CELL BIOCHEMISTRY AND BIOPHYSICS
·
2014
·Vol. 71
·期 1
·345-351
·
IF 2.38
Feng Tianda,Liu Yunhui,Li Chao,Li Zhen
The goal of this study was to assess the expression of poly ADP-ribose polymerase (PARP) and apoptosis-inducing factor (AIF) in the hippocampal CA1 region, and to find out whether nigranoic acid treatment exhibits protective effects on brain through PARP/AIF signaling pathway in cerebral ischemia–reperfusion animal model. Rats were randomly divided into three groups: Sham-surgery, ischemia–reperfusion, and nigranoic acid-treated. Rat models of middle cerebral artery occlusion were prepared using a way of thread occlusion. Rats in the nigranoic acid group were administered with 1 mg/kg intragastric nigranoic acid 6 and 2 h before brain ischemia, respectively. Following reperfusion, samples were collected at different time-points (6, 24, and 72 h) and each group was further divided into three subgroups. Apoptosis was measured using the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling method. The protein expression levels of AIF and PARP were detected using Western blot and AIF mRNA quantity was evaluated using the reverse transcription-polymerase chain reaction. Apoptosis, levels of AIF and PARP protein expression, and levels of AIF mRNA expression were significantly increased in the ischemia–reperfusion group compared with the sham-surgery group. However, apoptosis and the expression levels of AIF protein, PARP protein, and AIF mRNA at different time-points were significantly decreased in the nigranoic acid-treated group compared with the model group. We can judge that nigranoic acid has a strong protective effect on rat cerebral ischemia–reperfusion injury, and acts by downregulating nerve cell apoptosis by preventing the overactivation of PARP and AIF nuclear translocation.
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
MOLECULES
·
2023
·Vol. 28
·期 19
·6972
·
IF 4.6
Zheng Huang,Tong Xian,Xiangyi Meng,Huaisong Hu,Lixia Gao,Jiuhong Huang,Donglin Yang,Kepeng Ou,Bochu Wang,Yimei Zhang
Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that has been widely used for anti-tumor therapy by the generation of excessive highly cytotoxic ROS. However, the poor water solubility of the photosensitizer, reactive oxygen species (ROS) depleting by high concentrations of glutathione (GSH) in the tumor microenvironment and the activation of DNA repair pathways to combat the oxidative damage, will significantly limit the therapeutic effect of PDT. Herein, we developed a photosensitizer prodrug (CSP) by conjugating the photosensitizer pyropheophorbide a (PPa) and the DNA-damaging agent Chlorambucil (Cb) with a GSH-responsive disulfide linkage and demonstrated a multifunctional co-delivery nanoplatform (CSP/Olananoparticles (NPs)) together with DSPE-PEG2000and PARP inhibitor Olaparib (Ola). TheCSP/Ola NPsfeatures excellent physiological stability, efficient loading capacity, much better cellular uptake behavior and photodynamic performance. Specifically, the nanoplatform could induce elevated intracellular ROS levels upon the in situ generation of ROS during PDT, and decrease ROS consumption by reducing intracellular GSH level. Moreover, theCSP/Ola NPscould amplify DNA damage by released Cb and inhibit the activation of Poly(ADP-ribose) polymerase (PARP), promote the upregulation of γ-H2AX, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. In vitro investigations revealed thatCSP/Ola NPsshowed excellent phototoxicity and the IC50values ofCSP/Ola NPsagainst MDA-MB-231 breast cancer cells were as low as 0.05–01 μM after PDT. As a consequence, the co-delivery nanoplatform greatly promotes the tumor cell apoptosis and shows a high antitumor performance with combinational chemotherapy and PDT. Overall, this work provides a potential alternative to improve the therapeutic efficiency of triple negative breast cancer cell (TNBC) treatment by synergistically enhancing DNA damage and disrupting DNA damage repair.Keywords:chemo-photodynamic therapy;DNA damage repair;PARP inhibitor;co-delivery;GSH-responsive
研究领域:
癌症治疗
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药学
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Shuyi Zhou,Xixi Hou,Ling Li,LiHao Guo,Huili Wang,Longfei Mao,Leilei Shi,Miaomiao Yuan
Prostate cancer (PCa) is the second most frequently diagnosed cancer among men, causing a huge number of deaths each year. Traditional chemotherapy for PCa mostly focused on targeting androgen receptors. However, some of the patients would develop resistance to hormonal therapy. In these cases, it is suggested for these patients to administer treatments in combination with other chemotherapeutics. Current chemotherapeutics for metastatic castration-resistant PCa could hardly reach satisfying effects, therefore it is crucial to explore novel agents with low cytotoxicity. Herein, a common drug against the human immunodeficiency virus (HIV), the dolutegravir (DTG) was modified to become a series of dolutegravir-1,2,3-triazole derivatives. Among these compounds, the 4d and 4q derivatives were verified with high anti-tumor efficiency, suppressing the proliferation of the prostate cancer cells PC3 and DU145. These compounds function by binding to the poly (adenosine diphosphate-ribose) polymerase (PARP), inactivating the PARP and inducing DNA damage in cancer cells. It is noteworthy that the 4d and 4q derivatives showed almost no impact on normal cells and mice. Thereby, the results reveal that these dolutegravir-1,2,3-triazole compounds are potential chemotherapeutics for PCa treatment.
研究领域:
肿瘤学
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药理学
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化学生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 7.446
Cheng Wang,Lailiang Qu,Shang Li,Fucheng Yin,Limei Ji,Wan Peng,Heng Luo,Dehua Lu,Xingchen Liu,Xinye Chen,Lingyi Kong,Xiaobing Wang
PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and EZH2 inhibitors, and the most promising compound, 5a, showed good inhibitory activity against PARP-1 and EZH2 and good inhibitory effects on MDA-MB-231 (IC50 = 2.63 μM) and MDA-MB-468 (IC50 = 0.41 μM) cells with wild-type BRCA. Compared with that of olaparib, the growth inhibitory activities against these two cell types increased by approximately 15- and 80-fold, respectively, which was even more effective than the combination of olaparib and tazemetostat/GSK126. 5a can induce autophagy death of tumor cells and cause less damage to normal cells. Therefore, 5a, as a first-in-class dual PARP and EZH2 inhibitor, is a potential anticancer drug candidate for the treatment of TNBC.
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2016
·
IF 7.145
Yuanyuan Xu,Li Liu,Zhaoyin Wang,Zhihui Dai
A stable and reusable electrochemical biosensor for the label-free detection of poly(ADP-ribose) polymerase (PARP) is designed in this work. C-kit-1, a thiol-modified G-quadruplex oligonucleotide, is first self-assembled on a gold electrode surface. The G-quadruplex structure of c-kit-1 can specifically tether and activate PARP, resulting in the generation of negatively charged poly(ADP-ribose) polymer (PAR). On the basis of electrostatic attraction, PAR facilitates the surface accumulation of positively charged electrochemical signal molecules. Through the characterization of electrochemical signal molecules, the label-free quantification of PARP is simply implemented. On the basis of the proposed method, selective quantification of PARP can be achieved over the linear range from 0.01 to 1 U with a calculated detection limit of 0.003U. Further studies also demonstrate the applicability of the proposed method to biosamples revealing the broad potential in practical applications. Furthermore, inhibitor of PARP has also been detected with this biosensor. Meanwhile, benefited from self-assembly on solid surface, this biosensor possesses two important features, i.e., reusability and stability, which are desirable in related biosensors.
研究领域:
生物化学
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分子生物学
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分析化学
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DOI
PubMed
高影响因子
ARCHIV DER PHARMAZIE
·
2024
·
IF 4.3
Jiahong Su,Xingyue Wang,Sha Li,Xu Wu,Mingxing Li,Fukuan Du,Shuai Deng,Jing Shen,Yueshui Zhao,Zhangang Xiao,Yu Chen
Glycyrrhetinic acid (GA) is a naturally occurring triterpene compound. The aim of this study was to employ the pharmacophore hybrid strategy to merge GA with various dithiocarbamates and obtain novel compounds with better antitumor activities. We present a two-step synthetic protocol wherein the GA derivative underwent reaction with carbon disulfide and various secondary amines in a one-pot manner under mild conditions, facilitating the preparation of a series of structurally novel GA-dithiocarbamate derivatives. Bioassay screening revealed that the representative compound 3c demonstrated the capacity to reduce the mitochondrial membrane potential in Hep3B and Huh-7 cells, induce nuclear apoptosis, inhibit invasion and migration, and prompt both early and late apoptosis. Furthermore, our research findings indicated that this apoptotic phenomenon may be associated with the expression of Bcl-2, Bax, Bak, PARP, and cleaved-PARP proteins. Utilizing network pharmacology for predicting core targets and signaling pathways of compound 3c for hepatocellular carcinoma (HCC) treatment involved employing molecular docking models to demonstrate high affinity between compound and target protein. In conjunction with Western blot analysis, compound 3c may impact HCC through the PI3K-AKT-mTOR pathway.
研究领域:
药理学
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肿瘤学
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药物化学
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细胞生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Ge Li,Shan-shan Lin,Ze-lei Yu,Xin-hua Wu,Jing-wen Liu,Gui-hui Tu,Quan-yu Liu,Yuan-ling Tang,Qing-na Jiang,Jian-hua Xu,Qing-ling Huang,Li-xian Wu
Therapeutic targeting of the nuclear enzyme poly (ADP-ribose) polymerase 1 (PARP1) with PARP inhibitors (PARPis) in patients with a homologous recombination (HR)- deficient phenotype based on the mechanism of synthetic lethality has been shown tremendous success in cancer therapy. With the clinical use of various PARPis, emerging evidence has shown that some PARPis offer hope for breakthroughs in triple-negative breast cancer (TNBC) therapy, regardless of HR status. However, similar to other conventional cytotoxic drugs , PARPis are also subject to the intractable problem of drug resistance. Notably, acquired resistance to PARPis caused by point mutations in the PARP1 protein is hard to overcome with current strategies. To explore modalities to overcome resistance and identify patients who are most likely to benefit from PARP1-targeted therapy, we developed a proteolysis-targeted chimaera (PROTAC) to degrade mutant PARP1 in TNBC. Here, we investigated a PARP1 PROTAC termed “ NN3 ″, which triggered ubiquitination and proteasome-mediated degradation of PARP1. Moreover, NN3 degraded PARP1 with resistance-related mutations. Interestingly, compared with other reported PARP1 degraders, NN3 exhibited a unique antitumor mechanism in p53-positive breast cancer cells that effectively promoted ferroptosis by downregulating the SLC7A11 pathway. Furthermore, NN3 showed potent activity and low toxicity in vivo. In conclusion, we propose PROTAC-mediated degradation of PARP1 as a novel strategy against mutation-related PARPi resistance and a paradigm for targeting breast cancer with functional p53 via ferroptosis induction.
研究领域:
癌症生物学
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分子生物学
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药理学
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肿瘤学
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DOI
PubMed
高影响因子
MOLECULES
·
2020
·Vol. 25
·期 18
·4269
·
IF 3.267
Ji-Heng Wu,Yue-Ting Cao,Hong-Ye Pan,Long-Hu Wang
(1) Background: Toad venom (Bufonis Venenum, known as ‘Chansu’ in Chinese), the secretion of the ear-side gland and skin gland of Bufo gargarizans cantor or Duttaphrynus melanostictus Schneider, has been utilized to treat several diseases in China for thousands of years. However, due to the chemical variability of the components, systematic chemical composition and the key pharmacophores in toad venom have not yet fully understood. Besides, it contains a variety of effective compounds with different physiological activity and chemotypes, mainly including alkaloids, bufogenins, bufotoxins, and so on. The recent pharmacological researches have demonstrated that several bufogenins have remarkable pharmacological effects, such as anti-inflammatory, analgesic effects, and anti-tumor effects. Aim of the study: To identify the bioactive compounds and pharmacophores originating from toad venom based on analyzing spectrum-effect relationship by chemometrics and to explore the anti-cancer mechanism primarily. (2) Materials and methods: Fingerprint of the 21 batches of samples was established using HPLC (High Performance Liquid Chromatography). The anti-tumor activity of extracts were determined by in-vitro assays. Chemometric analysis was used to establish the spectrum-effect model and screen for active ingredients. Pharmacodynamic tests for the screened active compound monomers were conducted with in-vitro assays. Further anti-tumor mechanisms were investigated using western blot and flow cytometry. (3) Results: The established spectrum-effect model has satisfactory fitting effect and predicting accuracy. The inhibitory effect of major screened compounds on lung carcinoma cells A549 were validated in vitro, demonstrating that arenobufagin, telocinobufogenin, and cinobufotalin had significant anti-tumor effects. Through further investigation of the mechanism by western blotting and flow cytometry, we elucidated that arenobufagin induces apoptosis in A549 cells with the enhanced expression of cleaved PARP (poly (ADP-ribose) polymerase). These results may provide valuable information for further structural modification of bufadienolides to treat lung cancer and a method for discovery of anti-tumor active compounds. Conclusions: Our research offers a more scientific method for screening the principal ingredients dominating the pharmacodynamic function. These screened compounds (arenobufagin, etc.) were proven to induce apoptosis by overactivation of the PARP-pathway, which may be utilized to make BRCA (breast cancer susceptibility gene) mutant cancer cells more vulnerable to DNA damaging agents and kill them.Keywords:toad venom;spectrum-effect relationship;chemometrics;apoptosis
研究领域:
药理学
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肿瘤学
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化学计量学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY MECHANISMS AND METHODS
·
2025
·
IF 2.7
Lan Yang,Yewen Lin,Wenping Xu,Yang Zhang
Reactive oxygen species (ROS)-induced DNA oxidative damage is a significant manifestation of oxidative stress in the body and is closely associated with the onset and progression of various diseases. Although Pyripyropene A (PPPA) exhibits anti-tumor and anti-inflammatory activities, its antioxidant and protective effects against DNA oxidative injury remain unclear. In this study, using a hydrogen peroxide-induced oxidative injury model of L02 cells, it was found that PPPA could significantly reduce intracellular ROS and malondialdehyde (MDA) levels, enhance the activities of catalase (CAT) and reduced glutathione (GSH), and increase the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) clearance rate, confirming its antioxidant effect. Comet assay showed a reduction in DNA breakage, and down-regulation of phosphorylated histone (γ-H2AX) and 8-hydroxydeoxyguanosine (8-oxodG), indicating that it effectively alleviates DNA oxidative injury. Meanwhile, the upregulated expression of poly ADP-ribose polymerase (PARP) suggests that PPPA may promote repair by activating the DNA damage response (DDR). This study systematically clarify for the first time that PPPA exerts a protective effect by synergistically antioxidizing, reducing DNA injury, and potentially activating repair pathways, providing a theoretical basis for its application in neoplasm and oxidative stress-related diseases.
研究领域:
分子生物学
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药理学
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氧化应激
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肿瘤学
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毒理学
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细胞生物学
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药物代谢
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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
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药用植物学
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分子生物学
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抗衰老研究
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糖生物学
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中医药学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2016
·
IF 3.055
Keyou Li,Rui Zhou,Wang Wang Jia,Zhe Li,Jiazhou Li,Pengfei Zhang,Tiancun Xiao
Ethnopharmacological relevance: Zanthoxylum bungeanum ( ZB ), a Chinese herb medicine, has been shown to possess a wide range of biological activities including anti-tumor, anti-inflammatory, and anti-microbial activity and has long been used to treat a variety of skin diseases including psoriasis . However, the underlying mechanism of action has not been systematically elucidated. Aim of the study: to analyze the chemical composition of the hydro-distilled Zanthoxylum bungeanum essential oil (ZBEO), and to investigate its anti-proliferative activity on HaCaT cells as well as the underlying anti-psoriasis mechanisms. Materials and methods: The chemical composition of ZBEO was analyzed with gas chromatography coupled to mass spectrometry (GC-MS). HaCaT cells was exposed to different dose of ZBEO added in medium prior to morphologic features analysis as well as cell cycle arrest examination with Flow cytometry. Western blot analysis was employed to estimate the expression level of proteins including caspase-8/9/3, PARP, Bax and Bcl-2. Results: Thirty-nine compounds of the ZBEO were identified GC-MS. ZBEO-treated HaCaT cells showed typical apoptotic morphologic features by DAPI staining assay. The ZBEO significantly inhibited proliferation of HaCaT cells in a dose- and time-dependent manner and induced S phase arrest apoptosis in HaCaT cells. Furthermore, western blot analysis revealed that the ZBEO increased expression of cleaved caspase-8/9/3, PARP, and Bax, decreased Bcl-2 levels. Conclusion: ZBEO inhibits the proliferation of HaCaT cells, resulting from the induction of cellular apoptosis through both intrinsic and extrinsic pathways. ZBEO is a potential candidate that may be considered for development into an anti-psoriasis drug.
研究领域:
药理学
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皮肤科
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Yanjuan Huang,Xiuling Dai,Zilin Guan,Di Liu,Lingling Ren,Meixu Chen,Zishan Zeng,Jingwen Jiang,Yong Luo,Yuanfeng He,Min Huang,Chunshun Zhao
Due to a powerful DNA damage repair system and a lack of surface markers, there is currently no effective chemotherapy or tailored targeted therapies available for triple-negative breast cancer (TNBC) treatment. Herein, a tailored DNA damage nanoamplifier ( [email protected] /Pt(IV) C18 ) was engineered to simultaneously induce DNA damage and inhibit DNA reparation for highly efficient TNBC treatment. A newly synthesized Pt(IV) C18 prodrug , the DNA damaging inducer, and the hydrophobic poly(ADP-ribose) polymerases (PARPs) inhibitor niraparib, which is used as the DNA repair blocker, were concurrently encapsulated in highly biocompatible PEGylated liposomes to prepare [email protected] /Pt(IV) C18 , for enhanced cancer therapy and future clinical translation. [email protected] /Pt(IV) C18 with an appropriate size and excellent stability, effectively accumulated at the tumor site. After internalization by tumor cells, niraparib, a highly-selective hydrophobic PARP1 inhibitor, could exacerbate the accumulation of platinum-induced DNA lesions to induce excessive genome damage for synergistic cell apoptosis, which was evidenced by the upregulated γ-H 2 AX and cleaved-PARP levels. Importantly, [email protected] /Pt(IV) C18 exhibited remarkable antitumor efficacy on TNBC without BRCA mutants in vivo with little systemic toxicity. Inspired by the concept of “synthetic lethality”, this study provides an inspirational and clinically transformable nanobased DNA damaging amplification strategy for the expansion of TNBC beneficiaries and highly efficient TNBC treatment via DNA damage induction and DNA repair blocking.
研究领域:
肿瘤学
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纳米技术
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药理学
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癌症治疗
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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）