BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Xin Shen,Yiqun Xia,Hui Lu,Peisen Zheng,Junqi Wang,Yinghua Chen,Chenxin Xu,Chenyu Qiu,Yafei Zhang,Zhongxiang Xiao,Peng Zou,Ri Cui,Daoyong Ni
Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
SHOCK
·
2023
·
IF 3.1
Luo S,Lyu Z,Ge L,Li Y,Liu Y,Yuan Y,Zhao R,Huang L,Zhao J,Huang H,Luo Y
Background Protein kinase ataxia telangiectasia mutated (ATM) regulates the function of endothelial cells and responds quickly to endotoxin. However, the function of ATM in lipopolysaccharide (LPS) -induced blood-brain barrier (BBB) disruption remains unknown. This study aimed to investigate the role and underlying mechanism of ATM in the regulation of the BBB function in sepsis. Methods We used lipopolysaccharide (LPS) to induce BBB disruption in vivo and to establish an in vitro model of cerebrovascular endothelial cells. BBB disruption was assessed by measuring Evans blue leakage and expression of vascular permeability regulators. To investigate the role of ATM, its inhibitor AZD1390 and clinically approved doxorubicin, an anthracycline that can activate ATM, were administered as scheduled. To explore the underlying mechanism, protein kinase B (AKT) inhibitor MK-2206 was administered to block the AKT/dynamin-related protein 1 (DRP1) pathway. Results LPS challenge induced significant BBB disruption, ATM activation and mitochondrial translocation. Inhibiting ATM with AZD1390 aggravated BBB permeability as well as the following neuroinflammation and neuronal injury, while activation of ATM by doxorubicin abrogated these defects. Further results obtained in brain microvascular endothelial cells showed that ATM inhibition reduced the phosphorylation of DRP1 at serine (S) 637, promoted excessive mitochondrial fission, and resulted in mitochondrial malfunction. By activating ATM, doxorubicin increased the protein binding between ATM and AKT and promoted the phosphorylated activation of AKT at S473, which could directly phosphorylate DRP1 at S637 to repress excessive mitochondrial fission. Consistently, the protective role of ATM was abolished by the AKT inhibitor MK-2206. Conclusions ATM protects against LPS-induced BBB disruption by regulating mitochondrial homeostasis, at least in part, through the AKT/DRP1 pathway.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2020
·Vol. 27
·期 12
·13726-13734
·
IF 3.056
Liang Yiran,Dong Bizhang,Pang Nannan,Hu Jiye
Abamectin has been widely used in agriculture and animal husbandry. It has been shown that abamectin exposure could induce multiple toxic effects on non-target organisms, but the underlying mechanism is still largely unknown. In the current study, the mechanism of abamectin-induced cytotoxicity was investigated in mouse embryonic fibroblast cells. Abamectin treatment could cause oxidative stress in cells (beginning at 0.4 μg/ml, 0.5 μM) and the ROS overproduction was mainly induced by the impacts of abamectin on the activities of CAT (beginning at 4.4 μg/mL, 5 μM), SOD (beginning at 8.7 μg/mL, 10 μM), GPx (beginning at 4.4 μg/mL, 5 μM), and contents of GSH (beginning at 4.4 μg/mL, 5 μM), which are important components of the ROS elimination pathway in mammal cells. Abamectin could impair DNA integrity (as demonstrated by increased 8-OHdG/dG ratio) in cells, even at environmental level (0.4 μg/mL, NOAEL), and abamectin-induced oxidative stress was one of the main reasons for the DNA damage that occurred in cells. Moreover, pretreatment with the inhibitor of JNK and ATM/ATR signaling pathway could partially rescue the decreased cell viability, indicating that oxidative stress and DNA damage might be involved in abamectin-induced cytotoxicity. These findings could provide new insights into the mechanism of abamectin-induced cytotoxicity and should be useful for a more comprehensive assessment of the adverse effects of abamectin.
研究领域:
毒理学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
·
2021
·Vol. 110
·期 4
·964-975
·
IF 4.396
Yuzi Xu,Chuan Zhou,Jia Li,Yangbo Xu,Fuming He
The present study aims to reveal the osteogenic roles played by DNA damage response biomarkers through implementing isobaric tags for relative and absolute quantitation (iTRAQ) technique. First, sandblasted large-grit double acid-etched (SLA) titanium implant and strontium-incorporated (SLA-Sr) titanium implant were used for inserting in the tibiae of rats. iTRAQ technique was used to detect protein expression changes and identify differentially expressed proteins (DEPs). In total, 19,343 peptides and 4280 proteins were screened out. Among them, 91 and 138 DEPs were identified in the SLA-Sr group after implantation for 3 and 7 days, respectively. Ataxia-telangiectasia mutated (ATM) protein up-regulated on the 3rd day showed a trend of further up-regulation on the 7th day. Moreover, functional enrichment analyses were also conducted to explore the biological function of DEPs during the initial stage of osseointegration in vivo, which revealed that the biological functions of the DEPs on the 7th day were mainly related to “mismatch repair” and “mitotic G1 DNA damage checkpoint.” Analysis of the Reactome signaling pathway showed that ATM was associated with TP53's regulation and activation. Finally, DNA damage repair related genes were selected for validation at mRNA and protein expression levels. Real-time reverse transcription-polymerase chain reaction and immunohistochemistry validation results demonstrated that mRNA expression level of ATM was higher in SLA-Sr group. In conclusion, SLA-Sr titanium implant could initiate DNA damage repair by activating expression levels of ATM. This study was striving to reveal new faces of better osseointegration and shedding light on the biological function and underlying mechanisms of this important procedure.
研究领域:
蛋白质组学
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生物材料科学
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再生医学
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分子生物学
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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
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生殖生物学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports Medicine
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2025
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IF 10.6
Kaiyu Xu,Ying Zhang,Yongxuan Chen,Xiaojia Zhu,Yu Li,Longbao Lv,Xiechao He,Zhengfei Hu,Yifan Li,Maosen Ye,Dewei Jiang,Zhanlong He,Weihua Jin,Yanyan Li,Xiaomei Yu,Deng-Feng Zhang,Karl Herrup,Ping Zheng,Yong-Gang Yao,Dong-Dong Wu,Jiali Li
Ataxia-telangiectasia (A-T) is a hereditary neurodegenerative disorder caused by mutations in the ATM (ataxia-telangiectasia mutated) gene. Although existing rodent models reproduce some of the multi-systemic features of A-T, they notably fail to recapitulate the severe neurological manifestations, particularly the profound cerebellar atrophy and associated ataxia. To address this limitation, we have generated ATM-deficient rhesus macaques using CRISPR-Cas9. These macaques exhibit hallmark features of A-T, including growth retardation, lymphopenia, elevated a-fetoprotein levels, oculocutaneous telangiectasias, heightened sensitivity to ionizing radiation, and most critically, cerebellar atrophy, Purkinje cell loss, and early-stage cerebellar neurodegeneration leading to significant motor impairments. Single-nucleus transcriptomic profiling of the cerebellum revealed pronounced gene expression changes associated with ATM deficiency, particularly in molecular layer interneurons (MLIs), which are implicated in Purkinje cell loss. This non-human primate model provides deeper insights into the pathogenesis of A-T and represents a promising and valuable platform for developing therapeutic strategies.
研究领域:
神经生物学
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遗传学
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分子医学
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转化医学
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发育生物学
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基因编辑
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Xiaoliang Li,Mingyan Zhou,Zhe Zhu,Zhe Wang,Xuguang Zhang,Lu Lu,Zhenrui Xie,Bingshu Wang,Yipeng Pan,Junqing Zhang,Jian Xu
Ethnopharmacological relevance Alpinia officinarum Hance ( A . officinarum ), a perennial herb known for its medicinal properties, has been used to treat various ailments, such as stomach pain, abdominal pain, emesis, and digestive system cancers. A . officinarum is extensively cultivated in the Qiongzhong and Baisha regions of Hainan, and it holds substantial therapeutic value for the local Li people of Hainan. Kaempferol, a flavonoid derived from A . officinarum , has demonstrated anticancer properties in various experimental and biological studies. Nevertheless, the precise mechanisms through which it exerts its anti-hepatocellular carcinoma (HCC) effects remain to be comprehensively delineated. Aim of the study This investigation aims to elucidate the anti-HCC effects of kaempferol derived from A . officinarum and to delve into its underlying mechanistic pathways. Materials and Methods Using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) to identify active compounds in A. officinarum . HCCLM3 and Huh7 cells were used to study the anti-HCC effect of kaempferol from A . officinarum . The cytotoxicity and proliferation of kaempferol and A . officinarum were measured using CCK-8 and EDU staining. Wound-healing assays and three-dimensional tumor spheroid models were further used to evaluate migration and the anti-HCC activity of kaempferol. The cell cycle and apoptosis were evaluated by flow cytometry. Western blot and qRT-PCR were used to detect the expression of proteins and genes associated with the cell cycle checkpoints. Finally, bioinformatics was used to analyze the relationship between the differential expression of core targets in the ATM/CHEK2/KNL1 pathway and a poor prognosis in clinical HCC samples. Results UPLC-MS/MS was employed to detect five active compounds in A . officinarum , such as kaempferol. The CCK-8 and EDU assays showed that kaempferol and A . officinarum significantly inhibited the proliferation of HCC cells. A wound-healing assay revealed that kaempferol remarkably inhibited the migration of HCC cells. Kaempferol significantly suppressed the growth of tumor spheroids. In addition, kaempferol markedly induced G2/M arrest and promoted apoptosis of HCC cells. Mechanically, kaempferol significantly reduced the protein and mRNA expression levels of ATM, CHEK2, CDC25C, CDK1, CCNB1, MPS1, KNL1, and Bub1. Additionally, the combination of kaempferol and the ATM inhibitor KU55933 had a more significant anti-HCC effect. The results of bioinformatics showed that ATM, CHEK2, CDC25C, CDK1, and KNL1 were highly expressed in patients with HCC and cancer tissues, indicating that these genes have certain value in the clinical diagnosis of HCC. Conclusions Collectively, our results revealed that kaempferol from A . officinarum inhibits the cell cycle by regulating the ATM/CHEK2/KNL1 pathway in HCC cells. In summary, our research presents an innovative supplementary strategy for HCC treatment.
研究领域:
药理学
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肿瘤学
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细胞生物学
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分子生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yuao Feng,Zeliang Wu,Hui Liu,Rong Xu
Triple-negative breast cancer (TNBC) presents a formidable challenge due to its poorest prognosis and limited array of treatment options available. Photodynamic therapy (PDT) has emerged as a potent therapeutic modality to generate intratumoral toxic reactive oxygen species (ROS) in combating refractory triple-negative breast cancer (TNBC). However, its therapeutic efficacy is compromised due to insufficient tumor accumulation and therapeutic resistance. Herein, an “all-in-one” tumor-therapeutic nanomedicine named HA@IR780@KU55933@BSA (HIKB) which integrated photosensitizer IR780 with ATM kinase inhibitor KU55933 was designed to facilitate drug delivery and target specific pathways involved in tumor PDT treatment resistance. Co-delivery of IR780 and KU55933 exacerbated intracellular ROS production, mitochondrial dysfunction and DNA damage to form a potent anti-TNBC therapeutic cyclical feedback loop and then induced pyroptosis and apoptosis of TNBC cells by activating the Caspase3/GSDME signaling pathway and regulating apoptosis-related protein expression, respectively. In vivo evaluations in the TNBC orthotopic xenograft mouse model demonstrated that the designed HIKB NPs could accumulate in tumor tissues and exert synergistic therapeutic effects. Altogether, this study described a self-assembling strategy for constructing an all-in-one nanomedicine that effectively integrates multiple therapeutic modalities to provide a comprehensive and systemic approach to tumor suppression.
研究领域:
肿瘤学
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治疗学
·
纳米技术
·
癌症生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2026
·Vol. 54
·期 7
·gkag336
·
IF 15
Haoyun Liu,Ming Zhang,Zhanzhan Xu,Zexin Yang,Yichen Pan,Yongtai Bai,Xinhui Zhao,Weibin Wang,Yang Yang,Jiadong Wang
Emerging evidence suggests a critical interplay between glycolysis and DNA damage repair (DDR) during tumor progression. However, the precise molecular mechanisms coordinating these processes remain unclear. This study reveals a previously unrecognized role of the platelet isoform of phosphofructokinase-1 (PFKP) in homologous recombination (HR) repair. Our investigations demonstrated that ataxia-telangiectasia mutated (ATM) kinase phosphorylates PFKP at residue T278, promoting its transition from tetramers to dimers in response to ionizing radiation (IR) and high glucose (HG) stimulation. The nuclear localized dimeric PFKP recruits casein kinase 2 (CK2), which subsequently phosphorylates RAD51 at residue T13, thereby enhancing the RAD51-BRCA2 interaction and HR efficiency. Clinically, PFKP exhibits significant nuclear accumulation in diabetes-associated malignancies. Importantly, simultaneous targeting of glycolysis and the HR pathway increases tumor sensitivity to radiotherapy. These findings elucidate the pivotal role of PFKP as a metabolic molecular switch that balances glycolysis and DDR, offering new perspectives for the development of metabolically targeted anticancer strategies.
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DOI
PubMed
高影响因子
MULTIMEDIA TOOLS AND APPLICATIONS
·
2021
·Vol. 80
·期 8
·11471-11489
·
IF 2.757
Wang Zhiyang
According to the problem of spliced money in ATM (Automatic Teller Machine), the paper puts forward a template matching algorithm for recognition of left and right numbers based on one-dimensional gray scale projection. First it uses the Canny boundary detection algorithm to separate the banknote boundary from the R component image, and then preprocesses the image to make the subsequent processing easier; secondly applies the predefined location to divide the area of left and right numbers; thirdly calculates the one-dimensional gray scale projection curves of left and right numbers, based on which every character or number is divided; finally carries out the operation of template matching to obtain correlation coefficients of every character or number, comparing which with threshold it judges whether the left and right numbers are matched. For the transparent tape attached to the spliced money, a method based on the difference in object reflectivity to recognize the tape is designed. First it highlights the characteristics of the tape by preprocessing and binary morphological analysis of the B component image. Finally, it judges whether there is transparent tape on the surface of the banknote according to the set threshold value. Experimental results show that both number matching and tape detection can be completed, and algorithm can correctly recognize spliced money. The correct recognition rate of the algorithm reaches 100%, and the false positive rate、false negative rate are both 0. The processing is fast and simple, which meets the requirements of ATM.
研究领域:
计算机视觉
·
图像处理
·
纸币鉴伪
·
模式识别
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DOI
高影响因子
MOLECULAR CELL
·
2026
·
IF 16
Chen Nie,Wanchang Liu,Lei Zhang,Sai Ge,Mingyang Ma,Jundi Wang,Zhanzhan Xu,Yingyu Qin,Xiao Albert Zhou,Yang Liu,Weibin Wang,Jiadong Wang
Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin in human cancer cells. Mechanistically, IRAK1 phosphorylates spliceosomal serine/arginine (SR)-rich proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a “transcription repair bridge” to link transcriptional processes to HR repair and ultimately preserves genomic stability. Inhibiting IRAK1 axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer-cell chemosensitivity.
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DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS APPLICATIONS
·
2023
·
IF 2.9
Dianwen Yu,Hui Wang,Hui Liu,Rong Xu
Triple-negative breast cancer (TNBC), which accounts for 10%–20% of breast cancer cases, is characterized by a higher metastasis rate, higher recurrence risk, and worse prognosis. Traditional treatments such as chemotherapy, surgery, and radiotherapy have limited therapeutic effects. Although immune checkpoint blockade (ICB) therapy represented by anti-programmed death 1 (aPD-1) antibody has made further progress in treating TNBC, its therapeutic effect is still not optimistic. Ataxia telangiectasia mutated (ATM) is a critical factor in the DNA damage response (DDR) pathway, which is associated with the development of tumors. Recent studies have found that it can regulate the tumor immune microenvironment, affecting ICB responsiveness. Inhibition of ATM could enhance ICB therapy by promoting mitochondrial DNA cytoplasmic leakage and activating the innate immune signaling pathway. To explore the effect of ATM siRNA(siATM) on the ICB responsiveness of TNBC, we designed and synthesized nanoparticles using 1,2-dioleoyl-glycero-3-phosphatidylcholine (DOPC) liposomes to deliver siATM. In vitro and in vivo experiments demonstrated that DOPC/siATM could enhance the ability of siRNA to enter tumor cells and effectively inhibit the expression of ATM protein. Our study found that nanoparticles carrying siATM could activate cytotoxic T lymphocytes and regulate the immunosuppressive tumor microenvironment (ITM) by activating the cGAS-STING pathway. Its combination with aPD-1 may be a potential way to improve the efficacy of TNBC.
研究领域:
肿瘤学
·
免疫治疗
·
分子生物学
·
纳米技术
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）