OBJECTIVE: To screen the genetic risk factors related to severe hematology adverse effects (AEs) in patients with chronic myeloid leukemia (CML) treated with imatinib (IM), and explore the correlation of single nucleotide polymorphisms (SNPs) in IM drug metabolism and transport pathway gene polymorphism with the risk of severe hematology AEs. METHODS: 172 newly diagnosed Chinese Han patients in CML chronic phase (CML-CP) treated with IM were included and divided into severe hematology AEs group and non-severe hematology AEs group. The demographic characteristics and laboratory test results were compared between the two groups. 11 gene SNP sites in the included subjects were genotyped using SNaPshot multiplex SNPs technique. RESULTS: Compared with non-severe hematology AEs group, the severe hematology AEs group had higher white blood cell (WBC) and EOS% (both P < 0.05), but lower hemoglobin (Hb) and hematocrit (HCT) (both P < 0.01). For rs1045642 of ABCB1 gene, there were significant differences in the distribution of allele frequency and genotype frequency of this loci between severe hematology AEs group and non-severe hematology AEs group (both P < 0.05). Carriers of rs1045642 mutation allele A had an increased risk of severe hematology AEs (OR =2.09, 95% CI : 1.24-3.55, P =0.005). There was a significant difference in the distribution of NR1I2 gene rs3814055 genotype between severe hematology AEs group and non-severe hematology AEs group (P < 0.05). The additive model and recessive model of ABCB1 gene rs1045642 and the recessive model of NR1I2 gene rs3814055 were associated with the increased risk of severe hematology AEs (OR =2.14, 3.28, 5.54, all P < 0.05). CONCLUSION Peripheral blood WBC, EOS%, Hb and HCT in patients with newly diagnosed CML-CP are all related to the risk of severe hematology AEs. ABCB1 gene rs1045642 and NR1I2 gene rs3814055 related to the metabolism and transport pathway of IM are associated with severe hematology AEs after IM treatment in CML-CP patients, and they may be potential molecular markers to predict the risk of severe hematology AEs of CML patients treated by IM.
Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Polymorphism, Single Nucleotide ; Genotype ; ATP Binding Cassette Transporter, Subfamily B ; Gene Frequency ; Female ; Male ; Middle Aged ; Adult ; Asian People

Cancer multidrug resistance (MDR) impairs the therapeutic efficacy of various chemotherapeutics. Novel approaches, particularly the development of MDR reversal agents, are critically needed to address this challenge. This study demonstrates that tenacissoside I (TI), a compound isolated from Marsdenia tenacissima (Roxb.) Wight et Arn, traditionally used in clinical practice as an ethnic medicine for cancer treatment, exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells. TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin (DOX) and paclitaxel (PAC) by downregulating ABCB1 expression and reducing ABCB1 drug transport function. Mechanistically, protein arginine methyltransferase 1 (PRMT1), whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI-treated SW620/AD300 cells. SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine (aDMA) and enhanced PRMT1-EGFR interaction compared to their parental cells. Moreover, TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR, PRMT1-EGFR interaction, and EGFR downstream signaling in SW620/AD300 and KBV200 cells. These effects were significantly reversed by PRMT1 overexpression. Additionally, TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities. This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR, suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
Humans ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors* ; Drug Resistance, Neoplasm/drug effects* ; ErbB Receptors/genetics* ; Animals ; Cell Line, Tumor ; Drug Resistance, Multiple/drug effects* ; Methylation/drug effects* ; Saponins/administration & dosage* ; Mice ; Mice, Nude ; Mice, Inbred BALB C ; ATP Binding Cassette Transporter, Subfamily B/genetics* ; Doxorubicin/pharmacology* ; Paclitaxel/pharmacology* ; Female ; Repressor Proteins

OBJECTIVES: Fluorouracil chemotherapeutic drugs are the classic treatment drugs of gastric cancer. But the problem of drug resistance severely limits their clinical application. This study aims to investigate whether hypoxia microenvironment affects gastric cancer resistance to 5-fluorouracil (5-FU) and discuss the changes of gene and proteins directly related to drug resistance under hypoxia condition. METHODS: Gastric cancer cells were treated with 5-FU in hypoxia/normoxic environment, and were divided into a Normoxic+5-FU group and a Hypoxia+5-FU group. The apoptosis assay was conducted by flow cytometry Annexin V/PI double staining. The real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the expression level of hypoxia inducible factor-1α (HIF-1α), multidrug resistance (MDR1) gene, P-glycoprotein (P-gp), and vascular endothelial growth factor (VEGF) which were related to 5-FU drug-resistance. We analyzed the effect of hypoxia on the treatment of gastric cancer with 5-FU. RESULTS: Compared with the Normoxic+5-FU group, the apoptosis of gastric cancer cells treated with 5-FU in the Hypoxia+5-FU group was significantly reduced (P<0.05), and the expression of apoptosis promoter protein caspase 8 was also decreased. Compared with the the Normoxic+5-FU group, HIF-1α mRNA expression in the Hypoxia+5-FU group was significantly increased (P<0.05), and the mRNA and protein expression levels of MDR1, P-gp and VEGF were also significantly increased (all P<0.05). The increased expression of MDR1, P-gp and VEGF had the same trend with the expression of HIF-1α. CONCLUSIONS Hypoxia is a direct influencing factor in gastric cancer resistance to 5-FU chemotherapy. Improvement of the local hypoxia microenvironment of gastric cancer may be a new idea for overcoming the resistance to 5-FU in gastric cancer.
Humans ; Fluorouracil/therapeutic use* ; Vascular Endothelial Growth Factor A/metabolism* ; Stomach Neoplasms/drug therapy* ; Drug Resistance, Multiple ; Vascular Endothelial Growth Factors/metabolism* ; Hypoxia ; ATP Binding Cassette Transporter, Subfamily B/genetics* ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics* ; Cell Line, Tumor ; Cell Hypoxia ; RNA, Messenger/metabolism* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Tumor Microenvironment

Objective:b> Due to genetic factors might increase the risk of depression, this study investigated the genetic risk factors of depression in Chinese Han population by analyzing the association between 13 candidate genes and depression. Methods:b> 439 depression patients and 464 healthy controls were included in this case-control study. Case group consisted of 158 males and 281 females, aged (29.84±14.91) years old, who were hospitalized in three departments of the affiliated Brain Hospital of Guangzhou Medical University including Affective Disorders Department, Adult Psychiatry Department and Geriatrics Department, from February 2020 to September 2021. The control group consisted of 196 males and 268 females, aged (30.65±12.63) years old. 20 loci of 13 candidate genes in all subjects were detected by MALDI-TOF mass spectrometry. Age difference was compared using the student's t-test, the distributions of gender and genotype were analyzed with Pearson's Chi-square test. The analyses of Hardy-Weinberg equilibrium, allele frequency and the genetic association of depression were conducted using the corresponding programs in PLINK software. Results:b> PLINK analysis showed that SCN2A rs17183814, ABCB1 rs1045642, CYP2C19*3 rs4986893 and NAT2*5A rs1799929 were associated with depression before Bonferroni correction (χ²=10.340, P=0.001; χ²=11.010, P=0.001; χ²=9.781, P=0.002; χ²=4.481, P=0.034). The frequencies of minor alleles of above loci in the control group were 12.07%, 43.64%, 2.59% and 3.88%, respectively. The frequencies of minor alleles of loci mentioned above in the case group were 17.43%, 35.99%, 5.47% and 6.04%, respectively. OR values were 1.538, 0.726, 2.178 and 1.592, respectively. After 1 000 000 permutation tests using Max(T) permutation procedure, the four loci were still statistically significant, the empirical P-value were 0.002, 0.001, 0.003 and 0.042, respectively. However, only three loci including SCN2A rs17183814, ABCB1 rs1045642 and CYP2C19 rs4986893 had statistical significance after Bonferroni correction, the adjusted P-value were 0.026, 0.018 and 0.035, respectively. Conclusion:b> SCN2A rs17183814, ABCB1 rs1045642 and CYP2C19*3 rs4986893 were associated with depression's susceptibility in Chinese Han population. The A allele of SCN2A rs17183814 and CYP2C19*3 rs4986893 were risk factors for depression, while the T allele of ABCB1 rs1045642 was a protective factor for depression.
ATP Binding Cassette Transporter, Subfamily B/genetics* ; Adolescent ; Adult ; Alleles ; Arylamine N-Acetyltransferase/genetics* ; Case-Control Studies ; Clopidogrel ; Cytochrome P-450 CYP2C19/genetics* ; Depressive Disorder, Major/genetics* ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; NAV1.2 Voltage-Gated Sodium Channel ; Polymorphism, Single Nucleotide ; Young Adult

OBJECTIVES: Nephrotic syndrome is a common disease of the urinary system. The aim of this study is to explore the effect of astragalus polysaccharides (APS) on multidrug resistance gene 1 (MDR1) and P-glycoprotein 170 (P-gp170) in adriamycin nephropathy rats and the underlying mechanisms. METHODS: A total of 72 male Wistar rats were divided into a control group, a model group, an APS low-dose group, an APS high-dose group, an APS+micro RNA (miR)-16 antagomir group and an APS+miR-16 antagomir control group, with 12 rats in each group. Urine protein (UP) was detected by urine analyzer, and serum cholesterol (CHOL), albumin (ALB), blood urea nitrogen (BUN), and creatinine (SCr) were detected by automatic biochemical analyzer; serum interleukin-6 (IL-6), IL-1β, tumor necrosis factor α (TNF-α) levels were detected by ELISA kit; the morphological changes of kidney tissues were observed by HE staining; the levels of miR-16 and MDR1 mRNA in kidney tissues were detected by real-time RT-PCR; the expression levels of NF-κB p65, p-NF-κB p65, and P-gp170 protein in kidney tissues were detected by Western blotting; and dual luciferase was used to verify the relationship between miR-16 and NF-κB. RESULTS: The renal tissue structure of rats in the control group was normal without inflammatory cell infiltration. The renal glomeruli of rats in the model group were mildly congested, capillary stenosis or occlusion, and inflammatory cell infiltration was obvious. The rats in the low-dose and high-dose APS groups had no obvious glomerular congestion, the proliferation of mesangial cells was significantly reduced, and the inflammatory cells were reduced. Compared with the high-dose APS group and the APS+miR-16 antagomir control group, there were more severe renal tissue structure damages in the APS + miR-16 antagomir group. Compared with the control group, the levels of UP, CHOL, BUN, SCr, IL-6, IL-1β, TNF-α, and MDR1 mRNA, and the protein levels of p-NF-κB p65 and P-gp170 in the model group were significantly increased (all P<0.05); the levels of ALB and miR-16 were significantly decreased (both P<0.05). Compared with the model group, the levels of UP, CHOL, BUN, SCr, IL-6, IL-1β, TNF-α, and MDR1 mRNA, and the protein levels of pNF-κB p65 and P-gp170 in the low-dose and high-dose APS groups were significant decreased (all P<0.05); and the levels of ALB and miR-16 were significantly increased (both P<0.05). Compared with APS+miR-16 antagomir control group, the UP, CHOL, BUN, SCr, IL-6, IL-1β, and TNF-α levels, MDR1 mRNA, and the protein levels of p-NF-κB p65 and P-gp170 were significantly increased (all P<0.05). The levels of ALB and miR-16 were significantly decreased in the APS+miR-16 antagomir group compared with the APS+miR-16 antagomir control group (both P<0.05). CONCLUSIONS APS can regulate the miR-16/NF-κB signaling pathway, thereby affecting the levels of MDR1 and P-gp170, and reducing the inflammation in the kidney tissues in the adriamycin nephropathy rats.
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics* ; Animals ; Antagomirs ; Doxorubicin/toxicity* ; Genes, MDR ; Interleukin-6/metabolism* ; Kidney Diseases/genetics* ; Male ; MicroRNAs/metabolism* ; NF-kappa B/metabolism* ; Polysaccharides/pharmacology* ; RNA, Messenger ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism*

Currently, chemoresistance seriously attenuates the curative outcome of liver cancer. The purpose of our work was to investigate the influence of 6-shogaol on the inhibition of 5-fluorouracil (5-FU) in liver cancer. The cell viability of cancer cells was determined by MTT assay. Liver cancer cell apoptosis and the cell cycle were examined utilizing flow cytometry. Moreover, qRT-PCR and western blotting was used to analyse the mRNA and protein expression levels, respectively. Immunohistochemistry assays were used to examine multidrug resistance protein 1 (MRP1) expression in tumour tissues. In liver cancer cells, we found that 6-shogaol-5-FU combination treatment inhibited cell viability, facilitated G0/G1 cell cycle arrest, and accelerated apoptosis compared with 6-shogaol or 5-FU treatment alone. In cancer cells cotreated with 6-shogaol and 5-FU, AKT/mTOR pathway- and cell cycle-related protein expression levels were inhibited, and MRP1 expression was downregulated. AKT activation or MRP1 increase reversed the influence of combination treatment on liver cancer cell viability, apoptosis and cell cycle arrest. The inhibition of AKT activation to the anticancer effect of 6-shogaol-5-FU could be reversed by MRP1 silencing. Moreover, our results showed that 6-shogaol-5-FU combination treatment notably inhibited tumour growth in vivo. In summary, our data demonstrated that 6-shogaol contributed to the curative outcome of 5-FU in liver cancer by inhibiting the AKT/mTOR/MRP1 signalling pathway.
ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Apoptosis ; Catechols ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; Fluorouracil/pharmacology* ; Humans ; Liver Neoplasms/genetics* ; Multidrug Resistance-Associated Proteins ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism*

OBJECTIVE: To study the association between the expression of the MDR3 gene and the pathogenesis of parenteral nutrition-associated cholestasis (PNAC) in preterm infants. METHODS: Among the preterm infants who were admitted to the hospital from June 2011 to November 2017 and received parenteral nutrition for more than 14 days, 80 who did not develop PNAC were enrolled as non-PNAC group, and 76 who developed PNAC were enrolled as PNAC group. On days 1, 14, 30, 60 and 90 after birth, serum hepatobiliary biochemical parameters [alanine aminotransferase (ALT), total bilirubin (TBil), direct bilirubin (DBil), total bile acid (TBA) and gamma-glutamyl transpeptidase (γ-GT)], fibrosis indices [hyaluronic acid, laminin, procollagen III N-terminal peptide and type IV collagen] and clinical manifestations were observed. Real-time quantitative PCR was used to measure the mRNA expression of MDR3 in both groups, and the correlation between the mRNA expression of MDR3 and serum hepatobiliary biochemical parameters was analyzed. RESULTS: In the PNAC group, serum levels of hepatobiliary biochemical parameters and fibrosis indices increased on day 14 after birth and reached the peak on day 30 after birth, followed by a reduction on day 60 after birth. On days 14, 30, 60 and 90 after birth, the PNAC group had significantly higher serum levels of hepatobiliary biochemical parameters and fibrosis indices than the non-PNAC group (P<0.05). The PNAC group had higher relative mRNA expression of MDR3 in peripheral blood cells than the non-PNAC group (P<0.05). In the PNAC group, the relative mRNA expression of MDR3 in peripheral blood cells was negatively correlated with serum levels of hepatobiliary biochemical parameters (ALT, TBil, DBil, TBA and γ-GT) (P<0.001). CONCLUSIONS High mRNA expression of MDR3 in preterm infants may be associated with the development of PNAC, and further studies are needed to identify the mechanism.
ATP Binding Cassette Transporter, Subfamily B ; genetics ; Cholestasis ; genetics ; Humans ; Infant, Newborn ; Infant, Premature ; Parenteral Nutrition ; RNA, Messenger

Objective To explore the role of multidrug resistance gene-1(MDR1)gene in methotrexate(MTX)resistance in patients with rheumatoid arthritis(RA).Methods Fibroblast-like synoviocytes(FLS)from RA patients were infected with recombinant adenovirus Ad-EGFP-MDR1 to obtain MDR1 over-expressed RA FLS.The transcription level of MDR1 gene and the expression level of its coding product P-glycoprotein(P-gp) rotein were detected by real-time PCR and Western blot analysis.The efflux function was verified by rhodamine 123 efflux assay.The resistance to MTX was detected by MTT assay.Results RA FLS were infected with recombinant adenovirus Ad-EGFP-MDR1;72 hours later,the particles size in MDR1 over-expressed RA FLS increased,the cell volume became larger,and the growth rate decreased.The transcription level of MDR1(1.4325±0.3924 0.0650±0.0070;=6.035,=0.004),the expression level of P-gp protein(1.8667±0.2857 0.9367±0.0551;=5.536,=0.005),and the ability of extracellular rhodamine 123(979.43±196.81 1680.06±147.04;=-4.940,=0.008) in MDR1 over-expressed RA FLS were significantly higher than those of negative virus control RA-FLS,and the survival rate of MDR1 over-expressed RA FLS was significantly increased at each concentration of MTX(<0.05).Conclusion The high expression of MDR1 can affect the efflux ability to MTX by up-regulating the expression of P-gp,thus enhancing the drug resistance to MTX in RA FLS.
ATP Binding Cassette Transporter, Subfamily B ; genetics ; Arthritis, Rheumatoid ; drug therapy ; genetics ; Cells, Cultured ; Drug Resistance ; Fibroblasts ; drug effects ; Humans ; Methotrexate ; pharmacology ; Synovial Membrane ; cytology

OBJECTIVE: To explore the genetic etiology for a pedigree affected with progressive familial intrahepatic cholestasis (PFIC). METHODS: Target sequence capture and next generation sequencing (NGS) were applied for the proband. PCR and Sanger sequencing were used to verify the suspected mutation in his sister with similar symptoms and his parents. RESULTS: The proband and his sister manifested after birth with symptoms including jaundice, pruritus and developmental retardation. NGS has identified compound heterozygous mutations of ABCB11 gene, which encodes bile salt export pump protein (BSEP), namely c.2494C>T (p.Arg832Cys) and c.3223C>T (p.Gln1075*), in the proband, which were inherited from his father and mother respectively. His sister carried the same compound mutations. CONCLUSION Based on the phenotype and genetic testing, the patients were diagnosed as PFIC2 caused by mutation of the ABCB11 gene. The c.3223C>T is a novel nonsense mutation which may cause premature termination of translation. Above results have enriched the spectrum of ABCB11 mutations and provided new evidence for the molecular basis of PFIC, which also facilitated genetic counseling for this pedigree.
ATP Binding Cassette Transporter, Subfamily B, Member 11 ; genetics ; ATP-Binding Cassette Transporters ; Cholestasis, Intrahepatic ; genetics ; Female ; Genetic Testing ; Humans ; Male ; Mutation ; Pedigree ; Phenotype

OBJECTIVE: To analyze the relation between the signle nucleotide polymorphisms (SNP) of CYP3A5 gene and MDR1 gene loci and the risk of cytogenetic relapse in chronic myeloid leukemia (CML). METHODS: The clinical data of 90 patients with CML treated with imatinib in our hospital were collected.The patients were divided into 2 groups: non-relapse and relapse according to relapse and non-relapse, then the relation between the SNP of CYP3A5 gene and MRD1 gene loci and the risk of cytogenetic relapse in CML patients. RESULTS: The grouping result showed that the patients with non cytogenetic relapse accounted for 41 cases those were enrolled in non-relapse group, and patient-with cytogenetic relapse accounted for 49 cases those were enrolled in relapse group. The follow-up time was 36 months. The detection showed that the incidence of cytogenetic relapse in the patients with CC genotype was significantly higher than that in the patients with TT+CT genotype of C3435T and C1236T at MDR1 gene loci (P<0.05).Compared with the patients with CT+CC genotype in C3435T locus of MDR1 gene, the rate of cytogenetic relapse in the patients with TT genotype decreased significantly (P<0.05). Compared with patients with CT+CC phemotype of C3435T in MDR1 gene locus, the non-relapse survival time of TT genotypes was significantly prolonged (P<0.05). Compared with non-relapse group, the incidence of neutropenia (29.27% vs 71.43%) and blood toxicity (39.02% vs 61.22%) in the relapse group increased significantly (P<0.05). The imatinib dose (OR=2 95, 95% CI:1.37~7.76) and the C3435T genotype in MDR1 genes (OR=0.09, 95% CI:0.05~0.72) were the factors affecting the cytogenetic relapse of the patients with CML (both P<0.05). CONCLUSION The therapeutic dose of imatinib and the C3435T and C1236T genotypes in MDR1 gene have a certain effect on the cytogenetic relapse of CML patients. C3435T genotypes in the.MDR1 gene showed a certain predictive value for evaluating the risk of cytogenetic relapse, which can be used as a clinical biomarker.
ATP Binding Cassette Transporter, Subfamily B ; genetics ; Cytochrome P-450 CYP3A ; genetics ; Genotype ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Polymorphism, Single Nucleotide ; Recurrence