SENSORS AND ACTUATORS B-CHEMICAL
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2020
·
IF 7.1
Yong Liu,Ensheng Xu,Chao Xu,Wei Wei
As a tumor-related enzyme, PARP-1 activity is closely related to the occurrence of cancer. Sensitive detection of PARP-1 activity is of significance in the early diagnosis and treatment of cancer. Therefore, the gold nanorods (AuNRs) based biological nanoprobe was constructed for the visual and label-free detection of PARP-1 activity. dsDNA which activate PARP-1 was modified on AuNPs ( [email protected] ). MoO 4 2− is added to catalyze H 2 O 2 and KI to accelerate the etching of AuNRs. In the presence of PARP-1, hyperbranched poly (ADP-ribose) polymers (PAR) formed on the surface of [email protected] ( [email protected] @PAR). A large number of PO 4 3- of the PAR reacted with MoO 4 2− to generate PMo 12 O 40 3- . Thus, PO 4 3- diminished MoO 4 2− concentration in solution, preventing the etching of AuNRs. Therefore, PARP-1 prevented the etching of AuNRs. With the increasing concentration of PARP-1, the color of the solution changed from light blue to brown obviously. The method was applied to assay actual samples with satisfactory results. The strategy has the advantages of rapid quantitative analysis of PARP-1 activity with naked eyes, simple operation and good application prospect.
研究领域:
生物化学
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纳米医学
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肿瘤学
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产品关联
DOI
高影响因子
MOLECULES
·
2020
·Vol. 25
·期 2
·407
·
IF 3.267
Jiaguo Li,Dian Xiao,Lianqi Liu,Fei Xie,Wei Li,Wei Sun,Xiaohong Yang,Xinbo Zhou
In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug’s expected activity was lost after PPG protection. InBRCA1- andBRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.Keywords:Talazoparib;PARP inhibitor;prodrug;o-nitro-benzyl;photoactivatable protecting groups
研究领域:
药物化学
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肿瘤学
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生物化学
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DOI
PubMed
高影响因子
Oncology Letters
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2017
·Vol. 15
·期 3
·2881-2888
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IF 1.39
Xiaoning Liu,Jingjing Kang,Hui Wang,Tao Huang
Oridonin, the main active constituent of Rabdosia rubescens, is known to exert antitumor activity via the induction of apoptosis in numerous types of human cancer cells. However, the underlying regulatory mechanisms of mitochondrial ROS in oridonin‑induced HepG2 apoptosis remain largely unknown, due to limitations of subcellular imaging resolution. Previously, it has been suggested that mitochondria serve a potential role in sensing and signaling cellular redox changes in vital biological processes such as cell death and the abiotic stress response, based on studies involving the mitochondrial‑targeted redox‑sensitive green fluorescent protein (GFP). To address this, a mitochondrial‑targeted Grx1‑roGFP2 (mtGrx1‑roGFP2) biosensor was implemented to monitor real‑time mitochondrial redox changes of HepG2 cells in response to either H2O2/DTT or oridonin/SS31 treatment. It was determined that oridonin caused a perturbation in mitochondrial redox status, which in turn contributed to oridonin‑induced apoptosis. Furthermore, a novel mechanism underlying the regulation of mitochondrial redox changes in oridonin‑induced HepG2 apoptosis, presumably dependent on PARP cleavage, was proposed. In conclusion, the present study provides evidence in support of mitochondrial redox changes as a potential mediator in the apoptotic activities of oridonin in HepG2 cells, which provides insight into the molecular mechanisms by which mitochondrial redox signaling regulates oridonin‑induced apoptosis in cancer therapy, and the development of mitochondria‑specific oridonin as a promising novel anticancer therapeutic strategy.
研究领域:
癌症生物学
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细胞信号传导
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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
Redox Biology
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2018
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IF 7.126
Dong Hou,Zhaojian Liu,Xiuhua Xu,Qiao Liu,Xiyu Zhang,Beihua Kong,Jian-Jun Wei,Yaoqin Gong,Changshun Shao
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS). Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2023
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IF 3.5
Yufen Liao,Xin Wang,Guangyun Ran,Shiyu Zhang,Chutian Wu,Rong Tan,Ying Liu,Yan He,Ting Liu,Zhongxiu Wu,Ying Peng,Weiwei Li,Jiang Zheng
Columbin (CLB) is the most abundant (>1.0%) furan-containing diterpenoid lactone in herbal medicine Tinospora sagittate (Oliv.) Gagnep. The furano-terpenoid was found to be hepatotoxic, but the exact mechanisms remain unknown. The present study demonstrated that administration of CLB at 50 mg/kg induced hepatotoxicity, DNA damage and up-regulation of PARP-1 in vivo . Exposure to CLB (10 μM) induced GSH depletion, over-production of ROS , DNA damage, up-regulation of PARP-1 and cell death in cultured mouse primary hepatocytes in vitro . Co-treatment of mouse primary hepatocytes with ketoconazole (10 μM) or glutathione ethyl ester (200 μM) attenuated the GSH depletion, over-production of ROS, DNA damage, up-regulation of PARP-1, and cell death induced by CLB, while co-exposure to L -buthionine sulfoximine (BSO, 1000 μM) intensified such adverse effects resulting from CLB exposure. These results suggest that the metabolic activation of CLB by CYP3A resulted in the depletion of GSH and increase of ROS formation. The resultant over-production of ROS subsequently disrupted the DNA integrity and up-regulated the expression of PARP-1 in response to DNA damage, and ROS-induced DNA damage was involved in the hepatotoxicity of CLB.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
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2022
·Vol. 11
·期 1
·162-169
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IF 7.59
Ren-Jiang Kong,Xin-Yu Li,Jia-Qi Huang,Xiang Zhou,Fu-An Deng,Yan-Mei Li,Ling-Shan Liu,Shi-Ying Li,Hong Cheng
Tumor cells activate DNA repair pathways to combat the oxidative damage induced by reactive oxygen species (ROS), contributing to their resistance to photodynamic therapy (PDT). Herein, a self-delivery photodynamic sensitizer is developed to enhance oxidative damage by blocking the DNA repair pathway through poly(ADP-ribose) polymerase (PARP) inhibition. Specifically, the photodynamic sensitizer (CeOla) is constructed based on the self-assembly of the photosensitizer chlorine e6 (Ce6) and the PARP inhibitor olaparib (Ola). Of note is that carrier free CeOla has a high drug content and favorable water stability, which could be effectively internalized by tumor cells for robust PDT upon light irradiation. Moreover, CeOla could inhibit the activation of PARP, promote the upregulation of γ-H2AX and reduce the expression of Rad51, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. As a consequence, the self-delivery CeOla greatly promotes the tumor cell apoptosis and shows a high antitumor performance with low side effects. It serves as a novel platform for the development of self-delivery nanomedicine to overcome oxidative resistance in tumor treatment.
研究领域:
肿瘤学
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药理学
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纳米医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
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2021
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IF 3.196
Meng Ding,Lei Xu,Yumeng Zhang,Wei Li,Yuqing Zhao
20( R )-25-methoxyl-dammarane-3 β ,12 β ,20-triol (CN Patent: 201,010,107,476.7, AD-1) is a promising antitumor compound, was isolated from total hydrolyzed saponins extracted from Panax notoginseng leaves. A sensitive and rapid method for the simultaneous detection of AD-1 and its 8 major metabolites in rat feces was developed in this study. AD-1 (20 mg/kg) was orally administered to male rats by gastric intubation. Then, the feces samples were collected. After addition of internal standard (Mifepristone), feces samples were pretreated by protein precipitation followed by liquid-liquid extraction. Chromatographic separation was performed on an Angela C 18 column with gradient elution using a mobile phase composed of acetonitrile and water (containing 5 mM ammonium acetate) at a flow rate of 0.3 mL/min. The analytes were detected without any interference from the multiple reaction monitoring (MRM) mode using positive electrospray ionization. Calibration curves offered satisfactory linearity ( r > 0.995) within the determined ranges. Both intra-day and inter-day variances were lower than 15%, and the accuracy was within 85–115%. The fecal excretion recoveries of AD-1 (M0), metabolite 1 (M1), M2, M3, M4, M5, M6, M7 and M8 were 41.36%, 0.62%, 6.20%, 0.50%, 6.99%, 2.07%, 1.86%, 0.41% and 0.29%, respectively. The observed excretion profiles for AD-1 and its metabolites after oral administration are helpful to understand the poor oral bioavailability of AD-1, and will aid further investigations of AD-1 as a pharmacologically active component. Moreover, the in silico ADME (Absorption, Distribution, Metabolism, Excretion) predictions indicated that the metabolites were nontoxic and present passive gastrointestinal absorption. In previous studies, we found that M5, a metabolite of AD-1, has strong cytotoxicity against ovarian cancer cells. Further molecular docking studies showed that the most potent metabolite, M5, effectively binds to poly ADP-ribose polymerase-1 (PARP-1), which may provide novel solutions for treating ovarian cancer.
研究领域:
药理学
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药物代谢动力学
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计算生物学
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产品关联
DOI
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2025
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IF 5.4
Chunying Jiang,Shudan Yang,Yuting Wang,Liyuan Du,Miao-Miao Niu,Dongli Zhang
Poly (ADP-ribose) polymerase 1 (PARP-1) exhibits high expression levels in colorectal cancer (CRC) patients and participates in multiple DNA damage repair pathways, thereby emerging as an attractive target. Herein, we identified a series of PARP-1 inhibitors (termed as compounds 1-6) by pharmacophore modelling, virtual screening and biological evaluation. Enzyme inhibition assays demonstrated that compound-5 significantly inhibited PARP-1 activity (IC50 = 0.07 ± 0.01 nM) and exhibited high selectivity for PARP-1 among 63 different kinases. Molecular dynamic simulations indicated that compound-5 stably bound to the catalytic domain of PARP-1. Cellular assays demonstrated that compound-5 significantly inhibited the proliferation of a panel of human CRC cell lines (HCT116, SNU-1, Caco-2, HT-29). The data suggest that compound-5 may be a highly potent and selective PARP-1 inhibitor for CRC therapy.
研究领域:
药物化学
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肿瘤学
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结构生物学
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药理学
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计算生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
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2024
·
IF 14.3
Xin Peng,Xin Huang,Shaolu Zhang,Naixin Zhang,Shengfan Huang,Yingying Wang,Zhenxing Zhong,Shan Zhu,Haiwang Gao,Zixiang Yu,Xiaotong Yan,Zhennan Tao,Yuxiang Dai,Zhe Zhang,Xi Chen,Feng Wang,Francois X. Claret,Moshe Elkabets,Ning Ji,Yuxu Zhong,Dexin Kong
PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient-derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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转化医学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2023
·
IF 3.8
Hancheng Huang,Shuchun Wei,Xiaohan Wu,Mengke Zhang,Benhong Zhou,Debin Huang,Weiguo Dong
The pathophysiological mechanism of hepatic fibrosis (HF) is related to the excessive activation of the DNA repair enzyme poly ADP-ribose polymerase-1 (PARP-1). The drugs, targeting PARP-1, are scarce. Therefore, the lead compound, moderately inhibiting PARP-1, with anti-HF properties should be identified. This study screened dihydrokaempferol (DHK) from herbs based on preliminary studies to intervene in a CCl 4 -induced liver injury and HF model in mice. In vitro , the expression levels of PARP-1-regulated related proteins and phosphorylation were examined. The binding pattern of DHK and PARP-1 was analyzed using molecular docking and molecular dynamics platforms. The results showed that DHK could significantly attenuate CCl 4 -induced liver injury and HF in mice. Moreover, it could also attenuate the toxic effects of CCl 4 on HepG2 and inhibit α-SMA and Collagen 1/3 synthesis of LX-2 cells in-vitro . Molecular docking revealed that DHK could competitively bind to the Glu-988 and His-862 residues of the upstream DNA repair enzyme PARP-1, moderately inhibiting its overactivation. This led to maintaining NAD + levels and energy metabolism in hepatocytes and inhibiting the activation of PARP-1-regulated downstream signaling pathways (TGF-β1, etc. ), related proteins (p-Smd2/3, etc. ), and inflammatory mediators while acting indirectly. Thus, DHK could attenuate CCl 4 -induced liver injury and HF in mice in a different mechanism from those of the existing reported flavonoids. It was associated with inhibiting the expression of downstream pathways and related cytokines by competitively binding to PARP-1. This study might provide a basis and direction for the design and exploration of anti-HF lead compounds.
研究领域:
药理学
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肝病学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Ya-Ling Chen,Yi Wang,Qiu-Yu Fang,Tong Wang,Cong Chen,Tong-Yao Gao,Ming Wu,Wei-Ping Zhang,Yun-Bi Lu
Poly (ADP-ribose) polymerase-1 (PARP-1) activity significantly increases during cerebral ischemia/reperfusion. PARP-1 is an NAD + -consumption enzyme. PARP-1 hyperactivity causes intracellular NAD + deficiency and bioenergetic collapse, contributing to neuronal death. Besides, the powerful trigger of PARP-1 causes the catalyzation of poly (ADP-ribosyl)ation (PARylation), a posttranslational modification of proteins. Here, we found that PARP-1 was activated in the ischemic brain tissue during middle-cerebral-artery occlusion and reperfusion (MCAO/R) for 24 h, and PAR accumulated in the neurons in mice. Using immunoprecipitation, Western blotting, liquid chromatography-mass spectrometry, and 3D-modeling analysis, we revealed that the activation of PARP-1 caused PARylation of hexokinase-1 and lactate dehydrogenase-B, which, therefore, caused the inhibition of these enzyme activities and the resulting cell energy metabolism collapse. PARP-1 inhibition significantly reversed the activity of hexokinase and lactate dehydrogenase, decreased infarct volume, and improved neuronal deficiency. PARP-1 inhibitor combined with pyruvate further alleviated MCAO/R-induced ischemic brain injury in mice. As such, we conclude that PARP-1 inhibitor alleviates neuronal death partly by inhibiting the PARylation of metabolic-related enzymes and reversing metabolism reprogramming during cerebral ischemia/reperfusion injury in mice. PARP-1 inhibitor combined with pyruvate might be a promising therapeutic approach against brain ischemia/reperfusion injury.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
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2017
·Vol. 8
·期 8
·e2988
·
IF 5.965
Yan Siyuan,Liu Ling,Ren Fengxia,Gao Quan,Xu Shanshan,Hou Bolin,Wang Yange,Jiang Xuejun,Che Yongsheng
Deficiency of autophagy has been linked to increase in nuclear instability, but the role of autophagy in regulating the formation and elimination of micronuclei, a diagnostic marker for genomic instability, is limited in mammalian cells. Utilizing immunostaining and subcellular fractionation, we found that either LC3-II or the phosphorylated Ulk1 localized in nuclei, and immunoprecipitation results showed that both LC3 and Unc-51-like kinase 1 (Ulk1) interacted with γ -H2AX, a marker for the DNA double-strand breaks (DSB). Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, was found to enhance the autophagic flux concurring with increase in the frequency of micronuclei accrued upon inhibition of autophagy, and similar results were also obtained in the rasfonin-treated cells. Moreover, the punctate LC3 staining colocalized with micronuclei. Unexpectedly, deprivation of SQSTM1/p62 alone accumulated micronuclei, which was not further increased upon challenge with ST. Rad51 is a protein central to repairing DSB by homologous recombination and treatment with ST or rasfonin decreased its expression. In several cell lines, p62 appeared in the immunoprecipites of Rad51, whereas LC3, Ulk1 and p62 interacted with PARP-1, another protein involved in DNA repair and genomic stability. In addition, knockdown of either Rad51 or PARP-1 completely inhibited the ST-induced autophagic flux. Taken together, the data presented here demonstrated that both LC3-II and the phosphorylated Ulk1 localized in nuclei and interacted with the proteins essential for nuclear stability, thereby revealing a more intimate relationship between autophagy and genomic stability.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
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