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1.
Article in Chinese | WPRIM | ID: wpr-923032

ABSTRACT

Objective To investigate the effect of CYP3A5 and MDR1 gene polymorphisms on blood concentration of tacrolimus and creatinine level in uremic patients during the early phase after kidney transplantation in real clinical practice. Methods 131 patients who underwent kidney transplantation for the first time with triple immunotherapy based on tacrolimus in single-center from 2013 to 2017 were enrolled for retrospective study. Tacrolimus daily dose, blood concentration, blood concentration-to-dose ratio, and serum level were compared according to the various genotypes of CYP3A5 and MDR1 polymorphisms in renal transplantation recipients, respectively. Results The dosage of tacrolimus in CYP3A5*3/*3 (GG) kidney transplantation recipients within 4 weeks after kidney transplantation was lower than those of CYP3A5*1/*1 (AA) and CYP3A5*1/*3 (AG). The serum creatinine levels of patients whose tacrolimus concentration in the range of 10-13 ng/ml were close to the normal value. Conclusion CYP3A5 gene polymorphism affects the blood concentrations of tacrolimus in renal transplant recipients. No association has been found between the blood concentrations of tacrolimus and MDR1 gene polymorphism. Tacrolimus concentration in the range of 10-13 ng/ml might contribute to restore the early kidney graft function.

2.
Article in Chinese | WPRIM | ID: wpr-906205

ABSTRACT

Objective:To investigate the effect of notoginseng total saponins (TNS) on adriamycin (Adr) resistance in HepG2/Adr cells and the expression and activity of the mechanisms as the modulators of multi-drug resistance, so as to explore the possible mechanism of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) signaling pathways in reversing the resistance of HepG2/Adr cells mechanism. Method:Effect of TNS on HepG2/Adr cell proliferation was detected by thiazole blue (MTT) method. HepG2/Adr cells were treated with different concentrations (100, 50, 25, 0 mg·L<sup>-1</sup>) of TNS and (20 μmol·L<sup>-1</sup>) Adr respectively, and a blank group was set. The high-content screening platform was used to detect the accumulation of Adr in HepG2/Adr cells after 40 minutes, 3 hours and 6 hours. Western blot was used to detect the expression of P-glycoprotein /multidrug resistance/ATP binding cassette subfamily B member 1(P-gp/MDR1/ABCB1) and other drug resistance-related proteins and the main protein expression of ERK/Akt signaling pathway. The change of MDR1 on cell membranes was observed by laser confocal microscopy. Result:Compared with HepG2 cells, the expression of MDR1 in HepG2/Adr cells was significantly increased (<italic>P</italic><0.01). Compared with the Adr group, the half-inhibitory concentration (IC<sub>50</sub>) of TNS (25, 50, 100 mg·L<sup>-1</sup>) and Adr (20 μmol·L<sup>-1</sup>) co-administration group on HepG2/Adr cells <italic>in vitro</italic> significantly reduced (<italic>P</italic><0.01), and the highest reversal multiple was 10 times. Compared with the Adr group, the co-administration group could significantly increase the accumulation of Adr in the cells (<italic>P</italic><0.05) in a dose-dependent manner. Compared with the blank group, the co-administration group could significantly reduce MDR1, ABC semitransporter (ABCG2), multidrug resistance associated protein (MRP1), ERK, phosphorylated extracellular regulatory protein kinase (p-ERK), Akt, phosphorylated protein kinase B (p-Akt), mammals, rapamycin target protein (mTOR) and phosphorylated mammalian rapamycin target protein (p-mTOR) (<italic>P</italic><0.05), with the same results in the doxorubicin group. Compared with the blank group, there was no significant difference in the distribution and fluorescence intensity of MDR1 on the cell membrane between the Adr group and the notoginseng total saponins (25 mg·L<sup>-1</sup>) group. Compared with the blank group and the doxorubicin group, TNS could significantly reduce the distribution of MDR1 on the cell membrane (<italic>P</italic><0.05). Conclusion:TNS can inhibit the ERK/Akt pathway, reduce the expression of MDR1, and significantly increase the accumulation of doxorubicin in HepG2/Adr cells, which may be one of the mechanisms of notoginseng total saponins in reversing resistance.

3.
Acta Pharmaceutica Sinica B ; (6): 1885-1902, 2021.
Article in English | WPRIM | ID: wpr-888840

ABSTRACT

Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of

4.
Acta Pharmaceutica Sinica B ; (6): 1789-1812, 2021.
Article in English | WPRIM | ID: wpr-888835

ABSTRACT

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.

5.
Acta Pharmaceutica Sinica B ; (6): 1526-1540, 2021.
Article in English | WPRIM | ID: wpr-888818

ABSTRACT

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.

6.
Acta Pharmaceutica Sinica B ; (6): 1382-1396, 2020.
Article in English | WPRIM | ID: wpr-828801

ABSTRACT

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.

7.
Article in English | WPRIM | ID: wpr-764935

ABSTRACT

BACKGROUND: Increased expression of MDR1 gene is one of the major mechanisms responsible for multidrug resistance in cancer cells. Two alternative promoters, upstream and downstream, are responsible for transcription of MDR1 gene in the human. However, the molecular mechanism regarding the transactivation of MDR1 upstream promoter (USP) has not been determined. METHODS: Dual-luciferase reporter gene assays were used to assess the effect of Nkx-2.5 on MDR1 USP activity using reporter plasmids for human MDR1 USP and its mutants. MDR1 mRNA level was examined by quantitative real-time PCR. The direct binding of Nkx-2.5 to the USP of MDR1 was evaluated by promoter enzyme immunoassays and chromatin immunoprecipitation assays.


Subject(s)
Breast Neoplasms , Breast , Chromatin Immunoprecipitation , Drug Resistance, Multiple , Genes, Reporter , Humans , Immunoassay , Immunoenzyme Techniques , Phenotype , Plasmids , Real-Time Polymerase Chain Reaction , RNA, Messenger , Transcriptional Activation
8.
Acta Pharmaceutica Sinica B ; (6): 659-674, 2019.
Article in English | WPRIM | ID: wpr-774953

ABSTRACT

Precision medicine is a rapidly-developing modality of medicine in human healthcare. Based on each patient׳s unique characteristics, more accurate dosages and drug selection can be made to achieve better therapeutic efficacy and less adverse reactions in precision medicine. A patient׳s individual parameters that affect drug transporter action can be used to develop a precision medicine guidance, due to the fact that therapeutic efficacy and adverse reactions of drugs can both be affected by expression and function of drug transporters on the cell membrane surface. The purpose of this review is to summarize unique characteristics of human breast cancer resistant protein (BCRP) and the genetic variability in the BCRP encoded gene in the development of precision medicine. Inter-individual variability of BCRP/ can impact choices and outcomes of drug treatment for several diseases, including cancer chemotherapy. Several factors have been implicated in expression and function of BCRP, including genetic, epigenetic, physiologic, pathologic, and environmental factors. Understanding the roles of these factors in controlling expression and function of BCRP is critical for the development of precision medicine based on BCRP-mediated drug transport.

9.
Acta Pharmaceutica Sinica B ; (6): 1035-1049, 2019.
Article in English | WPRIM | ID: wpr-774924

ABSTRACT

Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality modulating the host response, pharmacokinetic herb-drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.

10.
Article in Chinese | WPRIM | ID: wpr-851057

ABSTRACT

Objective: To study the bi-direction transport behavior of brucine and strychnine in the MDCK-MDR1 cell monolayer model. Methods: MTT method was employed to confirm the safe concentration of brucine and strychnine towards MDCK-MDR1 cells. The effects of transport time, drug concentration, and P-glycoprotein inhibitor verapamil on cumulative absorption concentration (Ccum) and apparent permeability coefficient (Papp) of brucine and strychnine in MDCK-MDR1 monolayer cells were studied. Results: The Papp value of brucine and strychnine was larger than 1 × 10-5 cm/s and the ratio of Papp(BL→AP) vs Papp(AP→BL) was less than 2. Brucine/ strychnine combined with verapamil decreased the ratio of Papp(BL→AP) vs Papp(AP→BL). Conclusion: The absorption of brucine and strychnine in MDCK-MDR1 cell monolayer model was well and the passive transference was its main intestinal absorption mechanism. The P-gp inhibitor verapamil has a significant inhibitory effect on brucine and strychnine absorption. Brucine and strychnine may be a substrate of P-glycoprotein.

11.
Article in English | WPRIM | ID: wpr-773417

ABSTRACT

OBJECTIVE@#To evaluate the synergy of the Burkholderia signaling molecule cis-2-dodecenoic acid (BDSF) and fluconazole (FLU) or itraconazole (ITRA) against two azole-resistant C. albicans clinical isolates in vitro and in vivo.@*METHODS@#Minimum inhibitory concentrations (MICs) of antibiotics against two azole-resistant C. albicans were measured by the checkerboard technique, E-test, and time-kill assay. In vivo antifungal synergy testing was performed on mice. Analysis of the relative gene expression levels of the strains was conducted by quantitative reverse-transcription polymerase chain reaction (qRT-PCR).@*RESULTS@#BDSF showed highly synergistic effects in combination with FLU or ITRA with a fractional inhibitory concentration index of ⪕ 0.08. BDSF was not cytotoxic to normal human foreskin fibroblast cells at concentrations of up to 300 μg/mL. The qRT-PCR results showed that the combination of BDSF and FLU/ITRA significantly inhibits the expression of the efflux pump genes CDR1 and MDR1 via suppression of the transcription factors TAC1 and MRR1, respectively, when compared with FLU or ITRA alone. No dramatic difference in the mRNA expression levels of ERG1, ERG11, and UPC2 was found, which indicates that the drug combinations do not significantly interfere with UPC2-mediated ergosterol levels. In vivo experiments revealed that combination therapy can be an effective therapeutic approach to treat candidiasis.@*CONCLUSION@#The synergistic effects of BDSF and azoles may be useful as an alternative approach to control azole-resistant Candida infections.


Subject(s)
Antifungal Agents , Pharmacology , Burkholderia cenocepacia , Chemistry , Candida albicans , Physiology , Candidiasis , Drug Therapy , Drug Resistance, Fungal , Fatty Acids, Monounsaturated , Fluconazole , Pharmacology , Humans , Microbial Sensitivity Tests , Triazoles , Metabolism
12.
Article in English | WPRIM | ID: wpr-758887

ABSTRACT

Canine MDR1 gene mutations produce translated P-glycoprotein, an active drug efflux transporter, resulting in dysfunction or over-expression. The 4-base deletion at exon 4 of MDR1 at nucleotide position 230 (nt230[del4]) in exon 4 makes P-glycoprotein lose function, leading to drug accumulation and toxicity. The G allele of the c.-6-180T>G variation in intron 1 of MDR1 (single nucleotide polymorphism [SNP] 180) causes P-glycoprotein over-expression, making epileptic dogs resistant to phenobarbital treatment. Both of these mutations are reported to be common in collies. This study develops a more efficient method to detect these two mutations simultaneously, and clarifies the genotype association with the side effects of chemotherapy. Genotype distribution in Taiwan was also investigated. An oligonucleotide microarray was successfully developed for the detection of both genotypes and was applied to clinical samples. No 4-base deletion mutant allele was detected in dogs in Taiwan. However, the G allele variation of SNP 180 was spread across all dog breeds, not only in collies. The chemotherapy adverse effect percentages of the SNP 180 T/T, T/G, and G/G genotypes were 16.7%, 6.3%, and 0%, respectively. This study describes an efficient way for MDR1 gene mutation detection, clarifying genotype distribution, and the association with chemotherapy.


Subject(s)
Alleles , Animals , Dogs , Drug Therapy , Exons , Genotype , Introns , Methods , Oligonucleotide Array Sequence Analysis , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Phenobarbital , Taiwan
13.
Article in Chinese | WPRIM | ID: wpr-800856

ABSTRACT

Objective@#To assess the association of single nucleotide polymorphisms of multidrug resistance gene 1 (MDR1) with refractory epilepsy in children.@*Methods@#Peripheral blood samples were collected from 200 children with epilepsy and 100 healthy controls. Genomic DNA was extracted and subjected to PCR amplification, agarose gel electrophoresis and target site sequencing. Genotypes of rs1922242, rs2235048, rs10808072, rs868755 and rs1202184 loci of the MDR1 gene were analyzed.@*Results@#No significant difference was found in genotypic distribution and allelic frequencies of the rs1922242, rs2235048, rs10808072 and rs868755 loci between the drug-resistant and drug-sensitive groups. For the rs1202184 locus, a significant difference in genotypic distribution was found (P = 0.008). No significant difference was found in the frequencies of various haplotypes between the two groups.@*Conclusion@#Genotypes of the rs1202184 locus of the MDR1 gene are associated with refractory epilepsy in children, for which the AA genotype plays a dominant role.

14.
Article in English | WPRIM | ID: wpr-776892

ABSTRACT

Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B (RAB) and riccardin D (RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.


Subject(s)
ATP-Binding Cassette Transporters , Genetics , Metabolism , Antifungal Agents , Chemistry , Metabolism , Pharmacology , Azoles , Pharmacology , Biosynthetic Pathways , Genetics , Candida albicans , Chemistry , Metabolism , Cell Membrane , Chemistry , Metabolism , Coculture Techniques , Drug Resistance, Fungal , Ergosterol , Metabolism , Fungal Proteins , Genetics , Metabolism , Lipids , Chemistry , Molecular Structure , Permeability , Phenyl Ethers , Chemistry , Metabolism , Pharmacology , Sterols , Chemistry , Metabolism , Stilbenes , Chemistry , Metabolism , Pharmacology , Triterpenes , Chemistry , Metabolism , Pharmacology
15.
Chinese Pharmaceutical Journal ; (24): 122-128, 2018.
Article in Chinese | WPRIM | ID: wpr-858451

ABSTRACT

OBJECTIVE: To determine the effects of the amphiphilic block polymers, which have the same hydrophilic block with the different hydrophobic block, on the function of P-glycoprotein(P-gp). METHODS: The three different micelles were prepared by film dispersion method. The particle sizes and distributions were measured by dynamic light scattering. Critical micelle concentrations(CMC) were detected by fluorescence probe technique with the pyrene. Rhodamine 123, a specific probe substrate of P-gp, was applied to determine the effects of polymers on the function of P-gp using uptake and efflux method. RESULTS: The particle sizes of mPEG-PCL, mPEG-PDLLA, mPEG-PLGA were (55.9±0.2), (53.7±1.1) and (61.6±0.6)nm. The CMC values were 2.08, 5.42 and 26.4 μg·mL-1. R123 accumulation in Madin-Darby canine kidney/multidrug resistance 1(MDCK-MDR1)cell detected by uptake assay increased to a maximum in the presence of polymers at concentrations of 250 μg·mL-1 for mPEG-PCL, 1~25 μg·mL-1 for mPEG-PDLLA and mPEG-PLGA. In efflux assay, mPEG-PCL, mPEG-PDLLA, mPEG-PLGA decreased the percentage of efflux of R123 at concentrations above the CMC, below/at the CMC or below the CMC respectively, showed the similar RESULTS with uptake assay. CONCLUSION: The mPEG-PCL, mPEG-PDLLA, mPEG-PLGA polymers might have a potential to inhibit the efflux activity of P-gp, which was likely related to the structures of hydrophobic segments, concentrations and existing states of the polymers.

16.
Chinese Herbal Medicines ; (4): 255-262, 2018.
Article in Chinese | WPRIM | ID: wpr-842127

ABSTRACT

Objectives: To investigate the effects of bergapten of Angelicae Dahuricae Radix on the transport of vincristine and its possible mechanism. Methods: The apparent permeability coefficient (Papp) for the transport of vincristine through the membrane of MDCK-MDR1 cells was used as an indicator of the effect of bergapten on vincristine transport. Molecular docking was employed to predict the binding force between bergapten and P-glycoprotein (P-gp). The effects of bergapten on P-gp function and P-gp ATPase activity were determined by rhodamine 123 (Rho123) accumulation and activity analysis, respectively. 1,6-Diphenyl-1,3,5-hexatriene (DPH) was used to study the effects of bergapten on membrane fluidity, and Western blotting and quantitative real-time PCR assays were performed to analyze the effect of bergapten on the protein and mRNA expression of P-gp, respectively. These experiments clarified the effects of bergapten on the transport of vincristine and allowed exploration of the possible mechanism underlying the effects of bergapten. Results: The results showed that bergapten could inhibit the transport of vincristine in MDCK-MDR1 cells, and the binding force between bergapten and P-gp was weaker. Bergapten could reduce the accumulation of Rh123 in MDCK-MDR1 cells, increase the membrane fluidity, and upregulate P-gp protein and mRNA expression but it had no effect on P-gp ATPase activity. Conclusions: Overall, we concluded that the possible mechanism through which bergapten inhibits vincristine transport was related to the bergapten-mediated upregulation of P-gp protein and mRNA expression, membrane fluidity or P-gp enzyme activity.

17.
Article in Chinese | WPRIM | ID: wpr-710659

ABSTRACT

Objective To explore the feasibility and clinical significance of individualized formular administration of tacrolimus after renal transplantation based on the CYP3A5 and MDR1 gene polymorphism.Methods Total 129 renal transplantation recipients from Oct.1,2015 to July 30,2016 were included in this study and divided into 2 groups.In experimental group,tacrolimus was administrated by the individualized formula based on CYP3A5 and MDR1 gene polymorphism;in control group,tacrolimus was administrated by doctors' experience based on patient's body weight.The blood trough level of tacrolimus was determined 3 days after administration.The first blood trough level of tacrolimus,plasma creatinine level,acute rejection rate,and necessity for dialysis were compared between two groups.Results The first blood trough levels of tacrolimus in experimental and control groups were 9.24 ± 2.32 and 9.39 ± 3.47μg/L respectively (P>0.05).The tacrolimus levels of 7 cases in experimental group and 18 cases in control group were not in normal range (P<0.05).The plasma creatinine level at day 7 after surgery was 157.36 ± 110.55 μg/L in experimental group,and 174.01 ± 130.68μg/L in control group (P>0.05).Acute rejection was found in both two groups:2 in experimental group and 5 in control group (P > 0.05).There was significant difference in necessity for dialysis between two groups:4 in experimental group and 10 in control group (P<0.05).Conclusion The individualized formular administration of tacrolimus based on the CYP3A5 and MDR1 gene polymorphism is more feasible and reasonable than experimental administration,which is more easier to come to an appropriate blood level and would benefit the early recovery of renal function.

18.
Article in Chinese | WPRIM | ID: wpr-851909

ABSTRACT

Objective To explore the effect of microemulsion on the transport and mechanism of puerarin in blood brain barrier (BBB) cell model MDCK-MDR1. Methods MTT assay was used to evaluate the cytotoxicity of puerarin microemulsion and solution, and determine the appropriate concentration of administration. The bilateral transport characteristics of puerarin solution-microemulsion was investigated in MDCK-MDR1 monolayer. Immunohistochemical staining was used to study the expression of tight junction proteins, and the changes in cell membrane fluidity was studied by fluorescence bleaching recovery, and the changes of membrane potential was measured by anion probe combined with flow cytometry. The mechanism of the effect of microemulsion on puerarin transport was clarified. Results The MDCK-MDR1 showed no significant toxicity when the mass concentration of puerarin solution ranged from 50 to 300 μg/mL and the microemulsion dilution was over 500 times. The Papp value in absorption direction of puerarin solution on MDCK-MDR1 monolayer was 1.04 × 10-6 cm/s, and the Papp value of excretion direction was 1.05 × 10-6 cm/s. The Papp value of puerarin in microemulsion was significantly increased compared with that in solution (P < 0.05). Microemulsification could reduce the expression of Claudin-1, Occludin, ZO-1, and F-actin in MDCK-MDR1, promote cell membrane flow, and decrease cell membrane potential. Conclusion Microemulsion can promote the bilateral transport of puerarin in the BBB cell model MDCK-MDR1. The mechanism is closely connected with the opening of tight junctions, increasing the cell membrane fluidity, making the cell depolarizing and reducing membrane potential, and increasing the permeation of paracellular.

19.
Article in English | WPRIM | ID: wpr-812432

ABSTRACT

Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. Our previous study has shown that icariin could reverse MDR in MG-63 doxorubicin-resistant (MG-63/DOX) cells. It is reported that icariin is usually metabolized to icariside II and icaritin. Herein, we investigated the effects of icariin, icariside II, and icaritin (ICT) on reversing MDR in MG-63/DOX cells. Among these compounds, ICT exhibited strongest effect and showed no obvious cytotoxicity effect on both MG-63 and MG-63/DOX cells ranging from 1 to 10 μmol·L. Furthermore, ICT increased accumulation of rhodamine 123 and 6-carboxyfluorescein diacetate and enhanced DOX-induced apoptosis in MG-63/DOX cells in a dose-dependent manner. Further studies demonstrated that ICT decreased the mRNA and protein levels of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1). We also verified that blockade of STAT3 phosphorylation was involved in the reversal effect of multidrug resistance in MG-63/DOX cells. Taken together, these results indicated that ICT may be a potential candidate in chemotherapy for osteosarcoma.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B , Genetics , Metabolism , Antineoplastic Agents , Pharmacology , Apoptosis , Cell Line, Tumor , Cell Survival , Dose-Response Relationship, Drug , Doxorubicin , Metabolism , Pharmacology , Toxicity , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Flavonoids , Pharmacology , Gene Expression Regulation, Neoplastic , Humans , Multidrug Resistance-Associated Proteins , Genetics , Metabolism , Osteosarcoma , Drug Therapy , Metabolism , Pathology , Phosphorylation , Rhodamine 123 , Metabolism , STAT3 Transcription Factor , Metabolism , Triterpenes , Pharmacology
20.
Article in English | WPRIM | ID: wpr-773642

ABSTRACT

Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. Our previous study has shown that icariin could reverse MDR in MG-63 doxorubicin-resistant (MG-63/DOX) cells. It is reported that icariin is usually metabolized to icariside II and icaritin. Herein, we investigated the effects of icariin, icariside II, and icaritin (ICT) on reversing MDR in MG-63/DOX cells. Among these compounds, ICT exhibited strongest effect and showed no obvious cytotoxicity effect on both MG-63 and MG-63/DOX cells ranging from 1 to 10 μmol·L. Furthermore, ICT increased accumulation of rhodamine 123 and 6-carboxyfluorescein diacetate and enhanced DOX-induced apoptosis in MG-63/DOX cells in a dose-dependent manner. Further studies demonstrated that ICT decreased the mRNA and protein levels of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1). We also verified that blockade of STAT3 phosphorylation was involved in the reversal effect of multidrug resistance in MG-63/DOX cells. Taken together, these results indicated that ICT may be a potential candidate in chemotherapy for osteosarcoma.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B , Genetics , Metabolism , Antineoplastic Agents , Pharmacology , Apoptosis , Cell Line, Tumor , Cell Survival , Dose-Response Relationship, Drug , Doxorubicin , Metabolism , Pharmacology , Toxicity , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Flavonoids , Pharmacology , Gene Expression Regulation, Neoplastic , Humans , Multidrug Resistance-Associated Proteins , Genetics , Metabolism , Osteosarcoma , Drug Therapy , Metabolism , Pathology , Phosphorylation , Rhodamine 123 , Metabolism , STAT3 Transcription Factor , Metabolism , Triterpenes , Pharmacology
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