BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Ruoxin Tu,Yining Wang,Ru Xu,Shusheng Wang,Jiabin Cai,Lin Sun,Pengfei Gao
Despite therapeutic advances, hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide. While dihydrotanshinone I (DHT) shows promising anticancer potential, its molecular mechanisms in HCC remain unexplored. Here, we unveil a novel chemokine (C-C Motif) receptor 5(CCR5)-mediated regulatory network targeted by DHT in HCC treatment. This study identifies CCR5 as a crucial survival factor in HCC, uncovers a novel CCR5-Nuclear factor erythroid 2-related factor 2(NRF2) regulatory axis, and reveals a dual-targeting mechanism of DHT through direct CCR5 inhibition and Reactive oxygen species(ROS)-dependent cell death induction, validating its therapeutic efficacy by disrupting redox homeostasis. This study uncovers a novel CCR5-ROS-NRF2 signaling axis in HCC and establishes DHT as a promising therapeutic agent through its unique targeting mechanism. These findings provide new insights into HCC pathogenesis and present an innovative therapeutic strategy for HCC treatment.
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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生物化学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2024
·Vol. 52
·期 3
·188-197
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IF 4.4
Ying Liu,Yu Chen,Jingyu Zhang,Guangyun Ran,Zihao Cheng,Xin Wang,Yufen Liao,Xu Mao,Ying Peng,Weiwei Li,Jiang Zheng
Dihydrotanshinone I (DHTI) is a pharmacologically active component occurring in the roots of the herbal medicine Salvia miltiorrhiza Bunge. This study investigated DHTI-induced inhibition of CYP1A1, CYP1A2, and CYP1B1 with the aim to determine the potential effects of DHTI on the bioactivation of estradiol (E2), possibly related to preventive/therapeutic strategy for E2-associated breast cancer. Ethoxyresorufin as a specific substrate for CYP1s was incubated with human recombinant CYP1A1, CYP1A2, or CYP1B1 in the presence of DHTI at various concentrations. Enzymatic inhibition and kinetic behaviors were examined by monitoring the formation of the corresponding product. Molecular docking was further conducted to define the interactions between DHTI and the three CYP1s. The same method and procedure were employed to examine the DHTI-induced alteration of E2 metabolism. DHTI showed significant inhibition of ethoxyresorufin O-deethylation activity catalyzed by CYP1A1, CYP1A2 and CYP1B1 in a concentration-dependent manner (IC50 = 0.56, 0.44, and 0.11 μM, respectively). Kinetic analysis showed that DHTI acted as a competitive type of inhibitor of CYP1A1 and CYP1B1, whereas it noncompetitively inhibited CYP1A2. The observed enzyme inhibition was independent of NADPH and time. Molecular docking analysis revealed hydrogen bonding interactions between DHTI and Asp-326 of CYP1B1. Moreover, DHTI displayed preferential activity to inhibit 4-hydroxylation of E2 (a genotoxic pathway) mediated by CYP1B1. Exposure to DHTI could reduce the risk of genotoxicity induced by E2.
研究领域:
药理学
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生物化学
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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
FITOTERAPIA
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2013
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IF 2.231
Ming Cong,Cui-Min Hu,Yun-Feng Cao,Zhong-Ze Fang,Shu-Hong Tang,Jia-Rui Wang,Jun-Sheng Luo
Danshen is one of the most famous herbs in the world, and more and more danshen–prescribed drugs interactions have been reported in recent years. Evaluation of inhibition potential of danshen's major ingredients towards UDP-glucuronosyltransferases (UGTs) will be helpful for understanding detailed mechanisms for danshen–drugs interaction. Therefore, the aim of the present study is to investigate the inhibitory situation of cryptotanshinone and dihydrotanshinone I towards UGT enzyme-catalyzed propofol glucuronidation. In vitro the human liver microsome (HLM) incubation system was used, and the results showed that cryptotanshinone and dihydrotanshinone I exhibited dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation. Dixon plot and Lineweaver–Burk plot showed that the inhibition type was best fit to competitive inhibition type for both cryptotanshinone and dihydrotanshinone I. The second plot using the slopes from the Lineweaver–Burk plot versus the concentrations of cryptotanshinone or dihydrotanshinone I was employed to calculate the inhibition parameters (K i ) to be 0.4 and 1.7 μM, respectively. Using the reported maximum plasma concentration (C max ), the altered in vivo exposure of propofol increased by 10% and 8.2% for the co-administration of dihydrotanshinone I and cryptotanshinone, respectively. All these results indicated the possible danshen–propofol interaction due to the inhibition of dihydrotanshinone I and cryptotanshinone towards the glucuronidation reaction of propofol.
研究领域:
药理学
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中药学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2018
·
IF 3.412
Jingjing Luo,Xiaofeng Meng,Jianyu Su,Hang Ma,Wen Wang,Liming Fang,Huade Zheng,Yexia Qin,Tianfeng Chen
15,16-Dihydrotanshinone I (DI), a natural compound isolated from a traditional Asian functional food Salvia Miltiorrhiza Bunge, is known for its anticancer activity. However, poor solubility of DI limits its desirable anticancer application. Herein, polylactic-co-glycolic acid (PLGA) was functionalized with polyethylene glycol (PEG) and biotin to form copolymers PEG-PLGA (PPA) and biotin-PEG-PLGA (BPA). DI was encapsulated in copolymers PPA and BPA to obtain DI-PPA-NPs (NPs = nanoparticles) and DI-BPA-NPs, respectively. The particle size and its distribution, encapsulation efficiency, and in vitro releasing capacity of DI-BPA-NPs were characterized by biophysical methods. MTT assay was used to evaluate the antiproliferative activity of free DI, DI-PPA-NPs, and DI-BPA-NPs in human cervical cancer Hela cells. DI-BPA-NPs showed the highest cytotoxicity on Hela cells with an IC50 value of 4.55 ± 0.631 μM, while it was 8.20 ± 0.849 and 6.14 ± 0.312 μM for DI and DI-PPA-NPs in 72 h, respectively. The superior antiproliferative activity was supported by the fact that DI-BPA-NPs could be preferentially internalized by Hela cells, owing to their specific interaction between biotin and overexpressed biotin receptors. In addition, DI-BPA-NPs effectively inhibited Hela cell proliferation by inducing G2/M phase cycle arrest and decreasing the intracellular reactive oxygen species (ROS) level by 31.50 ± 2.29% in 5 min. In summary, DI-BPA-NPs shows improved antiproliferative activity against human cervical cancer as comparing with free DI, demonstrating its application potential in cancer therapy.
研究领域:
药理学
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纳米技术
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肿瘤学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Yanru Ren,Yicheng Feng,Kunyao Xu,Saisai Yue,Tiantian Yang,Kaili Nie,Man Xu,Haijun Xu,Xin Xiong,Fabian Körte,Mike Barbeck,Peisen Zhang,Luo Liu
Dihydrotanshinone I (DHT) is a natural component in Salvia miltiorrhiza and has been widely researched for its multiple bioactivities. However, poor solubility and biocompatibility of DHT limit its desirable application for clinical purposes. Herein, DHT was encapsulated with bovine serum albumin (BSA) to enhance bioavailability. Compared to free DHT, DHT–BSA NPs (nanoparticles) showed an improved solubility in normal saline and increased protection against hydrogen peroxide–induced oxidative damage in PC12 cells. In addition, DHT–BSA NPs administered by intravenous injection displayed a significant efficacy in the middle cerebral artery occlusion/reperfusion models, without any impact on the cerebral blood flow. In summary, DHT–BSA NPs show an enhanced bioavailability compared with free DHT and a successful penetration into the central nervous system for stroke therapy, demonstrating their application potential in cardio–cerebrovascular diseases.
研究领域:
药学
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神经科学
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纳米技术
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药物递送系统
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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）