EUROPEAN JOURNAL OF MEDICAL RESEARCH
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2025
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IF 3.4
Yun Chen,Yang Wang,Shuai Shen,Libin Zhang,Jun Liu,Xiangyun Yan,Hao Peng,Zheyuan Xu
RHDBB1 could arrest cell cycle in the TP53 mutant NCI-H596 cells; RHDBB1 promotes NSCLS by reducing DNA-PKcs dependent cells apoptosis; Targeting both TP53 and RHDBB1 may have beneficial effects on NSCLC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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高影响因子
Bioactive Materials
·
2023
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IF 18.9
Yong Mei,Xiaohua Qin,Zhenyu Yang,Shiyao Song,Xiaoting Liu,Chong Wu,Jieying Qian,Xiaowan Huang,Yunjiao Zhang,Weiling He
KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers. Therefore, a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53 . Herein, we present a novel self-assembled nanoparticle (HA-TPP/A) that are functionalized nano-carrier hyaluronic acid (HA)-TPP conjugate (HA-TPP) to degrade mutant p53 proteins (mutp53) and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways. The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria. Furthermore, these nanoparticles abrogated the gain-of-function (GOF) phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing, thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation. The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model, particularly in KRAS-TP53 double mutant expressing cancer cells, compared with single drug and combined free drug groups. Notably, HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53 , providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.
研究领域:
肿瘤学
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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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MICROCHEMICAL JOURNAL
·
2026
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IF 5.2
Shuo Zhang,Ting Yang,Rui Lu,Huarong Pang,Huakang Li,Bin Li,Yuzhe Song
Cb Ago selectively depletes wild-type TP53, eliminating background interference for mutant analysis. • Cas9 nickase generates ssDNA initiators to trigger EXPAR under isothermal conditions. • Amplified products disrupt G-quadruplex/ThT fluorescence, enabling a signal-off readout. • The assay achieves 0.14 fM detection limit and single-nucleotide resolution. • Validated in serum and cells; consistent with PCR; discriminates cancer from normal cells. Accurate detection of rare mutant TP53 in the presence of abundant wild-type background remains a major challenge for early diagnosis of colorectal cancer. Here, we report a background-reduced analytical strategy that integrates Cb Ago-mediated wild-type depletion with Cas9 nickase (Cas9n)/sgRNA-triggered exponential amplification reaction (EXPAR) for highly sensitive and specific mutant TP53 analysis. Cb Ago programmed with a guide DNA selectively cleaves wild-type TP53 while preserving the mutant target, thereby eliminating interference from the overwhelming wild-type background. The remaining mutant TP53 is then recognized by two Cas9n/sgRNA complexes, which generate single-stranded initiator fragments through polymerase-assisted strand displacement. These initiators trigger an EXPAR cascade that ultimately disrupts the G-quadruplex structure of a thioflavin T (ThT) fluorescent probe, producing a signal-off readout. The method achieves a detection limit as low as 0.14 fM with excellent single-nucleotide discrimination capability. Its practical utility is validated through recovery experiments, differentiation of cancer cells from normal cells, and high consistency with PCR-based methods in clinical tissue samples. This Cb Ago-Cas9n-EXPAR platform offers a robust and isothermal tool for early diagnosis of TP53-mutated colorectal cancer and can be readily reprogrammed for other clinically relevant single-nucleotide variants. Download: Download high-res image (123KB) Download: Download full-size image
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TALANTA
·
2021
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IF 6.057
Mengjia Xu,Shu Xing,Yang Zhao,Chao Zhao
Here, taking the advantage of single-stranded (ss) DNA specific nuclease (S1) and peptide nucleic acid (PNA), we demonstrated a novel, rapid, and label-free colorimetric nanosensor for the sensitive and accurate detection of SNPs based on the intrinsic peroxidase-like activity of hemin-functionalized single-walled carbon nanotubes (hemin-SWCNTs). PNA, a man-made mimic of DNA with extraordinary stability toward enzymatic degradation, can effectively protect DNA in the fully matched DNA/PNA duplexes from nuclease digestion. While the DNA in DNA/PNA duplexes containing a mismatch can be cleaved into small fragments. This difference can be visually monitored from the specific color change of TMB/H 2 O 2 system by employing the peroxidase activity of hemin-SWCNTs because of its different aggregation states responding to ssPNA or DNA/PNA duplex. Under optimized conditions, the SNPs in the human tumor suppressor gene TP53 have been successfully genotyped in a linear range of 50–1000 nM with a detection limit of 0.11 nM. Moreover, this platform can effectively discriminate a series of single-base mismatches. This assay avoids the assistance of sophisticated instruments and complicated modifications of probes or nanomaterials , and function well for both cell lysate samples and PCR amplicons from standard cell lines, implying its potential practical applications for bioanalysis and biosensors.
研究领域:
生物化学
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分子生物学
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纳米生物技术
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.5
Qixiang Fang,Chengyu You,Xi Xiao,Weiguang Yang,Longtu Ma,Qingchao Li,Yan Tao,Zhilong Dong
Cisplatin resistance remains a major challenge in bladder cancer. Although the tumor suppressor ASPP2 is a critical co-factor for TP53-mediated apoptosis, its role in metabolic reprogramming and cisplatin response remains unclear. This study aimed to delineate the mechanism by which ASPP2 regulates cisplatin sensitivity through metabolic reprogramming. We first assessed the clinical significance of ASPP2 using patient tissues and public databases, finding that its downregulation in bladder cancer is associated with poor patient survival. Through gain- and loss-of-function studies in vitro and in vivo, we further demonstrated that ASPP2 inhibits the mevalonate (MVA) pathway independently of TP53 status, thereby sensitizing cells to cisplatin-induced DNA damage and apoptosis. This chemosensitizing effect was specifically reversed by the addition of MVA pathway metabolites. Moreover, WWP2 was identified as the E3 ubiquitin ligase responsible for ASPP2 degradation via K48-linked ubiquitination. Finally, WWP2 silencing was shown to stabilize ASPP2, suppress the MVA pathway, and synergize with cisplatin to impede tumor growth in mouse models. Overall, the WWP2-ASPP2-MVA pathway axis is identified as a novel driver of cisplatin resistance in bladder cancer. These results establish a mechanistic basis for targeting this axis to restore chemosensitivity, offering a promising therapeutic strategy for recalcitrant disease.
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ENVIRONMENT INTERNATIONAL
·
2025
·
IF 9.7
Xiaojing Li,Huanqi Zhang,Peizhong Yu,Xiaozhe Chen,Yuhong Yang,Shiwen Xu
Chlorpyrifos (CPF), a typical organophosphorus pesticide, is frequently applied for pest control in households and agriculture worldwide. Liver, being the primary site for xenobiotic metabolism, is extremely vulnerable to drug threats. To elucidate the hepatotoxic mechanism of CPF and identify targets for its relief, the overlapping data between CPF-associated targets and liver injury-related genes were analyzed. It was found that CPF hepatotoxicity targets were mainly involved in oxidoreductase activity, fatty acid metabolism, glutathione metabolic process, response to biotic stimulus, ferroptosis, and mitochondrion disorders. TP53 molecular exhibited the strong binding stability with CPF, and TP53-mediated SLC7A11/GPX4 signaling suppression contributed to CPF-induced hepatotoxicity in Cyprinus carpio . CPF disrupted iron homeostasis by downregulating FTH, NCOA4, and FPN expressions, while simultaneously increasing ACSL4 expression to promote the accumulation of lipid peroxides MDA and LPO. Meanwhile, CPF reduced intracellular GPX4 levels, thereby diminishing lipid ROS scavenging capacity and triggering ferroptosis. Selenium (Se) could reverse CPF- and Erastin-induced ferroptosis and mitochondrial dysfunction. GSH depletion and GPX4 silencing reversed the alleviating effect of Se on CPF-induced lipid peroxidation, but they had little effect on iron contents. Meanwhile, Se addition also increased GSH contents and GPX4 protein expressions. The results revealed some targets of CPF-induced hepatotoxicity. These studies provided the theoretical basis for the future development of environmental monitoring and pollutant control strategies.
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Autophagy
·
2018
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IF 11.1
Peihua Luo,Zhifei Xu,Guanqun Li,Hao Yan,Yi Zhu,Hong Zhu,Shenglin Ma,Bo Yang,Qiaojun He
Sunitinib, a multikinase inhibitor approved for a number of cancer indications has a low response rate. Identifying mechanisms of resistance could lead to rational combination regimens that could improve clinical outcomes. Here we report that resistance to sunitinib therapy was driven by autophagic degradation of TP53/p53. Deletion of ATG7 or ATG5 suppressed TP53 degradation, as did knockdown of SQSTM1/p62. Mechanistically, the transport of TP53 from the nucleus to the cytoplasm was essential for the sunitinib-induced autophagic degradation of TP53 and did not require TP53 nuclear export signals (NESs). Moreover, TP53 degradation was achieved by the transport of its nuclear binding target, HMGB1, which shifted TP53 from the nucleus to the cytoplasm. The inhibition of HMGB1 sensitized cancer cells to sunitinib. Importantly, sunitinib induced the degradation of all TP53 proteins, except for TP53 proteins with mutations in the interaction domain of TP53 with HMGB1 (amino acids 313 to 352). In conclusion, our data identify an alternative HMGB1-mediated TP53 protein turnover mechanism that participates in the resistance of sunitinib and suggest HMGB1 as a potential therapeutic target for improving clinical outcomes of sunitinib.
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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PubMed
高影响因子
Journal of Ovarian Research
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2026
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IF 5.3
Li Xingying,Hu Xueyuan,Yang Jing,Yue Xiuyong,Deng Lilin,Xiong Qian
Background Bushen Huatan Formula (BSHT) shows promise in treating reproductive endocrine disorders, yet its mechanism in polycystic ovary syndrome (PCOS) remains unclear. This study aims to elucidate the specific mechanism of action of BSHT in treating PCOS. Methods PCOS model in rats was established by using a high-fat diet combined with letrozole gavage, and an in vitro model was constructed by stimulating human ovarian granulosa cells with dehydroepiandrosterone. Oestrus cycle changes were monitored throughout the BSHT intervention period via daily vaginal smear. Following intervention, ovarian histopathology and serum sex hormones, lipid profiles, oxidative stress, and ferroptosis markers were assessed. Network pharmacology predicted BSHT targets and pathways, validated in vitro/in vivo via TP53 pathway expression and downstream factors, oxidative stress, and key ferroptosis protein levels. Results High-dose BSHT effectively improved estrous cycle irregularities, reduced ovarian and uterine indexes, and repaired ovarian pathology in PCOS rats. BSHT treatment significantly improved endocrine profiles by reducing testosterone and luteinizing hormone levels while increasing follicle-stimulating hormone ( P < 0.001), and ameliorated dyslipidemia by lowering total cholesterol and low-density lipoprotein cholesterol while elevating high-density lipoprotein cholesterol ( P < 0.001). Mechanistically, BSHT suppressed oxidative stress and ferroptosis, as evidenced by decreased malondialdehyde, reactive oxygen species, lipid peroxides, Fe2 + and ACSL4, along with increased GSH and GPX4 ( P < 0.001). Both network pharmacology and experimental validation confirmed that these effects were mediated through inhibition of the TP53 signaling pathway and its downstream targets ( P < 0.001). The critical role of TP53 was further verified through intervention studies using ferroptosis inhibitors and TP53 agonists ( P < 0.001). Conclusion This study demonstrates that BSHT alleviates PCOS pathology by inhibiting ferroptosis and regulating lipid metabolism via the TP53 signaling pathway, providing a theoretical basis for novel therapeutic strategies.
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PLoS Genetics
·
2024
·Vol. 20
·期 3
·e1011170
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IF 4
Yonglin Ruan,Xuehui Li,Xinyi Wang,Gang Zhai,Qiyong Lou,Xia Jin,Jiangyan He,Jie Mei,Wuhan Xiao,Jianfang Gui,Zhan Yin
The regulatory mechanism of gonadal sex differentiation, which is complex and regulated by multiple factors, remains poorly understood in teleosts. Recently, we have shown that compromised androgen and estrogen synthesis with increased progestin leads to all-male differentiation with proper testis development and spermatogenesis in cytochrome P450 17a1 ( cyp17a1 )-/- zebrafish. In the present study, the phenotypes of female-biased sex ratio were positively correlated with higher Fanconi anemia complementation group L ( fancl ) expression in the gonads of doublesex and mab-3 related transcription factor 1 ( dmrt1 )-/- and cyp17a1 -/-; dmrt1 -/- fish. The additional depletion of fancl in cyp17a1 -/-; dmrt1 -/- zebrafish reversed the gonadal sex differentiation from all-ovary to all-testis (in cyp17a1 -/-; dmrt1 -/-; fancl -/- fish). Luciferase assay revealed a synergistic inhibitory effect of Dmrt1 and androgen signaling on fancl transcription. Furthermore, an interaction between Fancl and the apoptotic factor Tumour protein p53 (Tp53) was found in vitro . The interaction between Fancl and Tp53 was observed via the WD repeat domain (WDR) and C-terminal domain (CTD) of Fancl and the DNA binding domain (DBD) of Tp53, leading to the K48-linked polyubiquitination degradation of Tp53 activated by the ubiquitin ligase, Fancl. Our results show that testis fate in cyp17a1 -/- fish is determined by Dmrt1, which is thought to stabilize Tp53 by inhibiting fancl transcription during the critical stage of sexual fate determination in zebrafish.
Gonadal sex differentiation is known as the queen of problems in evolutionary biology, and the mechanisms that determine sexual fate vary widely among teleosts. Traditionally, Dmrt1 and androgen signaling have been essential for testis differentiation, and estrogen signaling has been essential for ovary differentiation. The all-testis phenotype observed in cyp17a1 -/- zebrafish, has led to the conclusion that androgen signaling is dispensable for testis differentiation in zebrafish. By analyzing a series of mutant zebrafish lines, we show here that Dmrt1 sufficiently promotes all-testis differentiation in cyp17a1 -deficient zebrafish albeit the compromised androgen and estrogen synthesis. In addition, we observed that zebrafish Dmrt1 and androgen signaling probably stabilize Tp53 by inhibiting the transcription of a ubiquitin ligase, Fancl. Our current study provides new insights into the interactive signals that regulate sexual fate determination in teleosts.
研究领域:
发育生物学
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分子生物学
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遗传学
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高影响因子
Chinese Journal of Integrative Medicine
·
2022
·Vol. 29
·期 3
·244-252
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IF 2.626
Wang Yuan-chun,Hui Jian-rong,Xiao Gang,Ma Qiao-lin
Objective To investigate the mechanism of the effect of Astragalus membranaceus ( A. membranaceus ) on lung adenocarcinoma at the molecular level to elucidate the specific targets according to the network pharmacology approach. Methods The active components of A. membranaceus and their potential targets were collected from the Traditional Chinese Medicine Systems Pharmacology Database. Lung adenocarcinoma-associated genes were acquired based on GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGKB, and Therapeutic Targets databases. The PI3K/AKT signaling pathway-related genes were obtained using Reactome portal. Networks of “ingredient-target” and “ingredient-target-pathway-disease” were constructed using the Cytoscape3.6.0 software. The relationships among targets were analyzed according protein-protein interaction (PPI) network. Finally, molecular docking was applied to construct the binding conformation between active ingredients and core targets. Cell counting kit 8 (CCK8) and Western blot assays were performed to determine the mechanism of the key ingredient of A. membranaceus . Results A total of 20 active components and their 329 targets, and 7,501 lung adenocarcinoma-related genes and 130 PI3K/AKT signaling pathway-related genes were obtained. According to Venn diagram and PPI network analysis, 2 mainly active ingredients, including kaempferol and quercetin, and 6 core targets, including TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR, were identified. The two important active ingredients of A. membranaceus , kaempferol and quercetin, exert the therapeutic effect in lung adenocarcinoma partly by acting on the 6 core targets (TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR) of PI3K/AKT signaling pathway. Expressions of potential targets in lung adenocarcinoma and normal samples were analyzed by using UALCAN portal and found that ERBB2 was overexpressed in lung adenocarcinoma tissues and upregulation of it correlated with clinicopathological characteristics. Finally, quercetin repressed viabilities of lung adenocarcinoma cells by targeting ERBB2 on PI3K/AKT signaling confirmed by CCK8 and Western blot. Conclusion Our finding unraveled that an active ingredient of A. membranaceus , quercetin, significantly inhibited the lung adenocarcinoma cells proliferation by repressing ERBB2 level and inactivating the PI3K/AKT signaling pathway.
研究领域:
药理学
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肿瘤学
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分子生物学
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生物信息学
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高影响因子
CANCER CELL
·
2020
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IF 26.602
Shuo Chen,Jia-Le Wu,Ying Liang,Yi-Gang Tang,Hua-Xin Song,Li-Li Wu,Yang-Fei Xing,Ni Yan,Yun-Tong Li,Zheng-Yuan Wang,Shu-Jun Xiao,Xin Lu,Sai-Juan Chen,Min Lu
Summary TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of inactivation and the absence of broadly applicable allosteric sites. Here we report the identification of small molecules, including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall β-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症研究
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高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-14
·
IF 9.6
Liu Min,Li Yuanyuan,Deng Zhilin,Zhang Ke,Huang Shuying,Xia Jiamin,Feng Yi,Liang Yundan,Sun Chengfu,Liu Xindong,Li Shurong,Su Bingyin,dong Yong,Huang Sizhou
Mutation in genes involved in DNA replication continuously disrupt DNA replication and give rise to genomic instability, a critical driver of oncogenesis. To prevent leukemia, immature T lymphocytes with genomic instability often undergo rapid cell death during development. However, the mechanism by which immature T lymphocytes undergo rapid cell death upon genomic instability has been enigmatic. Here we show that zebrafish mcm5 mutation leads to DNA damage in immature T lymphocytes and the immature T cells sensitively undergo rapid cell death. Detailed analyses demonstrated that the immature T lymphocytes undergo rapid apoptosis via upregulation of tp53 and downregulation of bcl2 transcription in mcm5 mutants. Mechanistically, Mcm5 directly binds to Stat1a and facilitates its phosphorylation to enhance bcl2a expression under the conditions of DNA replication stress. However, in mcm5 mutants, the absence of the Mcm5-Stat1 complex decreases Stat1 phosphorylation and subsequent bcl2a transcription, accelerating apoptosis of immature T lymphocytes with genomic instability. Furthermore, our study shows that the role of Mcm5 in T-cell development is conserved in mice. In conclusion, our work identifies a role of Mcm5 in regulating T cell development via Stat1-Bcl2 cascade besides its role in DNA replication, providing a kind of mechanism by which immature T cells with gene mutation-induced DNA damage are rapidly cleared during T lymphocyte development.
研究领域:
免疫学
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遗传学
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肿瘤学
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分子生物学
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高影响因子
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