JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2018
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IF 3.412
Lujia Li,Qingxue Fu,Mengxin Xia,Lei Xin,Hongyi Shen,Guowen Li,Guang Ji,Qianchao Meng,Yan Xie
Phytic acid (IP6) is a natural phosphorylated inositol, which is abundantly present in most cereal grains and seeds. This study investigated the effects of IP6 regulation on P-glycoprotein (P-gp) and its potential mechanisms using in situ and in vitro models. The effective permeability of the typical P-gp substrate rhodamine 123 (R123) in colon was significantly increased from (1.69 ± 0.22) × 10–5 cm/s in the control group to (3.39 ± 0.417) × 10–5 cm/s (p < 0.01) in the 3.5 mM IP6 group. Additionally, IP6 can concentration-dependently decrease the R123 efflux ratio in both Caco-2 and MDCK II-MDR1 cell monolayers and increase intracellular R123 accumulation in Caco-2 cells. Furthermore, IP6 noncompetitively inhibited P-gp by impacting R123 efflux kinetics. The noncompetitive inhibition of P-gp by IP6 was likely due to decreases in P-gp ATPase activity and P-gp molecular conformational changes induced by IP6. In summary, IP6 is a promising P-gp inhibitor candidate.
研究领域:
药理学
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细胞生物学
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药物递送
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DOI
PubMed
高影响因子
Biosensors-Basel
·
2023
·Vol. 13
·期 8
·764
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IF 5.4
Ruiting Chen,Hejing Chen,Huaping Peng,Yanjie Zheng,Zhen Lin,Xinhua Lin
Drug resistance in cancer is associated with overexpression of the multidrug resistance (MDR1) gene, leading to the failure of cancer chemotherapy treatment. Therefore, the establishment of an effective method for the detection of the MDR1 gene is extremely crucial in cancer clinical therapy. Here, we report a novel DNA biosensor based on an aligned multi-walled carbon nanotube (MWCNT) array modified electrode with 3D nanostructure for the determination of the MDR1 gene. The microstructure of the modified electrode was observed by an atomic force microscope (AFM), which demonstrated that the electrode interface was arranged in orderly needle-shaped protrusion arrays. The electrochemical properties of the biosensor were characterized by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Chronocoulometry (CC) was used for the quantitative detection of the MDR1 gene. Taking advantage of the good conductivity and large electrode area of the MWCNT arrays, this electrochemical DNA sensor achieved a dynamic range from 1.0 × 10−12M to 1.0 × 10−8M with a minimal detection limit of 6.4 × 10−13M. In addition, this proposed DNA biosensor exhibited high sensitivity, selectivity, and stability, which may be useful for the trace analysis of the MDR1 gene in complex samples.Keywords:multidrug resistant gene;multi-walled carbon nanotube array;electrochemical DNA biosensor;3D sensing interface
研究领域:
生物工程
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分析化学
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生物医学工程
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分子生物学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2017
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IF 3.649
Tingting Meng,Binbin Lu,Shihong Shao,Ming Yuan,Xuan Liu,Hong Yuan,Xuan Huang,Fuqiang Hu
P-glycoprotein (P-gp) is a major efflux transporter overexpressed on multidrug resistant tumor cells and responsible for pumping drugs out. If anti-tumor drugs are given when P-gp level is low, satisfactory treatment efficiency may be achieved. Thus, a P-gp down-regulating siRNA (siMDR1) and doxorubicin (DOX) were applied to eliminate multidrug resistant breast cancer cells (MCF-7/ADR). A redox-responsive glucolipid conjugate (CSO-ss-SA) was used to condense siRNA (CSO-ss-SA/siRNA) and encapsulate DOX (CSO-ss-SA/DOX) separately. They responded to the high reducing environment of tumor cells and fast released the payload. CSO-ss-SA/siMDR1 silenced MDR1 gene and resulted in a transient decrease of P-gp. Sequentially, DOX formulation (CSO-ss-SA/DOX or DOX·HCl) was delivered when P-gp was reduced to the lowest level. After pretreatment by CSO-ss-SA/siMDR1, cytotoxicity of CSO-ss-SA/DOX and DOX·HCl against MCF-7/ADR cells were 6.4 or 3.4-fold respectively of that treated by DOX·HCl alone, which exhibited increased cytotoxin sensitivity of drug resistant cells and maximized therapeutic outcomes. These results revealed that the sequential treatment strategy of CSO-ss-SA/siRNA and CSO-ss-SA/DOX hold potential in achieving an optimal overcoming multidrug resistance efficiency.
研究领域:
药学
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纳米技术
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癌症研究
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.2
Hainan Song,Weiwei Cao,Xiushi Chen,Siqi Peng,Wenlong Sun,Xiaojun Yang,Mahmoud Salah,Mohamed A. Farag,Yajing Fang
Effects of four flavonoid inhibitors (FIs, quercetin, kaempferol, luteolin, and flavone) at different concentrations on dynamically increasing dihydroquercetin (DHQ) uptakes and regulating P-glycoprotein (P-gp)’s mRNA and protein levels were evaluated in KB/MDR1 cells. DHQ’s bidirectional transport was measured in Caco-2 monolayers. The low uptakes of DHQ were dynamically increased by four FIs (better than elacridar) in the order of quercetin > luteolin > kaempferol > flavone. Four FIs significantly increased DHQ40’s uptakes in a dose-independent manner. Four FIs alone or with DHQ significantly decreased P-gp’s mRNA and protein expressions. DHQ was poorly absorbed (efflux ratios >20) in Caco-2 monolayers, especially at high concentrations. Four FIs improved DHQ’s absorption by significantly increasing (reversing) its influx (efflux) at most time points (1, 2, 4, and 6 h), especially for DHQ100 rather than DHQ40. Docking results explained that quercetin competitively occupies DHQ’s binding site or binds to the inhibitor site of P-gp. These results were valuable for improving DHQ absorption.
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高影响因子
ACS Applied Nano Materials
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2024
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IF 5.3
Qiuxiang Li,Guowei Zhao,Fengling Wu,Xilan Tang,Zhenggen Liao,Xinli Liang,Wei Dong
Imperatorin (IMP) has demonstrated potential in reversing drug resistance in various tumor cells; however, its limited clinical application and development are attributed to its poor water solubility and low bioavailability. The current work is intended to enhance the oral bioavailability of IMP and its efficacy in overcoming tamoxifen (TAM) resistance in breast cancer cells. We employed mPEG–PLLA and Cremophor RH60 (RH60) to prepare imperatorin nanomicelles (IMP-RH60/mPEG–PLLA). The freeze-dried powder of IMP-RH60/mPEG–PLLA demonstrated a porous structure, and upon reconstitution, the resulting solution exhibited clarity and transparency. The particle size was measured to be 25.48 ± 0.92 nm, with a zeta potential of −5.50 ± 1.06 mV. The encapsulation efficiency was determined to be 85.78 ± 0.84%, while the drug loading was found to be 2.66 ± 0.03%. In comparison to the active pharmaceutical ingredients (APIs) of IMP, IMP-RH60/mPEG–PLLA exhibited a significant increase in in vitro release, improved bioavailability in rats, and enhanced uptake by MCF-7/TAM cells. The coadministration of IMP-RH60/mPEG–PLLA and TAM effectively inhibited the proliferation, colony formation, migration, and invasion of MCF-7/TAM cells. This outcome could potentially be attributed to the downregulation of GST-π and MDR1 drug resistance genes, consequently augmenting the susceptibility of MCF-7/TAM cells to TAM. An experimental model of BALB/c nude xenograft, consisting of human breast cancer cells resistant to tamoxifen (TAM), was established in order to assess the potential in vivo reversal of TAM resistance through the use of IMP-RH60/mPEG–PLLA. The growth of xenografts was inhibited by IMP-RH60/mPEG–PLLA, and it induced apoptosis in tumor tissues through the downregulation of Ki-67, GST-π, and MDR1 gene expression. The findings indicated that the utilization of IMP-RH60/mPEG–PLLA micelles resulted in an enhancement of IMP’s bioavailability and its efficacy in overcoming TAM resistance.
研究领域:
药学
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肿瘤学
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纳米技术
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药理学
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DOI
高影响因子
DRUG METABOLISM AND DISPOSITION
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2020
·Vol. 48
·期 10
·1074-1083
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IF 3.231
Yingchun Chen,Cui Li,Yaodong Yi,Weijuan Du,Huidi Jiang,Su Zeng,Hui Zhou
Dehydrocorydaline (DHC), one of the main active components of Corydalis yanhusuo, is an important remedy for the treatment of coronary heart disease. Our previous study revealed a higher unbound concentration of DHC in the heart than plasma of mice after oral administration of C. yanhusuo extract or DHC, but the underlying uptake mechanism remains unelucidated. In our investigations, we studied the transport mechanism of DHC in transgenic cells, primary neonatal rat cardiomyocytes, and animal experiments. Using quantitative real-time polymerase chain reaction and Western blotting, we found that uptake transporters expressed in the mouse heart include organic cation transporter 1/3 (OCT1/3) and carnitine/organic cation transporter 1/2 (OCTN1/2). The accumulation experiments in transfected cells showed that DHC was a substrate of OCT1 and OCT3, with Km of 11.29 ± 3.3 and 8.96 ± 3.7 μM, respectively, but not a substrate of OCTN1/2. Additionally, a higher efflux level (1.71-fold of MDCK-mock) of DHC was observed in MDCK-MDR1 cells than in MDCK-mock cells. Therefore, DHC is a weak substrate for MDR1. Studies using primary neonatal rat cardiomyocytes showed that OCT1/3 inhibitors (quinidine, decynium-22, and levo-tetrahydropalmatine) prevented the accumulation of DHC, whereas OCTN2 inhibitors (mildronate and l-carnitine) did not affect its accumulation. Moreover, the coadministration of OCT1/3 inhibitors (levo-tetrahydropalmatine, THP) decreased the concentration of DHC in the mouse heart. Based on these findings, DHC may be accumulated partly by OCT1/3 transporters and excreted by MDR1 in the heart. THP could alter the distribution of DHC in the mouse heart.
研究领域:
药理学
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心脏病学
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分子生物学
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PubMed
高影响因子
LIFE SCIENCES
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2019
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IF 3.448
Enxia Zhang,Jiasi Liu,Lei Shi,Xin Guo,Ze Liang,Jiaxin Zuo,Hong Xu,Huaxin Wang,Xiaohong Shu,Shanshan Huang,Shubiao Zhang,Xiaohui Kang,Yuhong Zhen
Aims To investigate the effect of 7- O -geranylquercetin (GQ), a derivative of quercetin (Q), on reversing drug resistance in breast cancer MCF-7/ADR cells and reveal the mechanisms related to P-glycoprotein (P-gp). Main methods Cell viability was determined by MTT assay. Accumulation of adriamycin (ADR) in cells was determined by confocal fluorescence microscope and microplate reader while that of rhodamine (Rh) was measured by flow cytometry. Expression levels of P-gp and MDR1 gene in cells were detected by western blot and Real-Time PCR, respectively. Molecular docking of GQ and Q with P-gp was conducted using AutoDock program. Xenograft model was established by inoculating MCF-7/ADR cells in BALB/c-nude mice. Tumor bearing mice were administered with ADR via tail vein injection and/or GQ (Q) by gavage. Expression levels of P-gp in tissues were detected by western blot and immunohistochemistry. Key findings GQ could reverse drug resistance of MCF-7/ADR cells to ADR. GQ inhibited the efflux of ADR by down-regulating the expression of P-gp protein and its encoding gene MDR1 in MCF-7/ADR cells. Molecular modeling showed that GQ matched with P-gp better than Q. GQ enhanced the antitumor effects of ADR and decreased the expression of P-gp in mice and its activities were higher than that of Q. GQ could reverse drug resistance of MCF-7/ADR cells by down-regulating the expression of P-gp in vitro and in vivo. Significances The reversal effect of GQ on P-gp-mediated drug resistance indicates its potential as a reversal agent for drug resistance in cancer chemotherapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
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2022
·Vol. 27
·期 5
·160
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IF 3.115
Yuzhu Cao,Keqin Lu,Yawen Xia,Yufei Wang,Aiyun Wang,Yang Zhao
Background: The interactions between platelets and tumor cells are well-known to play important roles in the progression of malignant tumors. Danshensu, a main water-soluble component of Salvia miltiorrhiza, can resist platelet aggregation and exert significant anti-tumor effects on various types of tumors. However, whether Danshensu could inhibit the progression of malignant tumors by suppressing the activities of platelets had not been reported. Methods: The effects of Danshensu on the platelet activity and epithelial-mesenchymal transformation (EMT)-like invasive phenotype of SW620 colon cancer cells were assessed by stimulating with the supernatants from co-cultured platelets and SW620 cells with direct contact (SCP). The expression and secretion of proteins were determined by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Hematoxylin and eosin (H&E) staining was performed to analyzed the histopathology of tumor tissues and immunohistochemical staining was conducted to examine the protein expression in tumors. Results: Co-incubation of SW620 cells with platelets directly or SCP both generated long spindle-shaped invasive phenotype. Pretreatment of platelets with Danshensu (25 μM) inhibited the morphological changes of SW620 cells induced by SCP, which was associated with the inhibitory effects of Danshensu on platelet secretion. Danshensu diminished the secretion of a list of biological factors in SCP, including interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-1β and vascular endothelial growth factor (VEGF) that are all involved in tumor cell EMT and chemoresistance. Moreover, Danshensu up-regulated the expression of E-cadherin but down-regulated the levels of N-cadherin and Vimentin, resulting in the repression of SW620 cell migration. It was also shown that Danshensu enhanced the sensitivity of SW620 cells to oxaliplatin by suppressing the expression of MDR1. Furthermore, Danshensu could not only reduced the growth of subcutaneous tumors and liver metastasis that induced by SCP, but also down-regulated the expression of MDR1 in vivo. Mechanistic studies revealed that Danshensu suppressed the activation of the TGF-β/Smad signaling pathway. Conclusions: Danshensu attenuated EMT-like characteristics and chemoresistance by inhibiting secretion capability of platelets and activation of the TGF-β/Smad signaling pathway, suggesting that it may be optimized to be a therapeutic agent for fighting against colon cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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