FISH & SHELLFISH IMMUNOLOGY
·
2022
·
IF 4.622
Xin Zhao,Wenji Huang,Jiahong Guo,Ning Ji,Jianhua Feng,Yanjie Shi,Kangyong Chen,Jun Zou
PLAAT1 belongs to the PLAAT family and plays regulatory roles in cell growth, tumor suppression and phospholipid metabolism . However, whether PLAAT1 is involved in p53 mediated signaling has not been investigated. Here, we report that PLAAT1 promotes degradation of p53 in zebrafish. We found that the plaat1 gene was constitutively expressed in tissues including liver, kidney , spleen , intestine, eye and brain , with relative higher expression levels detected in the brain and eye. Overexpression of plaat1 led to inhibition of p53 and tnfα mRNA expression. Furthermore, it was shown that PLAAT1 interacted with p53 to facilitate p53 degradation via autophagy-lysosome dependent pathway. Our work indicates that PLAAT1 is involved in the interplay between p53 mediated cellular responses and autophagy.
研究领域:
分子生物学
·
细胞生物学
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遗传学
·
动物学
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DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2026
·
IF 11.4
Yan Liu,Haoran Jia,Xueying Guan,Jiansheng Guo,Jiawei Wang,Simin Xiang,Jiayun Chen,YiFan Liu,YongHao Li,GuoZhen Wang
Restoring wild-type p53 has long been viewed as a direct route to cancer therapy, yet clinical efforts have delivered only modest benefit. Here we show that a critical but underappreciated aspect of p53 biology is its ability to form biomolecular condensates that can be manipulated to selectively enhance specific properties. The modest benefit of current p53-dependent therapeutics stems, in part, from p53’s dual nature: alongside canonical tumor suppressor genes, wild-type p53 also boosts neuron-associated genes that can foster malignancy. Using live-cell super resolution imaging we find that endogenous p53 nucleates novel ∼50 nm condensates. Coactivators reinforce droplets, whereas antagonists dissolve them, revealing a previously unappreciated regulatory layer. Guided by these mechanisms, we engineered liquid–liquid phase separation (LLPS)-enhanced p53 constructs with greater condensation propensity (LLPSEp53s). These condensates act as a mesoscale hub that biases promoter occupancy and partner selection. Intriguingly, LLPSEp53s tilt the transcriptome: preferentially strengthen tumor-suppressive transcription while dampening neuro-oncogenic outputs. LLPSEp53s suppress proliferation across multiple cancer cell lines, including those refractories to wild-type p53, and curtails melanoma growth in immunocompetent mice without added toxicity. Our findings establish phase separation as an adjustable layer of p53 target selectivity and highlight condensate engineering as a tractable strategy to unleash the full antitumor potential of p53.
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2025
·
IF 3.5
Xiaofeng Ma,Wang chen,Zhihao Hu,Like Xie,Zhaobing Li,Huan Liu,Zili Li,Zhentao Jiang,Jiangwei Huang,Changrong Jiang,Ke Huang,Sujun Xiao
Background and aims The anthracycline chemotherapeutic agent doxorubicin (DOX) is widely used to treat cancer. However, DOX carries a high risk of adverse effects such as cardiovascular events. The aim of this study was to explore the role of Trim65 in DOX-induced cardiotoxicity (DIC) and its underlying mechanisms. Methods and Results Cellular studies were performed by exposing H9c2 cells (rat cardiomyocytes) to DOX. H9c2 cells were infected with lentivirus encoding negative control (LV-NC) or Trim65 (LV-Trim65). C57BL/6J mice were exposed to adeno-associated virus 9 (AAV9) containing cTnT promoter-encoded Trim65 sequence (AAV-Trim65) or AAV9 negative control sequence (AAV-NC) via tail vein injection. Furthermore, the following analysis were performed: cell viability, intracellular ROS production and lipid peroxidation. Echocardiography was used to measure the heart function of the mice. qPCR and western blotting were used to assess the expression of Trim65, p53, SLC7A11, and GPX4. According to our study, Trim65 expression was significantly downregulated in DIC. Overexpression of Trim65 exhibited considerable protection against to DIC, confirmed by both in vitro and in vivo experiments. In DOX-treated mice, mitochondria deformation was observed in the heart, as well as a high level of lipid peroxidation (signs of ferroptosis) and iron content, which were mitigated by overexpression of Trim65. Mechanistically, our study confirmed that DOX reduced the Trim65-mediated ubiquitination of p53, ultimately inhibiting the degration of p53. We also found that Trim65 mitigated DOX-induced ferroptosis via p53. Conclusion Collectively, our data demonstrated that Trim65 inhibits ferroptosis by degrading p53, thereby alleviating DIC. Therefore, Trim65 could be a promising target for the treatment of DIC.
研究领域:
分子生物学
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心血管病学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Yi Cai,Liduan Huang,Yanhong Hou,Peiwen Pang,Ying Zhou,Xuan Zhang,Yiyin Long,Huajian Li,Halimulati Muhetaer,Man Zhang,Bo Wu
Andrographolide, a diterpene compound derived from the medicinal plant Andrographis paniculata , possesses anti-inflammatory, antioxidant, antitumor, and antiviral properties. Injectable formulations containing andrographolide, such as Potassium Sodium Dehydroandrographolide Succinate for Injection (PSDS), are widely used in clinical practice to treat various diseases, including upper respiratory tract infections. However, clinical reports have highlighted that andrographolide-based herbal injections may induce acute kidney injury and other renal adverse effects, thereby restricting its clinical application. Despite these concerns, the molecular mechanisms underlying andrographolide-induced nephrotoxicity remain poorly understood. In this study, we demonstrated that andrographolide induces inflammation and fibrosis in renal tubular epithelial cells and mouse kidneys. Notably, we identified for the first time that andrographolide promotes cellular senescence in renal tubular epithelial cells and mouse kidneys while downregulating the expression and enzymatic activity of SIRT3. Mechanistic investigations revealed that andrographolide mediates kidney injury and senescence through inhibition of the SIRT3/p53 signaling pathway. Furthermore, andrographolide was found to disrupt the interaction between SIRT3 and p53, resulting in increased acetylation of p53 and upregulation of its downstream target genes involved in inflammation, fibrosis, and senescence. These findings elucidate the molecular mechanisms of andrographolide-induced nephrotoxicity and provide a scientific basis for developing strategies to reduce its toxic effects.
研究领域:
药理学
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分子生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Lele Ma,Huiying Zheng,Wanlin Xie,Weidi Sun,Qunying Yuan,Kun Song,Peiyu Xi,Fengli Qu,Hui Zhang
Cuproptosis, a copper-dependent form of regulated cell death driven by mitochondrial metabolism, holds promise as a therapeutic strategy for cancer. However, its efficacy is hampered by tumor metabolic heterogeneity and mutant p53 (mut-p53)-driven metabolic rewiring that blunts cuproptosis sensitivity. Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu 2+ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming. CuF16@246 comprises a PFSEA-coordinated copper framework with good colloidal stability and pH-dependent co-release of Cu 2+ and APR-246, enabling controlled Cu 2+ release and in situ APR-246 loading. Mechanistically, CuF16@246 triggers hallmarks of cuproptosis, including dihydrolipoamide S -acetyltransferase (DLAT) oligomerization and the depletion of the iron‑sulfur (Fe-S) cluster proteins ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS), while APR-246 converts mut-p53 toward a wild-type-like, DNA-binding-competent state, upregulates metabolic targets such as TP53-induced glycolysis and apoptosis regulator (TIGAR) and glutaminase 2 (GLS2), suppresses glycolysis, and enhances tricarboxylic acid (TCA) cycle flux, thereby sensitizing tumor cells to cuproptosis. In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers.
研究领域:
癌症生物学
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纳米医学
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分子治疗
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细胞死亡机制
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代谢工程
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产品关联
DOI
PubMed
高影响因子
Genes & Diseases
·
2026
·
IF 9.4
Tingting Ge,Hongyu Gao,Zhiran Zhang,Ling Qin,Tianbo Liu
To identify potential biomarkers implicated in ovarian cancer (OV) progression, we first conducted mRNA-sequencing to analyze gene expression profiles in OV and normal tissues. Among the differentially expressed genes, the E3 ubiquitin ligase CBL Proto-Oncogene C (CBLC) with a significant up-regulation in OV tissues (log 2 FC = 9.56, adj. P < 0.001) drew our attention. This elevated expression of CBLC was further validated in a cohort of OV ( n = 27) and normal ( n = 30) tissues. Clinically, a higher proportion of p53 wild-type patients with elevated CBLC expression were diagnosed at stage III or IV compared to those in the low CBLC expression group. Functional assays demonstrated that down-regulation of CBLC suppressed proliferation and metastasis, while promoting apoptosis both in vivo and in vitro . Conversely, CBLC overexpression exerted tumor-promoting effects. Mechanistically, we identified the tumor suppressor p53 as an interacting partner of CBLC. CBLC promoted ubiquitin-mediated degradation of p53, and this process was facilitated by the E2 ligase UBE2L6, known to transfer ubiquitin to the substrates through the E3 ubiquitin ligase, which was also found to interact with CBLC. Overexpression of UBE2L6 enhanced p53 ubiquitination, an effect that was abolished upon CBLC knockdown. Furthermore, p53 overexpression attenuated the proliferative and invasive capacities of CBLC-overexpressing TOV21G cells. In summary, our findings indicate that the CBLC-UBE2L6 axis promotes OV progression by driving ubiquitination-dependent degradation of p53, highlighting its potential as a therapeutic target in OV.
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DOI
高影响因子
Future Medicinal Chemistry
·
2022
·Vol. 14
·期 9
·
IF 4.767
Jiao Liu,Xiaoxuan Wang,Yuan Cheng,Yinghua Yu,Maofang Zhao,Jie Huang,Peiquan Yu,Qian Fu,Yilin Song,Yi Liu
Background: H2S is the third gas transmitter affecting the growth, reproduction and survival of cancer cells. However, the H2S anticancer and antitumor mechanism still needs to be further studied. Methods: Here, FHS-1 was synthesized utilizing excited-state intramolecular proton transfer to detect H2S in MCF-7 cells, and investigated the effects of varying concentrations NaHS on apoptosis. Results: The study found that FHS-1 detects H2S levels with high selectivity and pH stability and that H2S may regulate apoptosis in MCF-7 cells through the p53/mTOR/STAT3 pathway. Conclusion: Researching the influence of H2S on apoptosis can serve as a theoretical foundation for future research into H2S-related anticancer medicines, and the H2S probe can be used as an effective cancer screening tool.Graphical abstract
研究领域:
癌症生物学
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细胞信号传导
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药物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-20
·
IF 11.4
Fei Xiaobin,Zhu Changhao,Liu Peng,Liu Songbai,Ren Likun,Lu Rishang,Hou Junyi,Gao Yongjia,Wang Xing,Pan Yaozhen
Background Pancreatic cancer (PC) is a highly malignant gastrointestinal tumor, which is characterized by difficulties in early diagnosis, early metastasis, limited therapeutic response and a grim prognosis. Therefore, it is imperative to explore potential therapeutic targets for PC. Currently, although the involvement of the Pellino E3 Ubiquitin Protein Ligase 1 (PELI1) in the human growth of some malignant tumors has been demonstrated, its association with PC remains uncertain. Methods Bioinformatics, qRT-PCR, Western blot and IHC were used to detect the expression of PELI1 in pancreas or PC tissues and cells at mRNA and protein levels. The effects of PELI1 on the proliferation and metastatic ability of pancreatic cancer in vitro and in vivo were investigated using CCK8, cloning formation, EdU, flow cytometry, IHC, Transwell assay, wound healing, nude mice subcutaneous tumorigenesis and intrasplenic injection to construct a liver metastasis model. The interactions of PELI1 with proteins as well as the main functions and pathways were investigated by protein profiling, Co-IP, GST-pull down, Immunofluorescence techniques, immunohistochemical co-localization and enrichment analysis. The rescue experiment verified the above experimental results. Results The mRNA and protein expression levels of PELI1 in PC tissues were upregulated and were associated with poor prognosis of patients, in vitro and in vivo experiments confirmed that PELI1 can affect the proliferation and metastatic ability of PC cells. Co-IP, GST-pull down, and other experiments found that PELI1 interacted with Ribosomal Protein S3 (RPS3) through the FHA structural domain and promoted the polyubiquitination of RPS3 in the K48 chain, thereby activates the PI3K/Akt/GSK3β signaling pathway. Moreover, ubiquitinated degradation of RPS3 further reduces Tumor Protein P53 (p53) protein stability and increases p53 degradation by MDM2 Proto-Oncogene (MDM2). Conclusion PELI1 is overexpressed in PC, which increased ubiquitination of RPS3 proteins and activates the PI3K/Akt/GSK3β signaling pathway, as well as reduces the protective effect of RPS3 on p53 and promotes the degradation of the p53 protein, which facilitates the progression of PC and leads to a poor prognosis for patients. Therefore, PELI1 is a potential target for the treatment of PC.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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生物信息学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Haobo Han,Wenqi Chen,Jiebing Yang,Xiao Liang,Yudi Wang,Quanshun Li,Yan Yang,Kun Li
Introduction The nucleobase 2-amino-6-chloropurine-modified polyamidoamine (AP-PAMAM) was used as a carrier for p53 gene delivery to achieve the antitumor effects.Methods and materials The condensation of p53 plasmid was studied through gel retardation assay, and the transfection efficiency was evaluated through the transfection assay of pEGFP-N3 and pGL-3 plasmids. Using human cervical carcinoma cell line HeLa as a model, the inhibition of cell proliferation and migration was studied through flow cytometry, wound healing and Transwell migration assays, respectively. The p53 expression level was detected through quantitative polymerase chain reaction and Western blotting analyses.Results The carrier could condense p53 plasmid into stable nanoparticles at N/P ratios of 2.0, and higher transfection efficiency than polyamidoamine (PAMAM) could be obtained at all the N/P ratios studied. AP-PAMAM-mediated p53 delivery could achieve stronger antiproliferative effect than PAMAM/p53. The antiproliferative effect was identified to be triggered by the induction of cell apoptosis (apoptotic ratio of 26.17%) and cell cycle arrest at S phase. Additionally, AP-PAMAM/p53 transfection has been found to suppress the cell migration and invasion of cancer cells. Finally, the enhanced p53 expression level could be detected after p53 transfection at mRNA and protein levels.Conclusion The PAMAM derivative-mediated p53 delivery could be a promising strategy for achieving tumor gene therapy.
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Hao Tian,Quan Zuo,Siqi Zhang,Hongyi Huang,Dengfu Wu,Zihan Huang,Xiangding Liu,Lin Xie,Yiding Zhang,Hailong Zhang,Yekuan Shi,Suping Li,Ming-Rong Zhang,Rui Wang,Kuan Hu
The development of ideal peptide-based radiopharmaceuticals faces critical bottlenecks, primarily due to limited cellular internalization and insufficient deep tissue penetration of peptide carriers. To address this, we developed an intracellular targeting and DNA-adjacent radiotherapeutic strategy using stapled peptides. The MDM2/MDMX-targeting stapled peptide-based radiopharmaceuticals, denoted as [64Cu]Cu-DOTA-STP, exhibited prolonged circulation in the bloodstream and slow systemic clearance. Furthermore, in vitro studies demonstrated that nearly 50% of administered [64Cu]Cu-DOTA-STP was internalized, achieving efficient intracellular accumulation. In addition, [64Cu]Cu-DOTA-STP demonstrated high tumor accumulation, with a standard uptake value of up to 9.39 ± 1.52%ID/g. Finally, targeted radionuclide therapy confirmed that [64Cu]Cu-DOTA-STP effectively inhibited tumor growth, irrespective of p53 phenotypes. Taken together, this study leveraged PET imaging as a noninvasive and longitudinal tool to elucidate the in vivo fate of stapled peptides and demonstrated that stapled peptides can serve as ideal vehicles for developing intracellular protein-targeting radiopharmaceuticals, achieving efficient 64Cu-based targeted radionuclide therapy.
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产品关联
DOI
PubMed
高影响因子
Science China-Life Sciences
·
2025
·
IF 9.5
Feng Yue,Lin Zishen,Wang Haoran,Men Zhaoyue,Shen Jiakun,Ma Xi
Deoxynivalenol (DON) is a prevalent mycotoxin in animal feed that particularly impacts weaned piglets, causing liver damage, growth retardation, and posing significant public health risks. However, the precise mechanisms underlying DON-induced liver damage and optimal treatment approaches remain unclear. The pregnane X receptor (PXR) holds a pivotal position in hepatic xenobiotic elimination and drug metabolism. This research aimed to explore the involvement of PXR in DON-induced liver injury and evaluate the potential of the PXR agonist, 3-indolepropionic acid (IPA), to alleviate liver damage and associated diarrhea in weaned piglets under practical farming conditions. The results demonstrated that DON initiates p53-mediated hepatocyte apoptosis in weaned piglets. RNA-seq and hepatocyte-specific PXR knockout (PXR-HKO) mice revealed PXR’s regulatory role in DON-induced hepatocyte apoptosis. IPA reduces DON-induced hepatocyte apoptosis in piglets, mice, and hepatocyte cell lines by enhancing PXR expression and facilitating nuclear translocation. Furthermore, AlphaFold3 predictions and Co-IP assays demonstrate that DON diminishes PXR-p53 binding, thereby amplifying p53-mediated apoptotic transactivation. In conclusion, this study elucidates a novel mechanism by which PXR decreases its binding to p53 upon DON exposure, thereby promoting hepatocyte apoptosis. Additionally, it validates the positive impact of IPA in mitigating liver damage and diarrhea caused by DON in weaned piglets.
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DOI
PubMed
高影响因子
DEVELOPMENTAL CELL
·
2025
·
IF 8.7
Meng Wang,Kailin Liu,Wu Bao,Bingqing Hang,Xianjiong Chen,Xinyi Zhu,Guifang Li,Lihong Liu,Haoyi Xiang,Hai Hu,Yanhui Lu,Zhangfa Song,Jiaxin Chen,Yuhao Wang
The intestinal microbiota is a key environmental factor in the development of colorectal cancer (CRC). Here, we report that, in the context of mild colonic inflammation, the microbiota protects against colorectal tumorigenesis in mice. This protection is achieved by microbial suppression of the long non-coding RNA (lncRNA) Snhg9 . Snhg9 promotes tumor growth through inhibition of the tumor suppressor p53. Snhg9 suppresses p53 activity by dissociating the p53 deacetylase sirtuin 1 (SIRT1) from the cell cycle and apoptosis regulator 2 (CCAR2). Consequently, the depletion of the microbiota by antibiotics causes upregulation of Snhg9 and accelerates CRC progression. Moreover, Snhg9 is functionally conserved. Human SNHG9 promotes tumor growth via the same mechanism as mouse Snhg9 , despite their low sequence similarity.
研究领域:
医学
·
分子生物学
·
肿瘤学
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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）