Frontiers in Physiology
·
2025
·
IF 3.4
Ziqin Wei,Hongfang Mu,Fangfang Qiu,Minghui Zhao,Xiaojing Zhang,Wenbin Li,Hai Jia,Rong Wang
Objective Previous research has demonstrated that the hypoxic environment at high altitudes significantly alters the pharmacokinetics of many drugs, reducing their efficacy and increasing adverse effects. A key factor in this altered drug metabolism is the inhibition of ATP-binding cassette subfamily B member 1 (ABCB1), an efflux transporter protein, in the liver tissues of plateau rats. Rat ABCB1, encoded by the ABCB1A and ABCB1B genes, has two isoforms functionally analogous to human ABCB1. Histone acetylation, an epigenetic mechanism, may regulate ABCB1 transcription in hypoxic conditions by modifying chromatin structure and interacting with signaling pathways. However, its role in ABCB1 transcriptional regulation under hypoxia remains unclear. Based on this, the present study employed the BRL cell line to establish a hypoxia model, aiming to investigate the histone acetylation-mediated regulatory mechanisms of ABCB1 expression under hypoxic conditions, with the ultimate goal of providing novel theoretical foundations for rational drug use in high-altitude regions. Methods Establishment of BRL hypoxia model: BRL cell viability was detected by CCK-8 assay, and HIF-1α expression was measured by RT-qPCR and Western blot. After treating the BRL hypoxia model with HDAC inhibitors, ABCB1 and HDAC5 expression were detected by RT-qPCR, Western blot, and immunofluorescence. Rhodamine 123 accumulation assay was performed to examine the effect of HDAC inhibitors on ABCB1 functional activity. HDAC5 was targeted by siRNA technology to detect ABCB1 and H3K9ac expression. CUT&Tag assay was used to measure H3K9ac levels at the ABCB1 promoter region. After SAHA treatment of the BRL hypoxia model, SP1 expression was detected by RT-qPCR and Western blot. Combined treatment with SAHA and siRNA targeting SP1 was performed to detect ABCB1 expression. Co-immunoprecipitation and fluorescence colocalization assays were conducted to examine interactions among SP1, HDAC5, and ABCB1. Results After hypoxic culture for different durations, cell viability decreased while HIF-1α expression increased, indicating the successful establishment of the BRL hypoxia model. In the BRL hypoxia model, ABCB1 and SP1 expression decreased while HDAC5 expression increased. After SAHA treatment, ABCB1 and SP1 expression were upregulated while HDAC5 was downregulated. Rhodamine 123 accumulation assay showed that SAHA could enhance ABCB1 functional activity by inducing its expression. After HDAC5 was knocked down using siRNA, ABCB1 and H3K9ac expression increased, and ABCB1 functional activity was enhanced. CUT&Tag assay demonstrated that H3K9ac levels at the ABCB1B promoter region decreased in the BRL hypoxia model, while HDAC5 inhibition increased H3K9ac levels at this region. After SP1 was knocked down using siRNA, the inductive effect of SAHA on ABCB1 was blocked. Co-immunoprecipitation and fluorescence colocalization showed interactions among SP1, HDAC5, and ABCB1. Conclusion In BRL cells, HDAC5 may be recruited by SP1 to form a complex, reducing free HDAC5, increasing H3K9ac at the ABCB1B promoter, and activating ABCB1 transcription. In the BRL hypoxia model, disruption of the SP1-HDAC5 complex increased free HDAC5, lowered H3K9ac at the ABCB1B promoter, and suppressed ABCB1 transcription. These results suggest that HDAC inhibitors enhance ABCB1 expression in hypoxic environments, indicating that combining HDAC inhibitors with therapeutic agents could mitigate reduced drug efficacy and adverse effects caused by ABCB1 suppression.
研究领域:
药理学
·
分子生物学
·
表观遗传学
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DOI
PubMed
高影响因子
Plant Communications
·
2024
·
IF 9.4
Hong Wei,Heyuan Zhu,Wei Ying,Hilde Janssens,Miroslav Kvasnica,Johan M. Winne,Yongxiang Gao,Jiří Friml,Qian Ma,Shutang Tan,Xin Liu,Eugenia Russinova,Linfeng Sun
Brassinosteroids (BRs) are steroidal phytohormones indispensable for plant growth, development, and responses to environmental stresses. The export of bioactive BRs to the apoplast is essential for BR signalling initiation, which requires binding of BR molecule to the extracellular domains of the plasma membrane-localized receptor complex. We have previously shown that the Arabidopsis thaliana ATP-binding cassette (ABC) transporter, ABCB19, functions as a BR exporter, and together with its close homologue, ABCB1, positively regulate BR signalling. Here, we demonstrate that ABCB1 is another BR transporter. The ATP hydrolysis activity of ABCB1 was stimulated by bioactive BRs, and its transport activity was confirmed in proteoliposomes and protoplasts. Structures of ABCB1 in substrate-unbound (apo), brassinolide (BL)-bound, and ATP plus BL-bound states were determined. In the BL-bound structure, BL was bound to the hydrophobic cavity formed by the transmembrane domain, and triggered local conformational changes. Together, our data provide additional insights into the ABC transporter-mediated BR export.
研究领域:
植物生物学
·
分子生物学
·
结构生物学
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产品关联
DOI
PubMed
高影响因子
Clinical Pharmacology in Drug Development
·
2020
·Vol. 10
·期 1
·57-67
·
IF 1.903
Lu-Ning Sun,Guo-Xian Sun,Yu-Qing Yang,Ye Shen,Feng-Ru Huang,Li-Jun Xie,Juan Cheng,Hong-Wen Zhang,Xue-Hui Zhang,Yun Liu,Yong-Qing Wang
Sitafloxacin, a new fluoroquinolone, has strong antibacterial activity. We evaluated the effects of sitafloxacin granules in single-dose and multidose cohorts and the effects of ABCB1, UGT1A1 , and UGT1A9 genetic polymorphisms on the pharmacokinetics (PK) of sitafloxacin in healthy subjects. The single-dose study included 3 fasted cohorts receiving 50, 100, and 200 mg of sitafloxacin granules and 1 cohort receiving 50 mg of sitafloxacin granules with a high-fat meal. The multidose study included 1 cohort receiving 100 mg of sitafloxacin granules once daily for 5 days. PK parameters were calculated using noncompartmental parameters based on concentration-time data. The genotypes for ABCB1 , UGT1A1 , and UGT1A9 single-nucleotide polymorphisms were determined using Sanger sequencing. Subsequently, the association between sitafloxacin PK parameters and target single-nucleotide polymorphisms was analyzed. Sitafloxacin granules were well tolerated up to 200 and 100 mg in the single-dose and multidose studies, respectively. Sitafloxacin AUC and C max increased linearly within the detection range, and a steady state was reached within 3 days after the administration of multiple oral doses. Our findings showed that C max was lower in the ABCB1 (rs1045642) mutation group, whereas t 1/2 was longer in the UGT1A1 (rs2741049) and UGT1A9 (rs3832043) mutation groups. In conclusion, sitafloxacin granules were safe at single doses and multiple doses up to 200 and 100 mg/day, respectively, with a linear plasma PK profile. However, ABCB1 (rs1045642), UGT1A1 (rs2741049), and UGT1A9 (rs3832043) genetic polymorphisms are likely to influence the C max or t 1/2 and thereby merit further clinical evaluation.
研究领域:
药理学
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遗传学
·
临床研究
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DOI
PubMed
高影响因子
RESEARCH IN VETERINARY SCIENCE
·
2016
·
IF 1.504
Yong Sun,Tingting Guo,Dawei Guo,Li Guo,Li Chen,Yu Zhang,Liping Wang
Chicken P-glycoprotein (chP-gp), encoded by Abcb1 , determines the bioavailability because of its effect on pharmacokinetics of various drugs. However, comprehensive studies on chP-gp are still limited. In this study, the chicken full-length cDNA was first successfully cloned and then stably expressed in MDCK cell line. The open reading frame of chicken Abcb1 consists of 3864 nucleotides, encoding for a 1287-amino acid protein. Sequence alignments analysis showed that chicken P-gp had high identities with the homologues of turkey (95%), human (72%), pig (72%), rat (71%) and cattle (68%). The efflux ratio of rhodamine123 (Rho123, a human P-gp substrate) in ch Abcb1 transfected MDCK cells was significantly higher than that in the wild type MDCK cell (6.24 vs 1.64, P < 0.05), suggesting a good transporting function of chicken P-gp overexpressed in the transfected cell. Importantly, MDCK-ch Abcb1 cells, unlike Caco-2 cells, exhibited biphasic saturation kinetics in transporting Rho123. In conclusion, an MDCK cell line stably expressing ch Abcb1 was successfully established, which could provide a new cell model to screen its substrates and inhibitors and study the drug-drug interaction medicated via chicken P-gp.
研究领域:
药理学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Linlin Wang,Chen Ni,Kaili Zhang,Yuanyuan Yang,Ruoyang Chen,Xiaohan Lou,Yan Yan,Kexin Li,Ya Dong,Xiaohan Yao,Jiajia Wan,Xixi Duan,Fazhan Wang,YongJuan Li,Zhihai Qin
Chemotherapy resistance is still a great challenge for clinical treatment of lung cancer. Here, we found that doxorubicin (DOX) induced an increase of labile Zn 2+ in lung cancer cells, and these labile Zn 2+ protected tumor cells against DOX cytotoxicity. Nanoparticles encapsulating N,N,N′,N′-Tetrakis (2-pyridylmethyl)-ethylenediamine (TPEN) were then constructed to chelate labile Zn 2+ for tumor therapy. Application of nanoparticle-encapsulated TPEN at low dose not only avoided severe side effects caused by removing physiological Zn 2+ but also effectively chelated drug-induced labile Zn 2+ , and thereby enhanced DOX cytotoxicity. Mechanistically, nanosized TPEN inhibits ABCB1-mediated drug export potentiated by drug-induced labile Zn 2+ . Finally, the results unraveled that nanosized TPEN at low dose endowed DOX with the killing ability on resistant tumor cells. Taken together, our results demonstrate that chelating drug-induced labile Zn 2+ by nanosized TPEN at low dose enhances lung cancer chemotherapy by inhibiting ABCB1, providing a feasible strategy to overcome chemoresistance in lung cancer.
研究领域:
肿瘤学
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药理学
·
纳米技术
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产品关联
DOI
PubMed
高影响因子
HOLZFORSCHUNG
·
2016
·Vol. 71
·期 2
·179-188
·
IF 1.711
Min Yu,Kai Liu,Shengquan Liu,Haiyan Chen,Liang Zhou,Yamei Liu
Auxins as phytohormons, responsible for coordination of growing processes, also contribute to the formation of tension wood (TW) in trees, but the mechanism of this process is still unclear. In this study, it has been tried to induce TW formation in erect hybrid poplar trees (in opposite to inclined or bended trees) by treatment with exogenous indole-3-acetic acid (IAA, as one of the auxins) or N-1-naphthylphthalamic acid (NPA) as an auxin transport inhibitor. The treatment with IAA resulted in TW formation and, as expected, NPA treatment did not. The gelatinous fiber formation and higher cellulose content in the cell wall were unambiguous indicators for TW formation. Real-time polymerase chain reaction (PCR) analysis revealed that genes of PIN1 , ABCB1, and AUX2 involved in polar auxin transport were highly expressed in trees treated with exogenous IAA. Moreover, expressions of cellulose biosynthesis related genes of UGP1 , UGP2 and CesA13 were strongly up-regulated. These observations indicate that the accelerated intercellular polar auxin transport caused by exogenous IAA is accounted for TW formation, i.e. the signal transduction of auxin is affected, which then facilitates cellulose biosynthesis. In contrast, the transcript abundances of PIN1 and all selected cellulose synthases ( CesAs ) were decreased after NPA treatment via inhibiting the cellular auxin efflux with negative effects on plant’s primary growth. These results are interpreted that TW formation is closely associated with the acceleration of intercellular polar auxin transport.
研究领域:
植物学
·
分子生物学
·
林学
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产品关联
DOI
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 11
·1699
·
IF 4.8
Zheng Ye,Chao Hong,Min Jiang,Wenkui Zou,Yaning Ren,Mingfang Li,Xinyue Xue,Xiaoting Xie,Tong Zhang,Yue Ding
Background/Objectives: Breast cancer is the most prevalent malignancy among women, and paclitaxel (PTX) is a first-line chemotherapeutic, but chemoresistance driven by ATP-binding cassette (ABC) transporters limits its efficacy. Single-target ABC inhibitors fail due to toxicity and cooperative transporter activity, creating an urgent need for safe multi-target strategies. Membrane cholesterol-rich lipid rafts support ABC transporter function, making cholesterol a key chemoresistance target. This study explored a cholesterol-targeted approach for overcoming PTX resistance.Methods: A PTX-resistant breast cancer line (MCF-7/PTX) showing ABCB1/ABCC3 co-upregulation and enriched cholesterol rafts was established. The effects of Polyphyllin H (PPH), a steroidal saponin fromParis polyphylla, were compared with lovastatin, a biosynthetic cholesterol inhibitor. In vitro and in vivo assays investigated Polyphyllin H’s cholesterol binding and effects on transporters, PTX accumulation, and tumor growth.Results: PPH directly binds membrane cholesterol, disrupting lipid rafts, downregulating ABCB1/ABCC3, reducing drug efflux, and increasing intracellular PTX to restore sensitivity. PPH showed superior cholesterol-binding and resistance-reversal efficacy than lovastatin, with faster, stronger PTX-enhanced cytotoxicity and tumor suppression.Conclusions: PPH reverses PTX resistance by targeting cholesterol-lipid rafts to inhibit multiple ABC transporters. This offers a safer adjuvant for PTX-based breast cancer therapy and a translational framework for other drug-resistant malignancies.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
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天然产物化学
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产品关联
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2020
·Vol. 44
·期 3
·927-938
·
IF 3.417
Songhui Zhou,Ruicheng Wang,Hong Xiao
The resistance of cancer cells to carboplatin restricts their efficacy in the clinical setting, and a solution to reverse the resistance is urgently required for the treatment of ovarian cancer. An increasing number of studies have found associations between obesity and the incidence, and mortality rates of female cancer. However, the association between adipocytes and the resistance of ovarian cancer has rarely been reported. Based on this, the present study first revealed the inductive effect of adipocytes on the resistance of ovarian cancer to carboplatin using in vivo and in vitro experiments. Subsequently, it was identified that the angiopoietin‑like 4 (ANGPTL4) secreted by adipocytes played a vital role in the resistance of ovarian cancer using bioinformatics analysis, cellular and molecular biological experiments, as well as forward and backward validation. The glycosylated ANGPTL4 protein could bind with integrin α5β1 on the surface of ovarian cancer cells; following which, it could activate the c‑myc/NF‑κB pathway and stimulate the expression of the antiapoptotic protein Bcl‑xL, as well as the ABC transporter family members ABCB1, ABCC1 and ABCG2. Thus, inducing the resistance of ovarian cancer to carboplatin. In conclusion, targeting the adipocyte‑derived ANGPTL4 combined with the application of carboplatin contributes to the clinical treatment for ovarian cancer.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2017
·
IF 4.3
Ying Li,Meng Wang,Bu-Wei Huang,Yuan Ping,Jian You,Jian-Qing Gao
Although widely used in chemotherapy, free doxorubicin (Dox) might enhance cell malignancy undesirably. Liposomal Dox (Doxlipo) has been clinically approved for the treatment of breast cancer due to reduced systematical toxicity and increased tumor targeting, yet the transcriptome-wide elucidation of the Doxlipo formulations remains elusive. To this end, we explored the impact of two Dox liposomal formulations, Doxlipo mainly containing hydrogenated soy phosphatidylcholine or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, on the transcriptional pattern of MCF-7 cells. The two types of Dox liposomal formulations with different drug release kinetics were investigated to reveal the relationship between the formulation and tumor malignancy. Interestingly, we found that liposomal formulation significantly altered the transcriptional pattern of a wide range of genes. Under equivalent dosage of Dox, free Dox substantially changed the expression of ANK1, ACTA2, GPR87, GDF15, FZD6, and WNT4 in MCF-7 cells. Notably, free Dox induced much higher expression of ABCB1 and significantly enhanced the cell migration behavior in comparison with HSPC Doxlipo under a similar level of cytotoxicity. Finally, siRNA targeting GPR87 was codelivered with cationic Doxlipo to reduce the expression of malignancy-related genes. Our study, for the first time, provides an overview of the influence of formulation on the malignancy at transcriptional level and reveals the relationship between cytotoxicity and cell malignancy from the formulation aspect, offering valuable reference for the future formulation design for anticancer drug delivery.
研究领域:
药理学
·
肿瘤学
·
分子生物学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-15
·
IF 10.2
Pei Manman,Liu Kaiyuan,Qu Xiao,Wang Kairuo,Chen Qian,Zhang Yuanyuan,Wang Xinyue,Wang Zheng,Li Xinyao,Chen Feng,Qin Huanlong,Zhang Yang
Background The development of multidrug resistance (MDR) during postoperative chemotherapy for colorectal cancer substantially reduces therapeutic efficacy. Nanostructured drug delivery systems (NDDSs) with modifiable chemical properties are considered promising candidates as therapies for reversing MDR in colorectal cancer cells. Selenium-doped manganese phosphate (Se-MnP) nanoparticles (NPs) that can reverse drug resistance through sustained release of selenium have the potential to improve the chemotherapy effect of colorectal cancer. Results Se-MnP NPs had an organic–inorganic hybrid composition and were assembled from smaller-scale nanoclusters. Se-MnP NPs induced excessive ROS production via Se-mediated activation of the STAT3/JNK pathway and a Fenton-like reaction due to the presence of manganese ions (Mn 2+ ). Moreover, in vitro and in vivo studies demonstrated Se-MnP NPs were effective drug carriers of oxaliplatin (OX) and reversed multidrug resistance and induced caspase-mediated apoptosis in colorectal cancer cells. OX@Se-MnP NPs reversed MDR in colorectal cancer by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (e.g., ABCB1, ABCC1 and ABCG2). Finally, in vivo studies demonstrated that OX-loaded Se-MnP NPs significantly inhibited proliferation of OX-resistant HCT116 (HCT116/DR) tumor cells in nude mice. Conclusions OX@Se-MnP NPs with simple preparation and biomimetic chemical properties represent promising candidates for the treatment of colorectal cancer with MDR.
研究领域:
肿瘤学
·
纳米医学
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2021
·Vol. 12
·期 1
·167-179
·
IF 4.617
Wang Shuanghu,Tan Xueying,Zhou Quan,Geng Peiwu,Wang Jinhui,Zou Ping,Deng Aiping,Hu Jingbo
Multidrug resistance (MDR) is considered as a critical limiting factor for the successful chemotherapy, which is mainly characterized by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2. In this study, folate-targeted polymeric micellar carrier was successfully constructed to co-delivery of doxorubicin (DOX) and SIS3 (FA/DOX/SIS3 micelles), a specific Smad3 inhibitor which sensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic agents. The ratio of DOX to SIS3 in polymeric micelles was determined based on the anti-tumor activity against resistant breast cells. In addition, FA/DOX/SIS3 micelles exhibited a much longer circulation time in blood and were preferentially accumulated in resistant tumor tissue. Pharmacodynamic studies showed that FA/DOX/SIS3 micelles possessed superior anti-tumor activity than other DOX-based treatments. Overall, FA/DOX/SIS3 micelles are a promising formulation for the synergistic treatment of drug-resistant tumor. Graphical abstract
研究领域:
肿瘤学
·
药剂学
·
化疗
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2018
·
IF 7.877
Meng Wang,Jiahe Wu,Ying Li,Fangyuan Li,Xi Hu,Gang Wang,Min Han,Daishun Ling,Jianqing Gao
Stimuli-responsive nanomaterials have emerged as promising drug delivery systems for tumor therapy, as they can specifically respond to tumor-associated stimuli and release the loaded drugs in a controllable manner. However, most currently available stimuli-responsive nanomedicines rely on surrounding extreme stimulus to trigger the activity, which can be inefficient under dynamic and complex living conditions. Herein, we report a near-infrared (NIR) light-responsive nanocomposite, which can generate reactive oxygen species to efficiently trigger the decomposition upon NIR laser irradiation. This nanocomposite is fabricated by conjugating polyamidoamine-pluronic F68 and graphene oxide via diselenide bond, and encapsulating the NIR photosensitizer indocyanine green and chemotherapeutic drug doxorubicin (DOX) as payloads. Under NIR light, the nanocomposite shows lysosomal escape, controlled drug release , and nuclear trafficking of DOX inside multidrug resistant (MDR) MCF-7/ADR cells. Interestingly, this nanocomposite effectively down-regulates ABCB1 gene and P-glycoprotein of MCF-7/ADR cells, exhibiting significant cytotoxicity. In vivo anti-tumor study demonstrates an effective accumulation and superior therapeutic efficacy of this multifunctional nanocomposite in MCF-7/ADR tumors, representing a great potential for clinical treatment of MDR cancer.
研究领域:
纳米技术
·
癌症研究
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）