FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Keli Liu,Shaofan Hu,Reziyamu Wufuer,Qun Zhang,Lu Qiu,Zhengwen Zhang,Meng Wang,Yiguo Zhang
The levels of reactive oxygen species (ROS) and the extent of ensuing DNA damage significantly influence cancer initiation and progression. Of crucial importance, the aspartate protease DDI2 has been proposed to play a pivotal role in monitoring intracellular ROS levels (to trigger oxidative eustress or distress), as well as in the oxidative DNA damage repair, through redox homeostasis-determining factor Nrf1 (encoded by NFE2L1 ). However, the specific role of DDI2 in the multi-step process resulting in the development and progression of liver cancer remains elusive to date. In the present study, we employed the CRISPR/Cas9 gene editing system to create two nuanced lines of DDI2 knockout (i.e., DDI2 −/− and DDI2 insG/− ) from liver cancer cells. Subsequent experiments indicate that the knockout of DDI2 leads to increased ROS levels in hepatoma cells by downregulating two major antioxidant transcription factors Nrf1 and Nrf2 (encoded by NFE2L2 ), exacerbating endogenous DNA damages caused by ROS and not-yet-identified factors, thereby inhibiting cell proliferation and promoting apoptosis, and ultimately hindering in vivo malignant growth of xenograft tumor cells. Conversely, the restoration of DDI2 expression reverses the accumulation of ROS and associated DNA damage caused by DDI2 knockout, eliminating the subsequent inhibitory effects of DDI2 deficiency on both in vitro and in vivo growth of liver cancer cells. Collectively, these findings demonstrate that DDI2 deficiency impedes liver tumor growth by disrupting its survival environment, suggesting that DDI2 may serve as a novel therapeutic target for anti-cancer strategies aimed at modulating ROS or DNA damage processes.
研究领域:
肿瘤学
·
分子生物学
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医学遗传学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2024
·
IF 4
Xiaoyan Zhai,Hussein Hanibah,Nor Zakiah Nor Hashim,Juzheng Zhang,Xianli Ma,Lilan Wei,Xiaoqun Zhou
Platinum-based chemotherapeutics have played a critical role in oncology for decades. However, their broader utility is hindered by the advent of severe side effects and the emergence of drug resistance. The pursuit of alternative agents, particularly non-platinum (non-Pt) metal complexes, has gained momentum in current research. Designing efficacious non-Pt metal agents that target DNA poses a complex challenge. In this study, we present the strategic design, synthesis, and thorough characterization of two innovative copper(II) complexes leveraging adenine as a ligand, a potential avenue to overcome these challenges. Our investigation demonstrates the superior cytotoxicity of these copper(II) complexes compared to the benchmark cisplatin, with complex C2 exhibiting the most promising anticancer activity, showcasing an impressive IC 50 value of 4.51 μM in MGC-803 cells. Mechanistic insights underscore that complex C2 executes its cytotoxic effects by instigating DNA damage, orchestrating cell cycle arrest at the G2 phase, perturbing mitochondrial membrane potential, inducing ROS production, and ultimately triggering apoptotic pathways. These findings significantly emphasize the potential of designing novel adenine-based anticancer metal complexes targeting DNA, portraying a compelling trajectory for advancing anticancer drug development.
研究领域:
药理学
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肿瘤学
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生物化学
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产品关联
DOI
高影响因子
Translational Andrology and Urology
·
2022
·
IF 2.479
Shujun Sun,Kehua Jiang,Jin Zeng
Background To investigate the potential mechanisms of chemoradiotherapy resistance in patients with bladder cancer. Methods We assessed three bladder cancer cell lines (5637, J82, and TCCSUP) for their sensitivity to chemoradiotherapy. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression of specific genes after chemoradiotherapy or combined with olaparib. The Genome Cancer Atlas (TGCA) database was used to analyze possible radioresistance-related genes and the relationship between their expression and bladder cancer survival and prognostic indicators. Results The 5637 cell line showed the most significant sensitivity to chemoradiotherapy. The expression levels of DNA damage repair genes in 5637 cells did not significantly change after chemoradiotherapy. In contrast, the expression levels of BRCA1 and RBBP8 genes significantly increased in J82 and TCCSUP cells after chemoradiotherapy. After combination with olaparib, which is a poly (ADP-ribose) polymerase inhibitor that initiates DNA repair, 5637 cells were significantly inhibited by chemoradiotherapy. However, chemoradiotherapy inhibition on J82 cells was weakened when combined with olaparib. A high reactive expression of BRCA1 and RBBP8 after combination with olaparib suggested that olaparib was ineffective because it did not induce synthetic lethality in which inhibiting PARP by olaparib coincided with suppression of BRCA1/2 expression result in cancer cell death. Conclusions The expression levels of RBBP8 and BRCA1 genes were associated with sensitivity to radiotherapy and chemotherapy in bladder cancer, and an increase in reactive expression after treatment led to worse sensitivity. Therefore, the reactive expression levels of BRCA1 and RBBP8 after chemoradiotherapy may be useful in evaluating the efficacy of olaparib combination therapy.
研究领域:
肿瘤学
·
分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2025
·
IF 4.3
Fan Yanan,An Caizhelin,Wang Zhihui,Luo Jia,Wang Wenbin,Luo Qing,Song Guanbin
Hepatocytes are the primary functional cells in the liver, and the malignant transformation of hepatocytes significantly contributes to hepatocellular carcinoma (HCC) progression. Liver fibrosis and cirrhosis caused by extracellular matrix (ECM) remodeling during liver lesions is a pivotal driver of HCC. However, the impact of matrix stiffness on hepatocytes and the underlying molecular mechanisms are not fully understood. Herein, using gelatin/sodium alginate hydrogels with different stiffnesses to simulate the change of matrix stiffness during liver lesions, we found that matrix stiffening leads to a notable decrease in the expression of hepatocyte nuclear factor 4α (HNF4α) and functional hepatocyte genes and a significant increase in the expression of interleukin 6 (IL‒6) in human hepatocyte line L‒02 cells, indicating obvious damage of hepatocyte function. In addition, matrix stiffening causes extensive DNA damage to L‒02 cells. Mechanistically, matrix stiffening upregulates piezo‒type mechanosensitive ion channel component 1 (Piezo1) expression and activates extracellular signal‒regulated kinase 1/2 (ERK1/2) signaling. Piezo1 knockdown suppresses matrix stiffening‒induced functional impairment and DNA damage in L‒02 cells. Moreover, Piezo1 knockdown blocks matrix stiffening‒activated ERK1/2 signaling in L‒02 cells. U0126 (a selective inhibitor of ERK1/2 activation) treatment could rescue matrix stiffening‒induced functional impairment and DNA damage. Taken together, these findings demonstrate that matrix stiffening induces functional impairment and DNA damage in L‒02 cells via the Piezo1‒ERK1/2 signaling pathway, which provides evidence for a better understanding of the hepatocyte function damage caused by tissue mechanical microenvironment change in liver diseases and the mechanotransduction in this process. Graphical abstract An increase in matrix stiffness inhibits HNF4α expression and promotes IL‒6 expression in L‒02 cells. Meanwhile, matrix stiffening induces L‒02 cell DNA damage and upregulates the expression of γ‒H2AX and 53BP1. These findings prove that matrix stiffness is a crucial mechanical regulator of cellular functional impairment and DNA damage and plays an important role in liver disease.
研究领域:
医学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Jialu Zhang,Xiaoxuan Wang,Lu Guo,Shan Xiao,Dong Meng,Mengmeng Shang,Xiao Sun,Dandan Shi,Yading Zhao,Rui Liu,Shuting Huang,Xinyu Zeng,Jie Li
PARP inhibitor (PARPi)-based synthetic lethal therapies have displayed limited benefits in BRCA-proficient ovarian cancer. To potentiate the application of PARPi, an ultrasound contrast agent OLA-NDs for delivery of the PARPi olaparib (OLA) was established for enhancing DNA damage by blocking DNA repair. OLA-NDs were endowed with endogenous pH- and exogenous ultrasound (US)-responsiveness to target tumors, as well as contrast-enhanced US imaging for diagnostic and therapeutic integration. OLA-NDs could upregulate NOX4 to induce oxidative stress and sensitize BRCA wild-type A2780 cells to DNA oxidative damage through the utilization of ultrasound-targeted microbubble destruction (UTMD). In addition, the strategy further increased ROS production by interfering with mitochondrial function, thereby exacerbating DNA double-strand breaks (DSBs) and inducing mitochondria-mediated apoptosis. As a consequence, the combined application of UTMD and OLA-NDs demonstrated significant antitumor effects in vitro and in vivo . This combined strategy of amplifying oxidative damage improved lethality by promoting DNA DSBs and apoptosis with reduced adverse side effects, which would provide new insight for the clinical application of PARPi in BRCA-proficient ovarian cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF STORED PRODUCTS RESEARCH
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2025
·
IF 2.8
Xiangfei Li,Menghan Wang,Meng Ding,Xinyi Pang,Jing Sun,Yingjian Lu
Freeze-drying is a common method for preserving bacteria cells, but it can cause cell damage in the process of protection. Therefore, it is necessary to explore a cryoprotectant to improve cell survival during the process. This research aimed to explore the optimal cryoprotectant formulation of L. acidophilus FMNS-10 and its protection mechanism. The optimal cryoprotectant consisted of 10.7 % skim milk, 3 % sodium L-glutamate and 10 % D-trehalose, resulting in a survival rate of 91.69 % for L. acidophilus FMNS-10 after freeze-drying ( p < 0.05). Under this condition, the integrity of cell wall and membrane of L. acidophilus FMNS-10 was close to that of the fresh strain, which could be attributed to preventing ice crystal formation. Cryoprotectants demonstrated a significant protective effect on enzymatic activities. In the cryoprotectant-free group, the activities of β-galactosidase, L-LDH, Na + /K + -ATPase and the concentration of Ca 2+ decreased by 36.19 %, 51.82 %, 89.40 %, and 41.90 %, respectively. However, the cryoprotectant group were only 7.10 %, 1.66 %, 7.41 %, and 4.10 % reductions compared to the cryoprotectant-free group ( p < 0.05). These results indicated that the optimal cryoprotectant improved the survival rate of L. acidophilus FMNS- 10 by inhibiting the loss of enzyme activity. In addition, the optimal cryoprotectant significantly mitigated the DNA damage induced by freeze-drying. The reduction in enzyme and DNA damage may be attributed to complex cryoprotectants maintaining the stability of their three-dimensional structures and reducing structural disruption caused by freezing. Further analysis of storage stability revealed that the viable count of L. acidophilus FMNS-10 exceeded 10 7 CFU/mL when stored at −20 °C for 180 days. These findings provide a comprehensive theoretical foundation for how to freeze-dry Lactobacillus acidophilus.
研究领域:
微生物学
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食品科学
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产品关联
DOI
高影响因子
Environmental Science-Nano
·
2023
·Vol. 10
·期 2
·519-527
·
IF 7.3
Xujun Wang,Zihang Zeng,Tianhui Yang,Peng Zhang,Bo Feng,Taiping Qing
Graphene oxide, a typical two-dimensional carbon-based nanomaterial, has been broadly applied in different industries because of its unique mechanical, electric, and thermal properties. These extensive applications will unavoidably release graphene oxide into the natural environment. In order to further evaluate the environmental behavior and environmental toxicity of graphene oxide, we systematically investigated the interaction mechanism between graphene oxide and DNA molecules, particularly the light-driven graphene oxide for DNA damage. Under light irradiation conditions, the graphene oxide has a strong cutting ability to DNA with different sequences. The cleavage behavior of DNA by graphene oxide mainly targets free DNA, which is similar to the degradation of non-adsorbed pollutants by nanomaterial catalysts. Both electron paramagnetic resonance and reactive oxygen species scavenging experiments indicated that 1O2 and O2˙− could be responsible for this DNA cleavage. In addition, the influence of several environmental factors (pH, metal ions, and biomolecules) on the cleavage reaction was investigated in detail. The results showed that these factors had little effect on the DNA-cutting reaction. This study provides novel insights into the potential environmental risk of graphene oxide.
研究领域:
环境科学
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分子生物学
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产品关联
DOI
高影响因子
Oncotarget
·
2017
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IF 5.168
Hongzhen Bai,Min Wu,Hongjian Zhang,Guping Tang
Cell exposure to atmospheric polycyclic aromatic hydrocarbons (PAHs) is closely associated with DNA damage and genomic instability. We assessed the mechanisms of chronic and acute PAH exposure-induced genotoxicity in two human lung epithelial cell lines, A549 and NC-H1975. We sampled atmospheric PAHs at the Xixi Campus, Zhejiang University in Hangzhou, China during August (non-haze episode) and November (haze episode) 2015. We identified vehicle emissions as a dominant anthropogenic PAH source in our study. PAHs were extracted according to the United States Environmental Protection Agency Method TO-13A. We found that chronic PAH exposure saturated lung cell xenobiotic metabolic pathways, promoting intercellular reactive oxygen species production and accumulation. Chronic alteration of the cellular redox status resulted in DNA damage and genomic instability. Chronic PAH exposure also perturbed the cellular DNA damage response, inducing S phase arrest and inhibiting apoptosis. Dysregulation of PAH metabolism and the DNA damage response altered cellular homeostasis and increased cell susceptibility to subsequent PAH exposures, thereby enhancing the likelihood of genomic mutation and instability.
研究领域:
毒理学
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分子生物学
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环境科学
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Junqiu Zhai,Han Zhang,Wenzhi Zhu,Jiewei Deng,Xinyan Li,Tiangang Luan
Simultaneous in situ monitoring of base excision repair (BER) correlated enzymes like apurinic/apyrimidinic endonuclease 1 (APE1) and flap endonuclease 1 (FEN1) in living cells offers valuable insights into their roles in disease development and cytotoxicity caused by pollutants, but comprehensive analysis is currently hindered by diverse enzyme functions and limited methods. In this study, we developed a dual-activatable DNA fluorescent probe (AP-FLAP) to simultaneously visualize APE1 and FEN1 activities, revealing the BER-related DNA damage caused by various environmental pollutants within living cells. The AP-FLAP probe was designed by ingeniously integrating a dumbbell structure containing a 5′ flap and a hairpin structure containing AP sites into a single oligonucleotide probe. APE1 specifically hydrolyzed the AP sites, releasing a 5-carboxy-X-rhodamine (ROX) signal, while FEN1 recognized and cleaved the 5′ flap, releasing a 6-carboxyfluorescein (FAM) signal. The probe allowed for independent determination of APE1 and FEN1 activities with good specificity and sensitivity. Subsequently, we applied the AP-FLAP probe to investigate base damage induced by 1-methylphenanthrene (1-MP) and 6-chlorobenzo[a]pyrene (6-Cl-BaP) in human umbilical vein endothelial cells (HUVECs). Significant base damage by 1-MP and 6-Cl-BaP exposure was revealed, with a positive correlation of damage degree with different exposure concentrations from 0.1 to 100 μM. Notably, 6-Cl-BaP caused significant damage even at 0.1 μM, in a concentration-dependent manner. Our work provides a powerful tool for elucidating BER molecular mechanisms and DNA damage repair under environmental exposure and opens new avenues for developing multifunctional nucleic acid probes for a wide range of applications in chemical biology and biomedical research.
研究领域:
分子生物学
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细胞生物学
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环境毒理学
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产品关联
DOI
PubMed
高影响因子
JCI Insight
·
2025
·
IF 6.1
Ping Gao,Xinwei Cheng,Maochang Liu,Hui Peng,Guodong Li,Tianze Shang,Jianqiao Wang,Qianyan Gao,Chenglong Zhu,Zhenpeng Qiu,Chengliang Zhang
Tacrolimus-induced chronic nephrotoxicity (TICN) hinders its long-term use, but its mechanism remains unclear. Tacrolimus exerts its pharmacological effect by inhibiting calcineurin and its substrate NFAT. Whether the inhibition of other calcineurin substrates is related to TICN remains to be explored. Transcription factor EB (TFEB), a substrate of calcineurin, plays a crucial role in various homeostasis. Herein, we found that tacrolimus inhibited TFEB nuclear translocation and activity in mouse kidneys and HK-2 cells. Then, TFEB gain- and loss-of-function rescued the effect of tacrolimus in HK-2 cells. Furthermore, TFEB activation both by phosphorylation sites mutation and agonist rescued TICN in mice. To elucidate the mechanism of TFEB, we analyzed ChIP-seq data. Growth arrest and DNA damage-inducible 45α (GADD45α) was identified as a transcriptional target of TFEB via chromatin immunoprecipitation and dual luciferase reporter assays. And then we revealed that GADD45α overexpression rescued DNA damage and kidney injury caused by tacrolimus or TFEB knockdown in vitro, and vise versa. The protective effect of GADD45α against TICN and DNA damage was further demonstrated by overexpressing it in mice. In conclusion, the persistent inhibition of TFEB-GADD45α pathway by tacrolimus contributes to TICN. This study identifies a specific target for intervention of TICN.
研究领域:
药理学
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Linlin Han,Hongyan Tan,Jungjoon Lee,Peng Wang,Yuqing Zhao
Based on the significant biological activities and the remarkable physical and chemical properties of 1 H -1,2,3-triazole pharmacophore, we herein adopted the strategy of click chemistry to combine the triazole fragment and the unique scaffold of 25-OCH 3 -PPD ( AD-1 ) to design a series of potent compounds inducing apoptosis and DNA damage. The anti-proliferative effect was verified by MTT assay and colony formation assay. DNA double-stand breaks (DSBs) were obtained by observing the nuclear focus formation and the protein expression of γ-H2AX. Cell cycle arrest was evaluated by the cycle-related proteins such as CDK2, CDK4, CDK6, Cyclin D1 and P 21. Apoptosis was assessed by flow cytometry, mitochondrial membrane potential (MMP) detection and the expression of apoptosis-related proteins. Reactive oxygen species (ROS) generation was measured with 2′, 7′-dichlorofluorescein diacetate (DCFH-DA) staining. According to SAR analysis, the most potent compound 6a exhibited great inhibitory effect against A549 cells, which IC 50 value of 2.84 ± 0.68 μM. Furthermore, 6a remarkably induced DNA damage, cell cycle arrest and apoptosis in A549 cells. 6a treatment increased the levels of ROS. Network pharmacology and molecular docking predicted the potential signaling pathways and ligand-receptor interactions, and the results of western blotting showed that 6a inhibited the PI3K/Akt/Bcl-2 signaling pathway by decreasing PI3K and Bcl-2 and total level of Akt expression, while Bax and Cyt c were increasing in 6a -treated A549 cells. As mentioned above, 6a has a potent inhibitory effect in A549 cells through induction of DNA damage, apoptosis via ROS generation and modulation of PI3K/Akt/Bcl-2 signaling pathway.
研究领域:
药理学
·
肿瘤学
·
化学生物学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2022
·
IF 9.988
Wenjing Pu,Xuesheng Chu,Huiling Guo,Gang Huang,Ting Cui,Bingyan Huang,Xueyan Dai,Caiying Zhang
Cadmium (Cd) and excess molybdenum (Mo) have multiple organ toxicity, and testis is one of their important target organs, but the reproductive toxicity of Mo and Cd combined treatment is still unclear. To explore the effects of Mo and Cd co-exposure on DNA damage and autophagy from the insight of ATM/AMPK/mTOR axis in duck testes, we randomly assigned 40 healthy 8-day-old ducks to control, Mo (100 mg/kg Mo), Cd (4 mg/kg Cd), and Mo + Cd groups for 16 weeks. Results found that Mo and/or Cd exposure caused trace elements imbalance, oxidative stress with a decrease in the activities of GSH-Px, CAT , T-SOD and GSH content, an increase in the concentrations of H 2 O 2 and MDA and pathological damage. Additionally, Mo and/or Cd markedly raised DNA damage-related factors expression levels and 8-OHdG content, caused G1/S arrest followed by decreasing CDK2 and Cyclin E protein levels and increasing CDK1 and Cyclin B protein levels, and activated ATM/AMPK/mTOR axis by enhancing p-ATM/ATM, p-AMPK/AMPK and reducing p-mTOR/mTOR protein levels, eventually triggered autophagy by elevating LC3A, LC3B, Atg5, Beclin-1 mRNA levels and LC3II/LC3I, Beclin-1 protein levels and reducing P62, Dynein, mTOR mRNA levels and P62 protein level. Moreover, these changes were most apparent in the combined group. Altogether, the results reveal that autophagy caused by Mo and/or Cd may be associated with activating the DNA damage-mediated ATM/AMPK/mTOR axis in duck testes, and Mo and Cd co-exposure exacerbates these changes.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
✓ 已验证
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）