin after single or repeated doses. In vitro study demonstrated that when the concentration of fluvastatin was low ( 1 µmol/l), transport velocity of fluvastatin by HEK293-OATP1B1 with SLCO1B1 521TT (Km  = 11.4 µmol/l) and with SLCO1B1 521TCC (Km =15.1 µmol/l) tend to be the same. It suggests that the increased effect of SLCO1B1 T521C genotype on ER formulation of fluvastatin was mainly caused by lower blood concentrations. We recommend that formulation should be incorporated into future pharmacogenomics studies. © 2019 Shenyang Pharmaceutical University. Published by Elsevier B.V.This study aimed to clarify that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between imipenem and cilastatin. After co-administration with imipenem, the plasma concentrations and the plasma concentration-time curve (AUC) of cilastatin were significantly increased, while renal clearance and cumulative urinary excretion of cilastatin were decreased. At the same time, imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1 (hOAT1)-HEK293 and human OAT3 (hOAT3)-HEK293 cells. Probenecid, p-aminohippurate, and benzylpenicillin inhibited the uptake of imipenem and cilastatin in rat kidney slices and in hOAT1- and hOAT3-HEK 293 cells, respectively. The uptakes of imipenem and cilastatin in hOAT1- and hOAT3-HEK 293 cells were significantly higher than that in mock-HEK-293 cells. Moreover, the Km values of cilastatin were increased in the presence of imipenem with unchanged Vmax , indicating that imipenem inhibited the uptake of cilastatin in a competitive manner. When imipenem and cilastatin were co-administered, the level of imipenem was higher compared with imipenem alone both in vivo and in vitro. But, cilastatin significantly inhibited the uptake of imipenem when dehydropeptidase-1 (DPEP1) was silenced by RNAi technology in hOAT1- and hOAT3-HEK 293 cells. In conclusion, imipenem and cilastatin are the substrates of OAT1 and OAT3. OAT1 and OAT3 mediate the DDI between imipenem and cilastatin. Meanwhile, cilastatin also reduces the hydrolysis of imipenem by inhibiting the uptake of imipenem mediated by OAT1 and OAT3 in the kidney as a complement. © 2019 Published by Elsevier B.V. on behalf of Shenyang Pharmaceutical University.Based on the evidence that hemochromatosis, an iron-overload disease, drives hepatocellular carcinoma, we hypothesized that chronic exposure to excess iron, either due to genetic or environmental causes, predisposes an individual to cancer. Using pancreatic cancer as our primary focus, we employed cell culture studies to interrogate the connection between excess iron and cancer, and combined in vitro and in vivo studies to explore the connection further. Ferric ammonium citrate was used as an exogenous iron source. Chronic exposure to excess iron induced epithelial-mesenchymal transition (EMT) in normal and cancer cell lines, loss of p53, and suppression of p53 transcriptional activity evidenced from decreased expression of p53 target genes (p21, cyclin D1, Bax, SLC7A11). To further extrapolate our cell culture data, we generated EL-KrasG12D (EL-Kras) mouse (pancreatic neoplastic mouse model) expressing Hfe+/+ and Hfe-/- genetic background. p53 target gene expression decreased in EL-Kras/Hfe-/- mouse pancreas compared to EL-Kras/Hfe+/+ mouse pancreas. Interestingly, the incidence of acinar-to-ductal metaplasia and cystic pancreatic neoplasms (CPN) decreased in EL-Kras/Hfe-/- mice, but the CPNs that did develop were larger in these mice than in EL-Kras/Hfe+/+ mice. In conclusion, these in vitro and in vivo studies support a potential role for chronic exposure to excess iron as a promoter of more aggressive disease via p53 loss and SLC7A11 upregulation within pancreatic epithelial cells. © 2020 Shenyang Pharmaceutical University. Published by Elsevier B.V.In recent years, the continuous occurrence of multi-drug resistance in the clinic has made people pay more attention to the transporter. Changes in the expression and activity of transporters can cause corresponding changes in drug pharmacokinetics and pharmacodynamics. The drug-drug interactions (DDI) caused by transporters can seriously affect drug effectiveness and toxicity. In the development of pharmaceutical preparations, people have increasingly concerned about the effects and regulation of transporters in drug effects. To improve the targeting and physicochemical properties of drugs, the development of targeted agents is very rapid. Among them, novel nano-formulations are the best. With the continuous innovation and development of nano-formulation, its application has become more and more extensive. Nano-formulation has exerted certain advantages in the drug development based on transporters, and is also involved in the combination of targeted transporters. This review focuses on the application of novel nano-agents targeting transporters and the introduction of drug-transporter-based nano-formulations. © 2020 Shenyang Pharmaceutical University. Published by Elsevier B.V.
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