TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2026
·
IF 3.6
Haoguo Wang,Yiying Wang,Siyuan Huang,Jiahui Wang,Erxi Xu,Yufei Pang,Jiqing Shen,Changtai Luo,Jiyong Tan
This study investigates how environmental arsenic exposure induces cardiotoxicity via myocardial senescence by in vivo/in vitro models and evaluates the protective effects of quercetin. In vivo, 3-week-old male C57BL/6 mice were exposed to sodium arsenite (NaAsO 2 ) in drinking water at 10 or 20 mg/L for 6 weeks, with 22-month-old mice serving as a natural aging reference. In vitro, H9C2 rat cardiomyoblasts were treated with 6 μM NaAsO 2 for 24 h to establish a sub-lethal senescence model, followed by PBS or 60 μM quercetin for a further 24 h. Arsenic-exposed mice exhibited dose-dependent aging-like behavioral impairment, left ventricular systolic and diastolic dysfunction, and myocardial fibrosis, driven by P53/P21 upregulation. Network toxicology and in vitro assays revealed that arsenic directly binds a p53 cysteine residue, initiating senescence through the p53/p21 axis and altering pathways including PI3K-Akt and HIF-1. At 6 μM, NaAsO 2 increased the proportion of SA-β-gal-positive H9C2 cells and upregulated P53, P21, and IL-6 at both mRNA and protein levels. Network pharmacology identified TP53, AKT1, and EGFR as quercetin's core targets, with molecular docking and 100 ns dynamics simulations confirming stable, spontaneous binding. Co-treatment with 60 μM quercetin for 24 h reversed arsenic-induced senescence and downregulated these overactivated targets. Ultimately, this study provides evidence that arsenic drives myocardial senescence and associated with upregulation of the p53/p21 axis, highlighting quercetin as a promising multi-target botanical countermeasure for cardiovascular protection in arsenic-exposed populations.
✓ 已验证
DOI
高影响因子
CANCER LETTERS
·
2026
·
IF 11.8
Hui Wang,Yu Zhang,Dinghua Liu,Chang Liu,Shuang Wu,Zhuoyao Wu,Tianming Cui,Gongyao Yu,Yan Xu,Weitao Yang,Bingbo Zhang
The Warburg effect drives cancer cells to rely preferentially on glycolysis, resulting in diminished mitochondrial oxidative phosphorylation (OXPHOS). This metabolic phenotype limits the ability of excess copper (Cu) ions to trigger cuproptosis in dysfunctional mitochondria, leading to suboptimal therapeutic outcomes. Therefore, remodeling tumor energy metabolism to counteract the Warburg effect represents a pivotal strategy to enhance cuproptosis efficacy. Herein, we developed a Cu(I)-stabilized metal-organic framework nanoplatform (CuTz-1) encapsulated by Azurin (CuTz-1@Azurin) as a cuproptosis sensitizer. Mechanistically, Azurin increases p53 protein levels by intercepting MDM2-mediated ubiquitin-proteasome degradation. Elevated p53 subsequently inhibits pyruvate kinase M2 (PKM2) activity, suppressing glycolysis, while simultaneously promoting mitochondrial OXPHOS—collectively shifting cellular metabolism from glycolysis toward mitochondrial respiration and sensitizing tumor cells to Cu-induced proteotoxic stress. In addition, CuTz-1@Azurin triggers oxidative stress via reactive oxygen species (ROS) generation and glutathione (GSH) depletion, which act together with p53-mediated apoptosis to suppress tumor growth. Meanwhile, the oxidation of Cu(I) to paramagnetic Cu(II) enables real-time monitoring of the therapeutic process by magnetic resonance imaging (MRI). Both in vitro and in vivo results demonstrate good antitumor performance of CuTz-1@Azurin. This study highlights the potential of Azurin-mediated metabolic regulation as a promising strategy to potentiate cuproptosis for combined cancer therapy.
✓ 已验证
DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2026
·
IF 3.2
Ye Yuan,Chen Chen,Shengjie Zeng,Lianju Shen,Qing Jiang,Junke Wang
DBP exposure impaired BTB integrity in prepubertal male mice. • MBP induced G1-phase arrest, apoptosis, and DNA damage in Sertoli cells. • MBP impaired Sertoli cell viability and cytoskeletal organization through activation of the ATM/Chk2/p53 pathway. Dibutyl phthalate (DBP) has been recognized as an endocrine disrupting chemical, which poses significant threats to male reproductive health, though its precise mechanism of testicular toxicity has not been fully clarified. We combined in vivo and in vitro experiments with transcriptome sequencing to investigate the toxicity of DBP and its active metabolite monobutyl phthalate (MBP) in prepubertal male mice and Sertoli cells, and explored the underlying molecular mechanisms. The results showed that DBP affected testicular development and disrupted the blood-testis barrier (BTB) in mice. Through bioinformatic analysis, we validated that MBP promoted G1 phase cell cycle arrest, apoptosis, and DNA damage in Sertoli cells. Furthermore, the increased expression of p -ATM, p -Chk2, p-p53 indicated that the ATM/Chk2/p53 signaling pathway was activated upon MBP treatment. Inhibition of p53 or ATM expression partially reversed the pro-apoptotic and cell cycle-arrested phenotypes, whereas p53 overexpression reverted these phenotypic abnormalities. These findings indicated that prepubertal DBP exposure impaird BTB integrity and induced DNA damage in association with pathological activation of the ATM/Chk2/p53 signaling pathway, thereby contributing to Sertoli cell apoptosis and proliferative arrest. Download: Download high-res image (283KB) Download: Download full-size image
✓ 已验证
产品关联
DOI
PubMed
高影响因子
WORLD JOURNAL OF GASTROENTEROLOGY
·
2026
·Vol. 32
·期 6
·113529
·
IF 7.7
Mei-Yuan Zhang,Rui-Qian Sun,Qi Min,Yu-Qi Zhu,Shu-Kui Qin,Qing-Long Guo
BACKGROUND The clinical application of donafenib in advanced hepatocellular carcinoma (HCC) is restricted by its limited therapeutic efficacy and a variety of treatment-associated adverse events. These factors collectively underscore the need for more effective and well-tolerated therapeutic strategies. AIM To investigate the effects and underlying mechanisms of oroxylin A in combination with donafenib on HCC through in vivo and in vitro studies. METHODS The antitumor efficacy of oroxylin A, donafenib, and their combination was assessed in xenograft mouse models and MHCC-97H/PLC-PRF-5 cell lines. Tumor growth was monitored using fluorescence live imaging. Cell viability, colony formation, and apoptosis were assessed using Cell Counting Kit-8, clonogenic, and flow cytometry assays, respectively. Molecular mechanisms were investigated by assessing the expression of tumor protein p53 (TP53) signaling-related regulators via quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry. Public datasets and Kaplan-Meier analysis were used to analyzed the relationship between their expression and patient survival. RESULTS The combination of oroxylin A and donafenib demonstrated superior anti-tumor efficacy in vivo compared to monotherapies, without inducing significant hepatorenal toxicity. The combination therapy demonstrated a stronger anti-proliferative and pro-apoptotic effects than two monotherapies in two HCC cell lines. Mechanistically, the drug combination synergistically activated the TP53 signaling pathway. Oroxylin A primarily targeted the cyclin-dependent kinase 9-murine double minute 2 (MDM2)/MDM4 axis to stabilize TP53, while donafenib suppressed the vascular endothelial growth factor receptor/B-rapidly accelerated fibrosarcoma proto-oncogene serine/threonine kinase axis to activate TP53. Clinical data has verified that the upregulation of key components of this pathway (TP53, MDM2, MDM4, and cyclin-dependent kinase 9) in patients with HCC is associated with a poor overall survival. CONCLUSION Oroxylin A and donafenib exert a synergistic anti-tumor effect in HCC by co-activating the TP53 signaling pathway through distinct but complementary molecular axes. This combination strategy presents a promising and viable therapeutic approach to overcome the limitations of donafenib monotherapy in the treatment of HCC.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2018
·Vol. 234
·期 5
·7587-7599
·
IF 3.923
Junfa Yang,Yuchen Lu,Peipei Yang,Qingfeng Chen,Yang Wang,Qi Ding,Tao Xu,Xiaofeng Li,Changyao Li,Cheng Huang,Xiaoming Meng,Jun Li,Lei Zhang,Xiao Wang
Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA-145 (miR-145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E-box binding homeobox 2 (ZEB2). In addition, overexpression of miR-145 and p53 led to upregulation of the number of senescence-associated β-galactosidase-positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α-smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR-145 specifically targeted the 3′-untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E-box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR-145-ZEB2-p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis.
研究领域:
分子生物学
·
细胞生物学
·
肝病学
✓ 已验证
DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 67
·39082-39089
·
IF 3.049
Jingwen Li,Rong Ding,Hao Gao,Liangdong Guo,Xinsheng Yao,Youwei Zhang,Jinshan Tang
Natural products from fungi have remained a rich resource for drug discovery. Here we report the isolation of three new spirobisnaphthalenes, namely sacrosomycin A-C (1–3), and three known analogues (4–6), from the ethyl acetate extract of a nonsporulating endolichenic fungus derived from Peltigera elisabethae var. mauritzii. The structures of these compounds were elucidated by IR, UV, MS, and NMR. Biological functions of these compounds were evaluated using cultured human cancer cell lines. Short-term cell growth and long-term cell survival assays show that compound 5 demonstrated the strongest cancer cell growth inhibition effect. We reveal that compound 5 induced both cell cycle arrest at the G2/M phase and cell death. Using western blotting, luciferase reporter assay and quantitative PCR (qPCR), we show that compound 5 induced up-regulation of the P53–P21 pathway, supporting the cell cycle arrest and growth inhibition effect of this compound. In contrast, these compounds did not induce cell death in a normal cell line. These results demonstrate a potential anticancer effect of this rare family of spirobisnaphthalene compounds isolated from endolichenic fungi.
研究领域:
药理学
·
肿瘤学
·
天然产物化学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Xian Lin,Tengyu Lin,Xiaocheng Wang,Jiaxin He,Xu Gao,Shuyan Lyu,Qingwen Wang,Jian Chen
Background Rheumatoid arthritis (RA) is an autoimmune disease known as a leading cause of disability with considerable mortality. Developing alternative drugs and targets for RA treatment is an urgent issue. Sesamol is a phenolic compound isolated from natural food sesame ( Sesamum indicum L.) with various biological activities. Purpose The current research intended to illuminate the bioactivity and mechanisms of sesamol in RA fibroblast-like synoviocytes (FLS), and aimed to estimate the potential clinical application value of sesamol in RA treatment. Methods CCK-8, EdU, and flow cytometry assays, as well as transwell tests were applied to observe the effects of sesamol on the abnormal functions of RA-FLS. Moreover, synovial organoids and a collagen-induced arthritis (CIA) mouse model were constructed to further explore the therapeutic capacity of sesamol on RA. Furthermore, RNA sequencing combined with quantitative real-time PCR assay, Western blot as well as co-immunoprecipitation were employed to clarify the mechanism of sesamol in regulating RA progression. Results Sesamol suppressed the proliferation through inhibiting DNA replication, triggering cell cycle arrest and apoptosis of RA-FLS. Besides, sesamol impaired RA-FLS migration and invasion. Interestingly, sesamol inhibited the growth of constructed synovial organoids and alleviated RA symptoms in CIA mice. Moreover, RNA sequencing further implicated p53 signaling as a downstream pathway of sesamol. Furthermore, sesamol was shown to decrease p53 ubiquitination and degradation, thereby activating p53 signaling. Finally, bioinformatics analyses also highlighted the importance of sesamol-regulated networks in the progression of RA. Conclusions Our investigation demonstrated that sesamol served as a novel p53 stabilizer to attenuate the abnormal functions of RA-FLS via facilitating the activation of p53 signaling. Moreover, our study highlighted that sesamol might be an effective lead compound or candidate drug and p53 could be a promising target for the therapy of RA.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MedComm
·
2023
·Vol. 4
·期 5
·e352
·
IF 9.9
Jing Chen,Can Ren,Chong Yao,Mirko Baruscotti,Yi Wang,Lu Zhao
Enhanced P53 signaling may lead to hematopoietic disorders, yet an effective therapeutic strategy is still lacking. Our study, along with previous research, suggests that P53 overactivation and hematopoietic defects are major consequences of zinc deficiency. However, the relationship between these two pathological processes remains unclear. In this study, we observed a severe reduction in the number of hematopoietic stem cells (HSCs) and multi-lineage progenitor cells in zebrafish treated with the zinc chelator N , N , N ′, N ′-tetrakis(2-pyridylmethyl)ethylenediamine and showed the indispensable role of P53 signaling in the process. Next, we took advantage of HSCs-labeled transgenic zebrafish and conducted a highly efficient phenotypic screening for small molecules against P53-dependent hematopoietic disorders. Hydroxysafflor yellow A (HSYA), a natural chalcone glycoside, exhibited potent protection against hematopoietic failure in zinc-deficient zebrafish and strongly inhibited the P53 pathway. We confirmed the protective effect of HSYA in zinc-deficient mice bone marrow nucleated cells, which showed a significant suppression of P53 signaling and oxidative stress. Furthermore, the hematopoietic-protective activity of HSYA was validated using a mice model of myelotoxicity induced by 5-FU. In summary, our work provides an effective phenotypic screening strategy for identifying hematopoietic-protective agents and reveals the novel role of HSYA as a promising lead compound in rescuing hematopoietic disorders associated with P53 overactivation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2021
·
IF 6.291
Yajing Wang,Aoyun Li,Khalid Mehmood,Riaz Hussain,Rao Zahid Abbas,M. Tariq Javed,Yung-Fu Chang,Lianmei Hu,Jiaqiang Pan,Ying Li,Lijun Shi,Zhaoxin Tang,Hui Zhang
Long-term exposure to excessive fluoride causes chronic damage in the body tissues and could lead to skeletal and dental fluorosis. Cartilage damage caused by excessive fluoride intake has gained wide attention, but how fluoride accumulation blocks the development of chondrocytes is still unclear. Here, we report a negative correlation between the length and growth plate width after NaF treatments via apoptosis and autophagy, with shrinkage of cells, nuclear retraction, dissolution of chondrocytes. Whereas, fluoride exposure had no significant effect on the number and distribution of the osteoclasts which were well aligned. More importantly, fluoride exposure induced apoptosis of tibial bone through CytC/Bcl-2/P53 pathways via targeting Caspase3, Caspase9, Bak1, and Bax expressions. Meanwhile, the Beclin1, mTOR, Pakin, Pink, and p62 were elevated in NaF treatment group, which indicated that long-term excessive fluoride triggered the autophagy in the tibial bone and produced the chondrocyte injury. Altogether, fluoride exposure induced the chondrocyte injury by regulating the autophagy and apoptosis in the tibial bone of ducks, which demonstrates that fluoride exposure is a risk factor for cartilage development. These findings revealed the essential role of CytC/Bcl-2/P53 pathways in long-term exposure to fluoride pollution and block the development of chondrocytes in ducks, and CytC/Bcl-2/P53 can be targeted to prevent fluoride induced chondrocyte injury.
研究领域:
毒理学
·
细胞生物学
·
兽医学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 8.3
XiaoYang Qu,LiJuan Chen,JiangHua He,YuFei Fang,Jing Sun,ZhiYing Yu,Zhen Yang,ZiJing Zhang,JianBo Chen,Ling Dong
Background Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and has limited effectiveness of available clinical treatments. Ferroptosis of neurons is one of the main mechanisms of epilepsy. Arisaema Cum Bile (ACB) is a traditional Chinese medicine that is prepared by fermenting animals bile with Rhizoma Arisaematis rhizomes, has demonstrated therapeutic effects on epilepsy and other nervous system diseases. Furthermore, the active components responsible for the anti-epileptic effects of ACB and the intrinsic mechanisms are still unclear. Purpose This study aims to clarify the principal bioactive constituents of ACB and their mechanisms in the treatment of epilepsy. It also seeks to provide data support for its clinical application in antiepileptic combination therapy. Method Pentylenetetrazol injections were used to induce epilepsy in rats. ACB and brain metabolites were identified via UPLC-Q-Exactive Orbitrap MS/MS, and active components were predicted through bioinformatics analysis. In vivo , ACB and hyodeoxycholic acid (HDCA) were administered by gavage, and the effects on oxidative stress, inflammation, and cognitive impairment were evaluated. Additionally, ferroptosis-related protein and gene expression were analyzed using western blot, PCR, immunofluorescence, and flow cytometry. In vitro , using primary neurons and HT22 cells, with electrophysiology employed to assess neuronal activity and glutamate used to induce ferroptosis in HT22 cells, in order to explore how HDCA alleviates epilepsy by inhibiting neuronal ferroptosis. Result A total of 37 chemical components were identified from the ACB, of which 10 active constituents can cross the blood-brain barrier, including steroids and terpenoids. Bioinformatics analysis suggests that HDCA may be one of the key active components responsible for ACB anti-epileptic effects and ferroptosis may represent a crucial underlying therapeutic mechanism. Studies in animals have demonstrated that treatment with ACB and HDCA reduced the frequency and severity of seizures in epileptic rats, mitigated hippocampal neuronal damage, improved post-epileptic cognitive learning capacity, alleviated neuroinflammatory injury and decreased markers of ferroptosis. This neuroprotective effect likely occurs through activation of the p53/Nrf2/GPX4 signaling pathway. Further in vitro cell experiments demonstrated that HDCA can inhibit the generation of action potentials in primary hippocampal neurons, protects HT22 neurons from glutamate-induced cell death, an effect that is reduced by Nrf2 inhibitors. These findings corroborate earlier bioinformatics analyses, confirming that the neuroprotective effects of HDCA are closely linked to Nrf2-mediated ferroptosis pathways. Conclusion HDCA is a key component of ACB anti-epileptic effects, potentially inhibiting ferroptosis through the p53/Nrf2/GPX4 pathway to reduce epilepsy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Jiajian Wang,Yongnan Su,Lanqing Zhang,Hanchuan Mou,Wei Wu,Yunxin Xia,Fei Yu,Fan Yang,Jihong Zhang
ABPP identifies valine-containing protein (VCP) as a KBA01 direct action target. • KBA01 specifically degrades p53 R273 by targeting VCP. • Distinct from p53 degraders, KBA01 has a unique role in disrupting the dominant negative effect of p53 R273H Background Mutant p53 is closely associated with tumor proliferation and metastasis, making an attractive therapeutic target in cancer treatment. Buxus alkaloids exhibit antibacterial and antiviral properties, however, research into their antitumor potential remains limited. KBA01, a triterpenoid alkaloid isolated from the leaves and stems of Buxus bodinieri Levl, activates the p53 signaling pathway in colorectal cancer cells; however, its drug targets and mechanism of action remain unclear. Purpose To identify the molecular target of KBA01 and elucidate how it suppresses tumor growth through activation of the p53 signaling pathway. Methods Activity-based protein profiling (ABPP) assay was performed to identify the potential target of KBA01. Wound healing, cell colony formation and transwell assays were conducted to elucidate the effects of KBA01 on cell proliferation, migration, and invasion. Western blot, RT-qPCR, Immunoprecipitation (IP), Co-Immunoprecipitation (Co-IP), Electrophoretic mobility shift assay (EMSA), Chromatin immunoprecipitation (ChIP), and Luciferase reporter assays were applied to investigate the effects of KBA01 on p53 function. The colorectal cancer xenograft experiment was performed to evaluate the in vivo anticancer activity. Results KBA01 targets Valosin-containing protein (VCP), reducing its interaction with p53 R273H and thereby promoting the ubiquitination and degradation of mutant p53. Consequently, KBA01 disrupts the dominant negative effect of mutant p53. KBA01 elevated the p53 downstream targeted genes p21 and PUMA mRNA and protein levels, thereby activating the p53 signaling pathway and ultimately inhibiting tumor growth and metastasis in vitro . In addition, KBA01 inhibits the Wnt/β-catenin pathway in tumor cells harboring mutant p53. Further in vivo studies demonstrated that KBA01 significantly suppressed tumor growth in colorectal cancer xenograft models by inducing mutant p53 depletion and reactivating p53 downstream target genes, achieving a tumor inhibition rate of 61.39%. Conclusion These findings identify VCP as the molecular target of KBA01 and suggest that KBA01 selectively promotes the degradation of mutant p53 R273H, thereby alleviating its dominant-negative effect and restoring p53 signaling. Collectively, this study broadens the potential pharmacological applications of Buxus alkaloids and supports the further investigation of KBA01 as a lead compound for mutant p53-targeted therapy. Download: Download high-res image (255KB) Download: Download full-size image
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ELECTROANALYTICAL CHEMISTRY
·
2022
·
IF 4.598
Zhixian Liang,Meng Chen,Xing Huang,Yanli Tong,Qiyou Wang,Zuanguang Chen
Protein p53 induces cell growth arrest, differentiation, apoptosis and DNA repair. More than 50% of malignant tumors produce mutations in the p53 gene. Hence, p53 sequence-specific analysis helps in early cancer diagnosis, increasing the treatment success rate. The single nucleic acid amplification method limits sensitivity, so we innovatively integrated exonuclease III (ExoIII)-assisted target recycling amplification with multi-site enzyme polymerization labeling. The integration dramatically improved the biosensor’s sensitivity. Given the nonspecific reaction of ExoIII, we optimized the ExoIII amplification system to reduce false positives and background current. The single-strand DNA produced in the ExoIII system served as the bridge between the electrode and signal DNA tetrahedron (sTDN). Moreover, sTDN provided accurate enzyme loading and well-organized spatial arrangement for multi-site enzymatic labeling. Compared with single-stranded signal probes, sTDN modified by terminal transferase provided higher catalytic efficiency. Under the optimal experimental conditions, the cathodic current exhibited a logarithmic relation over 1.0–5.0 × 10 6 fM p53, with a detection limit of 0.47 fM. Applying this biosensor has successfully detected p53 in serum samples, providing a potential tool for cancer diagnosis and treatment.
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）