MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Zhihao Wu,Tao Shi,Qi Shao,Dongmei Chen,Peisheng Gao,Jie Wang,Ting Xu,Qingqing Meng,Shaoshun Li
Early detection and precise treatment for breast cancer are crucial, given its high global incidence rate. Hence, the development of novel imaging targets is essential for diagnosing and monitoring resistance to chemotherapy, which is pivotal for achieving precise and personalized treatment for breast cancer patients. In our previous work, we successfully developed a near-infrared (NIR) probe 1 for CYP1B1-targeted imaging. In this study, we aimed to investigate the utility of the probe as a NIR fluorescence and photoacoustic dual-mode imaging probe for the detection and surveillance of breast cancer. Western blotting of cancer cell lines has confirmed that CYP1B1 is widely expressed in breast cancer and gynecological cancer. In vitro NIR fluorescence imaging capability of the probe for tracking CYP1B1-positive tumor cells was validated by using confocal microscopy. Further studies, including in vivo fluorescence and photoacoustic dual-model imaging and ex vivo biological distribution analysis on a triple-negative breast cancer xenograft mouse model, demonstrated that the probe selectively accumulated in tumor tissue within as early as 0.5 h postinjection. The results of the surgical resection experiment revealed that the tumor could be entirely removed under the guidance of NIR imaging, thereby indicating the probe’s efficacy in surgical navigation. CYP1B1 expression was found to be upregulated in adriamycin (ADR)-resistant breast cancer cells, MCF-7/ADR. Consequently, the sensitivity of CYP1B1 overexpressed cells, MCF-7/1B1, to ADR was significantly reduced, with an IC50 value of 0.586 ± 0.0934 μM, compared to the parental MCF-7 cells with an IC50 value of 0.183 ± 0.0444 μM. In vivo and ex vivo imaging assays conducted on MCF-7/ADR tumor-bearing mice demonstrated that the probe was specifically enriched in tumor sites, suggesting its potential for monitoring chemotherapy resistance in breast cancer. This study expands the scope of application for NIR probe 1, establishing its utility in breast cancer diagnosis through fluorescence-photoacoustic dual-model imaging, monitoring of chemotherapy resistance, and guidance for surgical resection. This strategy paves the way for novel approaches to precise and personalized treatment for breast cancer patients.
研究领域:
肿瘤学
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医学影像学
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药物动力学
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DOI
PubMed
高影响因子
Nanomedicine
·
2019
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IF 4.717
Jun Zhang,Jia Song,Xiao Liang,Yunzhi Yin,Tiantian Zuo,Daijie Chen,Qi Shen
Aim: Enzyme CYP1B1 (CYP1B1) is usually overexpressed in multidrug resistance (MDR) breast cancer cells, which could metabolically inactivate docetaxel (DTX). Materials & methods: The cationic core–shell nanoparticles (hyaluronic acid/polyethyleneimine nanoparticles [HA/PEI NPs]) modified with hyaluronic acid (HA) were developed and coloaded with DTX and α-napthtoflavone (ANF, a CYP1B1 inhibitor) to overcome MDR in breast cancer induced by CYP1B1. Physicochemical characterization, MDR reversing effect in vitro and pharmacokinetics in vivo of HA/PEI NPs were evaluated. Results: The HA/PEI NPs exhibited spherical morphology with size of (193.6 ± 3.1) nm. The HA/PEI NPs could reverse MDR effectively by downregulating the expression of CYP1B1. The HA/PEI NPs improved the bioavailability of DTX. Conclusion: The HA/PEI NPs might be a promising strategy to overcome CYP1B1-mediated breast cancer MDR.
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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产品关联
DOI
PubMed
高影响因子
Journal of Gastrointestinal Oncology
·
2023
·
IF 2.1
Lei Jin,Ju Huang,Lei Guo,Bo Zhang,Qin Li,Hui Li,Mincheng Yu,Peiyi Xie,Qiang Yu,Zheng Chen,Shuang Liu,Yongfeng Xu,Yongsheng Xiao,Ming Lu,Qinghai Ye
Background Liver metastasis (LM) accounts for most colorectal cancer (CRC)-related deaths. However, how metastatic CRC cells gain the ability to survive and grow in liver remains largely unknown. Methods First, we screened differentially expressed genes (DEGs) between LM and paired primary tumors (PTs) in Gene Expression Omnibus (GEO) database, and identified cytochrome P450 1B1 ( CYP1B1) as the only common differential gene. Then, we verified messenger RNA (mRNA) and protein expression level in clinical specimens. After constructing stable up-regulated CYP1B1 versions of HCT116 and RKO CRC cells and stable down-regulated CYP1B1 versions of SW480 and HT29 CRC cells, cell proliferation assays, subcutaneous tumor formation, and mouse LM models were used to comprehend its function. Next, we used RNA-seq to uncover specific mechanisms of growth; cell cycle, polymerase chain reaction (PCR), western blot (WB) and GEO series (GSE) datasets were used to verify its mechanism. Last, gas chromatography tandem mass spectrometry (GC-MS/MS) was adopted to examine which fatty acids were changed. Results A significantly higher level of CYP1B1 was found in LM than in PT in paired clinical CRC LM samples (P<0.05). After CYP1B1 overexpression in HCT116 and RKO cells, cell proliferation abilities in vitro and in vivo were enhanced; LM of NOD.Cg-Prkdc scid Il2rg em1Smoc (NSG) mice were enhanced. And knockdown of CYP1B1 in SW480 and HT29 cells, cell proliferation abilities in vitro and in vivo were reduced; LM of NSG mice were declined (P<0.05). RNA-seq showed 59 common genes from upregulated genes of RKO overexpression group and downregulated genes of SW480 knockdown group were enriched in cell cycle and DNA replication. Further investigation revealed CYP1B1 regulated alternation of MCM5 , PCNA , and FEN1 genes, and G1/S transition in CRC cells. GC-MS/MS revealed long chain fatty acids (LCFAs) made a difference in SW480 knockdown group (P<0.05). Through adding LCFAs into SW480 and HT29 knockdown groups, cell proliferation abilities in vitro and in vivo were enhanced, and expressions of MCM5 , PCNA , FEN1 were upregulated (P<0.05). Conclusions CYP1B1 exerts a significant influence on LM of CRC by modulating tumor cell proliferation via “CYP1B1-LCFAs-G1/S transition”. This finding suggests CYP1B1 could be a promising target for CRC LM.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2019
·Vol. 47
·期 8
·919-927
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IF 3.354
Xu Mao,Jian Wang,Qian Wang,Lan Yang,Yilin Li,Hao Lin,Ying Peng,Jiang Zheng
The cytochrome P450 (P450) 1 family is an important phase I enzyme involved in carcinogen activation. Nitidine chloride (NC) is a pharmacologically active alkaloid with polyaromatic hydrocarbon found in the roots of Zanthoxylum nitidum (Roxb.) DC, a traditional medicinal herb widely used in China. We examined the inhibitory effects of NC on CYP1A1, 1B1, and 1A2. NC significantly inhibited CYP1A1- and 1B1-catalyzed ethoxyresorufin O-deethylation activity (IC50 = 0.28 ± 0.06 and 0.32 ± 0.02 μM, respectively) in a concentration-dependent manner, but only showed slight inhibition of CYP1A2 activity (IC50 > 50 μM). Kinetic analysis revealed that NC competitively inhibited CYP1B1 with a Ki value of 0.47 ± 0.05 μM, whereas NC caused a mixed type of inhibition on CYP1A1 with Ki and KI values of 0.14 ± 0.04 and 0.19 ± 0.09 μM, respectively. The observed enzyme inhibition neither required NADPH nor revealed time dependency. Molecular docking manifested the generation of strong hydrogen-bonding interactions of Ser116 in CYP1A1 and Ser127 in CYP1B1 with methoxy moiety of NC. Additionally, NC-induced alteration of estradiol (E2) metabolism was also investigated in the present study. Hydroxyestradiols, including 2-hydroxyestradiol [(2-OHE2) nontoxic] and 4-hydroxyestradiol [(4-OHE2) genotoxic] generated in recombinant enzyme incubation systems and cultured MCF-7 cells were analyzed, and NC was found to preferentially inhibit the nontoxic 2-hydroxylation activity of E2 mediated by CYP1A1. In conclusion, NC was a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. The remarkable inhibition on E2 2-hydroxylation might increase the risk of 4-OHE2–induced genotoxicity.
研究领域:
药理学
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毒理学
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生物化学
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酶学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Mei Wang,Na Luo,Yanpeng Gao,Guiying Li,Taicheng An
Derivatives of polycyclic aromatic hydrocarbons (PAHs) pose significant threat to environment and human health due to their widespread and potential hazards. However, adverse effects and action mechanisms of PAH derivatives on human health have not been attempted yet. Herein, we chose pyrene and its derivatives (1-hydroxypyrene, 1-nitropyrene, and 1-methylpyrene) to investigate adverse effect mechanism to human lungs using in vitro and in vivo methods. Results showed that pyrene derivatives have higher lung health risks than original pyrene. They can activate AhR, subsequently affecting expression of downstream target genes CYP1A1 and CYP1B1. The binding energies of pyrene and its derivatives ranged from −16.07 to −27.25 kcal/mol by molecular dynamics simulations, implying that pyrene and its derivatives acted as agonists of AhR and increased adverse effects on lungs. Specifically, 1-nitropyrene exhibited stabler binding conformation and stronger AhR expression. In addition, sensitivity of pyrene and its derivatives to AhR activation was attributed to type and number of key amino acids in AhR, that is, pyrene (Leu293), 1-nitropyrene (Cys333, Met348, and Val381), 1-hydroxypyrene (Leu293 and Phe287), and 1-methylpyrene (Met348). In summary, we provide a universal approach for understanding action mechanisms of PAH derivatives on human health, and their adverse effects should be taken seriously.
研究领域:
环境健康
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毒理学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2020
·
IF 4.192
Yi Zhao,Jia Lin,Milton Talukder,Shi-Yong Zhu,Mu-Zi Li,Hao-Ran Wang,Jin-Long Li
Di(2-ethylhexyl)phthalate (DEHP) is widely used as a plasticizer to improve product flexibility and workability. Lycopene (LYC) is a natural compound and has promising preventive potentials, especially antireproductive toxicity, but the specific underlying mechanism is yet to be fully defined. Our study investigated the effect of LYC on DEHP-induced spermatogenesis disorders. Male ICR mice were treated with DEHP (500 or 1000 mg/kg BW/day) and/or LYC (5 mg/kg BW/day) for 28 days. Our results indicated that LYC could relieve the DEHP-induced injury of seminiferous tubules and spermatogenic cells, swelling of endoplasmic reticulum (ER), and an increase of mitochondria. LYC prevented increased levels of nuclear damage to DNA and the deformity rate and decreased values of sperm motility, number, and density. Moreover, LYC treatment decreased DEHP-induced nuclear accumulation of aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT), and the expressions of their downstream target genes such as cytochrome P450-dependent monooxygenases (CYP) 1A1, 1A2, and 1B1 were markedly reduced to normal in the LYC treatment group. Our study showed that LYC can prevent DEHP-induced spermatogenic disorders via an AHR/ARNT signaling system. This study provided new evidence of AHR as a target for LYC, which can prevent DEHP-induced toxicity.
研究领域:
毒理学
·
生殖生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Mu-Zi Li,Yi Zhao,Hao-Ran Wang,Milton Talukder,Jin-Long Li
Di (2-ethylhexyl) phthalate (DEHP) is an environmentally persistent and bioaccumulative plasticizer. Accumulation of DEHP in the body can eventually cause kidney damage. As a type of natural carotenoid, lycopene (LYC) has a potential protective effect on renal cells, but the protective mechanism has not yet been elucidated. The major goal of this study was to see how effective LYC was at treating DEHP-induced nephrotoxicity in mice. ICR mice were treated with DEHP (500 mg/kg BW/day or 1000 mg/kg BW/day) or LYC (5 mg/kg BW/day) for 28 days. Through histopathology and ultrastructure, we found that LYC attenuated DEHP-induced renal tubular cell and glomerular damage. LYC relieved DEHP-induced kidney injury evidenced by lower levels of blood urea nitrogen (Bun), creatinine (Cre), and uric acid (Uric). Meanwhile, the reduced expression of kidney injury molecule-1 (Kim-1) also supported it. Notably, LYC can alleviate the activity or content of cytochrome P450 system (CYP450s) interfered with by DEHP. In addition, LYC treatment reduced nuclear accumulation of DEHP-induced aromatic hydrocarbon receptor (AhR) and AhR nuclear transporter (Arnt), and its downstream target genes such as cytochrome P450-dependent monooxygenase (CYP) 1A1, 1A2, and 1B1 expression significantly decreased to normal in the LYC treatment group. In summary, LYC can mediate the AhR/Arnt signaling system to prevent kidney toxicity in mice caused by DEHP exposure.
研究领域:
毒理学
·
药理学
·
分子生物学
·
环境健康
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产品关联
DOI
PubMed
高影响因子
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