JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-15
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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
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纳米医学
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药物递送系统
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 21
·13261
·
IF 6.208
Tsz Cheung Chong,Iris L. K. Wong,Jiahua Cui,Man Chun Law,Xuezhen Zhu,Xuesen Hu,Jason W. Y. Kan,Clare S. W. Yan,Tak Hang Chan,Larry M. C. Chow
Overexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimerAc15(Az8)2was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC50for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed thatAc15(Az8)2restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux. It did not down-regulate the cell surface BCRP level to enhance drug retention. It was not a transport substrate of BCRP and showed a non-competitive relationship with DOX in binding to BCRP. A pharmacokinetic study revealed that I.P. administration of 45 mg/kg ofAc15(Az8)2resulted in plasma concentration above its EC50(72 nM) for longer than 24 h. It increased the AUC of topotecan by 2-fold. In an in vivo model of BCRP-overexpressing S1M180 xenograft in Balb/c nude mice, it significantly reversed BCRP-mediated topotecan resistance and inhibited tumor growth by 40% with no serious body weight loss or death incidence. Moreover, it also increased the topotecan level in the S1M180 xenograft by 2-fold. Our results suggest thatAc15(Az8)2is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers.Keywords:multidrug resistance;breast cancer resistance protein;BCRP;ABCG2;flavonoid dimers
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
Drug Delivery and Translational Research
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2021
·Vol. 12
·期 1
·167-179
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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
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药剂学
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化疗
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药物递送系统
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DOI
PubMed
高影响因子
Frontiers in Oncology
·
2023
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IF 4.7
Song Jian,Ren Tingting,Duan Yanheng,Guo Haitao,Wang Gang,Gan Yu,Bai Mengcai,Dong Xiaotian,Zhao Zheng,An Jiaze
Background: Near-infrared fluorescence (NIRF) imaging has recently emerged as a promising tool for noninvasive cancer imaging. However, lack of tumor sensitivity and specificity restricts the application of NIRF dyes in surgical navigation.Methods: Herein, we investigated the imaging features of NIRF dye MHI-148 and indocyanine green (ICG) in live cell imaging and xenograft nude mice models. TCGA dataset analysis and immunohistochemistry were conducted to investigate the expression of OATPs or ABCGs in hepatocellular carcinoma (HCC) tissues. OATPs or ABCGs were knocked down and overexpressed in HCC cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Further, qRT-PCR ,Western blotting and the use of agonists or inhibitors targeting β-catenin signaling pathway were applied to explore its important role in regulation of OATP2B1 and ABCG2 expression.Results: Here we demonstrated that NIRF dye MHI-148 was biocompatible as indocyanine green (ICG) but with higher imaging intensity and preferential uptake and retention in hepatocellular carcinoma (HCC) cells and tissues. Moreover, our data indicated that membrane transporters OATP2B1 and ABCG2, which regulated by β-catenin signaling pathway, mediated tumor-specific accumulation and retention of MHI-148 in HCC cells. In addition, the treatment with β-catenin inhibitor significantly enhanced the accumulation of MHI-148 in HCC tissues and improved the efficacy of tumor imaging with MHI-148 in vivo.Conclusions: Our study uncovers a mechanism that links the distribution and expression of the membrane transporters OATP2B1 and ABCG2 to the tumor-specific accumulation of MHI-148, and provides evidence supporting a regulating role of the β-catenin signaling pathway in OATP2B1 and ABCG2- induced retention of MHI-148 inHCC tissues, and strategy targeting key components of MHI-148 transport machinery may be a potential approach to improve HCC imaging.
研究领域:
癌症生物学
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分子生物学
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医学成像
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2017
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IF 7.786
Wei Li,Xiaomeng Guo,Fenfen Kong,Hanbo Zhang,Lihua Luo,Qingpo Li,Chunqi Zhu,Jie Yang,Yongzhong Du,Jian You
Photodynamic therapy (PDT) and photothermal therapy (PTT) have captured much attention due to the great potential to cure malignant tumor. Nevertheless, photodynamic resistance of cancer cells has limited the further efficacy of PDT. Unfortunately, the resistance mechanism and efforts to overcome the resistance still have been rarely reported so far. Here, we report a nanosystem with specific tumor targeting for combined PDT and PTT mediated by near-infrared (NIR) light, which was established by covalently conjugating indocyanine green (ICG) and TNYL peptide onto the surface of hollow gold nanospheres (HAuNS). Our nanosystem (TNYL-ICG-HAuNS) was proved to possess significantly increased light stability, reactive oxygen species (ROS) production and photothermal effect under NIR light irradiation, thus presenting a remarkably enhanced antitumor efficacy. The up-regulation of nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) in cancer cells during PDT induced a significant increase of ABCG2 , NQO-1 and HIF-1α expression, causing PDT resistance of the cells. Interestingly, ABCG2 expression could almost keep a normal level in the whole PDT process mediated by TNYL-ICG-HAuNS. After repeated irradiations, TNYL-ICG-HAuNS could still produce almost constant ROS in cells while the Nrf2 expression reduced significantly. Furthermore, PDT resistance induced an obvious decrease of the internalization of free ICG, but didn't influence the cell uptake of TNYL-ICG-HAuNS. Our data explained that TNYL-ICG-HAuNS could overcome the photodynamic resistance of cancer cells, acting as a promising modality for simultaneous photothermal and photodynamic cancer therapy.
研究领域:
癌症治疗
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纳米技术
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生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nutrients
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2024
·Vol. 16
·期 20
·3549
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IF 4.8
Yiming Zhang,Shengying Zhu,Yueming Gu,Yanjing Feng,Bo Gao
Background/Objectives: Hyperuricemia (HUA) is a common metabolic disease caused by purine metabolic disorders in the body.Portulaca oleraceaL. (PO) is an edible wild vegetable. Methods: In this study, the regulatory effect of PO on HUA and its potential mechanism were initially elucidated through network pharmacology and experimental validation. Results: The results showed that PO from Sichuan province was superior to the plant collected from other habitats in inhibiting xanthine oxidase (XOD) activity. Berberine and stachydrine were isolated and identified from PO for the first time by UPLC-Q-Exactive Orbitrap MS. The potential molecular targets and related signaling pathways were predicted by network pharmacology and molecular docking techniques. Molecular docking showed that berberine had strong docking activity with XOD, and the results of in vitro experiments verified this prediction. Through experimental analysis of HUA mice, we found that PO can reduce the production of uric acid (UA) in the organism by inhibiting XOD activity. On the other hand, PO can reduce the body ‘s reabsorption of urate and aid in its excretion out of the body by inhibiting the urate transporter proteins (GLUT9, URAT1) and promoting the high expression of urate excretory protein (ABCG2). The results of H/E staining showed that, compared with the positive drug (allopurinol and benzbromarone) group, there was no obvious renal injury in the middle- and high-dose groups of PO extract. Conclusions: In summary, our findings reveal the potential of wild plant PO as a functional food for the treatment of hyperuricemia.
研究领域:
药理学
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代谢疾病
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植物化学
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分子生物学
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实验验证
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产品关联
DOI
PubMed
高影响因子
Bioengineered
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2021
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IF 3.269
Xia Zhao,Jing Wang,Liying Tang,Pei Li,Jing Ru,Yuzhi Bai
The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia. In vitro study revealed that WFA notably ameliorated UA-induced cell fibrosis and apoptosis. Taken together, WFA improves kidney function by decreasing UA via regulation of XOD and transporter genes in renal tubular cells.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
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2024
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IF 4.8
Jiajing Liao,Jin Qian,Lijuan Rao,Suqin Lin,Chen Wang,Linqian Xu,Bing Yuan,Jiayi Yuan,Yin Wan,Guiming Fu
Hyperuricemia is a metabolic disease caused by excessive production of uric acid or abnormal excretion of uric acid. Although most of the uric acid is excreted in the kidneys, the elimination of uric acid in the intestines still plays an important role. 3,5-dicaffeoylquinic acid (3,5-diCQA) is widely found in Chrysanthemum and Artemisia species, where it inhibits the activity of xanthine oxidase (XOD), a key enzyme in uric acid production. Therefore, a Caco-2 cell model was utilized to explore the mechanisms of 3,5-diCQA affecting uric acid excretion under high uric acid conditions, focusing on aspects such as intestinal uric acid transport, the intestinal barrier, and the MAPK signaling pathway. The results showed that 3,5-diCQA could reduce the oxidative stress and apoptosis induced by high uric acid, repair the intestinal barrier, upregulate the expression of ABCG2 and MRP4, promote the excretion of uric acid and inhibit the activation of MAPK signaling pathway. In addition, 3,5-diCQA could also regulate the expression of ABCG2 and MRP4 via the MAPK signaling pathway. These findings provide scientific evidence for dietary recommendations for individuals with hyperuricemia, suggesting that foods or supplements containing 3,5-diCQA may help manage uric acid levels.
研究领域:
药理学
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营养学
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细胞生物学
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代谢性疾病
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产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
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IF 6.9
Lei Wang,Yufeng Tao,Xuesong Wang,Yuhan Gan,Yuting Zeng,Shasha Li,Qing Zhu
Phellinus igniarius is an important medicinal and edible fungus with diverse biological activities. This study aimed to investigate the effects of aqueous extract from P. igniarius (API) on the treatment of hyperuricemia (HUA) and related kidney damage. The chemical constituents of API were determined. The therapeutic effects of API on HUA and renal injury were assessed in adenine/potassium oxonate (PO)-treated mice. The constituent analysis of API revealed a predominance of polysaccharides (33.4 %), followed by total flavonoids (9.1 %), and total triterpenoids (3.5 %). Compared to control, the adenine/PO treatment greatly elevated serum uric acid (UA) levels but this elevation was attenuated by API. In the liver, the expression and activity of xanthine oxidase (XOD) were increased by HUA which were diminished by API. Furthermore, API was found to enhance the expression of UA transporter ABCG2 in the kidney and intestine of HUA mice, suggesting elevating UA excretion. Additionally, API ameliorated HUA-induced renal injury, as indicated by reduced serum BUN/creatinine levels, decreased glomerular and tubular damage, and lowered fibrotic levels. Network pharmacology analysis predicted that P. igniarius may regulate mitochondrial function to improve HUA-related renal injury. This prediction was then substantialized by the API-induced upregulation of NAD+/NADH ratio, ATP level, SOD2 activity, and expression of SOD2/PCG-1α/PPARγ in the kidney of HUA mice. Our results demonstrate that API may effectively ameliorate HUA by reducing UA production in the liver and enhancing UA excretion in the kidney and intestine, and it might be a potential therapy to HUA-related renal injury.
研究领域:
药理学
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医学
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生物化学
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分子生物学
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DOI
PubMed
高影响因子
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