SENSORS AND ACTUATORS B-CHEMICAL
·
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
·
纳米医学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
TOXICOLOGY LETTERS
·
2023
·
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
·
毒理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2021
·
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
·
药物代谢动力学
·
计算生物学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2025
·
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
·
肿瘤学
·
结构生物学
·
药理学
·
计算生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
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
·
肝病学
·
分子生物学
·
毒理学
✓ 已验证
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
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
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
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.7
Ming Jiang,Xueyu Man,Moya Yang,Qiwei Yan,Haijuan Wu,Feng Yang,Youhuan Wei
DNA serves as the primary target for numerous metal complexes in suppression tumor cell proliferation, and Poly ADP ribose polymerase-1 (PARP-1) is critical for DNA repair. In this study, benzothiazole hydrazone was used as a framework to design and synthesize a series of Cu(II) complexes (Cu1-Cu3), which functions as novel PARP-1 inhibitors. These Cu(II) complexes not only effectively inhibited the proliferation of a panel of tumor cells (IC 50 range: 0.51–5.37 μM) but also exhibited potent PARP-1 inhibitory activity (IC 50 range: 0.45–1.52 μM). Notably, complex Cu3 had the most potent activities, exhibiting strong cytotoxicity against T98G cells (IC 50 = 0.51 μM) and significant PARP-1 inhibition (IC 50 = 0.45 μM). Additionally, Cu3 effectively inhibited the migration of T98G cells. Mechanistic studies revealed that Cu3 generated excessive reactive oxygen species (ROS), induced DNA damage, exacerbated DNA double-strand breaks by inhibiting PARP-1 activity, and promoted apoptosis in tumor cells via the mitochondrial pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TURKISH JOURNAL OF CHEMISTRY
·
2022
·Vol. 43
·期 5
·1290-1305
·
IF 1.151
TOK FATİH,KAYMAKÇIOĞLU BEDİA,İLHAN RECEP,YILMAZ SİNEM,KIRMIZIBAYRAK PETEK BALLAR,TOK TUĞBA TAŞKIN
Poly (ADP-ribose) polymerase (PARP) enzyme catalyzes the transfer of ADP-ribose into target proteins. Therefore, PARP is responsible for DNA repair, cell proliferation, and cell death. In this study, potential PARP enzyme inhibitors were designed and synthesized. The synthesized compounds were elucidated by Fourier-transform infrared spectroscopy, $^{1}$H NMR, $^{13}$C NMR, heteronuclear single-quantum correlation, and mass spectrometry, and their purity was checked via thin-layer chromatography, high-performance liquid chromatography, and elemental analysis. A total of 63 newly synthesized compounds were screened in terms of PARP inhibition by cellular PARylation assay in the HeLa cell line. It was found that 19 compounds significantly inhibited the H$_{2}$O$_{2}$-induced cellular PARylation. The chemosensitizer effect of these compounds in cancer cells treated with doxorubicin (doxo) was investigated. It was found that the combination of potent PARP inhibitors with doxo potentiated a cytotoxic effect, similar to that of olaparib. The results of the molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis revealed that compound 60 might be classified as a potential PARP inhibitor candidate. Taken together, all of the results suggested that carbohydrazide derivatives could be a promising lead for the treatment for cancer disorders.
✓ 已验证
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Yaqi Pu,Tianxin Li,Zihe Zhao,Qian Xu,Yi Jin,Huan Dou,Zhao Liu
Background Abdominal aortic aneurysm (AAA) is a prevalent and potentially fatal cardiovascular disease, yet the precise therapeutic mechanism of the bioactive compound Senkyunolide I (SEI) against AAA is not fully understood. Methods Utilizing an elastase/BAPN-induced AAA mouse model, this study employed integrated network pharmacology, proteomics (LiP-MS), and biophysical validation (molecular docking, MST) to identify and confirm PARP-1 as a direct target of SEI. The therapeutic effect of SEI was evaluated in vivo by monitoring aortic dilation and histopathology, and its inhibitory effect on TNF-α-induced macrophage migration was assessed in vitro . The functional role of the SEI-PARP-1 axis was further verified using PARP-1 inhibitors and macrophage-targeted PARP-1 overexpression. Results In the elastase/BAPN-induced AAA model, which mimics human AAA progression and rupture risk, SEI treatment attenuated disease progression by reducing aortic dilation, collagen deposition, and elastin degradation. SEI directly bound to and downregulated PARP-1 expression in both AAA tissues and large peritoneal macrophages (LPMs). It dose-dependently suppressed TNF-α-induced LPMs migration in vitro and restored the AAA-induced reduction in peritoneal LPMs proportion in vivo , an effect also seen with pharmacological PARP-1 inhibition. In contrast, macrophage-specific PARP-1 overexpression abolished SEI's protection and promoted LPMs migration into aortic lesions. Conclusion This study demonstrates that SEI attenuates AAA progression by targeting PARP-1 and inhibiting the migration of LPMs from the peritoneal cavity to the aortic lesion. These findings elucidate a novel pharmacological mechanism of SEI and underscore PARP-1 as a promising therapeutic target for AAA.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yating Cheng,Shanshan He,Zhihui Wei,Yuxuan Meng,Dun Su,Xiaomin Li,Shu Zhang,Rong-Rong He,Zifei Qin,Qi Xiang
Coix seed, a well-known traditional Chinese medicine, has been extensively used for its anti-aging properties. However, the biological mechanism of its polysaccharides remains unclear. This study systematically investigated the anti-aging effects and mechanism of purified Coix seed polysaccharide (CP1) for the first time. The structural analysis revealed that CP1 mainly consists of glucose linked by α-(1 → 4) and α-(1 → 6) glycosidic bonds and has an average molecular weight of 8.855 kDa. Further, CP1 exhibited strong scavenging activity of approximately 55.85 % against 1,1-diphenyl-2-trinitrobenzohydrazine, 71.30 % against 2,2′-bis-(3-ethylbenzothiazolin-6-sulfonic acid) diammonium salt, and 68.40 % against hydroxyl radicals. In Caenorhabditis elegans , CP1 significantly extended the lifespan by 3–5 days ( p < 0.001) and increased the survival by 78 % under oxidative stress condition ( p < 0.001). In addition, CP1 suppressed the activity of senescence-associated β-galactosidase in zebrafish ( p < 0.001) and reduced DNA damage in human skin fibroblasts ( p < 0.001). Mechanistically, CP1 mainly activates the p -AMPK/RICTOR/CREB3 pathway by interacting with PARP-1. Taken together, this study performs the structural characterization of a glucan polysaccharide from Coix seed and its anti-aging effects in different models. These findings can provide a theoretical basis and candidate molecule for anti-aging therapies.
研究领域:
天然产物化学
·
药用植物学
·
分子生物学
·
抗衰老研究
·
糖生物学
·
中医药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Rui Li,Weiheng Zhao,Chen Jin,Huihua Xiong
Platinum(II)–based drugs play an important role in many chemotherapeutic protocols, but their further clinical applications are hindered by the development of drug resistance and serious side effects. Therefore, to reverse cisplatin (CDDP) resistance in tandem with reduced side effects, nine novel platinum(IV) complexes modified with key pharmacophore of Olaparib were synthesized and evaluated for biological activities. Among them, the optimal complex 8–2 showed good inhibitory activity against PARP–1 and superior anticancer effects over CDDP on parental (MDA–MB–231, IC 50 = 1.13 μM) and CDDP –resistant triple–negative breast cancer (TNBC) cell line (MDA–MB–231/CDDP, IC 50 = 1.72 μM). Detailed mechanisms revealed that compared with Olaparib and CDDP, the enhanced intracellular accumulation of 8–2 could efficiently reverse CDDP resistance in MDA–MB–231/CDDP cells via inhibiting DNA repair–associated mechanisms, enhancing DNA damage, and activating mitochondrion–dependent apoptosis pathway. Furthermore, 8–2 obtained higher tumor growth inhibition rate (64.1 %) than CDDP (26.5 %) in MDA–MB–231/CDDP xenografts, but it did not induce significant toxicity in vivo and in intro , making it a potential drug candidate for the treatment of TNBC.
研究领域:
肿瘤学
·
药理学
·
化疗
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）